CA1187080A - 1-(cyclohexyl)-4-aryl-4-piperidine-carboxylic acid derivatives - Google Patents
1-(cyclohexyl)-4-aryl-4-piperidine-carboxylic acid derivativesInfo
- Publication number
- CA1187080A CA1187080A CA000369180A CA369180A CA1187080A CA 1187080 A CA1187080 A CA 1187080A CA 000369180 A CA000369180 A CA 000369180A CA 369180 A CA369180 A CA 369180A CA 1187080 A CA1187080 A CA 1187080A
- Authority
- CA
- Canada
- Prior art keywords
- alkyloxy
- group
- formula
- compound
- amino
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D211/60—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D211/62—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals attached in position 4
- C07D211/64—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals attached in position 4 having an aryl radical as the second substituent in position 4
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C29/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring
- C07C29/36—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring increasing the number of carbon atoms by reactions with formation of hydroxy groups, which may occur via intermediates being derivatives of hydroxy, e.g. O-metal
- C07C29/38—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring increasing the number of carbon atoms by reactions with formation of hydroxy groups, which may occur via intermediates being derivatives of hydroxy, e.g. O-metal by reaction with aldehydes or ketones
- C07C29/40—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring increasing the number of carbon atoms by reactions with formation of hydroxy groups, which may occur via intermediates being derivatives of hydroxy, e.g. O-metal by reaction with aldehydes or ketones with compounds containing carbon-to-metal bonds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/92—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with a hetero atom directly attached to the ring nitrogen atom
- C07D211/96—Sulfur atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/57—Nitriles
Abstract
ABSTRACT
Novel 1-(cyclohexyl-4-piperidinecarboxylic acid derivatives, bearing in the 4-position of the cyclohexyl ring a cyano group and aryl moiety, said compounds displaying useful anti-histaminic properties.
Novel 1-(cyclohexyl-4-piperidinecarboxylic acid derivatives, bearing in the 4-position of the cyclohexyl ring a cyano group and aryl moiety, said compounds displaying useful anti-histaminic properties.
Description
~8~7~3~3~
NOVEL 1 -(:;YCLOHEXYL)-4~ARYL-4-PI}:rRD: D~ECARBOXYLIC:
AC D: DER l~ATIVES.
Bac'cc~rou~d of the i~vent_on.
A D.~abe~ o~ 4~ ~yl-4-p~peridi~ecarbo~ylic: acid derl~ra~ves ~ave bee~ de eribed i~ J.. Pl~ 3. Pharmacol. r ;~3 (11)~ 8~;-870 (1,9711;
J. Mecl. Cb.esrL., lq, 16~19 (1976); ~ . .~ed. C~em., ~, 1248-1~;0 (1 976).
'r~Lese Ic;~ piperi~i~e deri~ re~ which may be repre3ented by t~e 1 0 form2Lla f~ C~0-C~;2 D.. ~l~yl-N X
p~ess a2algesic proper'de~.
1~ Japa~le~e Pat. No. J.; 3 . 053. 665 t}Ler~ a~e desc~i~ed a ~umber of l..(cyclo3~ pheD.ylpipsrid~e deri~ ros ~ich are represesst~d by t~ fo~Lul~
''~''' ~ JP;f~ 3 2 6 ~37~
7s ~? N/--\i The latter compou~ds are taught ~o be us~ful as depressa~t~ of the central ner~rous ~ystem.
The compourlds according to the preserLt inventlon differ from the aforementioned prior ar~ co~npou~dq e~e~tlally by the 5 nature 4f the particular substieuents ~ he 4-po3itio~ of the piperidine nucleus and /or in the 4-position of the cyc}ohexyl ~roup.
, Thi~ i~verltion is colloern~d wlth a novel series o l-(cyclo-hexyl)-4-aryl-4-pipcridi~ecarb/~xylic aoid deri~rative~ which ~ay l O structurally be represe~ted by the formula Rl O
NC f~( C-R :AND N~N~-R
Arl ~} ~A 2 Ar ~2 the pharmaceutically acceptable acid addition ~ales and stereo-chemically i~omeric form~ thereof, wherein:
Rl i~ a member selected from the group consi~ti~ o~ hyd o-gen and lower aLkyl;
R i~ a mesnber ~elected from the group con~istirLg of hydroxy, lower alkyloxy, aryllower alkyloxy, ~aryloxylower aL~loxy, lower alkyloxylower alkyloxy, am~olower alkyloxy, mono- ar~d di(lower alkyi)ami~o lower allcylcxy, ~l~pyr~olidinyl)-, (l-piperidinyl)- a~d (4-morpholinyl)lower all;yloxy, ami30, aryl Ic~wer alkyl amino, mono-20 and di(lower alkyl~amino, 1-~DYrrO1idinYI~ l-piperidi yl and 4-morpho-li~yl; and !
.
8(~
Ar an.d A~ are each ind~pendently elected from the group co~qisting of a~yl, thienyl and pyridinyl;
wherein aryl, ~s used in the defi~itions of R, Ar and Ar2, i5 a membe~ ~elec~ed from,the groul? consi ting of phenyl and subs,,ituted 5 phe~yl, said substi~uted phe~yl havi~g from 1 to 3 Rubstituents each independently selected from the group consi~tlng of lower alkyl, lower alkyloxy, halo, nitro, amir~o, cya~no, carboxyl, lower alkyloxy carbonyl, mono- and di(lower alkyl)ami~ocarbonyl a~d trifluoromethyl.
As u3ed in the ~oregoi~g defi~ition3 the terrn "halo" i~ generic 10 to fluoro, chlo~o, bromo and iodo a~d "lower alkyl" is meant to include straight a~d branched hydrocarbon radicals having from 1 to 6 carbon atoms such as, for e~ample, methyl, ethyl, l-rrethylethyl, 1, 1-dimethylethyl, propyl, 2-methylpropyl, butyl, pen~yl, hexyl and the like.
r The compounds of for~ula (I) can ge~erally be prepared by ~he reductive aminatio~ reactiorL of an appropriate 4-aryl-1-cyano-cylohexa~one of formula (II), wherein Ar is as previcusly described, with an appropriately ~ubstituted 4-aryl-4 piperidinecarboxylie acid deri~ative of formula (III), whereirLR, R a~d Ar are as previously
NOVEL 1 -(:;YCLOHEXYL)-4~ARYL-4-PI}:rRD: D~ECARBOXYLIC:
AC D: DER l~ATIVES.
Bac'cc~rou~d of the i~vent_on.
A D.~abe~ o~ 4~ ~yl-4-p~peridi~ecarbo~ylic: acid derl~ra~ves ~ave bee~ de eribed i~ J.. Pl~ 3. Pharmacol. r ;~3 (11)~ 8~;-870 (1,9711;
J. Mecl. Cb.esrL., lq, 16~19 (1976); ~ . .~ed. C~em., ~, 1248-1~;0 (1 976).
'r~Lese Ic;~ piperi~i~e deri~ re~ which may be repre3ented by t~e 1 0 form2Lla f~ C~0-C~;2 D.. ~l~yl-N X
p~ess a2algesic proper'de~.
1~ Japa~le~e Pat. No. J.; 3 . 053. 665 t}Ler~ a~e desc~i~ed a ~umber of l..(cyclo3~ pheD.ylpipsrid~e deri~ ros ~ich are represesst~d by t~ fo~Lul~
''~''' ~ JP;f~ 3 2 6 ~37~
7s ~? N/--\i The latter compou~ds are taught ~o be us~ful as depressa~t~ of the central ner~rous ~ystem.
The compourlds according to the preserLt inventlon differ from the aforementioned prior ar~ co~npou~dq e~e~tlally by the 5 nature 4f the particular substieuents ~ he 4-po3itio~ of the piperidine nucleus and /or in the 4-position of the cyc}ohexyl ~roup.
, Thi~ i~verltion is colloern~d wlth a novel series o l-(cyclo-hexyl)-4-aryl-4-pipcridi~ecarb/~xylic aoid deri~rative~ which ~ay l O structurally be represe~ted by the formula Rl O
NC f~( C-R :AND N~N~-R
Arl ~} ~A 2 Ar ~2 the pharmaceutically acceptable acid addition ~ales and stereo-chemically i~omeric form~ thereof, wherein:
Rl i~ a member selected from the group consi~ti~ o~ hyd o-gen and lower aLkyl;
R i~ a mesnber ~elected from the group con~istirLg of hydroxy, lower alkyloxy, aryllower alkyloxy, ~aryloxylower aL~loxy, lower alkyloxylower alkyloxy, am~olower alkyloxy, mono- ar~d di(lower alkyi)ami~o lower allcylcxy, ~l~pyr~olidinyl)-, (l-piperidinyl)- a~d (4-morpholinyl)lower all;yloxy, ami30, aryl Ic~wer alkyl amino, mono-20 and di(lower alkyl~amino, 1-~DYrrO1idinYI~ l-piperidi yl and 4-morpho-li~yl; and !
.
8(~
Ar an.d A~ are each ind~pendently elected from the group co~qisting of a~yl, thienyl and pyridinyl;
wherein aryl, ~s used in the defi~itions of R, Ar and Ar2, i5 a membe~ ~elec~ed from,the groul? consi ting of phenyl and subs,,ituted 5 phe~yl, said substi~uted phe~yl havi~g from 1 to 3 Rubstituents each independently selected from the group consi~tlng of lower alkyl, lower alkyloxy, halo, nitro, amir~o, cya~no, carboxyl, lower alkyloxy carbonyl, mono- and di(lower alkyl)ami~ocarbonyl a~d trifluoromethyl.
As u3ed in the ~oregoi~g defi~ition3 the terrn "halo" i~ generic 10 to fluoro, chlo~o, bromo and iodo a~d "lower alkyl" is meant to include straight a~d branched hydrocarbon radicals having from 1 to 6 carbon atoms such as, for e~ample, methyl, ethyl, l-rrethylethyl, 1, 1-dimethylethyl, propyl, 2-methylpropyl, butyl, pen~yl, hexyl and the like.
r The compounds of for~ula (I) can ge~erally be prepared by ~he reductive aminatio~ reactiorL of an appropriate 4-aryl-1-cyano-cylohexa~one of formula (II), wherein Ar is as previcusly described, with an appropriately ~ubstituted 4-aryl-4 piperidinecarboxylie acid deri~ative of formula (III), whereirLR, R a~d Ar are as previously
2 0 defined.
N~ R
Ar Ar ami~atio (~:) , (m) Sa~d reducti~re a~ atio~ ~e~c~on may co~re~e~ly ~e carr~ed out by catalytically hy~rogeDat~g ~ s~irr~d aDd he~ted ~xt~re o the reactant~ ~ a . 3uitable re c~on-i~sert orga~c solve~t accord~g to art~ LowE~ c~Ltaly1:ically ~ydrogenati2~g procedures. Suit~ble solve~ts 25 are, for example, water; lo~er a}~L~ ls, e.g., r~Letllanol, 2-propa~ol a:~d. ~e like; cycl~c ether~, e.g., 1~4-dioxane a~d the lilce;
î~L87~ JAB 3~6 ~aloge~at~d ~ydrocarbosl~, o.g., tric~70rometha~e a~d t~e li~ce;
~methyl~orss~a~nide; ~ir~ethyl s~ o:~ade a-t t~e like; or a mix~e of 2 or D:~ore ~i such solYerlts. The te~m "art-~own cataly~ca11y hytro-geUatirL~ procedure ~" ~ea~s that the ~eactio~ is carried out u~der 5 hydroge~ at~osphere i;ld i~ t}le pre~e~ce o~ a~L appropr;~Lte ca~aly~t such as, for exampla, p~llad~,u.m~ charcoal, plahnu~n-on-char-coal. a;ld t}~e lilce . I~ or~e~ to prev~t th~ u~desired further hyd~ o-ge~a~ion o certai~ ~'~ctio~l groups~ the rQac~ Lts a~d t~e react oD
product~ ~t ~ay ~e a~ ou~ ~o add a~ appronriate cat~lys~-10 poiso~ to the reaction~ ur~, e. g., t~io~:~hene aad t~e like.
The- compou~d~ of formula (IV) may , be prepared by reacti~g an appropriat~ cyclohexa~o~e of forslula (II) wit~ a appropriately ~ubstituted 4-piperid~ac~rb~x~rlic acid derivati~e of fl~ula (~) e~amine NC Nr~(/~--R
. . ~ A 2 (m) f~ation Arl ~~ \~/ `~
(Iy) If desi~ed, tl~ enamine of fonmulaO(IV) may he subsequently re~uced to fonm the co~pound of for~.ula (I).
I~he ~na m ~le fo~2la~0~ reac~oni~lay be car-ied out by ~r~
~g t~e reactant~ ~ogether i~ ~Le 3Jre~ence o a cat~lyeic a30t~t o~ a rela~relg- ~t:rong acid, e. ~., 4-~ot~Lylben~ey:Lesul~o~c aeid 20 asld t}~e like~ i~ a ~ lo reac~io~-~nert orga~c ~ol~eD.t suc~ as, ~ r e~sple, an aliph3tic-, alic~cl~c- or aromaic hydroc~r~on~
e. g., ~a.he~e, cyclonexane, meth~lbe:L2ene a~d t~e li~e. }n order to eD}~a~ce the reacffon -ate ~ornew~ olevated t3~pera~:ures are appropriate and p~e~era~y ~ae reaction is conduct&d at ~.he re~lux 25 ~empe-a~re OI thi~ reactioD. ~:~se. .~Sos~ pre~erably t~e reaclior .~
.
:~L87~8~
is ca~ d out us~d~r azeot~ opic re~so~al of the water which is fOL~ed dur~g the course oi~ r~actior~.
T~e reductio~ o~ the erLami~e of ~or~s~.ula (I~) may, for example, be carried out by s1:irr~g ~e e~am~e (IV~ a ui~Lble sol~re~t 5 i~ the prese~ce of ~ a~propriate reduc~ age..t r~uch aq, for e:~ample, a compl~Y ~etal hydride, e. g., odiu~2:L borohydride a~d t~e lice.
Suitable soi~euts are, ~or examplef al~llols, e.g. t metha~lol, 2-proparlol a~d the liXe; and cyclic~ether, e. g., tetr hydrofu~a~ I, 4-dioxa~ae a~d the li~ce, ~ desi~ed, ~ admixb~. e w~th water. Ele~rated 10 temperatur~ may be used to en~ e the rate of the reaction~
In order to avoid tbe undesired decomposition of the reduci~ age~t it may be ad~rantageous to carry out the reaction in alkaline medium, e. g., sodium methoxide in metha~ol, ~odium hydride in water and the 1ike.
The comp~unds of tormu1a (IV) are novel and, as usefu1 i~terrnetiate hereirL, they constitute an additi~ La1 feature of the prese~t i~vention.
I~e cor~p~d~ of formula (I) may also be prepar~d by reac1ing ar~ appropriately sub~tuted a~Jl-cya~o-cycl ohea~a~e 20 of ~o~ula (V) with a~. appropr~te 4-pipe~di~ecarbo~y3io acid deri~Jati~e of formula (m) followi~g art-k~ow~ N-alkyla~:Lg pro~e-dure 9 .
~:L the formulae (V) a~d (~I) R, Rl, Arl ar~d Ar2 are as previously desc~ib~ a~d W repre~t~ a~ appropriate le2v~:Lg group ~u~-h as, 25 or e~pl~, ~alo, e.g., chloro, bromo or iodc), or a sulo~yloxy gro~p, e. g., methyl3ul~0l:Lylo~y, ~-mehy~ph~nylsulfor~yloxy a~d the lik~.
~ )OW ~ R N~Llkylatlo:Q (I) Ar Ar (V)- (III) 87~8~
Sa~d N-alkyla on-~eac~o~ co~venie3~tly conducted in a~
i:~Lert orga~ic qol~r~t ~uch as, for example, an aromatic hydrocarbo~, e.g., be~ze~ç, met~ylbe2:Lzener di2n,et}Lylbe~zene a d the lilce; a lo~r aL~a~Lol, e. g., met}:larLol, etha~ol, 1 -butallol a~d the like; a 5 ketorLe,. e.g., 4-methy~-2-pe~ta~one. and ~he li}ce; a3~.et er, a.g., 1,4-d~oxa:~e, l,l'-qxybi~e~a2,e a~3.d.the li~e; N,N-dimet~ylforma~ide;
~itroberL ene a3~d the li}ce.
T~e adOdition of a~ appropriate ba~se such a~, for e~ample, a.~L alkali metal carboIlat~ or hydrogesL carbo~ate, or arl org~r~ic base such as, 10 fo~ exar~ple, N,N-ciethyle~:La~ami~e a~d the li~e may be ~t:llizec to pick u~ acid which i liberated duri~g the course ~f the . eacti4n.
certa~ ~ase~ add~,t;o~ Q an iad~de ~al~,. preferabl~ a~ aL~li metal iodide, is app~opriate. Somewhat ele~rated temperatures ,-~y be used to e~haD.ce t}:Le reactio~L rate.
The compou~Lds of formula (I) whereir~ R i9 hydroxy, said cornpound~ being represe~ted by the for~ula (I-a), may also be derived from the compound of formula (I) whereirL R is other than hydroxy, ~aid R beiD.g represented by Ra a~d said oompou~ds by the formula (I-b), by hydrolyzing (I-b).
zo Conversely, the compound~ of formula (I-a) may be conYerted into the corresponding compounda of formula (I-b) ollowing art-known esterification- or amidatio~ procedures.
R 1 o A~ ( ", 2 e ~t e ri~ic ation ' ~
or hydrolys~s amidatio~ ~ ~
Rl o C ~ < C 0 (I-a) J~ 326 7~80 The above hydroly3is reacti~n may generaLly be carried out by stirring and, if desired, heat~g a compound of formula (I-bJ in aqueous alkali~e or acidic medium quch as, for example, an aqueous potassiucr~ hydroxide solutiorl, respecti~rely an aqueous hydrogen 5 chloride solutio~. -~n case Ra represent3, for example, a phenylmethoxy radical the hydrolysis may also be replaced by art-known hydrogenolysis-proce-dures, e. g. by catalytically hydrogenating the starting compound (I-b) i~ the presence of an appropriate catalyst such as, for e~carnple, 10 palladium-or~-charcoal, platinum-on-charcoal and the like.
The esterification- or amidation reaction ~nay be carried out by stirring arld heatl~g the starti~g acid (I-a) with an appropriate alcohol or ami~e in a su~table reac~ion-i~ert organic sol~rent such as, for example, an aromatic hydrocarbo~, e. a,, benzerle and the like 15 in the presence of a catalytic amount of a strong acid, e. a., sulfuric acid, 4-methylberLze~esulfonic acid and the like. ~os~ preferably the reaction i5 carried out at the reflux temperature of the reaceion ~ixture under azeotropic re~noval of the water which is for.~ed durirLg the course of the re~action.
zo In certai~ cases it may be appropriate to convert pre~iously the carbox~rlic acid functiorL into the corresponding acid halide function and subseque~tly react the thus obtained acid halide with an appropriate alcohol or amine.
The compoun~ of ~ormula (I) may be con~rerted to the thera-peutically active non-~oxic acid addition~salt form by treatn~ent with an appropriate acid, such a3, for example, an lnorganic acid, such as hydrohalic acid, e. g., hydrochloric, hydrobromic and the like, and sulfuric acid, nitric acid, phosphoric acid a~d the like; or an organic acid, s~ch as, for example, acetic, propanoic, 2~hydroxy-acetic, 2-hydroxypropanoic, 2-oxopropanoic, propanedioic, butane-dioic, (Z ) -2 -butenedioic, (E ) -2 -butenedioic, 2 -hydroxybutanedioic, 2, 3-dihydroxybutanedioic, 2-hydroxy-l, 2, 3-propanetricarboxylic, , .
~L87~8~
benzoic, 3-phenyl-2-propenoic, a-hydroxybenzeneacetic, methane-sulfonic, ethane~ulfonic, benzenesulonic, 4-methylbenzenesulfonic, cyclohexa~esulfamic, 2-hydroxybeDzoic, ~-amir~o-2-hydroxybenzoic and the like acids.
CoMrersely the salt ~orm caIl be co~verted by treatrnent with alkali i~to the free base form.
It i~ obvio~ fr.o~l formu~a (I) that the compounds of this inve~tion may exist under diff~re~t stereochemically isom~ric form~.
Due to the substitutio~ of the cycLohexyl ring said compounds may be prese~t i~ two differen~ geometric i.~omeric forrns, r~amely cis- a~d tra~s fors~. hforeovér, the piperidi~e part will also exhibit optical isomerism wh*~ R is lower alkyl, and theie opticaL isomers are coz~ventio~ally designated "Ap(+)", "Ap(-), "Bp(+)" a~d "Bp(-)"
without reference to the absolute configuration of each isomer.
1~ . T~Lus,for the compound~ (I), the~e are only geometric isomers A a~d B when~ R~ is hydrogen but ~here are 8 diastereomet ic iso-me~s when R is lower alkyl. These isom~rs are designated "Ac-Ap (+)"
"Ac-Ap (^)", "Ac -Bp (+)", "Ac -Bp (-)", "8c-Ap (+)", "Bc-Ap ( ~)", . "Bc-Bp (+)" aIld "Bc-E~p (-)". It chould be appreciated that t~e3e isosners will occur as diastereomeric pair~ or racema~es designated "Ac-Ap (~ )", "Ac -Bp ( ), "Bc -Ap ( J" aud "Bc -Bp ( ~)", which may be resolved i~to their euantiome~s by art-k~ow~ procedures. The e racemate~ will ~ometime~ be ref~rred to ~imply as "Ac-Ap", "Ac-Bp", "Bc-Ap" and "Bc-Bp".
Fure ~tereochemically i~omeri~ forms of the compou~ds (I) may be obtai~ed by the application of art-known procedures.
Geometric i30~ers and pairs of diastere~isomer~ can be separated from each other by physical separatioIl methods such as selective cry~taLliæation arld chromatographic tech~iques, e. g., cou.~ter current distribution, colu~T~-chrosnatography a2~d the li~e. Pure enantiomers may be separated fro~n each other by the application of art-Xr,ow~ resolution tech~iques such as, for example, by formin~, dia-qtereo~eric salts or other derivative~ with pure optically active JAB 3~6 reagents, subjecting said diastereomeric ~alts and deri~atives to phyqical separation tech~ique~, e. g, selective cry~tallization a~d chromatography, and, finally, l~berating the desired enantiomer~
following art -k~own proc edure 5.
Pure ~t~reoe~æmically isomeric forms may also be derived from the corresponding pure stereochernically ~isomeric forms o~ the -appropriate starting materials, provided tha~ the r~actio~s occur stereosp~ciically Stereoche2~c~1ly iso~eric: Ior~n~ o ~e compou~q of or~nula (I) are rLat~rally intended to b~ ernbraced wl~in the scope o~ i i~Ye~t~o~
A great ~ er of ~ rmediate~ a~d ~rti:~lg materials ~ t~a foregoi~g preparal:io~ are know~ compou~ds a~d all of the~
ma~ be prepared accorclirLg to art-k~ow~ me~odologieq OT prepari~g ~i~nilar co~pau~d~ er of such preparation rrlethodi will be de~cribed hereafter ~ o~Lewhat ~ore detail.
Th~ inter~edia~es oi formula (~E) ca~ be pre~ared by a Mic~ael additio~ re~ctioD of an appropriate arylaceto~ ile (VI) wit~ a prope~oic acid ester (VII) a~d su~ equerlt hydrolysi3 of the t~lU3 obta~ed cyclic Mic~ael.adtilioD. react~on pro~uct iD. acldic ~e-m.
I~ the fo310~g roact~n ~ches~Le R2 repre~e~t au optionally ub~ -b~tod lower al~yl ra~ical.
Ar -C:H C:~ + C~2=~ co~ 2 i 1) I!vIichael addi~o 2 ) cyclizatio~
(~I) (vII~ 3 ) hyd~ oly~is Said Mic~ael a~itio~ reaction i5 Con~e~iaD.tly co~ducted oy Z5 ~tirs~irLg and, if desi~7 ha~g the reacta~Lts toge~er i~ a ~uitable ~ol~re~t such a, for example, a~ alXanol, e. g., etha~ol, I, l-dimethyl-otha~ol a~d ~e like; a~ aliphatic-, alicyclic- or aroma~c hyd~o-c~rbo~, e.g., ~-hexarLe, cyclohexa:~e, me~yl~e~ze~e a~ :he li~e;
., ` ~87~
i~ the pre~e~ce of ar~ appro~riate stro~g ~a3e, e.g,, 3~diu~ hydride, sodium methoxide a~d the lLlce, deperldirLg up~ll the 301~re~t used.
PreferaUy t~e reactio~ is conducted at tha re~lux te~pera~re o~
the reacti~ ~tU~2 .~
T~e hyd~olysis i~ ge~eral~y carried out by s~:irr~g a~d hea~g t~e Michael additio~eactio~ pr~duct iD, a~ue~us acidic me~ium, e. g., aque~u~ ~ydroc loric acid a~d the liXe.
The arylac0to~ ile (Vl:), u~e~d as a starting materlal ~erei~, ca:ll b~ p~e~a~ed by car~ng out the ~tPps of:
i~ reacti~g an appropriate ~rylmagr~e~i~ halide (~m) with paraforr~ldehyde f~llow~:Lg art~ ow~ Grignar~ reac~o~L
procedu~e;
i~) con~rer~g the alcohol f~:qActio~s of t~e thu obtaiDed arylmetb.yl alco~:Lol (IX~ ~o a~ appropr~ate ~e~L~rirLg gr~up W; a~
15 ~ii) qub-~ti~ti:rlg t~Le group W of th~ ~hus obt:a~ed ~ termediate (X) b~ a cya~o group. .
.
Arl-~gh~lo t- (HCOH)~ ~Lcbo~ Arl CH2OH
(Y~) , ~IX) W Arlc~z-W CN (V~) (X) 1:he Grig~Lar~ ~eactj.o:~ of (Vm) with parafQr~aldehyte .~ay be carriesl out by ~tirri~g a~d, if desired, hea~ng the r~acta~ts to~et}Ler i~ a su~table react~or~-i~ert or~nic sol~e~t 3uch a-~, for example, 20 a~ e~her, e.g., tetrahydrofllrarL, 1,4-dioxane aD.d t~e li}c~. Most pre~erably ~he reactio~ i-~ corLductsd a. t~e re~lux temperat~re of the react~on mi~re .
The con~ersio~ o the hyd..oxylfu~ction into a lea~ group may, for example, be carried out by s~irrirLg the alcoh~l (I~) with z5 a~ appropriate haloge~ g or ~ulfonylatiD~g age~.t, e . g,, thio~yl chloride, methanesulfo~yl chloride a~ld ~he like, i~ a suit~ble reactio~-~ert sol~Je~t, e. g,, meth:ylbe~zene a~:Ld t}~e Like.
l~e lea~ g group W i2~ (X) may be replaced by a c~o group by stirr~g (X) with a~L alkali m~t 1 cya~e, e. g., po~3siur;~
cyallide a~d the like, ~:L a ~ Lble s~l~renl:~ e. g., 2-propanc)~e a~d th~ li~ce.
The intermediates of formùla (III) can be derived Irom an appropriately sub-~ituted 4-cyanopiperidi~e, havi~g the for~nnla Rl ~ CN
P-N~_,)( Ar2 (X~) wherein Rl and ~r2 are as previously described and P represents an appropriate protectit~ group, following art-known proc~dures of converti~g ~itriles into amide¢., carboxylic acids a~d esters.
l~e p~ocedure to be u~ed as well a~ the ~ucceq~:io~ of t*e react:lorL ~tep~ ~ay~ .-depe3:~d upo~ Le ~abure of P and Rl.
For ega:mple, when P rapre~eut~ a 4~ e~ phe~ylsul~o~yl radioal 15 the. iDter~ediate3 (III) ca~ be prepa~ed ~y slirr~g a:~d, if desired, hea~ Lg (XI) i~ acidic ss~ediua~ i~ Le p~ese~ce of a reage~t o for~nu!a RO~, wherein ~ a~ previou~ly de~i~ed. ~hc~L A~Z repre . e .ts a t~i1u~omethyl3?}1erLyl radic~Ll it may occur tllat t~e C;~3-ra~cal i co:~ert~d ~to a -C;OC)R radical~
20 T}~e iuterr:2ediate~ (m) may al~o be deri~red f:ros~ a cya~de (XI) by fi~3tly hydrolyzi~g the c~e ~c~io~L i~ alkal~e mediu~ a2~d, wherL R is ot~er tha~ hy~rogeD., co~er~g the thus obtai~ed carbo-xylic ac~ LntO the de~ired carboxylic estQr, aDd qub~e~,uently eli-m~at~g the protecti~re group follow~g art~ owsl procedu-e~, e.g., 2:S by 3tirri.:Gg the iD.t~r~ediate~ ~ a ~ui~able sol~re~t i3~ the 3?rese~ce of a~L appropria~e t~traalkyla~s~o}~iu~ h~lide or in t}~e oreqence of a e of phe~ol and hydro~en bro~ide ~ acet:~c acld.
