|Publication number||US2600301 A|
|Publication date||Jun 10, 1952|
|Filing date||Jun 4, 1948|
|Priority date||Jun 4, 1948|
|Publication number||US 2600301 A, US 2600301A, US-A-2600301, US2600301 A, US2600301A|
|Inventors||James F Kerwin, Glenn E Ullyot|
|Original Assignee||Smith Kline French Lab|
|Export Citation||BiBTeX, EndNote, RefMan|
|Patent Citations (4), Referenced by (7), Classifications (5)|
|External Links: USPTO, USPTO Assignment, Espacenet|
Patented June 10, 1952 N- SUBSTITUTED-BETA HALO-ETHYL AMINES James F. Kerwin and Glenn E. Ullyot, Philadelphia, Pa., assignors to Smith, Kline & French of Pennsylvania Laboratories, Philadelphia, Pa., a corporation No Drawing. Application June 4, 1948, Serial N 0. 31,210
This invention relates to certain new chemical compounds, more particularly certain new halogen-containing amines and organic and inorganic salts thereof. The new chemical compounds according to this invention have utility as physiologically active agents and, more particularly, have adrenolytic or sympathicolytic activity.
From the broad standpoint the new compounds according to this invention have the structure shown by the following formula:
A is a member of thegroup consisting of aryl, substituted aryl, cyclohexyl, cyclopentyl and aralkyl groups.
W is a member of the group consisting of hydrogen and alkyl groups.
Y is a member of the group consisting of alkyl groups having less than eight carbon atoms.
Z is a member of the group consisting of aralkyl, substituted aralkyl, aryl and substituted aryl groups.
R, R1 and R2 are members of the group consisting of hydrogen and alkyl groups such that the sum of the carbon atoms in R, R1 and R2 does not exceed six.
X is a member of the group consisting of chlorine, bromine and fluorine.
More particularly, preferential compounds according to this invention will have the following structure:
VIV Y A-CH-g R R2 N X I Z 1 H in which:
A is a member of the group consisting of aryl, substituted aryl in which the substitution is chosen from the group consisting of alkyl groups containing not more than 4 carbon atoms, a hydroxy group, alkoxy groups containing not more than 4 carbon atoms, chlorine, bromine, fluorine, amino, acylamino containing not more than 4 carbon atoms, alkylamino containing not more than 8 carbon atoms, cyclohexyl, and aralkyl in which the alkyl part does not contain more than 4 carbon atoms.
I W is a member of the group consisting of hydrogen and an alkyl group containing not more than 3 carbon atoms.
6 Claims. (Cl. 260-57 0.9)
Y is a member of the group consisting of alkyl' containing not more than 4 carbon atoms.
Z is a member of the group consisting of aralkyl containing not more than 4 carbon atoms in the alkyl portion, substituted aralkyl in which the substitution is chosen from the group consisting of alkyl groups containing not more than 4 carbon atoms, a hydroxy group, alkoxy groups containing not more than 4 carbon atoms, chlorine, bromine, fluorine, amino, acylamino containing not more than 4 carbon atoms, alkylamino containing not more than 8 carbon atoms.
R, R1 and R2 are members of the group consisting of hydrogen and alkyl groups such that the sum of the carbon atoms in R, R1 and R2 does not exceed six.
X is a member of the group consisting of chlorine and bromine.
When in the several formulae given hereinafter in connection with description of procedure for the preparation of compounds according to this invention and as illustrative of specific compounds according to this invention the radicals are indicated by the symbols A, W, Y, Z, R, R1, R2 and X, they will be as given above.
The compounds in accordance with this invention and as identified by the above structural formula may be prepared variously by one of three general methods, from the following general description of which procedure for the preparation of the several compounds will be apparent to those skilled in the art.
The compounds used as starting materials for the synthesis of compounds of this invention are either known substances or being made obvious can be prepared by well known methods.
The organic and inorganic salts contemplated by this invention include by way of example salts of the bases formed with organic acids such, for example, as tartaric, suocinic, glycolic, camphorsulfonic, etc. and inorganic acids such as, for example, sulfamic, hydrochloric, hydrobromic, sulfuric, phosphoric, etc.
METHOD A A mixture of an aldehyde or ketone of the type and an amino alcohol of the type:
R R, mN-z x-b-on is reduced with hydrogen in the presence of a suitable hydrogenation catalyst, as, for. example,
platinum, palladium or Raney nickel with the production of an amino alcohol having the formula:
If desired, the aldehyde or ketone and amino alcohol may be first reacted to form an aldimine or ketimine and such catalytically reduced. However, proceeding as first outlined above will generally be most convenient.
