DE2365309A1 - 1,2-DIHYDRO-2-IMINOPYRIDINE DERIVATIVES, THEIR SALT, METHOD FOR THEIR MANUFACTURING AND THEIR USE AS BACTERICIDE - Google Patents

Description

"1,2 ~ dihydro-2-iminop3 'ridinderivate ^p, their salts, processes for their preparation and their use as bactericides ^l!

Priority: October 24, 1972, V.St.A., No. 299 986 March 8, 1973, V.St.A., No. 339 258

The invention relates to 1,2-dihydro-2-iininopyridine derivatives and their salts of the general formula I and II

(CH ₂ )

(D

(II)

in which R is the same or different and -a hydrogen, Fluorine, chlorine or bromine atom, an alkyl radical with 1 to 4 carbon atoms, an alkoxy radical with 1 to 4 carbon atoms, an alkyl mercapto radical with 1 to 4 carbon atoms, a benzyl, Phenäthyl-, Phenyl-, Phenylmercapto- or one by a fluorine, chlorine, bromine or iodine atom, an alkyl radical with 1 to

4 carbon atoms, an alkoxy radical with 1 to 4 carbon » L.

atoms or a trifluoromethyl group is a monosubstituted phenyl group, and R is in the 3- and / or 5-position when R is a halogen atom, R ¹ · a hydrogen ,. Fluorine, chlorine, bromine or iodine, an alkyl group with 1 to 9 carbon atoms, an alkoxy group with 1 to 4 carbon atoms, an alkyl mercapto group with 1 to 4 carbon atoms, an alkylsulfonyl group with 1 to 4 carbon atoms, a phenyl group. Phenyloxy, sulfamoyl or dialkylamidosulfonyl group with 1 to 4 carbon atoms in each alkyl radical, a trifluoromethyl or a fluorine, chlorine, bromine or iodine atom, an alkyl radical with 1 to 4 carbon atoms, an alkoxy radical with 1 to 4 carbon atoms or a Trifluoromnethylgrup-.pe mono substituted phenyl or Pheiiylo'xygruppe, m • has the value 1 or 2 and η has the value 2 or 3.

The invention also relates to a process for the preparation of the compounds of general formula I, which is characterized is that a 2-arenopyridine of the general formula III given below with an o-bromophenalkylene bromide brings the general formula IV given below to the reaction and, if appropriate, the compound obtained with an alkali metal alcoholate treated.

The process according to the invention is carried out according to the following reaction scheme:.

25th

^L 40982271170

> R- + oil TO + R '· ^ΒγΘ

The process according to the invention takes place in a solvent or solvent mixture in which the reactants can be dissolved and which has a boiling point of at least approximately. 100 ⁰ C possesses. Typical examples of suitable solvents are aromatic hydrocarbons, ethers, aliphatic alcohols or aryl-substituted aliphatic alcohols. Toluene and xylene are examples of preferred aromatic hydrocarbons. Examples of ethers used with preference are the monomethyl ether of diethylene glycol, the dimethyl ether of diethylene glycol (diglyme), the monomethyl ether of ethylene glycol and the dimethyl ether of ethylene glycol (glyme). A specific example of a preferably used aliphatic alcohol is n-amyl alcohol, while benzyl alcohol is a specific example of a preferred aryl-substituted aliphatic alcohol. By heating the mixture of the compound of general formula III with the compound of general formula IV in a solvent of the type described above or a solvent mixture to temperatures of from about 100 to about .140 ⁰ C for a period of several hours, preferably from etwa'3 up to 24 hours, the pyridine compound is the

general formula I obtained. This compound is converted into the imino compound of the general formula II by reacting it with a water-miscible alcohol and an alkali metal alcoholate having 1 to 3 carbon atoms. The reaction takes place at room temperature \\ ^r uring a period of about 1 to 4 hours.

The intermediates of the. General formula IV, in which ή has the value 2, can be prepared by reacting an o-bromobenzyl alcohol of the general formula VI with PBr ₇ at temperatures of about to 100 ^° C. for a period of about 1 to 6 hours. The resulting o-bromobenzyl bromides of the general formula VII are then reacted with sodium cyanide in the presence of water and a water-miscible alcohol to give the corresponding o-bromophenylacetonitriles of the general formula VIII. Treatment of these compounds with an alcohol in the presence of concentrated sulfuric acid gives the corresponding esters of the general formula IX. The reaction of the ester with lithium aluminum hydride yields the corresponding o-Bromphenäthanole by reacting with EBr ₇ - about ü to 100 ⁰ C for a period of about 1 to 6 hours, the corresponding O-Bromphenäthylbromide provide at temperatures of the general formula XI. The conversions explained above are given by the following reaction equations:

409822/1170

(VI)

CH ₂ OH

! H ₂ COOR

(ix)

LiAlH.