...~
JAs 326 ~37 I~ ~ome c~es it r~ay be ad~ra~tage~u~ el~ati~g i~ir~tly P and 3ub eque3~tly corl~rerti~g the GN rad.ical i~.to the de~ired est~r or amide radic:al.
Tho ~nter~ediate~ o~ fo~ula (XI)~ used a~ ~g 5 materials i~ the foreg~i~g reactio~, may be prepared by reac~g a~ appropri2~t~ tertiary a~ Le (XII), whereir~ P, Rl a~d W are a~
pre~rsou~ly deined, with a~l app:ropriate arylaceto~trile (XIII) ~n alXal~:Le medium. - `
C~ -CH
~ ~W
P i~ ' Ar~ C:~ CN (~I) C~2 -C}~2 -W
(XII) (~I) ~ai~ ~eactio~ i3 con~re~e~tly co~ducted by tirr~g a:~Ld hea~:Lg 10 t~e reacéanP toget~e2 ~ a ~table reac o~-i~rt orga::~c sol~7erLt ~uch ae, for exampLe, wat~r; a cyclic ~ther, e. g., tet:rahydro~ura;~, 1,4-~lioxane and the liXe; or a ~nixture of such sol~ent~, in ~e prese:cce of a~ appropriate ba~e, e.g., 30diu~ h~ro~ade, pota3sium c rb~at a~d t~Le li}~e.
The eompounLs o~ for~ula (I) a~d t~eir p~a~aceu~cally aeceptable acid addition salt~ ar~ pote~lt a~tihi ~Lmi~iC a~e~Lts and as such t~ey ca~ be u-qed to p~e~ar~. ~raluable msdicam~ts for huma~
aDd ~al t~erapy.
T~e u~e~ul a~ tam~c properties of the co~paunds o ~orr~la (I~
20 are demo~stxated ~ the ~ollowing tes~procedure.
.
PROTECTION OF ~TS FROM C;OMPC)UND 48/80 -~DUG D
Comps~u~d 48/80, a mLx~re of oligomers oot~i~ed by con-de~ at:ioD. of p-me~haxy~ met~yl-p~enylet~ylami~e a3~d ~orrnaldehyd.e ~L~8~30 ha3 been described as a potent hi~Lmiue releasing age~t (Ir~t. .~ c~.
Allergy, 13, 336 (19~8)~. The protecti~ from compou~d 48/80-in~
duced let~1 ci~culatory collapse a~pear~ to be a simple way o~
evalua~g qua~ ively the- a~iq~cam~c activ-i~r oi test-compau~d~.
Male rat~ o a3:L L~bre~ Wi~Lr ~t~a~rL, we~ghi~g 240-260 g were s~sed Le ex;?er~e~t. Aftar over~ight 3ta~atio~ the rat~ were tra~s-ferred t~ co~di~loned 1ab~ratorie~ (temp. = 21 t 1 G, relative hu~idity- 6; ~ ;%).
Tbe rat~ wcr~ t~eated subcuta~e~u~ s orall.y with a test co~pouud lQ c3r with l~he s~ re~t (NaC;1 ~o1utio:~, 0. 9%). C)~e hour after treatme~t there wa~ ~jected i~tra~erLous1y coI:npou~d 48/80, ~reahly di sol~red i;~ water, at a do~e of O. 5 mg/kg (0. Z ~:Ql/100 g of bod~ wei~ht).
kL con~ol experi~erlt~ wherei~ 250 sol~t-treated a~mals wer0 ' -j~cted Wit}:L the sta~dard do~e of compou~d 48/80~not more thaD. 2. 8~
of the a~:Limals ~ur~n~e~ i~ter 4 ~ouxs . Sur~a1 after 4 hour~ i5 the~ e-fore co~sider~d to be. a sae criterio~ of a pro~ecti~e e~'et t of drug ad~i~t~ation.
Tables I a~d II show for a nu~nber a~ co~pouDds of formuia (I) the oral doses (in ~ng/kg body wei~ht) at which the rats were protected ~gair~st con~pouDd 48/8Q~ Lduced 1etha1ity, The data represe~ted irL tab1es I and II are illtended to i11ustrate and ~ot to 1imit the scope af the prese~t i~re~tiOrL
~7~80 1~
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:~ view o~ t~eir useful a~hista~i~c ac~t~, the subject comp~unds ~ay be forrr:Lulated i~ o varioua pharmaceutica1 form~q for almi~istrati4D. purpc~es. To psepare the pharmaceu~'cal co~ si-tiou~ of ~ re~io~ ef;Eective a~L~ista~inic amourLt of the par~
5 tic~-la~ co~ps~u~d, in~b~se o~ ac~-addi~o~ ~lt for~, a ~ the active ~gredie~Lt i3 comb~ed ~ ~ti:~nat~ adAmixb~re wit~ a phar~aceu~ica1ly a~c~ptabl~ carrier,. whieh~ carrier may take a wide va~iety of for~
depend~:cLg on the forD:l of preparai:io~ desir~d for adr~is~at:~or~.
These pharmaceu~cal compositio~s àre desirably i~ wlitary do~age 10 form ~ui~able, preferably, for ad~i~ist~a1:~o~ orally, rectally or by parerLtesal ~jection. For e~ Lple, i~ prepar~ng the co~po~ition3 iu ~3~al do~age for~,: a~y of t~e usual pha~:maceutic~l media may be errlployed,. 3uch.a., for e~ple, water, glycols, oils,. alcohols a~d t~e li}~e ~SL the c~ e of oral liqu~d prepar~ion~ 3uch a~ ~u~perLsiorLs, 15 ~yrupst e}ixLrs a~ ss~lu~ion3; or soli~carrier~ such a~ rc~es, sugars, Xaoli~, lubr~ant3, bi~der~ kategsat~ age~t~ and t~e the case o~ po~dersJ pill~, cap~sule~ a~:Ld tabletq.. ;3ecause of their ease iD ad~ast~atio;~, tablet~ aD.d capsule~ repre~e~t the r2~0st a~a~tLgeous oral do~age- ~t form, in whioh case solid l?~ar-~:Laceutical carrier~ are o~vlou~ly emplo~ed. For parerLteral com~
po~itinc2~, ~he carrier will usuaLly coD~p~ise st~r;le wat2r, at lea~.t large part, thollgh ot~er ~gre~iellt~, for example, to ai~ 31ubility, may b~ ~clude~. ~ject;~ble olutio~s,. for exa~ple may be p:repared i:~ w~ich t~e car~ier co~pri_es ~ali~Le solu~a~, glu~os~ solutio~ or a ~aixtu~a of sali~ ~d g}uco~e solut~o:cL. ~jectable suspe~sion~ ~y al~o be prepared u:~ w~ch ca~e- appropriate li~,uid c~rr~er~, 3usp~diug agent3 a~d t~e like may'~e e~ploye~. A~id additio~ salt~ of (I), due to th~ir inc~ ea~ed water 30lubi~ity o~er the corre3po3~iDg base for~n, are obv~ou31y more suitable ~ the prepaxatio~ of a~ueous compositio~s.
It is e~p~c~lly advantage~uq to ~orr~ul~te the aforementio~
p}~ ac~lltica1 co~p~itions i:~ do~age u~it form for ea3e of ad-; . m~iqt:3~a~0D. and u~ o~nity of dosage. 30sage u~t ~or:s~s as usea the 3peci~ atio~ and claL~s herein refer .o physicaLly ~iscrete u~its suita~le as unitary dosages, each u~it Co~t3i~Lg a predet~r-;~irL~d qua~Ltity of ac~r~ i~gredie2~t caiculated to produce th~ de~ired t~erapeutic effect irL a~soc~atior~ w~th the required pha~.~aceu~cal JAs 326 ~8~8C~
carrier. xa~ple~ o~ such dosage u~it forms ar~ ~blets (i2:Lcludi~
~cored or coated t3blets~, caps~les, pills, p~wder paoket, waer~, ~jectable ~olu~io~ or suspe~ions, tea~ ~uls, tablespoo~uls a~d the like,. a~d 3egr~gated ~ult:ipleq t~ereof.
,.
l~Qe followi:cLg e~ple ara ;~te~a~ed to illus~r .~e a~ Lot to l~t the scope of ~e pre~e~t ~ e~iO~. UrLle~ o~cherw~se st;ated all p~rts therein are by weight.
8~8~
A. PREPARA~ION OF D!JTERMEDIATES
~ .
To a stirred a~d refluxing Grigr~a~d-co~nplex, previously prepared ~tarti~g fr,~om 39, 7 part~ of 1-bromo-4-fluoro-2-methyl-S be~zene a~t 5.1 par~s of magnesium in 225 parts of tetrahydrofuran, are added po~tio~wi3e 8. 4 part~ of paraformaldehyde. Upo~ comple-tio~, stirri~g is conti~:Lued for 1 hour at reflux. The reac~io~ mix~ure i9 cooled and pou~ed o;:Lto a mixture ~f cru~hed ice a~d acetic acid.
The product is extracted with trichloromethane. The e~ract is dried, filtered a~d ~Yap~rat~d, The residue is di~tilled, yielding 14 parts (47 . 6 ~ ) o 4 -fluor o -~ -methylbenze~eme thanol; bp. 1 1 0 C (wate r -j et).
Il~ a si~nilar maDner there i~ also prepared:
4-chloro-3-(t~i~luorome~hyl)berLzenemetha~ol; bp. 90C
at 0. 4 ~n. pressure.
~
. .
To 14. 3 parts of thio~yl chloride is added dropwise a 501u-tion of 14 parti of 4-fluoro-2-methylbe~zez~emethanal a~d 0. 9 par~s of N, N-dimethylformasnide i~ 45 parts of methylbenze~e.while coolirLg iD ice-water. Then there are added 13~ parts o methylben?~e~e arld stirrirLg 18 couti~ued for 1 hour t roorn temperature. The reaction mixture i~ e~raporatad, yieldi~g 17 part~ (100%) of l-(chloromethyl)-4-fluoro-2 methylbe~z;e~e aq a residue.
In a ~imilar ma~er there i al30 prepared:
I_chloro_~(chloromet~yl)~2-(trifluoromethyl)benzene; bp.
2 5 1 0 0 C at 1 0 s~Lm. pre s ~ur e.
i A mixt~re o 16 parts of 1-(chloromethyl)-4-fluoro-2-met~Lyl-be~3ene, 7. 8 parts o~ a solutio~ of pota3sium cyar~ide in a sr~all amo~Lnt of water, 0.1 par~ o pot~3~ium iodide a~d 240 part.e of 2-propano~e is 30 stirred and refluxed for Z2 hour3. The reactiorL mixture is cooled a~d filtered. The ~iltrate i8 e~raporatad. The residue is take~ up ;.LL water and the product i~ extracted with methyLbe~zene. The extract ls dried, filtered a~d e~aporated, yielding L3 par~s (87. 2%) of 4-fluoro-2 methylbenzelleacetonitrile a~ a re.~idue.
.~....
7~80 I~ a s~nilar marLne~ there is al~o prepared:
4-chloro-2-(trifluoromethyl)ben~ceneacetonitrile; bp, 83 ~C
at 0. Z mm. pressure.
Example IV
A mixture o:~ 2'21 part~ o~ 4-nuoroben2e~:Lsaceto~itrile, 700 parts of ~odium me~hoxide ~c~lu~ion 30% and 900 parts of di~ethyl-be~ze~e ia at:irred for 5 ~inute~. The~ there ar~ ad~ed d~opwi3e 309 parts of methyl 2-prop~Loat~ (e~cot~erffl;c reacti~n: tempera~re rises to 65C;). Upo~ cosx~,pletion, ~tirring i~ con~ued o~rer~;ght at ref:L~x temperature. The metha~ol i8 d;stilled of~ L irLter~al tempera~re of 110C: i9 reéLched. After coali~g, lOOO par~s of a hydro-cJloric acid 301ut~o~ oN are added d~opwi3e a~d the whole i9 tir.ed a:~ rei~hxed for 5 mi~su~3. Upo~ cool~L~, the layer~ are separated.
The orga~c phase i3 drie~ ilte~ed a~d evaporated. I'he re~idue i~ 3tirred a~d reLu:~ed for 4 hou~ togethe~ ~n'~ 500 part~ of acel~c acsd, ;00 part~ o~ water and 500 part3 of a hydrochlorac acid solut;o~. After cooli~, the product is ext~cted with ~ichloro-~etha3a~. r~ eæt~act i~ washed .succes~i~re1y? with water, w~t}L a ~iluted sodium hydroxLd~ ~olutio~ arLd aga~ wit~ water 'dll r:~ut:rali-za~io~, d~:sed, iilterecla~e~ orated. ~e re~idue i9 C2~yst~ i2ed fro~ 2-propa~ol, yie1d~ 134. ~ t~ ~f 1-(4-~uorophenyl)-4-oxocyc10he~ecarbor~ t~ile, r~p . ~1 . 8 ~ C .
FollowirLg the ~ame procedure and u~na a~ equivalent amou~t of a~ appropriate arylaceto~itrile as a starting materiaL
there are alsc~ prepared:
CN
~ ~r1 A~l ~p. or bp, i~ C
~ _ Z -pyridi~:Lyl mp . 90 . 1 2-OC~3 -C 6-~4 ~p. 1 70/0 . 03 .
2-OCH3, ~ C;l C;6H3 _ !
l8~
Ar . ¦ r~p- or ~p. ~ ~C
2 -C~3 -~ 6H4
N~ R
Ar Ar ami~atio (~:) , (m) Sa~d reducti~re a~ atio~ ~e~c~on may co~re~e~ly ~e carr~ed out by catalytically hy~rogeDat~g ~ s~irr~d aDd he~ted ~xt~re o the reactant~ ~ a . 3uitable re c~on-i~sert orga~c solve~t accord~g to art~ LowE~ c~Ltaly1:ically ~ydrogenati2~g procedures. Suit~ble solve~ts 25 are, for example, water; lo~er a}~L~ ls, e.g., r~Letllanol, 2-propa~ol a:~d. ~e like; cycl~c ether~, e.g., 1~4-dioxane a~d the lilce;
î~L87~ JAB 3~6 ~aloge~at~d ~ydrocarbosl~, o.g., tric~70rometha~e a~d t~e li~ce;
~methyl~orss~a~nide; ~ir~ethyl s~ o:~ade a-t t~e like; or a mix~e of 2 or D:~ore ~i such solYerlts. The te~m "art-~own cataly~ca11y hytro-geUatirL~ procedure ~" ~ea~s that the ~eactio~ is carried out u~der 5 hydroge~ at~osphere i;ld i~ t}le pre~e~ce o~ a~L appropr;~Lte ca~aly~t such as, for exampla, p~llad~,u.m~ charcoal, plahnu~n-on-char-coal. a;ld t}~e lilce . I~ or~e~ to prev~t th~ u~desired further hyd~ o-ge~a~ion o certai~ ~'~ctio~l groups~ the rQac~ Lts a~d t~e react oD
product~ ~t ~ay ~e a~ ou~ ~o add a~ appronriate cat~lys~-10 poiso~ to the reaction~ ur~, e. g., t~io~:~hene aad t~e like.
The- compou~d~ of formula (IV) may , be prepared by reacti~g an appropriat~ cyclohexa~o~e of forslula (II) wit~ a appropriately ~ubstituted 4-piperid~ac~rb~x~rlic acid derivati~e of fl~ula (~) e~amine NC Nr~(/~--R
. . ~ A 2 (m) f~ation Arl ~~ \~/ `~
(Iy) If desi~ed, tl~ enamine of fonmulaO(IV) may he subsequently re~uced to fonm the co~pound of for~.ula (I).
I~he ~na m ~le fo~2la~0~ reac~oni~lay be car-ied out by ~r~
~g t~e reactant~ ~ogether i~ ~Le 3Jre~ence o a cat~lyeic a30t~t o~ a rela~relg- ~t:rong acid, e. ~., 4-~ot~Lylben~ey:Lesul~o~c aeid 20 asld t}~e like~ i~ a ~ lo reac~io~-~nert orga~c ~ol~eD.t suc~ as, ~ r e~sple, an aliph3tic-, alic~cl~c- or aromaic hydroc~r~on~
e. g., ~a.he~e, cyclonexane, meth~lbe:L2ene a~d t~e li~e. }n order to eD}~a~ce the reacffon -ate ~ornew~ olevated t3~pera~:ures are appropriate and p~e~era~y ~ae reaction is conduct&d at ~.he re~lux 25 ~empe-a~re OI thi~ reactioD. ~:~se. .~Sos~ pre~erably t~e reaclior .~
.
:~L87~8~
is ca~ d out us~d~r azeot~ opic re~so~al of the water which is fOL~ed dur~g the course oi~ r~actior~.
T~e reductio~ o~ the erLami~e of ~or~s~.ula (I~) may, for example, be carried out by s1:irr~g ~e e~am~e (IV~ a ui~Lble sol~re~t 5 i~ the prese~ce of ~ a~propriate reduc~ age..t r~uch aq, for e:~ample, a compl~Y ~etal hydride, e. g., odiu~2:L borohydride a~d t~e lice.
Suitable soi~euts are, ~or examplef al~llols, e.g. t metha~lol, 2-proparlol a~d the liXe; and cyclic~ether, e. g., tetr hydrofu~a~ I, 4-dioxa~ae a~d the li~ce, ~ desi~ed, ~ admixb~. e w~th water. Ele~rated 10 temperatur~ may be used to en~ e the rate of the reaction~
In order to avoid tbe undesired decomposition of the reduci~ age~t it may be ad~rantageous to carry out the reaction in alkaline medium, e. g., sodium methoxide in metha~ol, ~odium hydride in water and the 1ike.
The comp~unds of tormu1a (IV) are novel and, as usefu1 i~terrnetiate hereirL, they constitute an additi~ La1 feature of the prese~t i~vention.
I~e cor~p~d~ of formula (I) may also be prepar~d by reac1ing ar~ appropriately sub~tuted a~Jl-cya~o-cycl ohea~a~e 20 of ~o~ula (V) with a~. appropr~te 4-pipe~di~ecarbo~y3io acid deri~Jati~e of formula (m) followi~g art-k~ow~ N-alkyla~:Lg pro~e-dure 9 .
~:L the formulae (V) a~d (~I) R, Rl, Arl ar~d Ar2 are as previously desc~ib~ a~d W repre~t~ a~ appropriate le2v~:Lg group ~u~-h as, 25 or e~pl~, ~alo, e.g., chloro, bromo or iodc), or a sulo~yloxy gro~p, e. g., methyl3ul~0l:Lylo~y, ~-mehy~ph~nylsulfor~yloxy a~d the lik~.
~ )OW ~ R N~Llkylatlo:Q (I) Ar Ar (V)- (III) 87~8~
Sa~d N-alkyla on-~eac~o~ co~venie3~tly conducted in a~
i:~Lert orga~ic qol~r~t ~uch as, for example, an aromatic hydrocarbo~, e.g., be~ze~ç, met~ylbe2:Lzener di2n,et}Lylbe~zene a d the lilce; a lo~r aL~a~Lol, e. g., met}:larLol, etha~ol, 1 -butallol a~d the like; a 5 ketorLe,. e.g., 4-methy~-2-pe~ta~one. and ~he li}ce; a3~.et er, a.g., 1,4-d~oxa:~e, l,l'-qxybi~e~a2,e a~3.d.the li~e; N,N-dimet~ylforma~ide;
~itroberL ene a3~d the li}ce.
T~e adOdition of a~ appropriate ba~se such a~, for e~ample, a.~L alkali metal carboIlat~ or hydrogesL carbo~ate, or arl org~r~ic base such as, 10 fo~ exar~ple, N,N-ciethyle~:La~ami~e a~d the li~e may be ~t:llizec to pick u~ acid which i liberated duri~g the course ~f the . eacti4n.
certa~ ~ase~ add~,t;o~ Q an iad~de ~al~,. preferabl~ a~ aL~li metal iodide, is app~opriate. Somewhat ele~rated temperatures ,-~y be used to e~haD.ce t}:Le reactio~L rate.
The compou~Lds of formula (I) whereir~ R i9 hydroxy, said cornpound~ being represe~ted by the for~ula (I-a), may also be derived from the compound of formula (I) whereirL R is other than hydroxy, ~aid R beiD.g represented by Ra a~d said oompou~ds by the formula (I-b), by hydrolyzing (I-b).
zo Conversely, the compound~ of formula (I-a) may be conYerted into the corresponding compounda of formula (I-b) ollowing art-known esterification- or amidatio~ procedures.
R 1 o A~ ( ", 2 e ~t e ri~ic ation ' ~
or hydrolys~s amidatio~ ~ ~
Rl o C ~ < C 0 (I-a) J~ 326 7~80 The above hydroly3is reacti~n may generaLly be carried out by stirring and, if desired, heat~g a compound of formula (I-bJ in aqueous alkali~e or acidic medium quch as, for example, an aqueous potassiucr~ hydroxide solutiorl, respecti~rely an aqueous hydrogen 5 chloride solutio~. -~n case Ra represent3, for example, a phenylmethoxy radical the hydrolysis may also be replaced by art-known hydrogenolysis-proce-dures, e. g. by catalytically hydrogenating the starting compound (I-b) i~ the presence of an appropriate catalyst such as, for e~carnple, 10 palladium-or~-charcoal, platinum-on-charcoal and the like.
The esterification- or amidation reaction ~nay be carried out by stirring arld heatl~g the starti~g acid (I-a) with an appropriate alcohol or ami~e in a su~table reac~ion-i~ert organic sol~rent such as, for example, an aromatic hydrocarbo~, e. a,, benzerle and the like 15 in the presence of a catalytic amount of a strong acid, e. a., sulfuric acid, 4-methylberLze~esulfonic acid and the like. ~os~ preferably the reaction i5 carried out at the reflux temperature of the reaceion ~ixture under azeotropic re~noval of the water which is for.~ed durirLg the course of the re~action.
zo In certai~ cases it may be appropriate to convert pre~iously the carbox~rlic acid functiorL into the corresponding acid halide function and subseque~tly react the thus obtained acid halide with an appropriate alcohol or amine.
The compoun~ of ~ormula (I) may be con~rerted to the thera-peutically active non-~oxic acid addition~salt form by treatn~ent with an appropriate acid, such a3, for example, an lnorganic acid, such as hydrohalic acid, e. g., hydrochloric, hydrobromic and the like, and sulfuric acid, nitric acid, phosphoric acid a~d the like; or an organic acid, s~ch as, for example, acetic, propanoic, 2~hydroxy-acetic, 2-hydroxypropanoic, 2-oxopropanoic, propanedioic, butane-dioic, (Z ) -2 -butenedioic, (E ) -2 -butenedioic, 2 -hydroxybutanedioic, 2, 3-dihydroxybutanedioic, 2-hydroxy-l, 2, 3-propanetricarboxylic, , .
~L87~8~
benzoic, 3-phenyl-2-propenoic, a-hydroxybenzeneacetic, methane-sulfonic, ethane~ulfonic, benzenesulonic, 4-methylbenzenesulfonic, cyclohexa~esulfamic, 2-hydroxybeDzoic, ~-amir~o-2-hydroxybenzoic and the like acids.
CoMrersely the salt ~orm caIl be co~verted by treatrnent with alkali i~to the free base form.
It i~ obvio~ fr.o~l formu~a (I) that the compounds of this inve~tion may exist under diff~re~t stereochemically isom~ric form~.
Due to the substitutio~ of the cycLohexyl ring said compounds may be prese~t i~ two differen~ geometric i.~omeric forrns, r~amely cis- a~d tra~s fors~. hforeovér, the piperidi~e part will also exhibit optical isomerism wh*~ R is lower alkyl, and theie opticaL isomers are coz~ventio~ally designated "Ap(+)", "Ap(-), "Bp(+)" a~d "Bp(-)"
without reference to the absolute configuration of each isomer.
1~ . T~Lus,for the compound~ (I), the~e are only geometric isomers A a~d B when~ R~ is hydrogen but ~here are 8 diastereomet ic iso-me~s when R is lower alkyl. These isom~rs are designated "Ac-Ap (+)"
"Ac-Ap (^)", "Ac -Bp (+)", "Ac -Bp (-)", "8c-Ap (+)", "Bc-Ap ( ~)", . "Bc-Bp (+)" aIld "Bc-E~p (-)". It chould be appreciated that t~e3e isosners will occur as diastereomeric pair~ or racema~es designated "Ac-Ap (~ )", "Ac -Bp ( ), "Bc -Ap ( J" aud "Bc -Bp ( ~)", which may be resolved i~to their euantiome~s by art-k~ow~ procedures. The e racemate~ will ~ometime~ be ref~rred to ~imply as "Ac-Ap", "Ac-Bp", "Bc-Ap" and "Bc-Bp".
Fure ~tereochemically i~omeri~ forms of the compou~ds (I) may be obtai~ed by the application of art-known procedures.
Geometric i30~ers and pairs of diastere~isomer~ can be separated from each other by physical separatioIl methods such as selective cry~taLliæation arld chromatographic tech~iques, e. g., cou.~ter current distribution, colu~T~-chrosnatography a2~d the li~e. Pure enantiomers may be separated fro~n each other by the application of art-Xr,ow~ resolution tech~iques such as, for example, by formin~, dia-qtereo~eric salts or other derivative~ with pure optically active JAB 3~6 reagents, subjecting said diastereomeric ~alts and deri~atives to phyqical separation tech~ique~, e. g, selective cry~tallization a~d chromatography, and, finally, l~berating the desired enantiomer~
following art -k~own proc edure 5.
Pure ~t~reoe~æmically isomeric forms may also be derived from the corresponding pure stereochernically ~isomeric forms o~ the -appropriate starting materials, provided tha~ the r~actio~s occur stereosp~ciically Stereoche2~c~1ly iso~eric: Ior~n~ o ~e compou~q of or~nula (I) are rLat~rally intended to b~ ernbraced wl~in the scope o~ i i~Ye~t~o~
A great ~ er of ~ rmediate~ a~d ~rti:~lg materials ~ t~a foregoi~g preparal:io~ are know~ compou~ds a~d all of the~
ma~ be prepared accorclirLg to art-k~ow~ me~odologieq OT prepari~g ~i~nilar co~pau~d~ er of such preparation rrlethodi will be de~cribed hereafter ~ o~Lewhat ~ore detail.
Th~ inter~edia~es oi formula (~E) ca~ be pre~ared by a Mic~ael additio~ re~ctioD of an appropriate arylaceto~ ile (VI) wit~ a prope~oic acid ester (VII) a~d su~ equerlt hydrolysi3 of the t~lU3 obta~ed cyclic Mic~ael.adtilioD. react~on pro~uct iD. acldic ~e-m.
I~ the fo310~g roact~n ~ches~Le R2 repre~e~t au optionally ub~ -b~tod lower al~yl ra~ical.
Ar -C:H C:~ + C~2=~ co~ 2 i 1) I!vIichael addi~o 2 ) cyclizatio~
(~I) (vII~ 3 ) hyd~ oly~is Said Mic~ael a~itio~ reaction i5 Con~e~iaD.tly co~ducted oy Z5 ~tirs~irLg and, if desi~7 ha~g the reacta~Lts toge~er i~ a ~uitable ~ol~re~t such a, for example, a~ alXanol, e. g., etha~ol, I, l-dimethyl-otha~ol a~d ~e like; a~ aliphatic-, alicyclic- or aroma~c hyd~o-c~rbo~, e.g., ~-hexarLe, cyclohexa:~e, me~yl~e~ze~e a~ :he li~e;
., ` ~87~
i~ the pre~e~ce of ar~ appro~riate stro~g ~a3e, e.g,, 3~diu~ hydride, sodium methoxide a~d the lLlce, deperldirLg up~ll the 301~re~t used.