The amino alcohol so produced is then reacted with a halogenated compound corresponding to the radical Z in the general formula above, such, for example, as benzyl chloride which will introduce the group Z shown in the general formula above. The reaction will be accomplished by heating together the secondary amine and the METHOD B ,A mixture of aldehyde and ketone of the type indicated in connection with Method A above and a primary amine of the type Z-NH2 are catalytical-ly reduced to form a secondary amine of the type The same secondary amine can be prepared by reduction of an aldehyde or ketone in which the group Z is included, such as benzaldehyde or benzyl methyl ketone, etc. in the presence of a primary :amine of the type The secondary amine so produced is then reacted with an alkylene halohydrin, such as ethylene bromhydrin, 1-bromo-2-propanol, or the like, or with an alkylene oxide, such as ethylene oxide, propylene oxide, or the like, to form an amino alcohol having the structure:
N-b-z z-oifi Z 1 H and the amino alcohol is finally treated with a halogenating agent as in Method A above for replacement of the hydroxyl group by a halogen group as X in the general formula given above.
METHOD C Compounds containing one or more hydroxyl groups attached to an aromatic nucleus in groups 4 A, Y or Z can be obtained from the corresponding methoxy containing B-hydroxyethylamines of the general formula by heating a methoxy-containing compound of the above type with a hydrohalide acid, such as concentrated hydrobromic acid. The methoxy grouping is converted into a hydroxy group and, simultaneously, the aliphatic hydroxy group is replaced by halogen to form a 5-haloethylamine.
The reaction according to this method will be made apparent by the following example:
CtH5CHgN-CHzCHgBr The following examples will be illustrative of .the various types of compounds and of specific compounds in accordance with this invention and procedure for their preparation and will, it is believed, serve to make fully apparent all of the compounds embraced by the general formula given above and the preparation thereof, respectively, it being noted that the utility indicated for the several compounds flows from the elements of the general structure common to all of them.
Example 1 N S-phenylisopropyl) -Nbenzyl-fi -c-hlorethylamine hydrochloride will be prepared by Method A above as follows:
Step 1.-A solution of 122 g. of ethanolamine, 268 g. of benzyl methyl ketone and 300 cc. of alcohol is shaken in an atmosphere of hydrogen in the presence of platinum catalyst. After removal of the catalyst and alcohol, the remainder was distilled in vacuo and the fraction boiling at 118-122/3 mm. has the formula:
Step 2.Six hundred grams of B-phenylisopropylaminoethanol, 416' g. of benzyl chloride, 238 g. of anhydrous potassium carbonate and 1000 cc. of alcohol are stirred and refluxed for six hours. Water is added to the reaction mixture and the organic material extracted into ether. Distillation yielded N-(e-phenylisopropyD-N- benzyl aminoethanol, a colorless oil boiling at 161-169/1 mm, corresponding to the formula:
This base is added to aqueous hydrochloric acid to give the hydrochloride salt melting at 201.5- 203.5 C.
Step 3.A solution of 17 g. of the hydrochloride salt, N-(p-phenylisopropyl)-N-benzylaminoethanol hydrochloride, and 13 g. of thionyl chloride in cc. of chloroform is heated at 50-60 for an hour. Removal of the solvent and recrystallization of the residue from alcohol and ether gives N-(fl-phenylisopropyl)-N-benzyl-pchlorethylamine hydrochloride, a solid, M. P. 144-147 0. corresponding to the formula:
Example 2 N-(fl-phenylisopropyl) -N-benzyl- 3-chlorethylamine hydrochloride will be prepared by Method B above as follows:
Step 1. Fifty-three grams of benzaldehyde and 67 g. of fi-phenylisopropylamine are mixed,
the water formed in the reaction is separated and s the residue hydrogenated in alcohol solution in the presence of platinum catalyst. Catalyst and solvent are removed and the product, N-benzyl-pphenylisopropylamine, distilled, B. P.' 190-195" C./22 mm. 1 a
Step 2.--Eighty-five grams of N-benzyl-pphenylisopropylamine, 24 g. of ethylene bromohydrin and 100 cc. of toluene are refluxed for four hours. The reaction mixture is filtered and the filtrate distilled. The fraction boiling at 178- 182 C. at 2 mm. corresponds to the formula:
QUE-( 311 Following the above procedure using optically active p-phenylisopropylamine, the product; compound will be optically active. Thus. where the d-isomer' of .fi-phenylisopropylamine is used in Step 1, dextrorotatory N- (fl-phenylisopropyl) -N- benzyl-p-chlorethylamine hydrochloride, M. P. 131.5-133" 0., [a] ==+37.9 (0:8.00 in ethanol), is formed as the end product.