R '

R '

CH ₂ Br

(viii)

₂ CH ₂ Br

The intermediate products of the general formula IV, in which η has the value 3, can be prepared by reacting a compound of the general formula XI with sodium cyanide in the presence of water and a water-miscible alcohol to form the corresponding o-bromophenylpropionitriles of the general formula XII. These compounds are reacted with an alcohol in the presence of concentrated sulfuric acid to give the corresponding esters of the general formula XIII. By reducing these compounds with lithium alurainiucihydride, the corresponding o-bromophenylpropanols are obtained, which, by reaction with PBr at temperatures of about 0 to 100 ^° C., for a period of about 1 to 6 hours, the corresponding o-bromophenylpropyl bromides of the general Formula XV result. The above-explained reactions are carried out by the following

Reaction equations reproduced:

409822/1170

CH ₀ CH ₀ Br NaCN 2 2 _

CH ₂ CH ₂ CN

RAW

CH ₂ CH ₂ CH ₂ OH LiAlH ₄

Br

(XIV)

PBr.

/ \ CH ₀ CH ₉ CH ₀ Br

CH ₂ CH ₂ COOR

(XV)

If the rest of the R ^! denotes an alkyl mercapto radical, the compounds of the general formula XI or XV can be prepared by nitrating an o-bromobenzyl alcohol of the general formula XVI at temperatures of about ⁰ ° C. with a mixture of nitric acid and sulfuric acid. The isomer mixture of nitrated 2-bromobenzyl alcohols obtained is separated in a manner known per se. Any isomer of. general formula XVII is then reduced to the corresponding amine of general formula XVIII with zinc and hydrochloric acid. The reaction of the amino compounds of the general formula XVIII with nitrous acid and then with sodium methyl mercaptide gives the corresponding methyl mercapto-2-bromobenzyl alcohol of the general type

Formula XIX. These reactions proceed according to the following reaction ^L 40982271170

equivalences:

CH ₂ OH

5 (XVI)

CH ₂ OH

Zn

HCl

(XVIl)

CH ₂ OH

(xviii)

1) ₂

2) AlkyXSNa

Alkyl-S

CH ₂ OH

(XIX)

The reaction of the compounds of the general formula XIX with "■ PBr ₇ in the manner described above yields the compounds of the general formula XI or XV in which R 'represents an alkylraercapto radical."

If the radical R ^{1 is} a trifluoromethyl group, the intermediate of the general formula VII can be prepared by reacting a trifluoromethylphenylmagnesium bromide of the general formula XX. v / ground with methyl iodide to form the corresponding trifluoromethyl - toluene of the general formula XXI. Reacting this compound with bromine at temperatures of about '20 ⁰ C in the presence of iron powder provides a bromsubsti * fcuier-. tes trifluoromethyltoluene of the general formula XXII. The reaction of this compound with bromine in the presence of light and a peroxide catalyst delivers the corresponding bromotrifluoromethylben ^ yl bromide of the general formula XXIII. These reactions _are% according to the following equations:

409822/1170

-Ο

CF,

CH ₃ I.

Br '

Iron file

^ [O

(XXII)

2 ° 2

CH ₂ Br

.__ } £ XXIII)

The starting compounds of the general formula III, in which R \ . ■ an optionally by a halogen atom, an alkyl radical, substituted an alkoxy group or a trifluoromethyl group Phenyl group means can by heating a j5- (N-Acetamido-IT-nitroso) -pyridine of the general formula ZZIV with an optionally substituted by a calogen atom, an alkyl radical, an alkoxy radical or a trifluoromethyl group-substituted benzene according to the method described in J. Chem. Soc. (London), 1940, p. 372 and , J. Chem. Soc. (London), 1954, p. 4516 getting produced. The product of the general formula XXV is a 3-substituted pyridine, in which the N-acetamido-N-nitroso group is used replaced by an optionally substituted phenyl group derived from the compound with which the 3- (N-acetamido-N-nitroso) pyridine was heated. That Product of the general formula XXV is then treated with sodium amide according to the in-J. Soot. Phys. Chem. Soc, -46 (1914), p. 1216 (Chem. Zentralblatt II, 1915, p. 1064)

implemented, to the aminopyridines of the general formula XXXII and XXXIII /

^L 409822/1170 ^J

NO O

I H

CCH-

ο-

R = halogen,

Alkyl, alkoxy,
CF ₃ or H

(XXV )