PreferaUy t~e reactio~ is conducted at tha re~lux te~pera~re o~
the reacti~ ~tU~2 .~
T~e hyd~olysis i~ ge~eral~y carried out by s~:irr~g a~d hea~g t~e Michael additio~eactio~ pr~duct iD, a~ue~us acidic me~ium, e. g., aque~u~ ~ydroc loric acid a~d the liXe.
The arylac0to~ ile (Vl:), u~e~d as a starting materlal ~erei~, ca:ll b~ p~e~a~ed by car~ng out the ~tPps of:
i~ reacti~g an appropriate ~rylmagr~e~i~ halide (~m) with paraforr~ldehyde f~llow~:Lg art~ ow~ Grignar~ reac~o~L
procedu~e;
i~) con~rer~g the alcohol f~:qActio~s of t~e thu obtaiDed arylmetb.yl alco~:Lol (IX~ ~o a~ appropr~ate ~e~L~rirLg gr~up W; a~
15 ~ii) qub-~ti~ti:rlg t~Le group W of th~ ~hus obt:a~ed ~ termediate (X) b~ a cya~o group. .
.
Arl-~gh~lo t- (HCOH)~ ~Lcbo~ Arl CH2OH
(Y~) , ~IX) W Arlc~z-W CN (V~) (X) 1:he Grig~Lar~ ~eactj.o:~ of (Vm) with parafQr~aldehyte .~ay be carriesl out by ~tirri~g a~d, if desired, hea~ng the r~acta~ts to~et}Ler i~ a su~table react~or~-i~ert or~nic sol~e~t 3uch a-~, for example, 20 a~ e~her, e.g., tetrahydrofllrarL, 1,4-dioxane aD.d t~e li}c~. Most pre~erably ~he reactio~ i-~ corLductsd a. t~e re~lux temperat~re of the react~on mi~re .
The con~ersio~ o the hyd..oxylfu~ction into a lea~ group may, for example, be carried out by s~irrirLg the alcoh~l (I~) with z5 a~ appropriate haloge~ g or ~ulfonylatiD~g age~.t, e . g,, thio~yl chloride, methanesulfo~yl chloride a~ld ~he like, i~ a suit~ble reactio~-~ert sol~Je~t, e. g,, meth:ylbe~zene a~:Ld t}~e Like.
l~e lea~ g group W i2~ (X) may be replaced by a c~o group by stirr~g (X) with a~L alkali m~t 1 cya~e, e. g., po~3siur;~
cyallide a~d the like, ~:L a ~ Lble s~l~renl:~ e. g., 2-propanc)~e a~d th~ li~ce.
The intermediates of formùla (III) can be derived Irom an appropriately sub-~ituted 4-cyanopiperidi~e, havi~g the for~nnla Rl ~ CN
P-N~_,)( Ar2 (X~) wherein Rl and ~r2 are as previously described and P represents an appropriate protectit~ group, following art-known proc~dures of converti~g ~itriles into amide¢., carboxylic acids a~d esters.
l~e p~ocedure to be u~ed as well a~ the ~ucceq~:io~ of t*e react:lorL ~tep~ ~ay~ .-depe3:~d upo~ Le ~abure of P and Rl.
For ega:mple, when P rapre~eut~ a 4~ e~ phe~ylsul~o~yl radioal 15 the. iDter~ediate3 (III) ca~ be prepa~ed ~y slirr~g a:~d, if desired, hea~ Lg (XI) i~ acidic ss~ediua~ i~ Le p~ese~ce of a reage~t o for~nu!a RO~, wherein ~ a~ previou~ly de~i~ed. ~hc~L A~Z repre . e .ts a t~i1u~omethyl3?}1erLyl radic~Ll it may occur tllat t~e C;~3-ra~cal i co:~ert~d ~to a -C;OC)R radical~
20 T}~e iuterr:2ediate~ (m) may al~o be deri~red f:ros~ a cya~de (XI) by fi~3tly hydrolyzi~g the c~e ~c~io~L i~ alkal~e mediu~ a2~d, wherL R is ot~er tha~ hy~rogeD., co~er~g the thus obtai~ed carbo-xylic ac~ LntO the de~ired carboxylic estQr, aDd qub~e~,uently eli-m~at~g the protecti~re group follow~g art~ owsl procedu-e~, e.g., 2:S by 3tirri.:Gg the iD.t~r~ediate~ ~ a ~ui~able sol~re~t i3~ the 3?rese~ce of a~L appropria~e t~traalkyla~s~o}~iu~ h~lide or in t}~e oreqence of a e of phe~ol and hydro~en bro~ide ~ acet:~c acld.
...~
JAs 326 ~37 I~ ~ome c~es it r~ay be ad~ra~tage~u~ el~ati~g i~ir~tly P and 3ub eque3~tly corl~rerti~g the GN rad.ical i~.to the de~ired est~r or amide radic:al.
Tho ~nter~ediate~ o~ fo~ula (XI)~ used a~ ~g 5 materials i~ the foreg~i~g reactio~, may be prepared by reac~g a~ appropri2~t~ tertiary a~ Le (XII), whereir~ P, Rl a~d W are a~
pre~rsou~ly deined, with a~l app:ropriate arylaceto~trile (XIII) ~n alXal~:Le medium. - `
C~ -CH
~ ~W
P i~ ' Ar~ C:~ CN (~I) C~2 -C}~2 -W
(XII) (~I) ~ai~ ~eactio~ i3 con~re~e~tly co~ducted by tirr~g a:~Ld hea~:Lg 10 t~e reacéanP toget~e2 ~ a ~table reac o~-i~rt orga::~c sol~7erLt ~uch ae, for exampLe, wat~r; a cyclic ~ther, e. g., tet:rahydro~ura;~, 1,4-~lioxane and the liXe; or a ~nixture of such sol~ent~, in ~e prese:cce of a~ appropriate ba~e, e.g., 30diu~ h~ro~ade, pota3sium c rb~at a~d t~Le li}~e.
The eompounLs o~ for~ula (I) a~d t~eir p~a~aceu~cally aeceptable acid addition salt~ ar~ pote~lt a~tihi ~Lmi~iC a~e~Lts and as such t~ey ca~ be u-qed to p~e~ar~. ~raluable msdicam~ts for huma~
aDd ~al t~erapy.
T~e u~e~ul a~ tam~c properties of the co~paunds o ~orr~la (I~
20 are demo~stxated ~ the ~ollowing tes~procedure.
.
PROTECTION OF ~TS FROM C;OMPC)UND 48/80 -~DUG D
Comps~u~d 48/80, a mLx~re of oligomers oot~i~ed by con-de~ at:ioD. of p-me~haxy~ met~yl-p~enylet~ylami~e a3~d ~orrnaldehyd.e ~L~8~30 ha3 been described as a potent hi~Lmiue releasing age~t (Ir~t. .~ c~.
Allergy, 13, 336 (19~8)~. The protecti~ from compou~d 48/80-in~
duced let~1 ci~culatory collapse a~pear~ to be a simple way o~
evalua~g qua~ ively the- a~iq~cam~c activ-i~r oi test-compau~d~.
Male rat~ o a3:L L~bre~ Wi~Lr ~t~a~rL, we~ghi~g 240-260 g were s~sed Le ex;?er~e~t. Aftar over~ight 3ta~atio~ the rat~ were tra~s-ferred t~ co~di~loned 1ab~ratorie~ (temp. = 21 t 1 G, relative hu~idity- 6; ~ ;%).
Tbe rat~ wcr~ t~eated subcuta~e~u~ s orall.y with a test co~pouud lQ c3r with l~he s~ re~t (NaC;1 ~o1utio:~, 0. 9%). C)~e hour after treatme~t there wa~ ~jected i~tra~erLous1y coI:npou~d 48/80, ~reahly di sol~red i;~ water, at a do~e of O. 5 mg/kg (0. Z ~:Ql/100 g of bod~ wei~ht).
kL con~ol experi~erlt~ wherei~ 250 sol~t-treated a~mals wer0 ' -j~cted Wit}:L the sta~dard do~e of compou~d 48/80~not more thaD. 2. 8~
of the a~:Limals ~ur~n~e~ i~ter 4 ~ouxs . Sur~a1 after 4 hour~ i5 the~ e-fore co~sider~d to be. a sae criterio~ of a pro~ecti~e e~'et t of drug ad~i~t~ation.
Tables I a~d II show for a nu~nber a~ co~pouDds of formuia (I) the oral doses (in ~ng/kg body wei~ht) at which the rats were protected ~gair~st con~pouDd 48/8Q~ Lduced 1etha1ity, The data represe~ted irL tab1es I and II are illtended to i11ustrate and ~ot to 1imit the scope af the prese~t i~re~tiOrL
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:~ view o~ t~eir useful a~hista~i~c ac~t~, the subject comp~unds ~ay be forrr:Lulated i~ o varioua pharmaceutica1 form~q for almi~istrati4D. purpc~es. To psepare the pharmaceu~'cal co~ si-tiou~ of ~ re~io~ ef;Eective a~L~ista~inic amourLt of the par~
5 tic~-la~ co~ps~u~d, in~b~se o~ ac~-addi~o~ ~lt for~, a ~ the active ~gredie~Lt i3 comb~ed ~ ~ti:~nat~ adAmixb~re wit~ a phar~aceu~ica1ly a~c~ptabl~ carrier,. whieh~ carrier may take a wide va~iety of for~
depend~:cLg on the forD:l of preparai:io~ desir~d for adr~is~at:~or~.
These pharmaceu~cal compositio~s àre desirably i~ wlitary do~age 10 form ~ui~able, preferably, for ad~i~ist~a1:~o~ orally, rectally or by parerLtesal ~jection. For e~ Lple, i~ prepar~ng the co~po~ition3 iu ~3~al do~age for~,: a~y of t~e usual pha~:maceutic~l media may be errlployed,. 3uch.a., for e~ple, water, glycols, oils,. alcohols a~d t~e li}~e ~SL the c~ e of oral liqu~d prepar~ion~ 3uch a~ ~u~perLsiorLs, 15 ~yrupst e}ixLrs a~ ss~lu~ion3; or soli~carrier~ such a~ rc~es, sugars, Xaoli~, lubr~ant3, bi~der~ kategsat~ age~t~ and t~e the case o~ po~dersJ pill~, cap~sule~ a~:Ld tabletq.. ;3ecause of their ease iD ad~ast~atio;~, tablet~ aD.d capsule~ repre~e~t the r2~0st a~a~tLgeous oral do~age- ~t form, in whioh case solid l?~ar-~:Laceutical carrier~ are o~vlou~ly emplo~ed. For parerLteral com~
po~itinc2~, ~he carrier will usuaLly coD~p~ise st~r;le wat2r, at lea~.t large part, thollgh ot~er ~gre~iellt~, for example, to ai~ 31ubility, may b~ ~clude~. ~ject;~ble olutio~s,. for exa~ple may be p:repared i:~ w~ich t~e car~ier co~pri_es ~ali~Le solu~a~, glu~os~ solutio~ or a ~aixtu~a of sali~ ~d g}uco~e solut~o:cL. ~jectable suspe~sion~ ~y al~o be prepared u:~ w~ch ca~e- appropriate li~,uid c~rr~er~, 3usp~diug agent3 a~d t~e like may'~e e~ploye~. A~id additio~ salt~ of (I), due to th~ir inc~ ea~ed water 30lubi~ity o~er the corre3po3~iDg base for~n, are obv~ou31y more suitable ~ the prepaxatio~ of a~ueous compositio~s.
It is e~p~c~lly advantage~uq to ~orr~ul~te the aforementio~
p}~ ac~lltica1 co~p~itions i:~ do~age u~it form for ea3e of ad-; . m~iqt:3~a~0D. and u~ o~nity of dosage. 30sage u~t ~or:s~s as usea the 3peci~ atio~ and claL~s herein refer .o physicaLly ~iscrete u~its suita~le as unitary dosages, each u~it Co~t3i~Lg a predet~r-;~irL~d qua~Ltity of ac~r~ i~gredie2~t caiculated to produce th~ de~ired t~erapeutic effect irL a~soc~atior~ w~th the required pha~.~aceu~cal JAs 326 ~8~8C~
carrier. xa~ple~ o~ such dosage u~it forms ar~ ~blets (i2:Lcludi~
~cored or coated t3blets~, caps~les, pills, p~wder paoket, waer~, ~jectable ~olu~io~ or suspe~ions, tea~ ~uls, tablespoo~uls a~d the like,. a~d 3egr~gated ~ult:ipleq t~ereof.
,.
l~Qe followi:cLg e~ple ara ;~te~a~ed to illus~r .~e a~ Lot to l~t the scope of ~e pre~e~t ~ e~iO~. UrLle~ o~cherw~se st;ated all p~rts therein are by weight.
8~8~
A. PREPARA~ION OF D!JTERMEDIATES
~ .
To a stirred a~d refluxing Grigr~a~d-co~nplex, previously prepared ~tarti~g fr,~om 39, 7 part~ of 1-bromo-4-fluoro-2-methyl-S be~zene a~t 5.1 par~s of magnesium in 225 parts of tetrahydrofuran, are added po~tio~wi3e 8. 4 part~ of paraformaldehyde. Upo~ comple-tio~, stirri~g is conti~:Lued for 1 hour at reflux. The reac~io~ mix~ure i9 cooled and pou~ed o;:Lto a mixture ~f cru~hed ice a~d acetic acid.
The product is extracted with trichloromethane. The e~ract is dried, filtered a~d ~Yap~rat~d, The residue is di~tilled, yielding 14 parts (47 . 6 ~ ) o 4 -fluor o -~ -methylbenze~eme thanol; bp. 1 1 0 C (wate r -j et).
Il~ a si~nilar maDner there i~ also prepared:
4-chloro-3-(t~i~luorome~hyl)berLzenemetha~ol; bp. 90C
at 0. 4 ~n. pressure.
~
. .
To 14. 3 parts of thio~yl chloride is added dropwise a 501u-tion of 14 parti of 4-fluoro-2-methylbe~zez~emethanal a~d 0. 9 par~s of N, N-dimethylformasnide i~ 45 parts of methylbenze~e.while coolirLg iD ice-water. Then there are added 13~ parts o methylben?~e~e arld stirrirLg 18 couti~ued for 1 hour t roorn temperature. The reaction mixture i~ e~raporatad, yieldi~g 17 part~ (100%) of l-(chloromethyl)-4-fluoro-2 methylbe~z;e~e aq a residue.
In a ~imilar ma~er there i al30 prepared:
I_chloro_~(chloromet~yl)~2-(trifluoromethyl)benzene; bp.
2 5 1 0 0 C at 1 0 s~Lm. pre s ~ur e.
i A mixt~re o 16 parts of 1-(chloromethyl)-4-fluoro-2-met~Lyl-be~3ene, 7. 8 parts o~ a solutio~ of pota3sium cyar~ide in a sr~all amo~Lnt of water, 0.1 par~ o pot~3~ium iodide a~d 240 part.e of 2-propano~e is 30 stirred and refluxed for Z2 hour3. The reactiorL mixture is cooled a~d filtered. The ~iltrate i8 e~raporatad. The residue is take~ up ;.LL water and the product i~ extracted with methyLbe~zene. The extract ls dried, filtered a~d e~aporated, yielding L3 par~s (87. 2%) of 4-fluoro-2 methylbenzelleacetonitrile a~ a re.~idue.
.~....
7~80 I~ a s~nilar marLne~ there is al~o prepared:
4-chloro-2-(trifluoromethyl)ben~ceneacetonitrile; bp, 83 ~C
at 0. Z mm. pressure.
Example IV
A mixture o:~ 2'21 part~ o~ 4-nuoroben2e~:Lsaceto~itrile, 700 parts of ~odium me~hoxide ~c~lu~ion 30% and 900 parts of di~ethyl-be~ze~e ia at:irred for 5 ~inute~. The~ there ar~ ad~ed d~opwi3e 309 parts of methyl 2-prop~Loat~ (e~cot~erffl;c reacti~n: tempera~re rises to 65C;). Upo~ cosx~,pletion, ~tirring i~ con~ued o~rer~;ght at ref:L~x temperature. The metha~ol i8 d;stilled of~ L irLter~al tempera~re of 110C: i9 reéLched. After coali~g, lOOO par~s of a hydro-cJloric acid 301ut~o~ oN are added d~opwi3e a~d the whole i9 tir.ed a:~ rei~hxed for 5 mi~su~3. Upo~ cool~L~, the layer~ are separated.
The orga~c phase i3 drie~ ilte~ed a~d evaporated. I'he re~idue i~ 3tirred a~d reLu:~ed for 4 hou~ togethe~ ~n'~ 500 part~ of acel~c acsd, ;00 part~ o~ water and 500 part3 of a hydrochlorac acid solut;o~. After cooli~, the product is ext~cted with ~ichloro-~etha3a~. r~ eæt~act i~ washed .succes~i~re1y? with water, w~t}L a ~iluted sodium hydroxLd~ ~olutio~ arLd aga~ wit~ water 'dll r:~ut:rali-za~io~, d~:sed, iilterecla~e~ orated. ~e re~idue i9 C2~yst~ i2ed fro~ 2-propa~ol, yie1d~ 134. ~ t~ ~f 1-(4-~uorophenyl)-4-oxocyc10he~ecarbor~ t~ile, r~p . ~1 . 8 ~ C .
FollowirLg the ~ame procedure and u~na a~ equivalent amou~t of a~ appropriate arylaceto~itrile as a starting materiaL
there are alsc~ prepared:
CN
~ ~r1 A~l ~p. or bp, i~ C
~ _ Z -pyridi~:Lyl mp . 90 . 1 2-OC~3 -C 6-~4 ~p. 1 70/0 . 03 .
2-OCH3, ~ C;l C;6H3 _ !
l8~
Ar . ¦ r~p- or ~p. ~ ~C
2 -C~3 -~ 6H4
3 -C~, 4 C l-C 6H3 3 -CH3 _ C ~4 _ ' 2 6H3 mp.147. 2 2 -8 r -C 6E~4 .
2-CH3, 4-F -C 6H3 2-C~39 s-Cl-C6~3 3, 4-(G~3)2-C6H3 2-C~3l 3-Cl-C6E~3
2-CH3, 4-F -C 6H3 2-C~39 s-Cl-C6~3 3, 4-(G~3)2-C6H3 2-C~3l 3-Cl-C6E~3
4 -C 2~I5 -C 6~4 .
xamDLs V
To a s~rred a~d reiluxL~g ~ix~re of 71 parts of 30dil~1 cya-~de, 99 parl:s of etha~ol a~sd 85 pa~tR of wates is added dropwise a ~oltltion of 134 parts of 2-(chloromet}:Lyl)-4-fluorol-met~yl
xamDLs V
To a s~rred a~d reiluxL~g ~ix~re of 71 parts of 30dil~1 cya-~de, 99 parl:s of etha~ol a~sd 85 pa~tR of wates is added dropwise a ~oltltion of 134 parts of 2-(chloromet}:Lyl)-4-fluorol-met~yl
5 bsnze~e i~ 99 part~ of et~i~l. UpGrL corD.pletio~::L/. stixri~g is CO~
~ed fi~st for 6 hour~ at reilu~e and ~u-ther o~rer~Light at ro~rn te~peratu~e. I~e et~a~ol ~ e~raparated a~ the re~idue i9 taXer~ up ~n 4-met~yl-2~p~ta~o:l:Le a~d water. r~e layer~ ~re ~eparated a~d the~ us-p~e is e~a~te~ e~ees ~e with d-methyl-2^~?e~ta-ro ~c~_ The ~ombi~:Led orga~ic pha~e~ a~ sh~ twice wi~ vater, dried, i~ilS red a~d e~raporated. r~e re~idue i-~ di-~tllled, ~eldi~ag 98 part~ o~ 5-fluoro~2-~e~hyl~e~2e~eacetonltrile; ~p. 124-128~C
a,t 10 ~m. p~SU~Q.
E;xaml~le VI
To a sti~red arLd hot solutio~ of 8. 5 parts of ~,N,N-t~iethyl-benxerLemetha~ami$~ium chloride, 40 part3 of so~ium hydroxide and 360 part3 o~ a ~odium hy~lroxide solutio~ 50% is added dropwise a s olutio~ of 72. 7 pa~ts of N, N -bi3(2 -chloroethyl) -4 -methylbe~zene -87~80 _ .
~ulfc~amide ~rLd ~S. 5 parts of 2, 4-dichlorobe~e~eaceton~t~le i~
90 part~ o~ tetrahy:lrofura~. IJpo~ COmplet~OrL, 3t~rr~Ilg i~ co~ued for 3 hou~q at 50C. I~e reaction m:LYt~re is co~led, 216 parts of r~et}~ylbeze~ and 480 parts of water are added a~d t~e layer3 5 are sep r~tedThe or~aDic pha3~ i~ wa3hed with water, dried, filtered a~d evaporated. T~e residue i oryst311ized ~~om 2-}?ropa~ol, y~eldi~g 28 pa~ 29%) of 4-(2,4-~iohlorophe~yl)~ methylphe~rL-o~yl)-4-piperidi;~ecarb~trile; mp. 14;C.
Follo~nng the ~3am2 procedure arLd u~i~g t~erei arL e~ rale~t amou3lt of a~ appropriate ary~laceto~tr~le t~ere are also i?repared: -4-(2-flu~rophenyl)^1-(4Enet31ylp~e~ylsulfonyl)-4 piperidi~Le-c~rbc~trile as a res~due;
4-(5-c:bloro-2 -;saet~c\xyphe~yl) -1 -(4-~ethylphenyl3ulonyl) -4 ~ pipe ridinec~rborLit~ile;
1-(4-methylphe~yl ulfo~:Lyl~-4~ (t:ri:luorome~yl)phenyl7 piperidi~eca~bo~ rile; and 4-(2-rs~eth~xyphe~ (4-~e~hylphe~:Lylsul~o~yl)-4-piperidi3e-carboDit~ile .
~ .
A solu~lon of 29. 6 parts of N,N-bi~(2-chloroethyl)-4-methyl-benzenesulfo~amide and 14. 9 parts of 4-fluoro-Z-rnePhylberLzeneaceto-nitrile i~ 90 parts of n:lethylben~eIle is added dropwiseto a solutio~ of 5, 6 parts of lithium am~de in Z70 parts of methylbe~z~ne at about 90C.
Upon cornpletion, the whole i~ heated to reflux and stirred cvernigh ~5 at reflux temperature. The reactio~L snixture i~ cooLed, p~ured onto wa~er and the layer~ are separated. The organic phase is dried, fil-tered alld e~aporated. The residue i9 crystalli2ed from 2_pro~anol, yielding 27 parti (72. 6%) of 4-(4-fluoro-2-methylphe~yl)-1-(4-methyl-phenylRul~o~yl)-4-piperidinecarbonitrile.
Follownng the same procedure a~d usi ~ equi~alent amounts of the appropriate starting materials there are also prepared:
4 -(3 -chlor o-2 -methylphenyl) -1 -(4-methylphenylsulIonyl) - ~ -piperidi:llecarboz~itrile;
37~ JAB 326 4-(5 -fluoro-Z -methylphenyl) -1 -(4-methylphenyl3ulfonyl) -l-piperidi~ecarbonitrile; mp. 1 68C;
(B)~4-(2-fluorophe~yl)-3-methyl 1-(4-methylphenyl~ulfo~yl)-4-piperidiD.ecarbo~itrile; mp. 154C; and (A)(~ (2 ~fl~orophenyl).3-methyl-1 -(4-methylphe~yl-sul~onyl) -4-piperid~ec~rbonitrile; mpO 135 C.
Exam~le VIII
A mixture of 35. 8 parts `of 4-(2-fluorophenyl)-1-(4-methyl-phe~ylsulfo~y}~-4-piperid~Lecarbonitrile and 50 parts o~ a sulfuric acid 301utioll 75% is stirred for 4 hours at about 150C. 1~2 Parts of ethanol are added dropwise. Uporl completion, stirri~g i5 continued for 5 hours at reflux te~nperature. The reactioIl mixture is cooled a~ld poured onto crushed ice. The whole i~ alkalized with ammonium hydroxide a~d the product iq extracted with dichlorometha~e. The extract is dried, filtered and evaporated, yieldi~g 17. 2 parts (68.4~) of ethyl 4-(2-fluorop~ienyl)-4-piperidi~ecarboxylate a a residue.
Following the qame hydrolyzing prored~:;re and sta~tir~g from the corre~pondi~g car~o~itrile there are a~so prepared:
ethyl 4-(3-methylphe~yl)-4-piperidiDecarboxylate hydro-2 0 chloride; and ethyl 4 -(2, 4-dichlorophenyl) -4 -piperid~ecarboxylate hydro-chloride.
xample IX
16.32 Part3 ~f 1-(4-rnet~yiphanylqulfo3lyl)-d-~^(tri~luoro^
2~ rnethyl)phe~y~7.4-piperl lnecarb~rLit~ile are added por~o~wise to 35 ~art~ of a sulf~r~c acid -~lut~o~ 75~ a~d t3:Le ~i~t~:e is q~red a~d heated. for l; hours at 1~;C. l~e~ there are added d~opwise 100 part~ of et}la~Lol. ~p~;~L co~:npletioD., ~ rrsrlg i~ co~tin~ed o~rer~i~ht at reilux. T~2 re~ctio~ ~ixt~re i~ cooled arLd p~ured o~to ice-water.
Ihe whole i~ aLkalized wifh a,~mo~iusrL hydrox:Lde a.d t}la proc~ct is ext~cted ~th dichloro~etha~e. The extract i dried, i~iltered a~d evaporate~d. The re~idu~ iq co~erted i~to the hydrochloride 3alt in 2,2'-o~bi~pro~a~e a~d 2-propa~ol. ~he salt i~ ~iltered oi~ and dried, yieldi~g 6 pa.rts (43 . ~%) of et}~yl 4- -(ethoxyca~bo~yl)-phe~y~ 4~pipe~ ec~rb~rlate hydrochlor~de; ~mp. 121~C. I
,, 1, JAs 325 ;1~87~80 z6 A ~ixture o~ 11.3 pa~tq of 1-(4-methylp~enylsulfor~ 4-rii~uoror~ethyl)phe~y,~7-4-pip~ridillecarboDltrile, 5. 6 part3 of potas iu~ hy~roxlde aD.d 220 ~?ar~s o 1,~-etha~ediol i3 ti:~red aD.d 5 reLuxed for 48 hous~ Le reactio~ m~re is co~led a~d poured outo iCo-WZl~er. lhe whole iq acidi~ied wi~. hydrochl~ric acid a~d the product i~ e.~act:ed with dc}l1oro~e~ane. l~e ext ract is dried7 ~lter~d ~U:Ld e~apo~ated, yieldi~.g 11 . 8 parts (100%) of 1 -(4-methyl-pheD.yl~ orLyl)-4_ -~t~'luoromethyl)~hen,y~ -pi?eridi~ecarboxyli::
1 0 acid as a ~esidue .
Follo~ t:he same hydrolyz~g psocedure aDd qta-ti~g ~rom the COrreSpO~ Lg ca~bo~tsil~ there ar~ al30 prepared:
4-(5-ch~oro-2..rnethox~phenyl) -1 -(4-methylpherLylsulfoIlyl)-4-piperidiIle arboxylic acid;
4-(Z-methox~~ Lyl)-l-(4-n~ethylphenylsu~'o~yl)-4-piperidi e-ca~boxy~ a~id as a re sidue;
4-(4-~luo~o-2-methylp~e~yl)-1-(4-methy}pherlyls~lfonyl)- '-piperidi~Lecaxboxy~ic acid;
4-(3 -chloro^Z -n~ethylp~Le~yl) ~ -methylphe~:Lylsul~o:~yl)-4 pip~ridi~ecar~oxylic acid;
~s-(5 -fluoro-2 -methylphe~nyl) -I -(4-methylphenylsulfonyl) -4 -piperidi~ecarboxylic acid; mp. 157C;
(B)-4-(2-fluorophellyl)-3-met~yl 1~(4-methylphe~ylsulfonyl)-4-piperid2~Lecarboxylic acid; mp. 186C; and (A)-( )-4-(2-fluoropheQyl)-3-met~yl~ methyLpherlylsul-forLyl)-4-piperid~ecarb~ylic acid as a residue.
To a 3tir2ed a~d refluxi~g mixture of 21 parts of 4-(5-chloro-2-methoxyphe~yl)~1-(4-methylphenyl~ulfo~yl)-4-piperidi~Lecarboxylic 30 acid and 270 parts of benzerle are added dropwise 3O parts of thio~yl chloride. Upon completioll, the whole is st:Lrred and refluxed for 4 hours. The reaction mixture is e~raporated a~d the -esidue is .~ ,.. .