Example 3 N (p-cyclohexylisopropyl) -N -ben2yl-B-chlor ethylamine hydrochloride will be prepared by Method A above as follows:
Step 1.Seventy grams of cyclohexylacetone are "added to;30 g. of .ethanolaminein' 75 cc. of alcohol and the solution shaken with hydrogen in the presence-o1 platinum catalyst. The solu-, tion is filtered from thecatalyst, the alcohol removed andthe residue distilled in vacuo- The fraction boiling at 154458720 mm., 'fl-cyclohexylisopropylaminoethanol, has the formulaz V n 'i e ecnaia CHFCH: IfiL-CHr-CHOH Step 2.-;-A mixture of 114 g. of-p-cyclohexylisopropylamino'ethanol, .178 g. of benzyl chloride, 69 g.--of anhydrouspotassiumcarbonate and cos of alcohol are stirred andrefluxed forsix. hours. The reactionmixture is diluted with 'watenand extracted with ether. The ether solution. is drie'danddistilledpthe product, ,NrQi-OYOIO: hexylisopropyl) -N-benzylaminoethanol. boils ,at- -17974 ,mm. The distillate. is converted; into its hydrochloride salt which melts at 12l.5-123 0.
Step 3.-Twenty-eight grams of N-(B-cyclohexylisopropyl) N benzylaminoethanol hydrochloride are added to 21 g. ofthionyl chloride in 50 cc. of chloroform and the solution heated to 55-60 for. an hour. The solvent is removed and the product, N-(p-cyclohexylisopropyl)-N- benzyl-p-chlorethylamine hydrochloride, recrystallized from a mixture of alcohol and ether, P. 145-147" C. 1 I I "T Example! N-(p methoxyphenylisopropyl)-N-benzyl 18- chlorethylamine hydrochloride will be prepared by Method A above as follows:
Step 1.A mixture of- 82 g. of p-methoxyphenylacetone and 31 g of ethanolamine is reduced as in Example 1 above to obtain p-methoxyphenylisopropylaminoethanol, an oil boiling at 154-'157/2 mm. and having the formula:
' Step 2.105 g. of p"-methoxyphenylisopropyl aminoethanol with 63 gof benzyl chloride are then reacted in the presence of potassium carbonate as described in Example 1 above to obtain N- (p-methoxyphenylisopropyl) -N benzylaminoethanol, an oil boiling at l95/l mm. and corresponding to the formula:
" N-CHr-CHr-CLHCX Exampl 5 madam.
This compoundwillbe prepared by thepmcedurc described in Example 4 above using, BA-d-imethoxyphenylacetone in place of p-methoxyphenylacetone inzstepil v This compound will be preparedzby. the procedure described in Example; 1 above using benzyl ethyl hetonejnplace.oi bcnzylmethylkctone in Step 1. Example-8 amed n.
This compound will benprepared by the, procedure described in connection withv Example 1 above using isopropanolamme in place of ethanolamlne in Step 1.
Examp -9 r s CH3 ca c 7 f j" -cm -on oilnlcr @sw t This ,.coinpound will beprepared.bytthedlmcedure descnbed-i-inz Example 2.- aboverusing; benzyl methyl ketone and B-phenylisopropylamineyin Step 1.
Example-10 This compound will be prepared according to the procedure described in Example 1- above using p-methylphenylacetonein place of; benzyl methyl ketone in Step 1.
This compoundzwillbe prepared according to the procedure described in Example-I above using pchlorophenylacetone in place-= ofbenzyl methyl ketone in Step 1. p p 7 Example 12 V V EH 5 This compound will. biepreparem according; the procedure; descrihedsinExa-mple 1 sheave llSi-Ilfljflr methoxybenzyk chloride'in place: ofbenzxl-chloe ride-in Step 2.
Example 1 3 1 :Y GEL-OH: 7 Nf-- CH2GH-G1E HGP Er c- 03:
This compound will be prepared according to the procedure described in: Example 1 above using pbromobenzyl chloride in place ofbenzyl chloride in Step 2.
Thiscompound will beprec r'ed r i' e procedure described. in Example '4aboveuslngpmethoxybenzyl" chloride i lac f e xl ch10 rideinStep-2: f f
This compound wi-Il: be prepared accordingg to the procedure, described in Example above-using, benzylacetoneinpl'ace-of; l:enzylumthyl. keboneein Step1:
' Emmplezfi This compound-*- will be; prepared by fheating 7N- benzyl-B-phenylisopropylamine,- which i s' ob;- tamed as desoribed -i'n Exampl'e 2'; withfl fluoro ethyl bromide-- in" a Ihanner similar thatdesoribed in' Step 2 'of 'Ex-ampl'e 2; Iii thisdnstance the [i-fiuorethyldminvie obtajined' -directl'y hip-disltillation; inrviacuo or by isolation ink the form: of
This compound will be prepared according to the procedure described in Example 1 above using 3- amino-Z-butanol in place of ethanolamine in Step 1.