37~8~
washed twic~ set~ylben2;e~e, y~eldi~g Z2 pa..ts (lOO~o) Of 4-(5-chloro-2 -~eth~E~enyl) ~1-(4 -met~Lylphenyl9ulr'0~yl) _A -piperi -di~ecarbo~l c~:Lloride.
Ir~ a ~ ma~er t~er~ a~e also prepared:
4 - (2 -me~oxyphe~yl) -1 - (4 -me thylphe~:LylsuL~o~y l) -4 -pipe rldi~e -ca~bol:Lyl chlor~de a~ a ~e~id~se;
m~thylphen.yl uL~rLyl)-4-r~(t~i1uoro~nethyl)phe~y~7-4-piperi~i~ecar~nyl c~lo~de a~ a re3idue; ----4-(4-i~uoro-2-~:net~Lylph~yl)_1-(4-met}:~ylphe~ylqulfonyl)- -1 0 piperidi~ecarb~l chlorid~ a~: a re~idue;
4~(3-chloro-2~rcL~t~y1pheD.yl)-i-(4-me~y1phenylsulfonyl). -p~perid~necarbo~y1 c~loride as a re~i~ue?
4-(5-n~oro-2-methyLphenyl)~ 4-methylphe~ylsulfonyl)-4-piperidi~ecarbonyL chloride as a residue;
(A~-3- m ethyl-1~4-m ethylphe~yl9ulfo~yl~-4-phe~yl-4-piperid~ne carbo~yl chloride;
(B 3 -4 -(2 -Luorophe:Lyl) -3 -methyl _1 -(4-methylphenylsulfonyl) -4 ~pipe ridi~ec arb onyl chloride;
(A)~ )-4-(2-fluorophenyl)-3-methyl-1-(4-methylphenylsulfonyl)-4-piperidi~ecarbo~yl ehLoride as a residue;
(B ) -( -) 3 -methyl- 1 -(4 -methylphenyl ~ulo~yL) -4 -phenyl - ' -piperidinecarbo~yl cbloride; and (B ) -(~) -3 -met~yl-l ~(4-methylphenylsulforlyl) -4-phe~Lyl-piperidi~ecarbo~yl chloride a~ a residue.
2 5 ~II
A ~ix~e of 360 5 part~ of 4-(3-chloro-2-r~ethy1phes:Lyl)-l -(4~s:net~y1phe~y1s~1fQ:I:Ly1)-4-piperid~nec~LrborLyl c~loride a~d 2~0 ~art~
of et~a~aol i.c stirre~ a~d reLux~d o~e~ht. T~e reactio~ ~3re i~
treat&sl Wi.t~L aoti~ted c~Lrcoal w~i1e not. ~he latt~r is i~ilter~d of~ a;~d t~e product i-~ allowed to cryst~allize fro~:L the ~iltrate by coo1~g spon-tan~u~ly to room ter;aperature. I~e psoduct i9 f~ltered of a;~d dr~ed, ~eld~g 33 part3 (8~ ) of e~yl ~-(3-c~loro-2-methylphe~y1)-1-(4-~ethyl~heJlylsulfo~yl)-4~iperiti~ec~L.bo~ylate; mp~ 13~
1~37 Followi~g the same e~terifyi~g procedure by reacting the corre3pondL~g acid chloride with the appropriate alcohol, there are al~o prepared:
e thyl 4 - (5 -chl o r o -2 - methoxyphenyl ) - I - (4 - methylphe~yl -5 3ulfo~yl)-4-piperid ~ec~rboxylate;
ethyl 4-(2-methoxyphenyl)-1-(~-methylphenylsulfonyl)-4-piperidinecarb~ylate;
~ thyl l-(~-methylphe~yls~lfonyl)~4_~3_(trifluoromethyl)-phe~Ly~7~4-piper~di~eca~boxylate;
ethyl 4-(4-fluoro-2-methylphe~yl)-1-(4-methylphenyl ulfo~yl)-4-pip~ridi~ecarboxylate; mp. 151 C;
ethyl 4~(5-fruoro-2 methylphenyl)-1-(4~methylphenylsulfo~yl)-4-piperidinecarb~cylate; mp. 94~;;
(A)-phenylmethyl 3-methyl 1-(4~-methylphellylsulfonyl)-4-1 5 phe~yl-4-piperidinecarboxylate;
(B).(ph~ylmethyl) 4-(2-1uorophe~yl)-3-m~hyl-1-(g-methyl-phenylsulf o~yl) -4 -pipe ridine c arb oxylate; mp. 1 1 0 C;
(A)(~) (phenylmethyl) 4-(2-fluorophesLyl)-3 me~hy~ (4-methylphenyl~ulfo~yl) -4-piperidi:~ecarboxylate;
(B)(t).. phe~ylmet~yi 3-methyl-1-(4-methylphenylsulfo~yl)-4 -pherLyl -4-piperidi~ecarboxylate;
(B)(-)-phenylmethyl 3-methyL-1-(4-met~ylphenyl3ulfoT~yl)-4 -phenyl -4 - pipe rid~e c arb clxylate; a~d (B)-phenylmethyl 3-methyl 1-(4-methylphe~ylsulfo~yl)-~-2S phenyl-4-piperidinecarboæylate.
~3~
~ ~ixt~re of 17 parts of ethy1 ~ c~loro-2-methoxypherLyl)~
met~ylpha~lsuL~o2Lyl)-4-piperidL~ecarboxylate, 7.; part3 of phe~:Lol arLd 135 part3 of a hy~robro~ic acid 301ut~o~ i:~ acetic aeid is 30 ~ o~ar~ight at ro~m t2mp~rature. The reaci~o~ mix~re i~ poured onto ~wat~r a~d the whole ls washed wit~ 2,2'-<~xybi~pro~ e. The aq~ue~u~ phase is alkalized with 30diu~ hydrox~e while coo1L~. l~e product i~ ext..acted wit~ tr1chloromethar~e. l'he e~i~act iq was~ed ,~ , ~37 with water, dried, filtered and evaporated. The residue is con~erted i~to the hydrochloride salt i~L Z~propa~oL alld 2, 2'-o~ybispropane, yieldiIlg 7 part3 (S5%) of ethyl 4-(5-chloro-Z-methoxypnenyl)-4-piperidinecarboxylate hydrochloride, ~ 1~
a, To a stirred a~ boil~g solutio~ OI 73 parts of (B)-( )-3-methyl -1 -(4 -methylpheD.ylsulfo~yl) -4-phe~yL -4 -piperidinecarboxylic acid in 3200 parts of 2-propanol is added a solutio~ of 24 parts of -methylbenzenemetha~amine, The solutio~ is allowed to cry~tal-lize. The product is ~iltered ofi~ a~d recrystallized three timeq f~om respecti~rely 4800, 400û ~nd 3200 partq of 2-propanol, yielding 27 parts (27 %) o~ (B ) -( -) -3 -methyl -l -(4 -m~thylpher~yl3ulfonyl) -4 ~phenyl-4-piperidinecarbe~ylio acid ~ ~ethylbe~ze~emethanarnille (1: l).
A rnix~cure Aof 27 parts of (B)-(-)-3-methyl-1-(4-methylphenyl-sul~onyl)-4-phenyl-4-piperidi~ecarboxylic a::id a-methylbenze~e-methanam~e (l: 1), 60 part3 of co~centrated hydrochlo~ic acid a~d 1000 par~s of water i~ ~tirred atld boiled for a while, The precipi~ated product i9 f ltered of, washed with water and ~oiled in watsr. The product i9 filtered off a~d dissolved ln trichloromethane. The latter is d~ied, filtered a~d evaporate~. The residue is 3tirred in Z, Z'^o~ybi3-propane, yield~g 18.4 part~ (94~) of (B~ )-3-methyL-l-(4-methyl-phe~ylsulfo~yl)-4-phe~yl-4-piperid~ecarboxylic acid.
b. To a stirred a~d refluxlng solution of lOOparts of ('~ )-3-methyl -1 -(4-methylphenylsulfo~yl) -4-phe~yl-4-piperidinecarboxylic acid irL 1600 par~s of 2-propa~ol is added a qolutio~ of 32.; part-~ of (+)-a-methylbenze~emethanami~e ~ 40~ part~ o 2-propanol. The reaction mix~re i3 allowed to crystallize. The product is ~iltered ofs and recryQtallized four times from respecti~rely 6400, 5600, 4300 ar:Ld 3200 part~ ~ 2-propa~ol. The product i`Q filtered o~ a~d recrystallized from 2~00 parts of2-propa~ol. It is filtered off agai~L, yieldi~g 22 parts, The filtrate is evaporated and the residue is added to the c~ystallized fraction of 22 part~, yieldi~Lg ~8 pa.ts (2I%) of (B)~ 3-met~yl-l-(4-~:nethylphe~ylsul~o~lyl) 4-phenyl-~-piperidi~ecarbo~ylic acid a-methylbe~ze~emetha~amine (l: l).
JAE~ 3 2 6 - ~87a~ 3 A mi~cture of ZS parts of (3)-(r)-3-methyl-1-~4-methylphe~yl-sulfo~yl)-4-phe~yl-4-piperidi~ecarboxylic acid a-methylbenze~e-metha~amine (1: 1), 60 pa~ts of co~ce~trated hydrochloric acid and 1000 parts of water i~ boiled for a while, The reaction mixture is f~ltered. The filtercake is washed wi~h water a~d stirred 1~ boiling water. The p~oduc:t is filtered off and di~sol~ed in trichlorometh~e.
The latter is dxied, filtered and e~raporated. The resitue is boiled i~
2, 2' -oxybispropa~e, yieldi~g 19. ~ parts (937O) of (B)-~r)-3-methyl-1~(4_methylphe~ylsu]4O~:Lyl)_4_phe~yl_4_piperid~eoarboxylic acid.
1. 0 A ~uspeTt~ioD. of 11 partq of ethyl l-(~}-methylphenyl~ulfo~yl)-4-~-(tri1uoromet}lyl)pherLy~7 4-piperidi~eca~boxylat~- a~d 8 parts o tet~aethylam~o~u~ bromide in 200 part3 of ethanQl i~ eleot.olyti-caLly deto~ylated at ~Z . 15V u~g a Hg-cat~Lade a~d a mlx~ure of Ag and AgC} ~5 refers~ce elect20de. The ethaD.ol 301ut~ot~. is; decanted ant the ~olve~lt i5 e~ps~rated. The re~idu~ i~ taken up diohloro-m~tha~e.. T~e latter i8 u~a~he~ ~ee ti:m8:~1 with water, dried~
filtered a2~d ~porated. The re~idue ic co~l~rerted i~to t~8 hydrochlo-ride salt ~ 2-p~opanol a~:Ld 2,2'~ xybi~propa~e.. T~e ~ lt is filtered ofand.dried, yielt~:g 6.9part (85.2'1o) of ethyl 4~ (~i~uo~o-methyl)pheD.y~-4 -p2 pe2id~:Lecarboxylat~ hydrochlo~ide .
1~ a similar ma~er there ~e also prepared:
ethyl 4-(2-me~ o~y~he~yl)~-pipcridi~Lecarboxylate hyd-o-c}~loride; :
ethyl 4-(4-~oro-2-meth~lphe~:Lyl)-4-piper~lnec~rboxylate;
a~ a re~idue;
ethyl 4 (3-chloro-2-~nethylp~e~yl)-4-piperid~Lec2rbo~ylate a~ a re~idue;
(B)-phe~ylmethyl 3-methyl-4-phenyl-4-piperid~carboxylate ethanedioate (1: 1);
.
87Q~
(A)-phe~ylmethyl 3-methyl-4-phenyl-4-piperidinecarboxy-late ai a residue;
ethyl 4-(5-~uoro-2-methylphe~yl)- -piperid~necarboxylate hydrochloride; n~ip, 198,8C;
(B)-phe~ylm~t~l 4-(2-~luorophenyl)-3-methyl-4-piperidi~e~
carboxylate hydrochloride; m p. 220C;
(A) (~ -pheny ~ ethyl 4-(2-~uorophe~yi)-3-~nethyl-4-piperidLnecarboxylate etha~edioat~ 1); m p. 170C;
(B)~(-)-phe~ylmethyl 3-meth~1-4-phenyl- -piperidir~ecar-boxylate hydrochloride; and (B~ )-phenylm ethyl 3-methyl-4-phe~yl-4-pipe~idLnecar-boxylate hydrockloride.
To a Qtirred aJ:Ld re~c~g r~xb~re of 14 par~s of 4-phenyl-4-piperidi:n.ecarborLyl ~hlaride~ hydrochloride a~d 130 par~s of methyl-be~ze~ are added drop~se 6. 9 parts of l-piperidinepropa~ol. Upon completio~, s~dr.~g i corLtillued ove~ight a~ reflux temperature.
'rhe methylbe~ze~e-phase is desa~ted arld th~ residual oil is '~oiled ~ ~ mlxture of 2,2'-c)xybisprop~e a::Ld ethaIlol. ~he precipitated psoduct i~ ~iltered o~ d dried, yieldi~g 14 par~s of 3~ piperidinyl)-s ?ropyl 4-pherLyl-4-pipe~di~ecarbcxylate d~hydrochloride mo~o-hyd2at~; r~p; 176.1C.
Fo~lo~g the sa~ne pr~cedure a:~d u~ing e~ul~aleD.t ~o~ts of the appropriat~ star~Lg materials the~e are also prepared:
2-(d.i~et~yla~o)ethyl 4-~henyil-~ piperidi~ecarboxylate roc~l~ride; mp. 230C;
3-(dimethyla~o)propyl 4-pherLyl-4-pipe~ ~ec~rboxylate dihy~l20chlorid~; mp . 1 5û C;
2-~-pyrrolidirLyl~et}~yl 4-phe~yl-4 pip~rid~ecarbo~ylate dihyd~ochloride; ~p. 185~G; a~d 2-(4-mor~olinyl)othyl g-phe~yl- -pipe~ai~ecarboxylate et~a~edioate ( 1 :1 ), ~Lp . 21 0 J C; .
JAB 32~
8~
A r~ix1~re ~f 4. 5 pa-t~ of 4-oxo~ pyrid~yl)cyclohexa:~e-carb~r~itrile, 5.2 parts o~ ethyl 4-phenyl-4-piperidi~ecar~oxylate, 1. }~art of 4-me~ylbe~ze~:Le~ulfo;~ic acid a~d 225 part~ of methyl-5 be~ze~e i ~tir~ed a~d~rei~uxed, o~re~ ugh~ us~g a wat~r-.~epa,ra~or.
The reactio~ m~ture i~ e~rapora~ed a2~d the r~sidue i~ c~ystallized from 2-propa~ol, y~elding 4. 5~?art~ (~o%) of ethyl 1-~-cya~o-4-(2 -pyridi~yl)-1 -cyclohexeI:Ly~;7.4-pbe~yl-4-piperidi:r~ecar~oxylate;
D:Lp . 1 60 G .
Follow~g the ~ame ptocedur~ a~d us~g e~,ui~ale~t amou~lta of l:he appropriately subst~blte~ cycloh~a~oIle3 and piperidines there are al~o pre~ared:
et~Lyl 1 ~4--cya~o~4-(4-~uoro~hesyl)-l~cycloh¢~xen-1-y~7~4-phe~yi-~-piperid~ecarbos~late as a residue;
et~yl 1 ~(4-cyaD.o-4-ph~:oyl -1 -cyclohe~ce~ yl) -4 -phe~yl - ~ -- p~peri~iDecarbo~late a~ a residue;
ethyl l~-cya~o-4-(4-~ethoxyphe~Lyl)-l-cyclohexe~-l-y~7-4-phe~Lyl-4-pipe~idiAecarb~xylate a~ a residua;
ethyl 1 -L4- - (4 -chlorophe~yl) 4 -cyæLo -1 -cyclohe:~:en o l -y~7 -2a 4-phe~yl4-pipe~ ecarb~xylate a~ a r~idue; a~d 1-~1-(4-cyanoa4-phe~yl-l-cyclohexen-l yl)-4_phenyl-4- piperi-dinylcarbouyypiperid~Iae.as a residue.
B. ~}-EPARATION OF FINAL COMPOUNDS.
xa~m~le XVIII
Z5 To a 3tirred mixture of 4. 5 parts of et~yl 1-~-cyano~ (2_ pyridi~yl)_l-cyclohe~eT-y~7- phenyl-4-piperid~ecarboxy~ate and 80 parts of ethaIlol are added portio~wi~e 0. 4 parts of sodium borohyd~ide.
UPOA completion, ~tirrirLg is co~ti~ued }irst over light at room tempe-;,; rature a~d further for 30 mi~utes at ref1u~. The reactio~ mixture is cooled and poured onto water. The oroduct is e.Ytracted with dichloro-..
,, 7~ AB 326 methane. The eYtraCt i~ dried, filtered ar~d e~raporated. The residue is crystalhzed from 2-propa~ol, yielding Z par~Y (35%) of ethyl cya~o-4-~2 -pyridi~yl)cyclohexyl~7-4 -phenyl -a -piperidine -carboxylate; mp. 157, 1 C.
Foll~ g the same procedu~e there are alsa prepared:
ethyl 1.(4~eyarLo_4_phe~ylcyclohexyl)_4_pherLyl_4_piperid~e-carboxylate; mp. 130, 5 C;
ethyl 1_~4-cya~o_4_(4_1rethQxyphe~yl)cyclohexy~7_4_phe:~yl-4-piperidirLe::axboxylate; mp. 122C;
ethyl l-~4-(4-chlorophe~Lyl)-4-c:yaD.ocyclohexy~7-4-ph~3yl-4-piperidinecarboxylate; mp. 155C; and 1 -phe~:Lyl-4-L4-phenyl-4-(1 -piperidi~ylcarbo~yl) -1 -piperidi~:Ly~7-cyclohexanecarbo~trila hydrochloride; rnp. Z83. 2JC, To 1 part of a. ~olutio~ of Z. ~rt3 of t~iophe~ in 40 part~ of et~a~ol are added 4. 7' parta of 1 -(4~fluoro-2 ~ethylpheIlyl) -oxo~
cyclohe~a~ecarbo~t~ile, 5.4 part o~ ethyl 4-phe2~yl-4-piperidine carboxyla~e hydroc}:Lloride, 2 parts o ~diu~ acet;Lte a~d 120 pa~t3 of e~a~ol. l~he whole i~ hy~roge~ated at ~3rs~al pr2ssure a:~d at roo~ ter~perat~e ~th 2 parts o~ adiurr:L-on~charcoal cataly~t l O~o .
Aft~r the calculated amc~t o~ hydroge~ is takerL up, t~e c~talyst ls iiltere~ of:E o~er ~y1O arLd the i~ilt~at~ is ~rapo~ated. F-om the residue, t}~e frce ba~e is liberat~d i3 ~e co~re~ o~al mz:r~er with arnmonium hydroxide a~l t~e product i3 ~racted wi~ ~ichloromethaD.e.
~e ext~act iq d~ied, f~lte~ed arLd e~porated. The resi~ue is ~uri-~ed by columD.-c:hromatog~a~y o~er ilica gel usi;7g a mixtare of t~i-chloromethane a~ e~ha~ol (98. 5:1. 5 ~ Yolume) as elue~t. The pure f~actio~s are coll~cted a~d t}~e elue~t i e~po~ated. The ~ esidue i~ c~y~Lllized fror~ et}~a~ol, yiel~ 3 part9 (33.4%) of ethyl 1-L~-cya;rlo-4 (4 uoro-2~m~thylphe~yl)cycloheYy~ phe~yl~L-piperi~i~e~arb~ te; mp. 135.2C.
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7~8 Exa~n~le XX.
Tc~ a ~irred ~i2b~re of 11. 7 pa-ts of ethyl 1-~-cya~:Lo-4-(4- uoroph nyl)- 1 -cyclohe.Ye~ y~7-4-~he:~yl-4-piperldi~ecarDax^
ylate9 ~ t of odi~r~etho~de solutio~ 30% and 320 pa~ts of metha~ol i~ added portlonwi3e 1 part of sodiu~n borohyd~de. Upo~
completio~, ~ r~g i~ con~ u~d o~er~ight at roo~L temperat~re.
The reac1:io~ ixture i~ poured o~to ice-~ater aD.d the product is ext~ac~ed ~vith tr~chloro~ne~a~e. Thè extrac~. is dried, flltered and evaporated. Th~ r~idue i9 ery~talli2ed f~o~ e~a~ol, yieldi~g 5, 9 part~ of (B)-et}:lyl 1 ~4-cyaDo-4-(4-i:luorophe~yl)-1-cyelohexyl7-4-phe~y~-4-piper~l~eca:~bc~cylate; mp. 145.8C:.
To Z: part~ of a ~ol~do~ of 2 pa~ of ~iop~o ~ 40 parts of eth ~ol are addéd 2~ par~ of 1-(4" uorophenyl~-4oæocyclo-hexa:~leca~bo~t~ile, 34 pa~ts ~ ethyl 4-ph~yl-4-piperidine-carboxylate hydrochlorid~ 15 parts o ~od~ acet:at~ and 400 part5 of otllanol. ~e whole i~ hydrog~ od at rlorrnal pr~ure a~ at room te2rLperatu~e ~ieh 5 pa St-Q of palladi~n-o~c~rcoal e~taly~t i ~ .
After the calculated a~ou3t o hyd:oge~ i5 take~ Up,l the cataly~t is fil -* ~ -tered off overH~o a~d th~ ~il~te is e vap~rated. Fron~ ~e resi~ue, ihe . .
i~ee ba~e i~ liberated L~ t~e co~ve~a ona~ma~erwit~am~r.ocLiur:~ydroxi~ea~Ld extracted wit~ dichlorometha~e. The ext~act is. dsied., ~ilter ed a~d ~vaporated. Irhe residue i~ partly (9. 6 part3) p?~s~ied by colu~-chro~atography over silica gel u illg a ~ix~re of tr~c~loror~e~h ~e a~d ~et}~ ol ~99:1 by ~olu~e) a~ elueD~t. T}~e puro ~ractions are col-lected a~d t:he elue~t i~ evapo~ated. Thë re~idu~ i~ con~rerte ~:Lto the hydrochloride ~alt ~ 2-propa~ol. .~ 7~m~ure f~aetior~ i9 filt ret of~ a~d the ~;l~ate i t~e~ted ~t~ ao~ated charcoal. T~e la~ter is ~ltored oi~ d the i~ at& iS e~aporated, yieldi~g 4. 8 parts of (A)-et~yl l-~-cya3~o-4-(4-nuorop~es~yl)cyolohexy~7-4-~i~e~:Ly1-~-piperidi~ecarb~xylate ~onohydroc~loride. mo~ohydrate; mp. 210.7C.
.
E:GLm~ XXI
To 1 part of a solu~!o~ of 2 part~ of t~iophene ~ 40 parts of et~a~ol are added 5.3 parts of 1-(5-chloro-2-methoxypD.enyl)-* Trademark JPB ~26 7a}~
4-axocyclobexa:~:LecarborLitrile, 5.4 parts of et;tl~l 4-~henyl-4-piperidi2~acarboxylate hyd~ochlor~de, 3 ~?art3 o: sodium acetate and Z00 part3 of etha~ol. l~e whola is hydroger~ated a~ ~ormal - p:ressure and a~ 50~C ~i~h 2 parts of plati:~Lum-a~-charcoal catalyst5 10%. Ater the c~lcu~te~d a~Lou~:Lt of kydroge:~ is :akerl up, ~e ca~-ly3t is filtered of a~d wa3hed with a ~t~re of acetic acid a~d etha~ol. T~e filtrate i~ e~raporated a~d water i~ added to the re idue.
T~e w~ole i~ alizes3 witl~; sodiu~ hydrox~de a~d t~e product is e~tracted with t:rici:Llo~o~:Le~cha~e. T~e eæt~act i~ wac}~ed ~t~:L water, 10 dried, ~iltese~ a~d e~pc~ated. T~e 2e~idue ia puriied by colum3~-chromatograp~ o~rer ~ilioa gel usi~g a m~ re of tric~loromotha~e a~d metha~ol (99:1 by ~rol~) a . elue~t.
The i~ir~t frac1~03 (A-~ or~e2~) iQ co~lected a~d the elue~t is e~raporated~
The re~idue i~ crystallized frQm 2,2' -~ybisprop~e, yield~ 0. 8 15 pa~t~ (8q~) o (A)-ehyl 1-~-(5-chloro_2~net~oxyphenyl) l_cyaDo_ cyclohe~ 4-phenyl-~-piperiti~ecarboxylatio; mp. 16;. ;~C.
~h~ 3ecolld ~ac~o~ (B-i~o~er) i~ collected a~d the elue~t i~
evaporated. Ihe residue i~ c~ystallized ~ro~ 2,2'-~xybisprolpa~e, yieldil~ 1.2 pa~t~ (12~) of (~ ethyl 1-~-(5-chloro-2-r~sethoxy-20 phe~l)-4-cya~ocyclohe~y~7 4~p~enyl--~-pi~rid~ecarboxylata;
~p. 131 . 8~C.
, Es~am~}e X~II
~ . .._ .
To 2 part9 of a ~olu~o~ of 2 parts o t~io1?h~e i::~ 40 part3 OI
et~a~ol ar~ a ded 4. 4 part~ of I -(4~ aorophe~yl)-~-axocyclohexa~e-2~ - carbc~ile, 5 pa~t~ of (B)-et}~yl 3-~thyl~4-pherLyl~4-plperidi~e-carb~xylate, 3 uarts of ~odiu~ aoeta~:e ai~d 160 parts of etharLol. l'he whole i~ ~yd~oge2~Lted at ~Lormal pre~-~ure a~d at 50~C with 2 pa-ts of paLladiu~-~ charcoal cataly~ 10%. Af~e~ the calc~1ated amou;cLt of hydrogesL i~ takea:L up, the cataly~t i~ filtered ai~ a:~Ld ~e filt~ate 30 i5 e~aporated. T~e residue i-~ pur~ ~ed by column-chromato~-2phy over sili.-a gel U~iDg a mi ~ture o~ tric~loro~2etharLe a~d ~etha~ol (98:2 by ~olu~e) as elue~t. T~e pure s-actio~ are collect~d arLd the elue~t is e~aporated. T~e residue is crysta1l;ze~ fr.on~ 2,2'-oxybis-propa~e, yieldillg 3.3 pa~ts (37%) of (Bc-B~)-ethyll-/~-cya~o-'-(4-87~3~V
fluor~phenyl)cyclohexy37_3-methyl-4-phërlyi-4-piperidi~ecarb~ late:
~p. 133.3C.
To 1 pa~t o a qolu~do~ of 2 parta of thiophe~e i~ ~ p~rts of ~a~ol ar~ added d. ~L parts o~ 1 -(4-1uoro~henyl)-4-oxocyclo-5 hexaDes:arbo~tr~le, S par~ of (A)-ethyl 3-~net~yl-4-p~e~yl-4-piperidi~ecarb~rlate a~d 160 parts of e~ha~ol. Tne whole is hydro~e~ted at nor~al pres~ure~a~d at 50C ~th 2 parts of palladiu~ charcoal catalyst 10%. Ater tho calculated amo~t of hydroge~ is taXe~ up, the ca~aly~t is ~:~tered of~ a~d t~e filtrate 10 i~ e~raporated. The residue ii crystallized ~rom acetorLitrile, rieIding 2. 6 part~ (28%) of (Bc-Ap)-~hy~ cya~Lo-4 ( ~uarophenyl)cyclohexy~;7-3 -~ethyl -4-phe~1-4-~iperidinecarbo~ylate;
rr~p. 125. 9~G.
Exam~le XXIlI ..
To 1 part o~ a solutio~ of 2 parts of thiopherLe in 10 parts o~
ethanol are added 4. 4 parts of 1-(4-fluorophenyl)-4-oxocyclohe~xane-carborLitrile, 4 partq of 4-phenyl-4-piperidiDecarboxa~nide a d 120 parts of methanol. The whole is hydroger~ated at rlormal pre~sure and at 50C with 2 parts of palladi~m-or~-charcoal catalyst 10%. After the 20 calculated a~nou~t of hydrogen is taken up; the cataLyst i~ fil~ered off and the filtrate is e~aporated. The re~idue is purified by col~-chromatography o~rer ~ilica gel:
Elutio~ ~with a mixture of trichloromethane and metha~ol (99:1 by trolum~) yields the A-isos~er which i9 cry~tallized from 2, 2'-oxybis-25 propa~e. The product ii filtered off a~d recrystallized from etha~ol~yield~g 0. 5 parts (6~) of (A) 1 -~-cya~o-4-(4-fluorophe~yl)cyclo-hexy~7-4-phenyl-4-piperidi~ecarboxamide; mp. 171. ~ ic~
Elution with a mixture of trichlorometha~e and metha~ol (97:3 by ~rollLme) yields the B-i omer which i9 crystallized from 2, 2'~oxybis-30 propane. The product is filtered off a~d recrystallized from ~thanol,yieldirLg 1 part (12%) of (B)~ cya.o-~-(4-f1uorophenyl)cyclohe~Yy'.7-4 phe~yl-4-piperidinecarboxamide; mp. 243. 1 ~C.
37~ JAB 326 A mixture o~ 4. 3 parts of 1 -t4-fluorophenyl)-4-oxocyclohexa~e-carbo~i~rile, 5, 3 pa-t~ of 4~ chlorop'nenyl)-i~, N-dim~thyl-l-piperi-di~ecarbox~mide a~d zoa parts of methanol is hydrogenated at normal press~Lre a~d a~ 50~(~ ~ith 2 par~s of platinurrl-on-charcoal catalyst ;%
~fter the calculated amount of hydroge~ i taken up, the catalyst i5 filtered off arld the filtrate is evapora~ed. The residue is purified by columr~-chromatography o~rer 3ili~a gel U9iD.g a mixt~e of trichloro-methane and methanol (99:1 by volu~e) as eluent. The pure fractio~c~
are collected and the eluent i~3 e~aporated. Tne resldue i3 crystallized from a m xture of 2-propanol and 2, 2'-oxybispropa~e. The product is filtered off (tne mother liquor i~ set aside) and dried, yield~g 2 pa~ts of (A + B)-4-(4-chlorophenyl)-1-~-cyano-4-(4-fluorop'nenyl)cyclo-hexy~7~N, N-dimethyl-4-piperidirLecarboxamide; mp. 1 8a. 4''C.
From the mother liquor ~see abo~e), a~other fraction is crystallized, yielding 1. 5 parts of (A)-4-(4-chloropherLyl)~ cyano-4-(4-fluoro-phe~yl)cyclohexy~ , N-dimethyl-4-piperidirlecarboxamide; mp.
212. 2C.
Example XXV
To i part cf a sc~lutio~ o 2. par~ o thiophene ~ 40 parts of et~anol are added 1 . 2: parts of 1 -(Js -~luorophenyl) -~ -oxocyclohe~:ane -carbc~t~ile, Z parts of (A)-e~Lyl 3-~ethyl-4-(4-methoxyphe~yl)- -pipe~id~ecar'oaxylate ethar~edioate (1:1), 2 part~ o:~ socliu~ acetat2 a3ld 120 parts of etha~ol. Th~ whole is b,ydroge~ted at ~ormal press~r~ and zt ~oam ter~peratlare wi~ Z pi~rts of palladium-an-charcoal catalyst lO~o. After t~e c~lculated amou~t o~ h~droge~ i~
take~ up, the ca1:alyst iR ~ilt~red off o~re~ lo a~d washed with acetic acid. T~e i~trate is evapo~:ated. Fror~ Le residue., '~e free ba3e is li~erate~ ~ the con~e~t~o~ ~er with a~s~mo~ hydro~de and extracted wi* dioblor.omet~a~e. The extract is ~ried, filtered aDd e~aporated. Th~ re~idue is pu~ii~ied ~y colum~-chromatogr~phy o~er ~ilica gel U3:Lllg a mixture 2~ t::ichloromethane a~Ld ~thar~ol (98:2 by ~rolume) a3 eluent. l~e pure f.actioD.s are collected ~ud the elue~t i9 , _..
37~ AB 326 e~aporated. l~he re~idue is co~Yerted into the hydrochlor~te salt i~
-ethanol a~d 2-propanol. The salt is filtered off a~d dried, yieldi~g 0. 6 parts (21, 6%) ~f (Bc-Ap)-etllyl 1-~4-cyano_~-(4-~luo~ophe;lyl)-cyclohexy~ (4-methoxyphenyl)-3-methyl~4~pipe~idinecarboxylate . 5 monohydrochloride; mp'. Z40. 9~C.
To 1. part of a ~olul:io~ of 2 parta of thiophe~e i~ 40 parts of etha~ol a~e added 13 pa.r1:a of 1-( -iluorophe~yl)-4-oxocyclohexa~e-c~rbon~tril~, 18.4 }?arts of (A)-phe~ylmet~yl 3-methyl-4-phe~yl-4-piperidir~ecarbo:~late a~d 200 part3 ~f Z-propa~ol. The whole i~
10 ~:Lyd~og~ated a~ r~or~l pre 3ure a~d at ;0G with 2 part~ of pla~n~-oD~-charcoal cataly~t 5~. After t~ calculal:ed a~o~t of hydroge~
is take~ up, ~e catalyst i~ flltered off arLd the f~ ratP i~ e~raporate~.
T:he resi~ue i5 purified by colu~-ch~o~tography over 5ilica gel u~g a ~re o t~ich~or~met~L3:~e a2~d met}~a~ol (9~:2 by ~rolu~ne) 15 a~ elue~t. The ~ir~t fractio~ is collected a~ e elue~t is evaporated.
From the ~e~idue, t~o Ac-Ap f~actio~ separated by HPI.C Usi::Lg a r~i~re of ~ e, triehlo~omet~ane all~ metha~ol (1Q0:100:0.;
by ~olume) a3 eluer~t. T~Le pu:re f~ac~oa. i~ collected a~d the elue:~t i~ e~aporated, yield~g 1. 5 par~ (5~) of (Ac-Ap)- (phe~yl~ethyl) zo 1-~ cyaao-4-(4-fluorophe~yl)cyclohexyy-3-methyl-4-phe~yl~
pip~:~idine~arboxylate .
_ . _ _ _ _ ...~ . . .. .. .. .. . .. .
To 1 ~art o~ a s~lutio3~ of 2 ~7arts o thiophe~:Le i::~ 40 parl:s of et~a~ol a~e a~d2d 3.; parts of 1-(4-~uo2opheD.yl)-4-oxocyclo~
hexa3~0ca~0~t:rile, 6 pa:rts of (:13) (ph~y~ethyl) 4-(2-fluorop~
2.~ 3~methyl-4^piperidi~eo~rb~ Lte hydrochlo~i~e, 4 ~rts of pc~ta3~ium ace~te a~d 160 part~ of 2 propa~ol. lrhie whole i~ hydroge~Lat~d at rlormal pre~sure a~d at 50aC ~t}:L 2 parta of plati~ ch rcoal cataly~t 5%. A~ter t~e calc~lated amou:~t of hyd~ogerL is tak~ up, t~e caSalyst i~ filtered o~f a~d the ~ ate i~ e~raporated. T~e residu* is 30 ~ke~- up in trichloromet~e. T~ ~att2r i~ washed with wat2r ~o . rercLo~e t~e icsrgaric material. The orga~ic pha3~ iS dried, i~ltered a~d e~p~rated. 1~0 reqidue i~ purii~ied by colum~ chroma..ography o~r ~ilica gel ux~g a ~x~ure o~ tric~loromet~a~e a~d ~retha~:Lol JA~ 326 ~ 7~
(98:2 by ~olume) as eluerLt. The pure fraction3 are collected and the eluent i~ e~raporated. The E~c-Bp-fraction i~ sepa~ated by E~PLC usin~
a mixh~re of t:richloromethane, he~ane a~ld methanol (100:100:0. 5 by volurne). T}~e pure fraction i9 collected a~ld the eluert is e~aporated.
S The rPsidue is co~ rert~d i~to the hydrochloride salt in 2-propa~ol.
Th~ salt i~ filtered off ar~d dried, yieldi~g ~. 4 part~ o~ (Bc-Bp)-(pheuylmethyl) 1-L~4-cya~o 4-(4-fluorophenyl)c:yclohexy~
(2-fluorophenyl)_3_methyl 4-piperid~rLeca-b~xylate ~onohydrochloride;
mp. 239. 4C.
To 1 part Qf a sc~lutio~L of 2 part~ of thiophe~e ~:L 40 pa~t~
of etha~cl are ad~ed 13 part~ of 1-( - uoropherLyl)~ xocyclo-hexa~ecarl~o~it~ile, 18 . ~ part3 of (A) -phe~yl~L~t~Lyl ~ -r~ethyl -~ -phe~yl 4 -pipe rid~Le cas~oxylate a~d 1 6Q part~ o~ 2 -I?ropa:~ol . l~e whole is h~rdroge~ated a~ normal pre~sure a~d at 501C wlt~ 2 parts 15 of pla~u~-o~ s:~arc~al cataly~t 5%. Ater t~le calculate~ arnou;:Lt of hy~roge~ is ta:XesL up, t~se ta~lyst ~s ~iltered of~ a3ld the filtr3te is e~aporated. T~e resi~ue i9 p~ri~ed by col~-chror~ta~;aphy o~rer ~ilica gel usi:~g a rr~ ure of t~ichlororcLet{~ans ar~d ~ethanol (~8:2 by Yolu~ne) a~ eluerLt. I~e pu~e Bc Ap ~act~o~ is collected and t}~e 20 oluent i~ e~rap4rated. The re~idue is corL~7arted iDto the hydroc~loride Jalt i~L 2~propa~ol. l~e salt is f~ltered of~ a~:Ld dried, yieldi~ 8.
part o~ (Bc~Ap)-p}:~e~Lyl~ethyl l-~-cya~o~4-( ~1uorophe~yl)-cyclohexy,~7-3~ Let~yl~4-p~e~yl 4-piperidinecarbo~ylate r:~orLohy~ro-chlo~ido; ~p . . 2~3 . 6 C .
: To 1 pa~t o~ a iolut~o~. of ~. part~ of t~iopheD.e irL 40 part~
of et}lanol are a~ed 6. 6 ~art~ of 1-(4-fluorop}~e~yl)-4 a~ocyclo-hexa~ecarb~::Litrile, 10. 5 part3 of (B)-phe:r~yl~ethyl 3-~ethyl-4-pheD.yl-4-pip~ri~ caxboxylate hydrocl:Llo~de, 6 parts of pota~siu~
acet~te a~ld 200 ~a~t~ of 2-propa~ol. I~e whole is hydroge3~ted at ~o~mal p~essure a~d at 50~G with 4 parts o~ plal:i~usn-~n-charcoal cataly~t 5% . After t~e calculated. amou~t o~ ~Lydroge~ i.c taXe~ u~, the catalyst i3 t~ltered o~ arLd washed wi~h acetic acid. r~e ~iltrate is e~rapora~ed a~d the residu~ is take~ up in water. The whole is alkalized with 30dium hydro~ide arLd the protuct is ext~acted with trichlorometha~e. The extract ii ~,va hed with water, dried, filtered a~d c~rapoYated. The residue i~ pur~tied by colu~ chromatography 5 o~rer ilica gel us~g a rnixture of trichlorometha~Le a~d metha~ol (98:2 by volurne) ai eluer~t. The pure fraction~ are collected and the elueQt is evaporated. Fror~ the re3idua, the Ac-Bp-fraction ls separated by HPLC us~g a mix~ure of he~ane, trichloromethane and metha~ol (100:100:0. 5 by volume) a~ elue~t. The pure fraction i9 10 collected and the elue~t is evaporated~, yieldirLg 0. 8 parts (5~) of (Ac-Bp)-phenylmethyl l_L4_cyaIlo-4_(4_fluorophe~yl)cyclohex~
3 -methyl-4-pheD.yl-4-piperidlnecarbo~ylal:e kL a qinQilar maD~er there are also prepared:
(Bc-Bp)-ohenylmethyl l-~-cyano-4-(4-flllorophenyl)cyclo-lo hexy~7-3-methyl-4-phe~yl-4-piperidinecarboxylate; mp. 131C;
( ~c -Bp)-phenylmethyl 1 . ~4-cyano-~-(4 fluoropherlyl)cyclo hexy~7-4-(2 fluorophenyl)-3-methyl-4-piperidinecarboxylate;
(Bc-Ap)( )-pheuylmethyl . l-~-cyallo-4.-(4-fluorophe~yl)-cyclohexy~7-4 -(2 -fluorophe~yl) -3 ~methyl-4 -piperidinecarboxylate ZO monohydrochloride; mp. 213. ~1 C;
(Ac-Ap~ ( ~ )-pllenylmethyl 1 -~4 -cya~o-4-(4-fluorophe~yl)cyclo-hexy~7-4-~2-fluorophe~yl)-3 methyl-4-piperidi~ecarb~xylate;
(B c -B p) (~) -phenylme ~hyl 1 -L4 cya~lo - - (4 ~Iuor ophenyl) cycl o -hexy~7-3-methyl-4-phenyl-4-piperid~eca~bo~yLate; ~d (Bc-Bp) (-)-phenylmethyl 1 ~4-cyano 4-(4-fluorophe~yl)cyclo-hexy~7~3 -methyl-4-phe~yl~^pipe ridinecarb~xylate.
ExamE~.. X~I
A ~:Li~e a 10. 9 pa~ts o~ e~yl l~ c~ o~-(4~ftuo~o-cycloh~ 4~ pipe~di~c~-b~la~P, 11 . 2 pa~t3 30 o p~ ~ hyd~txcide, 50 pa~t~ of ~ater a~Ld 96 p~rt~ o~ Z~propa:rlol a ~i~red;. a~ ~e~ e~d fo~ 4 hc~a. l~ Cti~ 3 ~il~red hot o~v~r~y~o a~ t~e ~t~at~ i~ poused o~o 300 pa:ct~ ~ ~te~ e ~le ~ sLe~l~ acetic acs~ to p~ 6~7. Th~ p~cipitate~
:
J~ 326 3'7~
pro~uc~ ilter~d o~ hed ~:hr~e tim~ ~th water arL~ co~e~t2d iSLto t~ roc~lo~de ~alt i~;gt~ L ~:Ld; 2-pr~pæLol l~e- salt i3 ~ltcrcd ~ d su~pe~de~ i:CL a ~alu.tio~ ~f 1. 4 pa~t~ o~ pota9~iu~
~rd~ e ~n l iO pa~ c~ ~ate2 . T~:Le f~e~ ba~e i~ ~x~ac~ ~ur 5 t~ wi~ 70 ~a~t~ o~ I t 1 I-~xy~ise~ha~e. ~he ac~,ue~us phase is 3~pa~ate.. ~d ~i:ir2e~ or a w~ile c~3: a r~.vap~r to ~emo~e all t~aceq ~ la l'~ e~e, lrh~ ~ear aq~,ueous phase i~ a idi~ed ~ a 10%
ac~tic ac~d ~al~ti~ to p~ 6. ~L~ p~ecioitat~s~ pro~uc~ ilt~r~d off, edws~a~ a~tdriedo~roaghtatabc~u~105~e, y~eld~3g 5.4 past3 (66. ~1%) a I -~-cyar:o-4~(4-1uorophe~yl)cycioheæy~ phe~yl-~-pipe~di~ec~rb~ acid; r~p. 231~1Co .. .. . .. .. .
FoLlowi:~g the same procedure there a:re also prepa~ed:
~N~ z . . 1 Ba ~ e/Salt I
Ar Ar . R ~o~ ¦ mp. ~ C
, , ... __ ~
4 - F -C 6H4 ~ 6H~ - ~ - HCl I ~3 0 0 4-F C6H4 3-Cl-C6~4 . H H:Cl.H20 284. 7 4-F~6H4 4-F-C6H4 HHCl 1/2H~0 2~1.2 2 -C~3 -G6~4 ~ 6K~ H HCl ~3 00 4_~ C 6~ 2 ~0~ 3 -~ 6~4 ~ ~Cl . ~2 2~1 . 8 4-F -C 6}~1 ~ OCH3 C: 6~4 ~ }iCl . ~ - - 2 81 . 8 4 - F -C 6E~,L 2 - F -C ~ :~ EI ElCI +3 o O
.
Eam21e XXV~I
A~xtuse of 1.2.part~ of (B~-phe~yk:~thyl 1-L~-~ya~o-4-1 5 (4 ~ i!1uor ophenyl )cycl ohexy~7~ 3 ~ met~yl ~ - j?h ezyl --4 -pi~e ridi~ecarbo -xylate in 80 pa~t3 ot 2-propaELol i~ hydro~e~:Lated at D.ormal pres~u~e JA~3 3 2 6 l~t7a~8~
~6 ~:Ld a~ room temperature wit~ 1 part of palladium-a~-charcoal c~talr3t 10% . A~er the calculated a~ou3~t of hydroge~ is taken up, ther~ i~ added a p<~ siu~ hydro~id~ solu~io~ e precipi~ate~l pro~uc~ e~t~r~ ~olu~io~.. T:he c~talyst i iltered of a~d the 2-propa201 5 i~ e~Japoratod. I~e agueou3 pha~e i~ washed w~th 2,2'-oxgbispropa~e aD.d ~eut~aliz~d wit~ a 10~ aceSic acid 3alui:ion. T~ preclpil:ated pro~uct is i~iltered of E a~d converted i:~to the hydroc:hloride salt in 2-propa~ol. The erude salt is orys1alllzed from e~anol, yieldi:;~g O. 8 part3 (73%) of (Bc-Bp~ r-cya~o-~ (4-iluorophexLyi)cyclohexy~7-1 0 3 -me~yl-4 -phe~yl-4-pip~rid~ecarb~xylic acid rnorlohydrochloride;
3 0 0 " ~
.. .. .... _ . , .
A ~x~are of 0. 8 partQ o~ (Ao~8p)-phe~yl~e~yl 1-~-c~a~o~4~(4-iluorophenyl)cyclohexy~ 3-~e~yl-4~phenyl-~-piperi-di~ecarba~ylate a~d 90 ~a~ts of tetrahydro~ura~ i~ hy~rogenated at 15 rLcrmal pres~ure a~ at ro~ temperatZ~re wl~ 1 part of palladiu~n-o~-c~arcoal ca~lyst 107~. Af~er. t~e calculate~ amou~t of hydroge~ -is takeu up, the ca~aly t i~ f;ltered off a~d the ~lt~ate i~ e~raporated.
The re~idue is con~rerte i~to the hydroc}Lloride ~alt i~ e~LarLOl a~Ld 2, 2'-~xybi~propaIle. T~ salt iq i!~ltered o:~ and dried, yieldi~ 0. 5 20 }?a~t~ (68q~) o~ (Ac-Bp)~ cyar~o-4-(4~ orophe:rsyl)cyclohe.Y~
3~met~yl~-phenyl-4-piperid~ecarbo~lic acid monohydrochloride;
~p.. 209,2C.
A ~x~e QI 3 . 4 par~ of (Bc-Bp~-(p~e:~:Lyl~ne~ayl) 1~4-cya3:Lo-4 - ~4 -1uorophe~L~l)cyclohe~y~7-4 -(2 ~fluoropherlyl) -3 -~ethyl -4-piperidinecar~cylate a2ld 135 pa~ts o~ totrahrdro~uraIl i s hydro-~ena~ed at ~or:~al press~re a~d at roo~ tempera~re with 2 part~
of palladium-o~-charcoal ca~Lly3~ 10%. A~ter the calculate~ amou~t of hydrogen is ~ken up, ~e caLtalyst is .4;ltered oi~f a:nd washed with rnet3:1anol saturated wi~ a~orLia. The ~lt:ra~ i9 e~raporated a2ld the residue i~ ~Lk~sL up ~:n a ~Qi~re or pc~ si~ ~ydrox:id~ a~d water.
The w~ole i~ he~ wl~ ~ic~loros~e~a~e. Ihe al}cali:~le aqueous ;.
JAB ~2~
~8~7~
ph~3e i~ u~ d with a;3~ ac ~tic acid ~alutiol:L 10%. T~e predpit~Lted produc~ i9 i~iltered o~, wa3he~ with water, d~i~d and co~orted ~to the hydrochlorite salt in methanol. The ~alt ~ ;iltered ofs and dried, ~seldiDg 2 pa~ts t66%) of (~3c-Bp)~ cya~o-4-5 ( ~fluorophenyl)c:yclohe~ 4-(2-fluorophe~yl~-3~methyl-4-pi~er~-- di~ecarbo~ylic acid monQhr~roc lor~e; mp. 300. 6C.
A ~:ure of 7 part:s of (Bc-Ap?-phenylmethyl l-ç~-cya~o-4-(4-Luorophe~yl~ cyclohexy~7-3-~e~yl~4-phe~yl-d~piperidi~ecar-boxyla~e a~Ld 2, O parts of tet~ahydrofs~ra:~. is hydsoge~a~e . a~ ;Lormal 1 0 pre 8 sure aD.d at room t mperatur~ 2 parts of palladiurn~ -char -- coal cataly~t 10%. After ~:Le calculate~ a~:Lo~t of hydrogerl is take~
up, the catalsr3t i~ filtered o~ a:~d t~e f;lt:rate i9 e~raporated. T~e re~idue i~ corlverte~ iIltO the ~rydrochloride 3alt irL a mi:~bure OI
D:~0th~0l and 2,2'-~xy isp~opan~ e ~alt is ~lltered o~f a~d dried, yieldin3 1 pa~t (16~) of (}3c-Ap)~ cya~ (4-Luorophenyl)-cyclohexy~ -3 -~ethg~l -4 -ph~yl -4 -pipe ridiD.ecar~c~xylic ac~ d mo~o -hydroc~Ade mo~lohydrate; mp. 291. 8"C.
A r~t~re of l. 5 partJ of (AG-~P)-(Phe~Y~thY1) 1-C~-cya2lo-4-(4~1uorophe2Lyl)cycloh~y~7-3-methyl~4-~?heYlyl- pip~ridi:~e-~ ca~rbo?~ylato a~ad 9~ parts of tetrahydrofura~ hydrogeDated at ~orD~al pre~ure a~d at roo~:L t~mperatllre w~ 1 part o pallad~
orL-chareoal cataly~t 10%. A~te~ calculated a2aou~l~ o~ hydroge~ is ta~ce~ up, th~ catalyst i~ iltered of~ and t~e filt~at~ is e~rapc~rated.
The .. e ~iduc i~ ce~ up ~ wate r arLd po~.tas ~ ydrox~de . The whole ~5 ~ hed wit~2; ~io~:~oro~etha~e. ~e alkali~e aq.ueous ~sha e is ~euts~alized wsth a~ acetic acid solut:io~ 10%. The precipit2Lted product i~ i~l:er~d oi~:,. wa3hed with ~rater, ~`ec~ a3~,d co~verted ~to :he hyd~o-ch;loride ~alt ~ met~ ol and 2,2'-~Jbi~pr~ e, y~eldi~g 0. 6 pa.t~
(42%) of (Ac-~p)~ cyans-4-(4-~luoropheD.yl)cyclo~exy,~-3-met~yl-30 4-phe~yl 4-pipe~idi~ecarbo~:ylic acid ~o~ohydrochlo$ide mo~o-hydrate; mp. 2 61 . 6 C; .
8~ -A mixture of 0, 9 parts o~ (Ac~Bp)-phe~ylmethyl l-.~-cya~
4-(4 fluorophenyl)cyclohe~Yy~ -4 (~-~uorophenyL) 3-nnethyL-~-piperi-di~ecarboxylate a~d 90 parts of tetrahydrofuran is hydrogenated at ~or~al pre3sure a~d ~t room tempera~ure with 1 part of paLladium-on-5 charcoal catalyst lO~O,~After the calculated amou~t of hydroges~ i~ takenup, the catalyst i8 filtered of and washed with mathanol ~ah~rated with ammonia, The fil~rate i~ evap~rated a~d the residue i3 taken up i~ a mixture of water and pota33it}m hy~roxide. The whole is washed with trichlorcmetharLe. The al};ali~e aqueou~ phase is neutralized with an 10 ace~ic acid.solutio~. 10%, The precipitated product i~ filtered off a~d converted iD.to the hydrochloride salt in me~char~ol a~d 2, 2'-oxybis-propa~e. The salt is filtered off a~d d~ed~ yieldi~g 0. 3 part~ (3~%) of (Ac-Bp)~ cyano-4-(4_fluoropherlyl)cyclohexyl7^4-(2-fluoro-phenyl) 3-met}~5rL-4~pip~ridinecarboxyiic acid monohyd2ochloride moz~ohydrate; mp. 242. 2-244. 4C.
Example XXVII:L - -~ ~ A mixture of 0. 7 parts o~,i(Ac-Apj (;~)-phe~ylmethyl l -~4-cyano 4-(4 fluoropher~yl)cyclohe~ 7 4-(2-~1uorophe~yl)-3-cnethyl-4-piperidi~ecarbaxyLa~2 a:nd 90 par~s o~ tetrahydrofu~a:l is hydro~erLated at ~ormal pressure aud at ro~m tempera~ure with 1 patt of palladium-o~charcoaL catalyst 10%, After the calculated amount of hydroge~ i~
taken up, the cataly~t iq filtered off. The filt~r-cake is washed with ~etha~ol ~aturated with ammo:nia, and the filt~ate i3 evaporated. The regitUe i9 tak~rL up i~ water a4d pota~sium hydroxide. The whole i3 waahed with trichlorome:ha~e. The alkal3ne agueous phase i9 neutra-llzed with a:ll acetic acid solution 10%. ~he precipitated product i9 filtered off, washed with water, dried and converted i~to the hydro-chloride ~alt i~ metha~ol and 2, 2'-oxybispropane. The salt is filtered off and d~ied, yieldiIl~ 0. 3 part~ (a9~,) Of (Ac-Ap) ( )~ cyano~-(4-fluorophenyl)cyclohexy.l7-4-(Z~fluorophenyl)-3_r3ethyl-4-piperidine-c arb oxylic acid monohydr oc~l oride; mpO 28 2. 7 G .
Ia a similar ~na~er th~re i also prepared:
(Bc-Ap) (~ 4-cyauo-4-(a-fluorophenyl)cyclohexy~7-4-(~-fluorophenyl)-3-methyl-4-piperidi~ecarboxylic acid monohydro-chloride, mp. 288. 8C.
~.....
J~ 32 ~87 Exasn~le XXIX
~ m~YtLLre o~ 4 parts of (Bc-Bp) (-)-pheuylme :hyl 1 -~-cyano-4-(4-fluorophenyl)cyclohe.Yy~7-3 ~methyl-4-pherLyl-4_piperidi~ecar-bo~rlate a~d 225 par~ts of t~trahydrofura~ i~ hydroge~ated at normzl S pres~lre and at room temperature with 2 parts of palladium-on-charcoal catalyst 10%, Afte~ the calculated amou~ of hydroge~ i5 taker~. up, the cat~ly~t i3 filtered of~ a~d wa~hed ~nth metha~ol sa~urated with ammonia. The filtrate is e~raporated. The re~idue is co~verted into the hydrochloride jalt i~ methakoL The salt is filtered off and dried, yield~g 3 partq (82%) of (Bc-Bp)O(~ 4-cyano- -(4-fluoro-phenyl)cyclohexy~7-3-methyl-4-phenyl~-piperidi~eca~boxylic acid ~nonohydrochlor;de; mp. 298. 1 C
ID a ~imilar ma~er there is also prepared:
(Bc-Bp)~ cyano-4-(4-fluorophenyl)cyclohe.Yy~7-3-15 methyl-4-phe~yl-4-piperidinecarboxylic acid monohydrochloride;
~p. 29 ~. 9 ~ C :
~ed fi~st for 6 hour~ at reilu~e and ~u-ther o~rer~Light at ro~rn te~peratu~e. I~e et~a~ol ~ e~raparated a~ the re~idue i9 taXer~ up ~n 4-met~yl-2~p~ta~o:l:Le a~d water. r~e layer~ ~re ~eparated a~d the~ us-p~e is e~a~te~ e~ees ~e with d-methyl-2^~?e~ta-ro ~c~_ The ~ombi~:Led orga~ic pha~e~ a~ sh~ twice wi~ vater, dried, i~ilS red a~d e~raporated. r~e re~idue i-~ di-~tllled, ~eldi~ag 98 part~ o~ 5-fluoro~2-~e~hyl~e~2e~eacetonltrile; ~p. 124-128~C
a,t 10 ~m. p~SU~Q.
E;xaml~le VI
To a sti~red arLd hot solutio~ of 8. 5 parts of ~,N,N-t~iethyl-benxerLemetha~ami$~ium chloride, 40 part3 of so~ium hydroxide and 360 part3 o~ a ~odium hy~lroxide solutio~ 50% is added dropwise a s olutio~ of 72. 7 pa~ts of N, N -bi3(2 -chloroethyl) -4 -methylbe~zene -87~80 _ .