Example 18 N-C-CHr-CLHCI I Q-om OH:
This compound will be prepared according to the procedure described in Example 1 above using 2- amino-2-methyl-1-propanol in place of ethanolamine in Step 1.
Example 19 CH\ on: of, GH-OH2CH CHri This compound will be prepared according to the procedure described in Example 1 above using cyclopentylacetone in place of benzyl methyl ketone in Step 1.
Example 20 This compound will be prepared according to the procedure described in Example 2 above using benzyl methyl ketone and aniline in Step 1.
Example 21 Example 22 CH: OH;
This compound will be prepared according to the procedure described in Example 1 above using B- methyl-fl-phenylacetone in place of benzyl methyl ketone in Step 1.
10 Example 23 This compound will be prepared by treating N (3,4 dimethoxyphenylisopropyl)-N-benzylaminoethanol, the intermediate obtained in the preparation of Example 6, with concentrated hydrobromic acid according to general Method C.
In the foregoing examples hydrochlorides and hydrobromides are exemplified. However, it will be understood that the foregoing examples will illustrate other organic and inorganic salts by the substitution in the several formulae for the HCl or HBr group of the desired acid group.
The foregoing examples illustrate the salts contemplated by this invention. The bases contemplated by this invention will be formed by interacting the salts with one molecular equivalent of a strong alkali, such as sodium hydroxide, potassium hydroxide, lithium hydroxide, or the like, in aqueous solution, say, for example, a 10 %-40% solution. The foregoing examples will serve to illustrate the structure of the bases contemplated by this invention with elimination of the acid group from the formulae. It will be appreciated that the salts contemplated by this invention may be prepared by neutralizing the bases with the desired acid.
The compounds contemplated by this invention will be various optically inactive or optically active.
What we claim and desire to protect by Letters Patent is:
1. A compound havin the structure in which R and R are members of the group consisting of hydrogen, alkyl groups containing not more than 4 carbon atoms, a methoxy group, a hydroxy group, fluorine, chlorine and bromine and X is a member of the group consisting of chlorine and bromine; and acid addition salts of said compounds.
2. A compound having the following structure CHa QEHHEH 3. A compound having the structure 4. A compound having the structure I CH3 1 1 5. A compound having the structure 6. A compound having the structure JAMES F. KERWIN. GLENN E. ULLYOT.
REFERENCES CITED UNITED STATES PATENTS Number Name Date 1,949,247 Eisleb Feb. 27, 1934 2,006,114 Rosenmund et a1. June 25, 1935 5 2,276,618 Kulz Mar. 17, 1942 FOREIGN PATENTS Number Country Date 536,881 Great Britain MayBO, I941 10 OTHER REFERENCES Blicke et a1: J. Am. Chem. Soc., VOL-61,1 1
Kulz et aL: Ber. deut. Chem, vol. 72, 2161- 15 2767 (1939).
Nickerson et aL: Federation Proceedings, Vol.
The following references are of record in the 20 file of this patent:
|Cited Patent||Filing date||Publication date||Applicant||Title|
|US1949247 *||May 28, 1931||Feb 27, 1934||Winthrop Chem Co Inc||Alkylolamine-derivatives and process of preparing them|
|US2006114 *||Feb 8, 1933||Jun 25, 1935||Rosenmund Karl Wilhelm||Aliphatic-aromatic amine and process of making same|
|US2276618 *||Aug 9, 1939||Mar 17, 1942||N-phenylaliphatic bihxdroxithenyl-|
|GB536881A *||Title not available|
|Citing Patent||Filing date||Publication date||Applicant||Title|
|US3320319 *||Aug 6, 1965||May 16, 1967||Degussa||1-(aryl)-2-methyl-2-aliphatic amino-propanes|
|US3962238 *||Feb 27, 1973||Jun 8, 1976||Centre Europeen De Recherches Mauvernay "Cerm"||Ethers of n-propanol amine|
|US8916728 *||Jun 25, 2010||Dec 23, 2014||Arkema France||Process for preparing alkylalkanolamines|
|US20120116126 *||Jun 25, 2010||May 10, 2012||Christophe Ruppin||Process For Preparing Alkylalkanolamines|
|USRE30577 *||Feb 27, 1979||Apr 14, 1981||Centre Europeen De Recherches Mauvernay||Ether of n-propanol amine|
|CN102459150A *||Jun 25, 2010||May 16, 2012||阿肯马法国公司||Process for preparing alkylalkanolamines|
|EP2445863A1 *||Jun 25, 2010||May 2, 2012||Arkema France||Process for preparing alkylalkanolamines|
|U.S. Classification||564/381, 564/376, 564/374, 564/454|