~ulfc~amide ~rLd ~S. 5 parts of 2, 4-dichlorobe~e~eaceton~t~le i~
90 part~ o~ tetrahy:lrofura~. IJpo~ COmplet~OrL, 3t~rr~Ilg i~ co~ued for 3 hou~q at 50C. I~e reaction m:LYt~re is co~led, 216 parts of r~et}~ylbeze~ and 480 parts of water are added a~d t~e layer3 5 are sep r~tedThe or~aDic pha3~ i~ wa3hed with water, dried, filtered a~d evaporated. T~e residue i oryst311ized ~~om 2-}?ropa~ol, y~eldi~g 28 pa~ 29%) of 4-(2,4-~iohlorophe~yl)~ methylphe~rL-o~yl)-4-piperidi;~ecarb~trile; mp. 14;C.
Follo~nng the ~3am2 procedure arLd u~i~g t~erei arL e~ rale~t amou3lt of a~ appropriate ary~laceto~tr~le t~ere are also i?repared: -4-(2-flu~rophenyl)^1-(4Enet31ylp~e~ylsulfonyl)-4 piperidi~Le-c~rbc~trile as a res~due;
4-(5-c:bloro-2 -;saet~c\xyphe~yl) -1 -(4-~ethylphenyl3ulonyl) -4 ~ pipe ridinec~rborLit~ile;
1-(4-methylphe~yl ulfo~:Lyl~-4~ (t:ri:luorome~yl)phenyl7 piperidi~eca~bo~ rile; and 4-(2-rs~eth~xyphe~ (4-~e~hylphe~:Lylsul~o~yl)-4-piperidi3e-carboDit~ile .
~ .
A solu~lon of 29. 6 parts of N,N-bi~(2-chloroethyl)-4-methyl-benzenesulfo~amide and 14. 9 parts of 4-fluoro-Z-rnePhylberLzeneaceto-nitrile i~ 90 parts of n:lethylben~eIle is added dropwiseto a solutio~ of 5, 6 parts of lithium am~de in Z70 parts of methylbe~z~ne at about 90C.
Upon cornpletion, the whole i~ heated to reflux and stirred cvernigh ~5 at reflux temperature. The reactio~L snixture i~ cooLed, p~ured onto wa~er and the layer~ are separated. The organic phase is dried, fil-tered alld e~aporated. The residue i9 crystalli2ed from 2_pro~anol, yielding 27 parti (72. 6%) of 4-(4-fluoro-2-methylphe~yl)-1-(4-methyl-phenylRul~o~yl)-4-piperidinecarbonitrile.
Follownng the same procedure a~d usi ~ equi~alent amounts of the appropriate starting materials there are also prepared:
4 -(3 -chlor o-2 -methylphenyl) -1 -(4-methylphenylsulIonyl) - ~ -piperidi:llecarboz~itrile;
37~ JAB 326 4-(5 -fluoro-Z -methylphenyl) -1 -(4-methylphenyl3ulfonyl) -l-piperidi~ecarbonitrile; mp. 1 68C;
(B)~4-(2-fluorophe~yl)-3-methyl 1-(4-methylphenyl~ulfo~yl)-4-piperidiD.ecarbo~itrile; mp. 154C; and (A)(~ (2 ~fl~orophenyl).3-methyl-1 -(4-methylphe~yl-sul~onyl) -4-piperid~ec~rbonitrile; mpO 135 C.
Exam~le VIII
A mixture of 35. 8 parts `of 4-(2-fluorophenyl)-1-(4-methyl-phe~ylsulfo~y}~-4-piperid~Lecarbonitrile and 50 parts o~ a sulfuric acid 301utioll 75% is stirred for 4 hours at about 150C. 1~2 Parts of ethanol are added dropwise. Uporl completion, stirri~g i5 continued for 5 hours at reflux te~nperature. The reactioIl mixture is cooled a~ld poured onto crushed ice. The whole i~ alkalized with ammonium hydroxide a~d the product iq extracted with dichlorometha~e. The extract is dried, filtered and evaporated, yieldi~g 17. 2 parts (68.4~) of ethyl 4-(2-fluorop~ienyl)-4-piperidi~ecarboxylate a a residue.
Following the qame hydrolyzing prored~:;re and sta~tir~g from the corre~pondi~g car~o~itrile there are a~so prepared:
ethyl 4-(3-methylphe~yl)-4-piperidiDecarboxylate hydro-2 0 chloride; and ethyl 4 -(2, 4-dichlorophenyl) -4 -piperid~ecarboxylate hydro-chloride.
xample IX
16.32 Part3 ~f 1-(4-rnet~yiphanylqulfo3lyl)-d-~^(tri~luoro^
2~ rnethyl)phe~y~7.4-piperl lnecarb~rLit~ile are added por~o~wise to 35 ~art~ of a sulf~r~c acid -~lut~o~ 75~ a~d t3:Le ~i~t~:e is q~red a~d heated. for l; hours at 1~;C. l~e~ there are added d~opwise 100 part~ of et}la~Lol. ~p~;~L co~:npletioD., ~ rrsrlg i~ co~tin~ed o~rer~i~ht at reilux. T~2 re~ctio~ ~ixt~re i~ cooled arLd p~ured o~to ice-water.
Ihe whole i~ aLkalized wifh a,~mo~iusrL hydrox:Lde a.d t}la proc~ct is ext~cted ~th dichloro~etha~e. The extract i dried, i~iltered a~d evaporate~d. The re~idu~ iq co~erted i~to the hydrochloride 3alt in 2,2'-o~bi~pro~a~e a~d 2-propa~ol. ~he salt i~ ~iltered oi~ and dried, yieldi~g 6 pa.rts (43 . ~%) of et}~yl 4- -(ethoxyca~bo~yl)-phe~y~ 4~pipe~ ec~rb~rlate hydrochlor~de; ~mp. 121~C. I
,, 1, JAs 325 ;1~87~80 z6 A ~ixture o~ 11.3 pa~tq of 1-(4-methylp~enylsulfor~ 4-rii~uoror~ethyl)phe~y,~7-4-pip~ridillecarboDltrile, 5. 6 part3 of potas iu~ hy~roxlde aD.d 220 ~?ar~s o 1,~-etha~ediol i3 ti:~red aD.d 5 reLuxed for 48 hous~ Le reactio~ m~re is co~led a~d poured outo iCo-WZl~er. lhe whole iq acidi~ied wi~. hydrochl~ric acid a~d the product i~ e.~act:ed with dc}l1oro~e~ane. l~e ext ract is dried7 ~lter~d ~U:Ld e~apo~ated, yieldi~.g 11 . 8 parts (100%) of 1 -(4-methyl-pheD.yl~ orLyl)-4_ -~t~'luoromethyl)~hen,y~ -pi?eridi~ecarboxyli::
1 0 acid as a ~esidue .
Follo~ t:he same hydrolyz~g psocedure aDd qta-ti~g ~rom the COrreSpO~ Lg ca~bo~tsil~ there ar~ al30 prepared:
4-(5-ch~oro-2..rnethox~phenyl) -1 -(4-methylpherLylsulfoIlyl)-4-piperidiIle arboxylic acid;
4-(Z-methox~~ Lyl)-l-(4-n~ethylphenylsu~'o~yl)-4-piperidi e-ca~boxy~ a~id as a re sidue;
4-(4-~luo~o-2-methylp~e~yl)-1-(4-methy}pherlyls~lfonyl)- '-piperidi~Lecaxboxy~ic acid;
4-(3 -chloro^Z -n~ethylp~Le~yl) ~ -methylphe~:Lylsul~o:~yl)-4 pip~ridi~ecar~oxylic acid;
~s-(5 -fluoro-2 -methylphe~nyl) -I -(4-methylphenylsulfonyl) -4 -piperidi~ecarboxylic acid; mp. 157C;
(B)-4-(2-fluorophellyl)-3-met~yl 1~(4-methylphe~ylsulfonyl)-4-piperid2~Lecarboxylic acid; mp. 186C; and (A)-( )-4-(2-fluoropheQyl)-3-met~yl~ methyLpherlylsul-forLyl)-4-piperid~ecarb~ylic acid as a residue.
To a 3tir2ed a~d refluxi~g mixture of 21 parts of 4-(5-chloro-2-methoxyphe~yl)~1-(4-methylphenyl~ulfo~yl)-4-piperidi~Lecarboxylic 30 acid and 270 parts of benzerle are added dropwise 3O parts of thio~yl chloride. Upon completioll, the whole is st:Lrred and refluxed for 4 hours. The reaction mixture is e~raporated a~d the -esidue is .~ ,.. .
37~8~
washed twic~ set~ylben2;e~e, y~eldi~g Z2 pa..ts (lOO~o) Of 4-(5-chloro-2 -~eth~E~enyl) ~1-(4 -met~Lylphenyl9ulr'0~yl) _A -piperi -di~ecarbo~l c~:Lloride.
Ir~ a ~ ma~er t~er~ a~e also prepared:
4 - (2 -me~oxyphe~yl) -1 - (4 -me thylphe~:LylsuL~o~y l) -4 -pipe rldi~e -ca~bol:Lyl chlor~de a~ a ~e~id~se;
m~thylphen.yl uL~rLyl)-4-r~(t~i1uoro~nethyl)phe~y~7-4-piperi~i~ecar~nyl c~lo~de a~ a re3idue; ----4-(4-i~uoro-2-~:net~Lylph~yl)_1-(4-met}:~ylphe~ylqulfonyl)- -1 0 piperidi~ecarb~l chlorid~ a~: a re~idue;
4~(3-chloro-2~rcL~t~y1pheD.yl)-i-(4-me~y1phenylsulfonyl). -p~perid~necarbo~y1 c~loride as a re~i~ue?
4-(5-n~oro-2-methyLphenyl)~ 4-methylphe~ylsulfonyl)-4-piperidi~ecarbonyL chloride as a residue;
(A~-3- m ethyl-1~4-m ethylphe~yl9ulfo~yl~-4-phe~yl-4-piperid~ne carbo~yl chloride;
(B 3 -4 -(2 -Luorophe:Lyl) -3 -methyl _1 -(4-methylphenylsulfonyl) -4 ~pipe ridi~ec arb onyl chloride;
(A)~ )-4-(2-fluorophenyl)-3-methyl-1-(4-methylphenylsulfonyl)-4-piperidi~ecarbo~yl ehLoride as a residue;
(B ) -( -) 3 -methyl- 1 -(4 -methylphenyl ~ulo~yL) -4 -phenyl - ' -piperidinecarbo~yl cbloride; and (B ) -(~) -3 -met~yl-l ~(4-methylphenylsulforlyl) -4-phe~Lyl-piperidi~ecarbo~yl chloride a~ a residue.
2 5 ~II
A ~ix~e of 360 5 part~ of 4-(3-chloro-2-r~ethy1phes:Lyl)-l -(4~s:net~y1phe~y1s~1fQ:I:Ly1)-4-piperid~nec~LrborLyl c~loride a~d 2~0 ~art~
of et~a~aol i.c stirre~ a~d reLux~d o~e~ht. T~e reactio~ ~3re i~
treat&sl Wi.t~L aoti~ted c~Lrcoal w~i1e not. ~he latt~r is i~ilter~d of~ a;~d t~e product i-~ allowed to cryst~allize fro~:L the ~iltrate by coo1~g spon-tan~u~ly to room ter;aperature. I~e psoduct i9 f~ltered of a;~d dr~ed, ~eld~g 33 part3 (8~ ) of e~yl ~-(3-c~loro-2-methylphe~y1)-1-(4-~ethyl~heJlylsulfo~yl)-4~iperiti~ec~L.bo~ylate; mp~ 13~
1~37 Followi~g the same e~terifyi~g procedure by reacting the corre3pondL~g acid chloride with the appropriate alcohol, there are al~o prepared:
e thyl 4 - (5 -chl o r o -2 - methoxyphenyl ) - I - (4 - methylphe~yl -5 3ulfo~yl)-4-piperid ~ec~rboxylate;
ethyl 4-(2-methoxyphenyl)-1-(~-methylphenylsulfonyl)-4-piperidinecarb~ylate;
~ thyl l-(~-methylphe~yls~lfonyl)~4_~3_(trifluoromethyl)-phe~Ly~7~4-piper~di~eca~boxylate;
ethyl 4-(4-fluoro-2-methylphe~yl)-1-(4-methylphenyl ulfo~yl)-4-pip~ridi~ecarboxylate; mp. 151 C;
ethyl 4~(5-fruoro-2 methylphenyl)-1-(4~methylphenylsulfo~yl)-4-piperidinecarb~cylate; mp. 94~;;
(A)-phenylmethyl 3-methyl 1-(4~-methylphellylsulfonyl)-4-1 5 phe~yl-4-piperidinecarboxylate;
(B).(ph~ylmethyl) 4-(2-1uorophe~yl)-3-m~hyl-1-(g-methyl-phenylsulf o~yl) -4 -pipe ridine c arb oxylate; mp. 1 1 0 C;
(A)(~) (phenylmethyl) 4-(2-fluorophesLyl)-3 me~hy~ (4-methylphenyl~ulfo~yl) -4-piperidi:~ecarboxylate;
(B)(t).. phe~ylmet~yi 3-methyl-1-(4-methylphenylsulfo~yl)-4 -pherLyl -4-piperidi~ecarboxylate;
(B)(-)-phenylmethyl 3-methyL-1-(4-met~ylphenyl3ulfoT~yl)-4 -phenyl -4 - pipe rid~e c arb clxylate; a~d (B)-phenylmethyl 3-methyl 1-(4-methylphe~ylsulfo~yl)-~-2S phenyl-4-piperidinecarboæylate.
~3~
~ ~ixt~re of 17 parts of ethy1 ~ c~loro-2-methoxypherLyl)~
met~ylpha~lsuL~o2Lyl)-4-piperidL~ecarboxylate, 7.; part3 of phe~:Lol arLd 135 part3 of a hy~robro~ic acid 301ut~o~ i:~ acetic aeid is 30 ~ o~ar~ight at ro~m t2mp~rature. The reaci~o~ mix~re i~ poured onto ~wat~r a~d the whole ls washed wit~ 2,2'-<~xybi~pro~ e. The aq~ue~u~ phase is alkalized with 30diu~ hydrox~e while coo1L~. l~e product i~ ext..acted wit~ tr1chloromethar~e. l'he e~i~act iq was~ed ,~ , ~37 with water, dried, filtered and evaporated. The residue is con~erted i~to the hydrochloride salt i~L Z~propa~oL alld 2, 2'-o~ybispropane, yieldiIlg 7 part3 (S5%) of ethyl 4-(5-chloro-Z-methoxypnenyl)-4-piperidinecarboxylate hydrochloride, ~ 1~
a, To a stirred a~ boil~g solutio~ OI 73 parts of (B)-( )-3-methyl -1 -(4 -methylpheD.ylsulfo~yl) -4-phe~yL -4 -piperidinecarboxylic acid in 3200 parts of 2-propanol is added a solutio~ of 24 parts of -methylbenzenemetha~amine, The solutio~ is allowed to cry~tal-lize. The product is ~iltered ofi~ a~d recrystallized three timeq f~om respecti~rely 4800, 400û ~nd 3200 partq of 2-propanol, yielding 27 parts (27 %) o~ (B ) -( -) -3 -methyl -l -(4 -m~thylpher~yl3ulfonyl) -4 ~phenyl-4-piperidinecarbe~ylio acid ~ ~ethylbe~ze~emethanarnille (1: l).
A rnix~cure Aof 27 parts of (B)-(-)-3-methyl-1-(4-methylphenyl-sul~onyl)-4-phenyl-4-piperidi~ecarboxylic a::id a-methylbenze~e-methanam~e (l: 1), 60 part3 of co~centrated hydrochlo~ic acid a~d 1000 par~s of water i~ ~tirred atld boiled for a while, The precipi~ated product i9 f ltered of, washed with water and ~oiled in watsr. The product i9 filtered off a~d dissolved ln trichloromethane. The latter is d~ied, filtered a~d evaporate~. The residue is 3tirred in Z, Z'^o~ybi3-propane, yield~g 18.4 part~ (94~) of (B~ )-3-methyL-l-(4-methyl-phe~ylsulfo~yl)-4-phe~yl-4-piperid~ecarboxylic acid.
b. To a stirred a~d refluxlng solution of lOOparts of ('~ )-3-methyl -1 -(4-methylphenylsulfo~yl) -4-phe~yl-4-piperidinecarboxylic acid irL 1600 par~s of 2-propa~ol is added a qolutio~ of 32.; part-~ of (+)-a-methylbenze~emethanami~e ~ 40~ part~ o 2-propanol. The reaction mix~re i3 allowed to crystallize. The product is ~iltered ofs and recryQtallized four times from respecti~rely 6400, 5600, 4300 ar:Ld 3200 part~ ~ 2-propa~ol. The product i`Q filtered o~ a~d recrystallized from 2~00 parts of2-propa~ol. It is filtered off agai~L, yieldi~g 22 parts, The filtrate is evaporated and the residue is added to the c~ystallized fraction of 22 part~, yieldi~Lg ~8 pa.ts (2I%) of (B)~ 3-met~yl-l-(4-~:nethylphe~ylsul~o~lyl) 4-phenyl-~-piperidi~ecarbo~ylic acid a-methylbe~ze~emetha~amine (l: l).
JAE~ 3 2 6 - ~87a~ 3 A mi~cture of ZS parts of (3)-(r)-3-methyl-1-~4-methylphe~yl-sulfo~yl)-4-phe~yl-4-piperidi~ecarboxylic acid a-methylbenze~e-metha~amine (1: 1), 60 pa~ts of co~ce~trated hydrochloric acid and 1000 parts of water i~ boiled for a while, The reaction mixture is f~ltered. The filtercake is washed wi~h water a~d stirred 1~ boiling water. The p~oduc:t is filtered off and di~sol~ed in trichlorometh~e.
The latter is dxied, filtered and e~raporated. The resitue is boiled i~
2, 2' -oxybispropa~e, yieldi~g 19. ~ parts (937O) of (B)-~r)-3-methyl-1~(4_methylphe~ylsu]4O~:Lyl)_4_phe~yl_4_piperid~eoarboxylic acid.
1. 0 A ~uspeTt~ioD. of 11 partq of ethyl l-(~}-methylphenyl~ulfo~yl)-4-~-(tri1uoromet}lyl)pherLy~7 4-piperidi~eca~boxylat~- a~d 8 parts o tet~aethylam~o~u~ bromide in 200 part3 of ethanQl i~ eleot.olyti-caLly deto~ylated at ~Z . 15V u~g a Hg-cat~Lade a~d a mlx~ure of Ag and AgC} ~5 refers~ce elect20de. The ethaD.ol 301ut~ot~. is; decanted ant the ~olve~lt i5 e~ps~rated. The re~idu~ i~ taken up diohloro-m~tha~e.. T~e latter i8 u~a~he~ ~ee ti:m8:~1 with water, dried~
filtered a2~d ~porated. The re~idue ic co~l~rerted i~to t~8 hydrochlo-ride salt ~ 2-p~opanol a~:Ld 2,2'~ xybi~propa~e.. T~e ~ lt is filtered ofand.dried, yielt~:g 6.9part (85.2'1o) of ethyl 4~ (~i~uo~o-methyl)pheD.y~-4 -p2 pe2id~:Lecarboxylat~ hydrochlo~ide .
1~ a similar ma~er there ~e also prepared:
ethyl 4-(2-me~ o~y~he~yl)~-pipcridi~Lecarboxylate hyd-o-c}~loride; :
ethyl 4-(4-~oro-2-meth~lphe~:Lyl)-4-piper~lnec~rboxylate;
a~ a re~idue;
ethyl 4 (3-chloro-2-~nethylp~e~yl)-4-piperid~Lec2rbo~ylate a~ a re~idue;
(B)-phe~ylmethyl 3-methyl-4-phenyl-4-piperid~carboxylate ethanedioate (1: 1);
.
87Q~
(A)-phe~ylmethyl 3-methyl-4-phenyl-4-piperidinecarboxy-late ai a residue;
ethyl 4-(5-~uoro-2-methylphe~yl)- -piperid~necarboxylate hydrochloride; n~ip, 198,8C;
(B)-phe~ylm~t~l 4-(2-~luorophenyl)-3-methyl-4-piperidi~e~
carboxylate hydrochloride; m p. 220C;
(A) (~ -pheny ~ ethyl 4-(2-~uorophe~yi)-3-~nethyl-4-piperidLnecarboxylate etha~edioat~ 1); m p. 170C;
(B)~(-)-phe~ylmethyl 3-meth~1-4-phenyl- -piperidir~ecar-boxylate hydrochloride; and (B~ )-phenylm ethyl 3-methyl-4-phe~yl-4-pipe~idLnecar-boxylate hydrockloride.
To a Qtirred aJ:Ld re~c~g r~xb~re of 14 par~s of 4-phenyl-4-piperidi:n.ecarborLyl ~hlaride~ hydrochloride a~d 130 par~s of methyl-be~ze~ are added drop~se 6. 9 parts of l-piperidinepropa~ol. Upon completio~, s~dr.~g i corLtillued ove~ight a~ reflux temperature.
'rhe methylbe~ze~e-phase is desa~ted arld th~ residual oil is '~oiled ~ ~ mlxture of 2,2'-c)xybisprop~e a::Ld ethaIlol. ~he precipitated psoduct i~ ~iltered o~ d dried, yieldi~g 14 par~s of 3~ piperidinyl)-s ?ropyl 4-pherLyl-4-pipe~di~ecarbcxylate d~hydrochloride mo~o-hyd2at~; r~p; 176.1C.
Fo~lo~g the sa~ne pr~cedure a:~d u~ing e~ul~aleD.t ~o~ts of the appropriat~ star~Lg materials the~e are also prepared:
2-(d.i~et~yla~o)ethyl 4-~henyil-~ piperidi~ecarboxylate roc~l~ride; mp. 230C;
3-(dimethyla~o)propyl 4-pherLyl-4-pipe~ ~ec~rboxylate dihy~l20chlorid~; mp . 1 5û C;
2-~-pyrrolidirLyl~et}~yl 4-phe~yl-4 pip~rid~ecarbo~ylate dihyd~ochloride; ~p. 185~G; a~d 2-(4-mor~olinyl)othyl g-phe~yl- -pipe~ai~ecarboxylate et~a~edioate ( 1 :1 ), ~Lp . 21 0 J C; .
JAB 32~
8~
A r~ix1~re ~f 4. 5 pa-t~ of 4-oxo~ pyrid~yl)cyclohexa:~e-carb~r~itrile, 5.2 parts o~ ethyl 4-phenyl-4-piperidi~ecar~oxylate, 1. }~art of 4-me~ylbe~ze~:Le~ulfo;~ic acid a~d 225 part~ of methyl-5 be~ze~e i ~tir~ed a~d~rei~uxed, o~re~ ugh~ us~g a wat~r-.~epa,ra~or.
The reactio~ m~ture i~ e~rapora~ed a2~d the r~sidue i~ c~ystallized from 2-propa~ol, y~elding 4. 5~?art~ (~o%) of ethyl 1-~-cya~o-4-(2 -pyridi~yl)-1 -cyclohexeI:Ly~;7.4-pbe~yl-4-piperidi:r~ecar~oxylate;
D:Lp . 1 60 G .
Follow~g the ~ame ptocedur~ a~d us~g e~,ui~ale~t amou~lta of l:he appropriately subst~blte~ cycloh~a~oIle3 and piperidines there are al~o pre~ared:
et~Lyl 1 ~4--cya~o~4-(4-~uoro~hesyl)-l~cycloh¢~xen-1-y~7~4-phe~yi-~-piperid~ecarbos~late as a residue;
et~yl 1 ~(4-cyaD.o-4-ph~:oyl -1 -cyclohe~ce~ yl) -4 -phe~yl - ~ -- p~peri~iDecarbo~late a~ a residue;
ethyl l~-cya~o-4-(4-~ethoxyphe~Lyl)-l-cyclohexe~-l-y~7-4-phe~Lyl-4-pipe~idiAecarb~xylate a~ a residua;
ethyl 1 -L4- - (4 -chlorophe~yl) 4 -cyæLo -1 -cyclohe:~:en o l -y~7 -2a 4-phe~yl4-pipe~ ecarb~xylate a~ a r~idue; a~d 1-~1-(4-cyanoa4-phe~yl-l-cyclohexen-l yl)-4_phenyl-4- piperi-dinylcarbouyypiperid~Iae.as a residue.
B. ~}-EPARATION OF FINAL COMPOUNDS.
xa~m~le XVIII
Z5 To a 3tirred mixture of 4. 5 parts of et~yl 1-~-cyano~ (2_ pyridi~yl)_l-cyclohe~eT-y~7- phenyl-4-piperid~ecarboxy~ate and 80 parts of ethaIlol are added portio~wi~e 0. 4 parts of sodium borohyd~ide.
UPOA completion, ~tirrirLg is co~ti~ued }irst over light at room tempe-;,; rature a~d further for 30 mi~utes at ref1u~. The reactio~ mixture is cooled and poured onto water. The oroduct is e.Ytracted with dichloro-..
,, 7~ AB 326 methane. The eYtraCt i~ dried, filtered ar~d e~raporated. The residue is crystalhzed from 2-propa~ol, yielding Z par~Y (35%) of ethyl cya~o-4-~2 -pyridi~yl)cyclohexyl~7-4 -phenyl -a -piperidine -carboxylate; mp. 157, 1 C.
Foll~ g the same procedu~e there are alsa prepared:
ethyl 1.(4~eyarLo_4_phe~ylcyclohexyl)_4_pherLyl_4_piperid~e-carboxylate; mp. 130, 5 C;
ethyl 1_~4-cya~o_4_(4_1rethQxyphe~yl)cyclohexy~7_4_phe:~yl-4-piperidirLe::axboxylate; mp. 122C;
ethyl l-~4-(4-chlorophe~Lyl)-4-c:yaD.ocyclohexy~7-4-ph~3yl-4-piperidinecarboxylate; mp. 155C; and 1 -phe~:Lyl-4-L4-phenyl-4-(1 -piperidi~ylcarbo~yl) -1 -piperidi~:Ly~7-cyclohexanecarbo~trila hydrochloride; rnp. Z83. 2JC, To 1 part of a. ~olutio~ of Z. ~rt3 of t~iophe~ in 40 part~ of et~a~ol are added 4. 7' parta of 1 -(4~fluoro-2 ~ethylpheIlyl) -oxo~
cyclohe~a~ecarbo~t~ile, 5.4 part o~ ethyl 4-phe2~yl-4-piperidine carboxyla~e hydroc}:Lloride, 2 parts o ~diu~ acet;Lte a~d 120 pa~t3 of e~a~ol. l~he whole i~ hy~roge~ated at ~3rs~al pr2ssure a:~d at roo~ ter~perat~e ~th 2 parts o~ adiurr:L-on~charcoal cataly~t l O~o .
Aft~r the calculated amc~t o~ hydroge~ is takerL up, t~e c~talyst ls iiltere~ of:E o~er ~y1O arLd the i~ilt~at~ is ~rapo~ated. F-om the residue, t}~e frce ba~e is liberat~d i3 ~e co~re~ o~al mz:r~er with arnmonium hydroxide a~l t~e product i3 ~racted wi~ ~ichloromethaD.e.
~e ext~act iq d~ied, f~lte~ed arLd e~porated. The resi~ue is ~uri-~ed by columD.-c:hromatog~a~y o~er ilica gel usi;7g a mixtare of t~i-chloromethane a~ e~ha~ol (98. 5:1. 5 ~ Yolume) as elue~t. The pure f~actio~s are coll~cted a~d t}~e elue~t i e~po~ated. The ~ esidue i~ c~y~Lllized fror~ et}~a~ol, yiel~ 3 part9 (33.4%) of ethyl 1-L~-cya;rlo-4 (4 uoro-2~m~thylphe~yl)cycloheYy~ phe~yl~L-piperi~i~e~arb~ te; mp. 135.2C.
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7~8 Exa~n~le XX.
Tc~ a ~irred ~i2b~re of 11. 7 pa-ts of ethyl 1-~-cya~:Lo-4-(4- uoroph nyl)- 1 -cyclohe.Ye~ y~7-4-~he:~yl-4-piperldi~ecarDax^
ylate9 ~ t of odi~r~etho~de solutio~ 30% and 320 pa~ts of metha~ol i~ added portlonwi3e 1 part of sodiu~n borohyd~de. Upo~
completio~, ~ r~g i~ con~ u~d o~er~ight at roo~L temperat~re.
The reac1:io~ ixture i~ poured o~to ice-~ater aD.d the product is ext~ac~ed ~vith tr~chloro~ne~a~e. Thè extrac~. is dried, flltered and evaporated. Th~ r~idue i9 ery~talli2ed f~o~ e~a~ol, yieldi~g 5, 9 part~ of (B)-et}:lyl 1 ~4-cyaDo-4-(4-i:luorophe~yl)-1-cyelohexyl7-4-phe~y~-4-piper~l~eca:~bc~cylate; mp. 145.8C:.
To Z: part~ of a ~ol~do~ of 2 pa~ of ~iop~o ~ 40 parts of eth ~ol are addéd 2~ par~ of 1-(4" uorophenyl~-4oæocyclo-hexa:~leca~bo~t~ile, 34 pa~ts ~ ethyl 4-ph~yl-4-piperidine-carboxylate hydrochlorid~ 15 parts o ~od~ acet:at~ and 400 part5 of otllanol. ~e whole i~ hydrog~ od at rlorrnal pr~ure a~ at room te2rLperatu~e ~ieh 5 pa St-Q of palladi~n-o~c~rcoal e~taly~t i ~ .
After the calculated a~ou3t o hyd:oge~ i5 take~ Up,l the cataly~t is fil -* ~ -tered off overH~o a~d th~ ~il~te is e vap~rated. Fron~ ~e resi~ue, ihe . .
i~ee ba~e i~ liberated L~ t~e co~ve~a ona~ma~erwit~am~r.ocLiur:~ydroxi~ea~Ld extracted wit~ dichlorometha~e. The ext~act is. dsied., ~ilter ed a~d ~vaporated. Irhe residue i~ partly (9. 6 part3) p?~s~ied by colu~-chro~atography over silica gel u illg a ~ix~re of tr~c~loror~e~h ~e a~d ~et}~ ol ~99:1 by ~olu~e) a~ elueD~t. T}~e puro ~ractions are col-lected a~d t:he elue~t i~ evapo~ated. Thë re~idu~ i~ con~rerte ~:Lto the hydrochloride ~alt ~ 2-propa~ol. .~ 7~m~ure f~aetior~ i9 filt ret of~ a~d the ~;l~ate i t~e~ted ~t~ ao~ated charcoal. T~e la~ter is ~ltored oi~ d the i~ at& iS e~aporated, yieldi~g 4. 8 parts of (A)-et~yl l-~-cya3~o-4-(4-nuorop~es~yl)cyolohexy~7-4-~i~e~:Ly1-~-piperidi~ecarb~xylate ~onohydroc~loride. mo~ohydrate; mp. 210.7C.
.
E:GLm~ XXI
To 1 part of a solu~!o~ of 2 part~ of t~iophene ~ 40 parts of et~a~ol are added 5.3 parts of 1-(5-chloro-2-methoxypD.enyl)-* Trademark JPB ~26 7a}~
4-axocyclobexa:~:LecarborLitrile, 5.4 parts of et;tl~l 4-~henyl-4-piperidi2~acarboxylate hyd~ochlor~de, 3 ~?art3 o: sodium acetate and Z00 part3 of etha~ol. l~e whola is hydroger~ated a~ ~ormal - p:ressure and a~ 50~C ~i~h 2 parts of plati:~Lum-a~-charcoal catalyst5 10%. Ater the c~lcu~te~d a~Lou~:Lt of kydroge:~ is :akerl up, ~e ca~-ly3t is filtered of a~d wa3hed with a ~t~re of acetic acid a~d etha~ol. T~e filtrate i~ e~raporated a~d water i~ added to the re idue.
T~e w~ole i~ alizes3 witl~; sodiu~ hydrox~de a~d t~e product is e~tracted with t:rici:Llo~o~:Le~cha~e. T~e eæt~act i~ wac}~ed ~t~:L water, 10 dried, ~iltese~ a~d e~pc~ated. T~e 2e~idue ia puriied by colum3~-chromatograp~ o~rer ~ilioa gel usi~g a m~ re of tric~loromotha~e a~d metha~ol (99:1 by ~rol~) a . elue~t.
The i~ir~t frac1~03 (A-~ or~e2~) iQ co~lected a~d the elue~t is e~raporated~
The re~idue i~ crystallized frQm 2,2' -~ybisprop~e, yield~ 0. 8 15 pa~t~ (8q~) o (A)-ehyl 1-~-(5-chloro_2~net~oxyphenyl) l_cyaDo_ cyclohe~ 4-phenyl-~-piperiti~ecarboxylatio; mp. 16;. ;~C.
~h~ 3ecolld ~ac~o~ (B-i~o~er) i~ collected a~d the elue~t i~
evaporated. Ihe residue i~ c~ystallized ~ro~ 2,2'-~xybisprolpa~e, yieldil~ 1.2 pa~t~ (12~) of (~ ethyl 1-~-(5-chloro-2-r~sethoxy-20 phe~l)-4-cya~ocyclohe~y~7 4~p~enyl--~-pi~rid~ecarboxylata;
~p. 131 . 8~C.
, Es~am~}e X~II
~ . .._ .
To 2 part9 of a ~olu~o~ of 2 parts o t~io1?h~e i::~ 40 part3 OI
et~a~ol ar~ a ded 4. 4 part~ of I -(4~ aorophe~yl)-~-axocyclohexa~e-2~ - carbc~ile, 5 pa~t~ of (B)-et}~yl 3-~thyl~4-pherLyl~4-plperidi~e-carb~xylate, 3 uarts of ~odiu~ aoeta~:e ai~d 160 parts of etharLol. l'he whole i~ ~yd~oge2~Lted at ~Lormal pre~-~ure a~d at 50~C with 2 pa-ts of paLladiu~-~ charcoal cataly~ 10%. Af~e~ the calc~1ated amou;cLt of hydrogesL i~ takea:L up, the cataly~t i~ filtered ai~ a:~Ld ~e filt~ate 30 i5 e~aporated. T~e residue i-~ pur~ ~ed by column-chromato~-2phy over sili.-a gel U~iDg a mi ~ture o~ tric~loro~2etharLe a~d ~etha~ol (98:2 by ~olu~e) as elue~t. T~e pure s-actio~ are collect~d arLd the elue~t is e~aporated. T~e residue is crysta1l;ze~ fr.on~ 2,2'-oxybis-propa~e, yieldillg 3.3 pa~ts (37%) of (Bc-B~)-ethyll-/~-cya~o-'-(4-87~3~V
fluor~phenyl)cyclohexy37_3-methyl-4-phërlyi-4-piperidi~ecarb~ late:
~p. 133.3C.
To 1 pa~t o a qolu~do~ of 2 parta of thiophe~e i~ ~ p~rts of ~a~ol ar~ added d. ~L parts o~ 1 -(4-1uoro~henyl)-4-oxocyclo-5 hexaDes:arbo~tr~le, S par~ of (A)-ethyl 3-~net~yl-4-p~e~yl-4-piperidi~ecarb~rlate a~d 160 parts of e~ha~ol. Tne whole is hydro~e~ted at nor~al pres~ure~a~d at 50C ~th 2 parts of palladiu~ charcoal catalyst 10%. Ater tho calculated amo~t of hydroge~ is taXe~ up, the ca~aly~t is ~:~tered of~ a~d t~e filtrate 10 i~ e~raporated. The residue ii crystallized ~rom acetorLitrile, rieIding 2. 6 part~ (28%) of (Bc-Ap)-~hy~ cya~Lo-4 ( ~uarophenyl)cyclohexy~;7-3 -~ethyl -4-phe~1-4-~iperidinecarbo~ylate;
rr~p. 125. 9~G.
Exam~le XXIlI ..
To 1 part o~ a solutio~ of 2 parts of thiopherLe in 10 parts o~
ethanol are added 4. 4 parts of 1-(4-fluorophenyl)-4-oxocyclohe~xane-carborLitrile, 4 partq of 4-phenyl-4-piperidiDecarboxa~nide a d 120 parts of methanol. The whole is hydroger~ated at rlormal pre~sure and at 50C with 2 parts of palladi~m-or~-charcoal catalyst 10%. After the 20 calculated a~nou~t of hydrogen is taken up; the cataLyst i~ fil~ered off and the filtrate is e~aporated. The re~idue is purified by col~-chromatography o~rer ~ilica gel:
Elutio~ ~with a mixture of trichloromethane and metha~ol (99:1 by trolum~) yields the A-isos~er which i9 cry~tallized from 2, 2'-oxybis-25 propa~e. The product ii filtered off a~d recrystallized from etha~ol~yield~g 0. 5 parts (6~) of (A) 1 -~-cya~o-4-(4-fluorophe~yl)cyclo-hexy~7-4-phenyl-4-piperidi~ecarboxamide; mp. 171. ~ ic~
Elution with a mixture of trichlorometha~e and metha~ol (97:3 by ~rollLme) yields the B-i omer which i9 crystallized from 2, 2'~oxybis-30 propane. The product is filtered off a~d recrystallized from ~thanol,yieldirLg 1 part (12%) of (B)~ cya.o-~-(4-f1uorophenyl)cyclohe~Yy'.7-4 phe~yl-4-piperidinecarboxamide; mp. 243. 1 ~C.
37~ JAB 326 A mixture o~ 4. 3 parts of 1 -t4-fluorophenyl)-4-oxocyclohexa~e-carbo~i~rile, 5, 3 pa-t~ of 4~ chlorop'nenyl)-i~, N-dim~thyl-l-piperi-di~ecarbox~mide a~d zoa parts of methanol is hydrogenated at normal press~Lre a~d a~ 50~(~ ~ith 2 par~s of platinurrl-on-charcoal catalyst ;%
~fter the calculated amount of hydroge~ i taken up, the catalyst i5 filtered off arld the filtrate is evapora~ed. The residue is purified by columr~-chromatography o~rer 3ili~a gel U9iD.g a mixt~e of trichloro-methane and methanol (99:1 by volu~e) as eluent. The pure fractio~c~
are collected and the eluent i~3 e~aporated. Tne resldue i3 crystallized from a m xture of 2-propanol and 2, 2'-oxybispropa~e. The product is filtered off (tne mother liquor i~ set aside) and dried, yield~g 2 pa~ts of (A + B)-4-(4-chlorophenyl)-1-~-cyano-4-(4-fluorop'nenyl)cyclo-hexy~7~N, N-dimethyl-4-piperidirLecarboxamide; mp. 1 8a. 4''C.
From the mother liquor ~see abo~e), a~other fraction is crystallized, yielding 1. 5 parts of (A)-4-(4-chloropherLyl)~ cyano-4-(4-fluoro-phe~yl)cyclohexy~ , N-dimethyl-4-piperidirlecarboxamide; mp.
212. 2C.
Example XXV
To i part cf a sc~lutio~ o 2. par~ o thiophene ~ 40 parts of et~anol are added 1 . 2: parts of 1 -(Js -~luorophenyl) -~ -oxocyclohe~:ane -carbc~t~ile, Z parts of (A)-e~Lyl 3-~ethyl-4-(4-methoxyphe~yl)- -pipe~id~ecar'oaxylate ethar~edioate (1:1), 2 part~ o:~ socliu~ acetat2 a3ld 120 parts of etha~ol. Th~ whole is b,ydroge~ted at ~ormal press~r~ and zt ~oam ter~peratlare wi~ Z pi~rts of palladium-an-charcoal catalyst lO~o. After t~e c~lculated amou~t o~ h~droge~ i~
take~ up, the ca1:alyst iR ~ilt~red off o~re~ lo a~d washed with acetic acid. T~e i~trate is evapo~:ated. Fror~ Le residue., '~e free ba3e is li~erate~ ~ the con~e~t~o~ ~er with a~s~mo~ hydro~de and extracted wi* dioblor.omet~a~e. The extract is ~ried, filtered aDd e~aporated. Th~ re~idue is pu~ii~ied ~y colum~-chromatogr~phy o~er ~ilica gel U3:Lllg a mixture 2~ t::ichloromethane a~Ld ~thar~ol (98:2 by ~rolume) a3 eluent. l~e pure f.actioD.s are collected ~ud the elue~t i9 , _..
37~ AB 326 e~aporated. l~he re~idue is co~Yerted into the hydrochlor~te salt i~
-ethanol a~d 2-propanol. The salt is filtered off a~d dried, yieldi~g 0. 6 parts (21, 6%) ~f (Bc-Ap)-etllyl 1-~4-cyano_~-(4-~luo~ophe;lyl)-cyclohexy~ (4-methoxyphenyl)-3-methyl~4~pipe~idinecarboxylate . 5 monohydrochloride; mp'. Z40. 9~C.
To 1. part of a ~olul:io~ of 2 parta of thiophe~e i~ 40 parts of etha~ol a~e added 13 pa.r1:a of 1-( -iluorophe~yl)-4-oxocyclohexa~e-c~rbon~tril~, 18.4 }?arts of (A)-phe~ylmet~yl 3-methyl-4-phe~yl-4-piperidir~ecarbo:~late a~d 200 part3 ~f Z-propa~ol. The whole i~
10 ~:Lyd~og~ated a~ r~or~l pre 3ure a~d at ;0G with 2 part~ of pla~n~-oD~-charcoal cataly~t 5~. After t~ calculal:ed a~o~t of hydroge~
is take~ up, ~e catalyst i~ flltered off arLd the f~ ratP i~ e~raporate~.
T:he resi~ue i5 purified by colu~-ch~o~tography over 5ilica gel u~g a ~re o t~ich~or~met~L3:~e a2~d met}~a~ol (9~:2 by ~rolu~ne) 15 a~ elue~t. The ~ir~t fractio~ is collected a~ e elue~t is evaporated.
From the ~e~idue, t~o Ac-Ap f~actio~ separated by HPI.C Usi::Lg a r~i~re of ~ e, triehlo~omet~ane all~ metha~ol (1Q0:100:0.;
by ~olume) a3 eluer~t. T~Le pu:re f~ac~oa. i~ collected a~d the elue:~t i~ e~aporated, yield~g 1. 5 par~ (5~) of (Ac-Ap)- (phe~yl~ethyl) zo 1-~ cyaao-4-(4-fluorophe~yl)cyclohexyy-3-methyl-4-phe~yl~
pip~:~idine~arboxylate .
_ . _ _ _ _ ...~ . . .. .. .. .. . .. .
To 1 ~art o~ a s~lutio3~ of 2 ~7arts o thiophe~:Le i::~ 40 parl:s of et~a~ol a~e a~d2d 3.; parts of 1-(4-~uo2opheD.yl)-4-oxocyclo~
hexa3~0ca~0~t:rile, 6 pa:rts of (:13) (ph~y~ethyl) 4-(2-fluorop~
2.~ 3~methyl-4^piperidi~eo~rb~ Lte hydrochlo~i~e, 4 ~rts of pc~ta3~ium ace~te a~d 160 part~ of 2 propa~ol. lrhie whole i~ hydroge~Lat~d at rlormal pre~sure a~d at 50aC ~t}:L 2 parta of plati~ ch rcoal cataly~t 5%. A~ter t~e calc~lated amou:~t of hyd~ogerL is tak~ up, t~e caSalyst i~ filtered o~f a~d the ~ ate i~ e~raporated. T~e residu* is 30 ~ke~- up in trichloromet~e. T~ ~att2r i~ washed with wat2r ~o . rercLo~e t~e icsrgaric material. The orga~ic pha3~ iS dried, i~ltered a~d e~p~rated. 1~0 reqidue i~ purii~ied by colum~ chroma..ography o~r ~ilica gel ux~g a ~x~ure o~ tric~loromet~a~e a~d ~retha~:Lol JA~ 326 ~ 7~
(98:2 by ~olume) as eluerLt. The pure fraction3 are collected and the eluent i~ e~raporated. The E~c-Bp-fraction i~ sepa~ated by E~PLC usin~
a mixh~re of t:richloromethane, he~ane a~ld methanol (100:100:0. 5 by volurne). T}~e pure fraction i9 collected a~ld the eluert is e~aporated.
S The rPsidue is co~ rert~d i~to the hydrochloride salt in 2-propa~ol.
Th~ salt i~ filtered off ar~d dried, yieldi~g ~. 4 part~ o~ (Bc-Bp)-(pheuylmethyl) 1-L~4-cya~o 4-(4-fluorophenyl)c:yclohexy~
(2-fluorophenyl)_3_methyl 4-piperid~rLeca-b~xylate ~onohydrochloride;
mp. 239. 4C.
To 1 part Qf a sc~lutio~L of 2 part~ of thiophe~e ~:L 40 pa~t~
of etha~cl are ad~ed 13 part~ of 1-( - uoropherLyl)~ xocyclo-hexa~ecarl~o~it~ile, 18 . ~ part3 of (A) -phe~yl~L~t~Lyl ~ -r~ethyl -~ -phe~yl 4 -pipe rid~Le cas~oxylate a~d 1 6Q part~ o~ 2 -I?ropa:~ol . l~e whole is h~rdroge~ated a~ normal pre~sure a~d at 501C wlt~ 2 parts 15 of pla~u~-o~ s:~arc~al cataly~t 5%. Ater t~le calculate~ arnou;:Lt of hy~roge~ is ta:XesL up, t~se ta~lyst ~s ~iltered of~ a3ld the filtr3te is e~aporated. T~e resi~ue i9 p~ri~ed by col~-chror~ta~;aphy o~rer ~ilica gel usi:~g a rr~ ure of t~ichlororcLet{~ans ar~d ~ethanol (~8:2 by Yolu~ne) a~ eluerLt. I~e pu~e Bc Ap ~act~o~ is collected and t}~e 20 oluent i~ e~rap4rated. The re~idue is corL~7arted iDto the hydroc~loride Jalt i~L 2~propa~ol. l~e salt is f~ltered of~ a~:Ld dried, yieldi~ 8.
part o~ (Bc~Ap)-p}:~e~Lyl~ethyl l-~-cya~o~4-( ~1uorophe~yl)-cyclohexy,~7-3~ Let~yl~4-p~e~yl 4-piperidinecarbo~ylate r:~orLohy~ro-chlo~ido; ~p . . 2~3 . 6 C .
: To 1 pa~t o~ a iolut~o~. of ~. part~ of t~iopheD.e irL 40 part~
of et}lanol are a~ed 6. 6 ~art~ of 1-(4-fluorop}~e~yl)-4 a~ocyclo-hexa~ecarb~::Litrile, 10. 5 part3 of (B)-phe:r~yl~ethyl 3-~ethyl-4-pheD.yl-4-pip~ri~ caxboxylate hydrocl:Llo~de, 6 parts of pota~siu~
acet~te a~ld 200 ~a~t~ of 2-propa~ol. I~e whole is hydroge3~ted at ~o~mal p~essure a~d at 50~G with 4 parts o~ plal:i~usn-~n-charcoal cataly~t 5% . After t~e calculated. amou~t o~ ~Lydroge~ i.c taXe~ u~, the catalyst i3 t~ltered o~ arLd washed wi~h acetic acid. r~e ~iltrate is e~rapora~ed a~d the residu~ is take~ up in water. The whole is alkalized with 30dium hydro~ide arLd the protuct is ext~acted with trichlorometha~e. The extract ii ~,va hed with water, dried, filtered a~d c~rapoYated. The residue i~ pur~tied by colu~ chromatography 5 o~rer ilica gel us~g a rnixture of trichlorometha~Le a~d metha~ol (98:2 by volurne) ai eluer~t. The pure fraction~ are collected and the elueQt is evaporated. Fror~ the re3idua, the Ac-Bp-fraction ls separated by HPLC us~g a mix~ure of he~ane, trichloromethane and metha~ol (100:100:0. 5 by volume) a~ elue~t. The pure fraction i9 10 collected and the elue~t is evaporated~, yieldirLg 0. 8 parts (5~) of (Ac-Bp)-phenylmethyl l_L4_cyaIlo-4_(4_fluorophe~yl)cyclohex~
3 -methyl-4-pheD.yl-4-piperidlnecarbo~ylal:e kL a qinQilar maD~er there are also prepared:
(Bc-Bp)-ohenylmethyl l-~-cyano-4-(4-flllorophenyl)cyclo-lo hexy~7-3-methyl-4-phe~yl-4-piperidinecarboxylate; mp. 131C;
( ~c -Bp)-phenylmethyl 1 . ~4-cyano-~-(4 fluoropherlyl)cyclo hexy~7-4-(2 fluorophenyl)-3-methyl-4-piperidinecarboxylate;
(Bc-Ap)( )-pheuylmethyl . l-~-cyallo-4.-(4-fluorophe~yl)-cyclohexy~7-4 -(2 -fluorophe~yl) -3 ~methyl-4 -piperidinecarboxylate ZO monohydrochloride; mp. 213. ~1 C;
(Ac-Ap~ ( ~ )-pllenylmethyl 1 -~4 -cya~o-4-(4-fluorophe~yl)cyclo-hexy~7-4-~2-fluorophe~yl)-3 methyl-4-piperidi~ecarb~xylate;
(B c -B p) (~) -phenylme ~hyl 1 -L4 cya~lo - - (4 ~Iuor ophenyl) cycl o -hexy~7-3-methyl-4-phenyl-4-piperid~eca~bo~yLate; ~d (Bc-Bp) (-)-phenylmethyl 1 ~4-cyano 4-(4-fluorophe~yl)cyclo-hexy~7~3 -methyl-4-phe~yl~^pipe ridinecarb~xylate.
ExamE~.. X~I
A ~:Li~e a 10. 9 pa~ts o~ e~yl l~ c~ o~-(4~ftuo~o-cycloh~ 4~ pipe~di~c~-b~la~P, 11 . 2 pa~t3 30 o p~ ~ hyd~txcide, 50 pa~t~ of ~ater a~Ld 96 p~rt~ o~ Z~propa:rlol a ~i~red;. a~ ~e~ e~d fo~ 4 hc~a. l~ Cti~ 3 ~il~red hot o~v~r~y~o a~ t~e ~t~at~ i~ poused o~o 300 pa:ct~ ~ ~te~ e ~le ~ sLe~l~ acetic acs~ to p~ 6~7. Th~ p~cipitate~
:
J~ 326 3'7~
pro~uc~ ilter~d o~ hed ~:hr~e tim~ ~th water arL~ co~e~t2d iSLto t~ roc~lo~de ~alt i~;gt~ L ~:Ld; 2-pr~pæLol l~e- salt i3 ~ltcrcd ~ d su~pe~de~ i:CL a ~alu.tio~ ~f 1. 4 pa~t~ o~ pota9~iu~
~rd~ e ~n l iO pa~ c~ ~ate2 . T~:Le f~e~ ba~e i~ ~x~ac~ ~ur 5 t~ wi~ 70 ~a~t~ o~ I t 1 I-~xy~ise~ha~e. ~he ac~,ue~us phase is 3~pa~ate.. ~d ~i:ir2e~ or a w~ile c~3: a r~.vap~r to ~emo~e all t~aceq ~ la l'~ e~e, lrh~ ~ear aq~,ueous phase i~ a idi~ed ~ a 10%
ac~tic ac~d ~al~ti~ to p~ 6. ~L~ p~ecioitat~s~ pro~uc~ ilt~r~d off, edws~a~ a~tdriedo~roaghtatabc~u~105~e, y~eld~3g 5.4 past3 (66. ~1%) a I -~-cyar:o-4~(4-1uorophe~yl)cycioheæy~ phe~yl-~-pipe~di~ec~rb~ acid; r~p. 231~1Co .. .. . .. .. .
FoLlowi:~g the same procedure there a:re also prepa~ed:
~N~ z . . 1 Ba ~ e/Salt I
Ar Ar . R ~o~ ¦ mp. ~ C
, , ... __ ~
4 - F -C 6H4 ~ 6H~ - ~ - HCl I ~3 0 0 4-F C6H4 3-Cl-C6~4 . H H:Cl.H20 284. 7 4-F~6H4 4-F-C6H4 HHCl 1/2H~0 2~1.2 2 -C~3 -G6~4 ~ 6K~ H HCl ~3 00 4_~ C 6~ 2 ~0~ 3 -~ 6~4 ~ ~Cl . ~2 2~1 . 8 4-F -C 6}~1 ~ OCH3 C: 6~4 ~ }iCl . ~ - - 2 81 . 8 4 - F -C 6E~,L 2 - F -C ~ :~ EI ElCI +3 o O
.
Eam21e XXV~I
A~xtuse of 1.2.part~ of (B~-phe~yk:~thyl 1-L~-~ya~o-4-1 5 (4 ~ i!1uor ophenyl )cycl ohexy~7~ 3 ~ met~yl ~ - j?h ezyl --4 -pi~e ridi~ecarbo -xylate in 80 pa~t3 ot 2-propaELol i~ hydro~e~:Lated at D.ormal pres~u~e JA~3 3 2 6 l~t7a~8~
~6 ~:Ld a~ room temperature wit~ 1 part of palladium-a~-charcoal c~talr3t 10% . A~er the calculated a~ou3~t of hydroge~ is taken up, ther~ i~ added a p<~ siu~ hydro~id~ solu~io~ e precipi~ate~l pro~uc~ e~t~r~ ~olu~io~.. T:he c~talyst i iltered of a~d the 2-propa201 5 i~ e~Japoratod. I~e agueou3 pha~e i~ washed w~th 2,2'-oxgbispropa~e aD.d ~eut~aliz~d wit~ a 10~ aceSic acid 3alui:ion. T~ preclpil:ated pro~uct is i~iltered of E a~d converted i:~to the hydroc:hloride salt in 2-propa~ol. The erude salt is orys1alllzed from e~anol, yieldi:;~g O. 8 part3 (73%) of (Bc-Bp~ r-cya~o-~ (4-iluorophexLyi)cyclohexy~7-1 0 3 -me~yl-4 -phe~yl-4-pip~rid~ecarb~xylic acid rnorlohydrochloride;
3 0 0 " ~
.. .. .... _ . , .
A ~x~are of 0. 8 partQ o~ (Ao~8p)-phe~yl~e~yl 1-~-c~a~o~4~(4-iluorophenyl)cyclohexy~ 3-~e~yl-4~phenyl-~-piperi-di~ecarba~ylate a~d 90 ~a~ts of tetrahydro~ura~ i~ hy~rogenated at 15 rLcrmal pres~ure a~ at ro~ temperatZ~re wl~ 1 part of palladiu~n-o~-c~arcoal ca~lyst 107~. Af~er. t~e calculate~ amou~t of hydroge~ -is takeu up, the ca~aly t i~ f;ltered off a~d the ~lt~ate i~ e~raporated.
The re~idue is con~rerte i~to the hydroc}Lloride ~alt i~ e~LarLOl a~Ld 2, 2'-~xybi~propaIle. T~ salt iq i!~ltered o:~ and dried, yieldi~ 0. 5 20 }?a~t~ (68q~) o~ (Ac-Bp)~ cyar~o-4-(4~ orophe:rsyl)cyclohe.Y~
3~met~yl~-phenyl-4-piperid~ecarbo~lic acid monohydrochloride;
~p.. 209,2C.
A ~x~e QI 3 . 4 par~ of (Bc-Bp~-(p~e:~:Lyl~ne~ayl) 1~4-cya3:Lo-4 - ~4 -1uorophe~L~l)cyclohe~y~7-4 -(2 ~fluoropherlyl) -3 -~ethyl -4-piperidinecar~cylate a2ld 135 pa~ts o~ totrahrdro~uraIl i s hydro-~ena~ed at ~or:~al press~re a~d at roo~ tempera~re with 2 part~
of palladium-o~-charcoal ca~Lly3~ 10%. A~ter the calculate~ amou~t of hydrogen is ~ken up, ~e caLtalyst is .4;ltered oi~f a:nd washed with rnet3:1anol saturated wi~ a~orLia. The ~lt:ra~ i9 e~raporated a2ld the residue i~ ~Lk~sL up ~:n a ~Qi~re or pc~ si~ ~ydrox:id~ a~d water.
The w~ole i~ he~ wl~ ~ic~loros~e~a~e. Ihe al}cali:~le aqueous ;.
JAB ~2~
~8~7~
ph~3e i~ u~ d with a;3~ ac ~tic acid ~alutiol:L 10%. T~e predpit~Lted produc~ i9 i~iltered o~, wa3he~ with water, d~i~d and co~orted ~to the hydrochlorite salt in methanol. The ~alt ~ ;iltered ofs and dried, ~seldiDg 2 pa~ts t66%) of (~3c-Bp)~ cya~o-4-5 ( ~fluorophenyl)c:yclohe~ 4-(2-fluorophe~yl~-3~methyl-4-pi~er~-- di~ecarbo~ylic acid monQhr~roc lor~e; mp. 300. 6C.
A ~:ure of 7 part:s of (Bc-Ap?-phenylmethyl l-ç~-cya~o-4-(4-Luorophe~yl~ cyclohexy~7-3-~e~yl~4-phe~yl-d~piperidi~ecar-boxyla~e a~Ld 2, O parts of tet~ahydrofs~ra:~. is hydsoge~a~e . a~ ;Lormal 1 0 pre 8 sure aD.d at room t mperatur~ 2 parts of palladiurn~ -char -- coal cataly~t 10%. After ~:Le calculate~ a~:Lo~t of hydrogerl is take~
up, the catalsr3t i~ filtered o~ a:~d t~e f;lt:rate i9 e~raporated. T~e re~idue i~ corlverte~ iIltO the ~rydrochloride 3alt irL a mi:~bure OI
D:~0th~0l and 2,2'-~xy isp~opan~ e ~alt is ~lltered o~f a~d dried, yieldin3 1 pa~t (16~) of (}3c-Ap)~ cya~ (4-Luorophenyl)-cyclohexy~ -3 -~ethg~l -4 -ph~yl -4 -pipe ridiD.ecar~c~xylic ac~ d mo~o -hydroc~Ade mo~lohydrate; mp. 291. 8"C.
A r~t~re of l. 5 partJ of (AG-~P)-(Phe~Y~thY1) 1-C~-cya2lo-4-(4~1uorophe2Lyl)cycloh~y~7-3-methyl~4-~?heYlyl- pip~ridi:~e-~ ca~rbo?~ylato a~ad 9~ parts of tetrahydrofura~ hydrogeDated at ~orD~al pre~ure a~d at roo~:L t~mperatllre w~ 1 part o pallad~
orL-chareoal cataly~t 10%. A~te~ calculated a2aou~l~ o~ hydroge~ is ta~ce~ up, th~ catalyst i~ iltered of~ and t~e filt~at~ is e~rapc~rated.
The .. e ~iduc i~ ce~ up ~ wate r arLd po~.tas ~ ydrox~de . The whole ~5 ~ hed wit~2; ~io~:~oro~etha~e. ~e alkali~e aq.ueous ~sha e is ~euts~alized wsth a~ acetic acid solut:io~ 10%. The precipit2Lted product i~ i~l:er~d oi~:,. wa3hed with ~rater, ~`ec~ a3~,d co~verted ~to :he hyd~o-ch;loride ~alt ~ met~ ol and 2,2'-~Jbi~pr~ e, y~eldi~g 0. 6 pa.t~
(42%) of (Ac-~p)~ cyans-4-(4-~luoropheD.yl)cyclo~exy,~-3-met~yl-30 4-phe~yl 4-pipe~idi~ecarbo~:ylic acid ~o~ohydrochlo$ide mo~o-hydrate; mp. 2 61 . 6 C; .
8~ -A mixture of 0, 9 parts o~ (Ac~Bp)-phe~ylmethyl l-.~-cya~
4-(4 fluorophenyl)cyclohe~Yy~ -4 (~-~uorophenyL) 3-nnethyL-~-piperi-di~ecarboxylate a~d 90 parts of tetrahydrofuran is hydrogenated at ~or~al pre3sure a~d ~t room tempera~ure with 1 part of paLladium-on-5 charcoal catalyst lO~O,~After the calculated amou~t of hydroges~ i~ takenup, the catalyst i8 filtered of and washed with mathanol ~ah~rated with ammonia, The fil~rate i~ evap~rated a~d the residue i3 taken up i~ a mixture of water and pota33it}m hy~roxide. The whole is washed with trichlorcmetharLe. The al};ali~e aqueou~ phase is neutralized with an 10 ace~ic acid.solutio~. 10%, The precipitated product i~ filtered off a~d converted iD.to the hydrochloride salt in me~char~ol a~d 2, 2'-oxybis-propa~e. The salt is filtered off a~d d~ed~ yieldi~g 0. 3 part~ (3~%) of (Ac-Bp)~ cyano-4-(4_fluoropherlyl)cyclohexyl7^4-(2-fluoro-phenyl) 3-met}~5rL-4~pip~ridinecarboxyiic acid monohyd2ochloride moz~ohydrate; mp. 242. 2-244. 4C.
Example XXVII:L - -~ ~ A mixture of 0. 7 parts o~,i(Ac-Apj (;~)-phe~ylmethyl l -~4-cyano 4-(4 fluoropher~yl)cyclohe~ 7 4-(2-~1uorophe~yl)-3-cnethyl-4-piperidi~ecarbaxyLa~2 a:nd 90 par~s o~ tetrahydrofu~a:l is hydro~erLated at ~ormal pressure aud at ro~m tempera~ure with 1 patt of palladium-o~charcoaL catalyst 10%, After the calculated amount of hydroge~ i~
taken up, the cataly~t iq filtered off. The filt~r-cake is washed with ~etha~ol ~aturated with ammo:nia, and the filt~ate i3 evaporated. The regitUe i9 tak~rL up i~ water a4d pota~sium hydroxide. The whole i3 waahed with trichlorome:ha~e. The alkal3ne agueous phase i9 neutra-llzed with a:ll acetic acid solution 10%. ~he precipitated product i9 filtered off, washed with water, dried and converted i~to the hydro-chloride ~alt i~ metha~ol and 2, 2'-oxybispropane. The salt is filtered off and d~ied, yieldiIl~ 0. 3 part~ (a9~,) Of (Ac-Ap) ( )~ cyano~-(4-fluorophenyl)cyclohexy.l7-4-(Z~fluorophenyl)-3_r3ethyl-4-piperidine-c arb oxylic acid monohydr oc~l oride; mpO 28 2. 7 G .
Ia a similar ~na~er th~re i also prepared:
(Bc-Ap) (~ 4-cyauo-4-(a-fluorophenyl)cyclohexy~7-4-(~-fluorophenyl)-3-methyl-4-piperidi~ecarboxylic acid monohydro-chloride, mp. 288. 8C.
~.....
J~ 32 ~87 Exasn~le XXIX
~ m~YtLLre o~ 4 parts of (Bc-Bp) (-)-pheuylme :hyl 1 -~-cyano-4-(4-fluorophenyl)cyclohe.Yy~7-3 ~methyl-4-pherLyl-4_piperidi~ecar-bo~rlate a~d 225 par~ts of t~trahydrofura~ i~ hydroge~ated at normzl S pres~lre and at room temperature with 2 parts of palladium-on-charcoal catalyst 10%, Afte~ the calculated amou~ of hydroge~ i5 taker~. up, the cat~ly~t i3 filtered of~ a~d wa~hed ~nth metha~ol sa~urated with ammonia. The filtrate is e~raporated. The re~idue is co~verted into the hydrochloride jalt i~ methakoL The salt is filtered off and dried, yield~g 3 partq (82%) of (Bc-Bp)O(~ 4-cyano- -(4-fluoro-phenyl)cyclohexy~7-3-methyl-4-phenyl~-piperidi~eca~boxylic acid ~nonohydrochlor;de; mp. 298. 1 C
ID a ~imilar ma~er there is also prepared:
(Bc-Bp)~ cyano-4-(4-fluorophenyl)cyclohe.Yy~7-3-15 methyl-4-phe~yl-4-piperidinecarboxylic acid monohydrochloride;
~p. 29 ~. 9 ~ C :
Claims (8)
- claim 1 continued (V) with a compound of the formula (III) wherein W represents an appropriate leaving group said N-alkylation reaction being conducted in an inert organic solvent selected from an aromatic hydrocarbon, a lower alkanol, a ketone, an ether, N,N-dimethylformamide or nitrobenzene, in the presence of an appropriate base at ele-vated temperatures, or c) a compound of the formula (I-a) may be hydrolyzed from a compound of the formula (I-b) said hydrolysis reaction being carried out by stirring a compound of formula (I-b) in aqueous alkaline or acidic medium, or in the instance wherein Ra represents a phenyl-methoxy radical the hydrolysis may be replaced by hydro-genolysis-procedures, as by catalytically hydrogenating the starting compound (I-b) in the presence of an appro-priate catalyst selected from palladium-on-charcoal or platinum-on-charcoal, or d) converting the compounds of formula (I-a) into the corresponding compounds of formula (I-b) following esteri-fication- or amidation procedures, the esterification- or amidation reaction being carried out by stirring and heating the starting acid (I-a) with an appropriate alcohol or amine in a suitable reaction-inert organic solvent at the reflux temperature of the reaction mixture under azeotropic removal of the water which is formed during the course of the reaction or alternatively previously converting the carboxylic acid function into the corresponding acid halide function and subsequently reacting the thus obtained acid halide with an appropriate alcohol or amine and, if desired, the compounds of formula (I) may be converted to the therapeutically active non-toxic acid addition salt form by treatment with an appropriate acid and, further, if desired, preparing stereochemically iso-meric forms of compound (I).
- 2. A process for preparing a chemical compound selected from the group consisting of 1-[4-cyano-4-(4-fluorophenyl) cyclohexyl]-3-methyl-4-phenyl-4-piperidinecarboxylic acid, the pharmaceutically acceptable acid addition salts and stereochemically isomeric forms thereof, characterized by hydrogenating phenylmethyl 1-[4-cyano-4-(4-fluorophenyl) cyclohexyl]-4-(2-phenyl)-3-methyl-4-piperidinecar-boxylate in the presence of palladium-on-charcoal catalyst, and, if desired, preparing pharmaceutically acceptable acid addition salts of stereochemical isomeric forms thereof.
- 3. A process for preparing a chemical compound having the formula (IV) the pharmaceutically acceptable acid addition salts and stereo-chemically isomeric forms thereof, wherein:
R is a member selected from the group consisting of hydrogen and lower alkyl;
R is a member selected from the group consisting of hydroxy, lower alkyloxy, aryllower alkyloxy, aryloxylower alkyloxy, lower alkyloxylower alkyloxy, aminolower alkyloxy, mono- and di(lower alkyl)amino lower alkyloxy, (1-pyrrolidinyl)-, (1-piperidinyl)- and (4-morpholinyl)lower alkyloxy, amino, aryllower alkylamino, mono-and di(lower alkyl)amino, 1-pyrrolidinyl, 1-piperidinyl and 4-morpho-linyl; and Ar1 and Ar2 are each independently selected from the group consisting of aryl, thienyl and pyridinyl;
wherein aryl, as used in the definitions of R, Ar1 and Ar2, is a member selected from the group consisting of phenyl and substituted phenyl, said substituted phenyl having from 1 to 3 substituents each independently selected from the group consisting of lower alkyl, lower alkyloxy, halo, nitro, amino, cyano, carbonyl, lower alkyloxycarbonyl, mono-and di(lower alkyl)aminocarbonyl and trifluoromethyl, characterized by reacting a compound of the formula (II) with a compound of the formula (III) the enamine formation reaction being carried out by stirring the reactants together in the presence of a catalytic amount of a relatively strong acid in a suitable reaction-inert organic solvent at the reflux temperature of the reaction mixture. - 4. A chemical compound having the formula (I) , the pharmaceutically acceptable acid addition salts and stereo-chemically isomeric forms thereof, wherein:
R1 is a member selected from the group consisting of hydrogen and lower alkyl;
R is a member selected from the group consisting of hydroxy, lower alkyloxy, aryllower alkyloxy, aryloxylower alkyloxy, lower alkyloxylower alkyloxy, aminolower alkyloxy, mono- and di(lower alkyl)amino lower alkyloxy, (1-pyrrolidinyl)-, (1-piperidinyl)- and (4-morpholinyl)lower alkyloxy, amino, aryllower alkyl amino, mono-and di(lower alkyl)amino, 1-pyrrolidinyl, 1-piperidinyl and 4-morpho-linyl; and Ar1 and Ar2 are each independently selected from the group consisting of aryl, thienyl and pyridinyl;
wherein aryl, as used in the definitions of R, Ar1 and Ar2, is a membere selected from the group consisting of phenyl and substituted phenyl, said substituted phenyl having from l to 3 substituents each independently selected from the group consisting of lower alkyl, lower alkyloxy, halo, nitro, amino, cyano, carboxyl, lower alkyloxycarbonyl, mono- and di(lower alkyl)aminocarbonyl and trifluoromethyl whenever prepared or produced by the process of claim 1 or by any obvious chemical equivalent thereof. - 5. A chemical compound selected from the group consisting of 1-[4-cyano-4-(4-fluorophenlyl)cyclohexyl]-3-methyl-4-phenyl-4-piperi-dinecarboxylic acid, the pharmaceutically acceptable acid addition salts and stereochemically isometric forms thereof whenever prepared or produced by the process of claim 2 or by any obvious chemical equivalent thereof.
- 6. A chemical compound having the formula (IV) , the pharmaceutically acceptable acid addition salts and stereo-chemically isomeric forms thereof, wherein:
R1 is a member selected from the group consisting of hydrogen and lower alkyl:
R is a member selected from the group consisting of hydroxy, lower alkyloxy, aryllower alkyloxy, aryloxylower alkyloxy, lower alkyloxylower alkyloxy, aminolower alkyloxy, mono- and di(lower alkyl)amino lower alkyloxy, (1-pyrrolidinyl)-, (1-piperidinyl)- and (4-morpholinyl)lower alkyloxy, amino, aryllower alkylamino, mono-and di(lower alkyl)amino, 1-pyrrolidinyl, 1-piperidinyl and 4-morpho-linyl; and Ar1 and Ar2 are each independently selected from the group consisting of aryl, thienyl and pyridinyl;
wherein aryl, as used in the definitions of R, Ar1 and Ar2, is a member selected from the group consisting of phenyl and substituted phenyl, said substituted phenyl having from 1 to 3 substituents each independently selected from the group consisting of lower alkyl, lower alkyloxy, halo, nitro, amino, cyano, carboxyl, lower alkyloxycarbonyl, mono- and di(lower alkyl)aminocarbonyl and, trifluoromethyl whenever prepared or produced by the process of claim 3 or by by any obvious chemical equivalent thereof. - 7. A process for preparing a compound of the formula selected from the group consisting of:
(I) AND
(IV) the pharmaceutically acceptable acid addition salts and stereo-chemically isomeric forms thereof, wherein:
R1 is a member selected from the group consisting of hydrogen and lower alkyl;
R is a member selected from the group consisting of hydroxy, lower alkyloxy, aryllower alkyloxy, aryloxylower alkyloxy, lower alkyloxylower alkyloxy, aminolower alkyloxy, mono-and di(lower alkyl)amino lower alkyloxy, (1-pyrrolidinyl)-, (1-piperidinyl)-and (4-morpholinyl)lower alkyloxy, amino, aryllower alkyl amino, mono and di(lower alkyl)amino, 1-pyrrolidinyl, 1-piperidinyl and 4-morpholinyl; and Ar1 and Ar2 are each independently selected from the group consisting of aryl, thienyl and pyridinyl;
wherein aryl, as used in the definitions of R, Ar1 and Ar2, is a membere selected from the group consising of phenyl and substituted phenyl, said substituted phenyl having from 1 to 3 substituents each independently selected from the group consisting of lower alkyl, lower alkyloxy, halo, nitro, amino, cyano, carboxyl, lower alkyloxy carbonyl, mono- and di(lower alkyl)aminocarbonyl and trifluoromethyl, characterized by a) reacting a compound of the formula (II) with a compound of the formula (III) wherein R, R1 and Ar2 are as previously defined, said reaction being carried out by catalytically hydrogenating a stirred and heated mixture of the reactants in a suitable reaction-inert organic solvent under hydrogen atmosphere and in the presence of an appropriate catalyst selected from pall-dium-on-charcoal or platinum-on-charcoal;
or reacting compound (II) with compound (III) to form an enamine of the formula (IV) said enamine formation reaction being carred out by stirring the reactants together in the presence of a cata-lytic amount of a relatively strong acid in a suitable re-action-inert organic solvent and conducted at the relux temperature of the reaction mixture;
or b) reacting a compound of the formula (V) with a compound of the formula (III) wherein W represents an appropriate leaving group said N-alkylation-reaction being conducted in an inert organic solvent selected from an aromatic hydrocarbon, a lower alkanol, a ketone, an ether, N,N-dimethylformamide or nitrobenzene, in the presence of an appropriate base at ele-vated temperatures, or c ) a compound of the formula (I-a) may be hydrolyzed from a compound of the formula (I-b) said hydrolysis reaction being carried out by stirring a compound of formula (I-a) in aqueous alkaline or acidic medium, or in the instance wherein Ra represents a phenyl-methoxy radical the hydrolysis may be replaced by hydro-genolysis-procedures, as by catalytically hydrogenating the starting compound (I-b) in the presence of an appro-priate catalyst selected from palladium-on-charcoal or platinum-on-charcoal, or d) converting the compounds of formula (I-a) into the corresponding compounds of formula (I-b) following esteri-fication- or amidation procedures, the esterification- or amidation reaction being carried out by stirring and heating the starting acid (I-a) with an appropriate alcohol or amine in a suitable reaction-inert organic solvent at the reflux temperature of the reaction mixture under azeotropic removal of the water which is formed during the course of the reaction or alternatively previously converting the carboxylic acid function into the corresponding acid halide function and subsequently reacting the thus obtained acid halide with an appropriate alcohol or amine and, if desired, the compounds of formula (I) may be converted to the therapeutically active non-toxic acid addition salt form by treatment with an appropriate acid and, further, if desired, preparing stereochemically iso-meric forms of compound (I). - 8. A chemical compound having the formula selected from the group consisting of:
(I) AND
the pharmaceutically acceptable acid addition salts and stereo-chemically isomeric forms thereof, wherein:
R1 is a member selected from the group consisting of hydrogen and lower alkyl;
R is a member selected from the group consisting of hydroxy, lower alkyloxy, aryllower alkyloxy, aryloxylower alkyloxy, lower alkyloxylower alkyloxy, aminolower alkyloxy, mono- and di(lower alkyl)amino lower alkyloxy, (1-pyrrolidinyl)-, (1-piperidinyl)- and (4-morpholinyl)lower alkyloxy, amino, aryllower alkyl amino, mono-and di(lower alkyl)amino, 1-pyrrolidinyl, 1-piperidinyl and 4-morpho-linyl; and Ar1 and Ar2 are each independently selected from the group consisting of aryl, thienyl and pyridinyl;
wherein aryl, as used in the definitions of R, Ar1 and Ar2, is a membere selected from the group consising of phenyl and substituted phenyl, said substituted phenyl having 1 to 3 substituents each independently selected from the group consisting of lower alkyl, lower alkyloxy, halo, nitro, amino, cyano, carboxyl, lower alkyloxy carbonyl, mono- and di(lower alkyl)aminocarbonyl and trifluoromethyl whenever prepared or produced by the process of claim 7 or by any obvious chemical equivalent thereof.
1. A process for preparing a chemical compound having the formula (I) , the pharmaceutically acceptable acid addition salts and stereo-chemically isomeric forms thereof, wherein:
R1 is a member selected from the group consisting of hydroxy, lower alkyloxy, aryllower alkyloxy, aryloxylower alkyloxy, lower alkyloxylower alkyloxy, aminolower alkyloxy, mono- and di(lower alkyl)amino lower alkyloxy, (1-pyrrolidinyl)-, (1-piperidinyl)- and (4-morpholinyl)lower alkyloxy, amino, aryllower alkyl amino, mono-and di(lower alkyl)amino, 1-pyrrolidinyl, 1-piperidinyl and 4-morpho-linyl; and Ar1 and Ar2 are each independently selected from the group consisting of aryl, thienyl and pyridinyl;
wherein aryl, as used in the definitions of R, Ar1 and Ar2, is a membere selected from the group consising of phenyl and substituted phenyl, said substituted phenyl having from 1 to 3 substituents each independently selected from the group consisting of lower alkyl, lower alkyloxy, halo, nitro, amino, cyano, carboxyl, lower alkyloxy carbonyl, mono- and di(lower alkyl)aminocarbonyl and trifluoromethyl, characterized by a) reacting a compound of the formula (II) Claim 1 continued with a compound of the formula (III) wherein R, R1 and Ar2 are as previously defined, said reaction being carried out by catalytically hydrogenating a stirred and heated mixture of the reactants in a suitable reaction-inert organic solvent under hydrogen atmosphere and in the presence of an appropriate catalyst selected from palla-dium-on-charcoal or platinum-on-charcoal;
or alternatively compound II may be reacted with compound III and subsequently reducing the enamine of formula (IV) which is formed intermediately, said compound (IV) having the formula (IV) said enamine formation reaction being carried out by stirring the reactants together in the presence of a cata-lytic amount of a relatively strong acid in a suitable reaction-inert organic solvent and conducted at the reflux temperature of the reaction mixture, the reduction of the enamine of formula (IV) being carried out by stirring the enamine (IV) in a suitable solvent in the presence of an appropriate reducing agent at elevated temperatures, or b) reacting a compound of the formula
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US11492480A | 1980-01-24 | 1980-01-24 | |
| US114,924 | 1980-01-24 | ||
| US06/191,631 US4369184A (en) | 1980-01-24 | 1980-09-29 | 1-(Cyclohexyl)-4-aryl-4-piperidinecarboxylic acid derivatives |
| US191,631 | 1994-02-04 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1187080A true CA1187080A (en) | 1985-05-14 |
Family
ID=26812674
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000369180A Expired CA1187080A (en) | 1980-01-24 | 1981-01-23 | 1-(cyclohexyl)-4-aryl-4-piperidine-carboxylic acid derivatives |
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| Country | Link |
|---|---|
| US (1) | US4369184A (en) |
| EP (1) | EP0034415B1 (en) |
| AU (1) | AU538130B2 (en) |
| BG (2) | BG35465A3 (en) |
| CA (1) | CA1187080A (en) |
| CS (1) | CS221818B2 (en) |
| DE (1) | DE3163787D1 (en) |
| DK (1) | DK152670C (en) |
| ES (2) | ES8204421A1 (en) |
| FI (1) | FI76562C (en) |
| GR (1) | GR71898B (en) |
| HK (1) | HK81088A (en) |
| HU (1) | HU183293B (en) |
| IE (1) | IE50706B1 (en) |
| IL (1) | IL61968A (en) |
| LU (1) | LU88220I2 (en) |
| MA (1) | MA19046A1 (en) |
| MY (1) | MY8700593A (en) |
| NL (1) | NL930017I2 (en) |
| NO (1) | NO1994012I1 (en) |
| NZ (1) | NZ196117A (en) |
| PH (1) | PH16611A (en) |
| PL (2) | PL127483B1 (en) |
| SU (1) | SU1230467A3 (en) |
| YU (1) | YU48446B (en) |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| JPS6322584A (en) * | 1986-07-15 | 1988-01-30 | Senjiyu Seiyaku Kk | 1-hydroxy-5-oxo-5h-pyrido(3,2-a)phenoxazine-3-carboxylic acid ester |
| DE4108527A1 (en) * | 1991-03-15 | 1992-09-17 | Basf Ag | NEW 1- (4-CYANO-4-ARYL-CYCLOHEXYL) PIPERAZINE, THEIR PRODUCTION AND USE |
| WO1995025518A1 (en) * | 1994-03-18 | 1995-09-28 | Ciba-Geigy Ag | Aqueous solution of levocabastine for ophthalmic use |
| US5661163A (en) * | 1995-06-07 | 1997-08-26 | Merck & Co., Inc. | Alpha-1a adrenergic receptor antagonists |
| ES2243994T5 (en) | 1996-04-19 | 2009-10-29 | Grifols Inc. | PROCEDURE FOR THE VIRIC INACTIVATION OF LIOFILIZED BLOOD PROTEINS. |
| US6267986B1 (en) | 1999-09-24 | 2001-07-31 | Ranbaxy Laboratories Limited | Process for the preparation of a controlled drug delivery system containing pseudoephedrine and a long acting antihistamine |
| US20020146409A1 (en) * | 2001-01-30 | 2002-10-10 | Herring Steven W. | Methods for stabilizing lyophilized blood proteins |
| DE60333205D1 (en) * | 2002-08-30 | 2010-08-12 | Nycomed Gmbh | HISTAMINIKA FOR THE TREATMENT OF ALLERGIC RHINITIS |
| EP1976513B1 (en) | 2006-01-06 | 2016-08-24 | Sunovion Pharmaceuticals Inc. | Cycloalkylamines as monoamine reuptake inhibitors |
| WO2007143158A2 (en) | 2006-06-01 | 2007-12-13 | Schering-Plough Healthcare Products, Inc. | Sustained release pharmaceutical formulation comprising phenylephrine |
| NZ573174A (en) | 2006-06-01 | 2012-01-12 | Msd Consumer Care Inc | Sustained release pharmaceutical dosage form containing phenylephrine |
| AU2008343045A1 (en) * | 2007-12-21 | 2009-07-09 | Msd Consumer Care, Inc. | Enhancing photostabilization of oxymetazoline |
| PT2780015T (en) | 2011-11-18 | 2017-03-23 | Heptares Therapeutics Ltd | Muscarinic m1 receptor agonists |
| US10259787B2 (en) | 2016-10-14 | 2019-04-16 | Heptares Therapeutics Limited | Substituted cyclohexanes as muscarinic M1 receptor and/or M4 receptor agonists |
| GB201617454D0 (en) | 2016-10-14 | 2016-11-30 | Heptares Therapeutics Limited | Pharmaceutical compounds |
| GB201810239D0 (en) | 2018-06-22 | 2018-08-08 | Heptares Therapeutics Ltd | Pharmaceutical compounds |
| GB201819960D0 (en) | 2018-12-07 | 2019-01-23 | Heptares Therapeutics Ltd | Pharmaceutical compounds |
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| DE1206436B (en) * | 1957-07-05 | 1965-12-09 | Janssen Pharmaceutica Nv | Process for the preparation of derivatives of 2,2-diaryl-4- (4'-phenyl-piperidino) -butyronitriles |
| NL127792C (en) * | 1965-06-29 |
-
1980
- 1980-09-29 US US06/191,631 patent/US4369184A/en not_active Expired - Lifetime
-
1981
- 1981-01-08 GR GR63814A patent/GR71898B/el unknown
- 1981-01-16 AU AU66255/81A patent/AU538130B2/en not_active Expired
- 1981-01-21 CS CS81435A patent/CS221818B2/en unknown
- 1981-01-22 DK DK029381A patent/DK152670C/en not_active IP Right Cessation
- 1981-01-22 MA MA19247A patent/MA19046A1/en unknown
- 1981-01-22 PH PH25120A patent/PH16611A/en unknown
- 1981-01-23 LU LU88220C patent/LU88220I2/xx unknown
- 1981-01-23 FI FI810193A patent/FI76562C/en not_active IP Right Cessation
- 1981-01-23 DE DE8181300313T patent/DE3163787D1/en not_active Expired
- 1981-01-23 IE IE125/81A patent/IE50706B1/en not_active IP Right Cessation
- 1981-01-23 EP EP81300313A patent/EP0034415B1/en not_active Expired
- 1981-01-23 HU HU81148A patent/HU183293B/en unknown
- 1981-01-23 YU YU18381A patent/YU48446B/en unknown
- 1981-01-23 SU SU813233002A patent/SU1230467A3/en active
- 1981-01-23 ES ES498793A patent/ES8204421A1/en not_active Expired
- 1981-01-23 PL PL1981233921A patent/PL127483B1/en unknown
- 1981-01-23 IL IL61968A patent/IL61968A/en not_active IP Right Cessation
- 1981-01-23 PL PL1981229365A patent/PL127679B1/en unknown
- 1981-01-23 BG BG8150518A patent/BG35465A3/en unknown
- 1981-01-23 CA CA000369180A patent/CA1187080A/en not_active Expired
- 1981-01-26 NZ NZ196117A patent/NZ196117A/en unknown
- 1981-12-30 ES ES508441A patent/ES8307219A1/en not_active Expired
-
1987
- 1987-12-30 MY MY593/87A patent/MY8700593A/en unknown
-
1988
- 1988-10-06 HK HK810/88A patent/HK81088A/en not_active IP Right Cessation
-
1993
- 1993-03-02 NL NL930017C patent/NL930017I2/en unknown
- 1993-06-16 BG BG97872A patent/BG60472B2/en unknown
-
1994
- 1994-08-30 NO NO1994012C patent/NO1994012I1/en unknown
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