XXXII

The compounds of the general formula III in which R is a fluorine atom or in which one of the radicals R is a fluorine atom and the other radical is an alkoxy radical can be prepared by reacting a 3-aminopyridine of the general formula XXVI or a 3-alkoxy-5-aminopyridine with amyl nitride and fluoroboric acid according to the method described in J. Am. Chem. Soc, Vol., 69 (194-7), p. 2443. The -3-fluoropyridine of the general formula XXVII obtained is then treated with sodium amide to the method described by Chichibabin et al., J. Russ. Phys. Chem. Soc, Vol. 46 (1914), p. 1216, converted into a mixture of 2-amino-3-fluoropyridine and 2-amino-5-fluoropyridine, which is separated in a manner known per se. The process proceeds according to the following reaction scheme:

NH.

TPI

(XXVII )

Z = H or alkoxy

40982 2/1170

-10 -

Compounds of the general formula IV, in which R ^! a phenyl group optionally substituted by a halogen atom, an alkyl or alkoxy group or a trifluoromethyl group can be prepared by reacting an amino-substituted o-bromobenzoic acid of the general formula ZZVIII with acetic anhydride and then with nitrous acid. The N-acetamido obtained -N-nitroso-o-bi ^ mbenzoic acid of the general formula ZZIZ v / ird then with eenzene or an 'R-substituted benzene, in which II means a halogen atom, an alkyl or alkoxy radical or a trifluorroethyl group, to the above-described "v The aryl-substituted o-bromobeiizoic acid is then reduced to the aryl-substituted o-bromobenzyl alcohol of the general formula ZZZI with LiAlE ^, or 'AlIl _7. The implementation is ongoing

15 following reaction scheme: COOH

COQH

1) (CH ₃ CO) ₂ O

2) ENT ₀

Br

NO

• CCH.

(XXVIIl)

(XXIX)

= Halogen, alkyl, H ,. Alkoxy or CF ₃

CH ₂ OH

COOH

409822/1170

BATH ORIGINAL

The pyridinium compounds of the general formula I represent Intermediate products for the production of dihydropyridobenzodiazopines and benzodiazocines !! with CNS-stimulating and_rauskel-. relaxing properties of the general formula Ia '

(R) _m Τ ³ I i U-HR ¹ da)

represents, in which R, R ', m- and η have the preceding meaning.

10 ■■ ....

They are also valuable bactericides. To determine the bactericidal action, the compounds are based on the compounds described in "The" Hicrobial. World ¹¹ , RY Stan! Er, M. Doudoroff and EA Adelberg, • Prentice-Hall, Inc. Englevood Cliffs, NJ, 3rd edition, p . 858 described biological- tesis examined. Pathogenic microorganisms include Staphylococcus Äureus (1), Streptococcus pyogenes (2), Salmonella schottmuelleri (3) $ Salmonella gallinarum (4), Pseudomonas aeruginosa (5), Proteus vulgaris (6), Escherichia coli (7), Pasturella multocida (8 ) and I ^ cobacterium

20 tuberculosis (9) used.

L _ ■■ -

irw - 40 9822/1170

Sterile agar plates are inoculated with aera test organism, and " then a number of glass cylinders are placed on the surface of the agar plates to form a number of small ones Cups turned upside down. A known dilution of the compounds to be tested is added to each beaker, and the whole The plate is then incubated until there is significant bacterial growth he follows. The compounds of the invention also diffuse the beaker into the agar and create an inhibition zone. To this I-Jeise can determine the minimum Uemm concentration that creates a recognizable zone of inhibition. The results are summarized in the table below.

Micro Verb, from
Beisn. 12
rv ~: - / - v 35 Minimal inhibitory concentration, y / ml Verb, from
Example 3 ^: Verb. Of
Ex ·. 6th organism . 6.25 Verb, from
BeisO. 10,
Poalvn 3 12.5 3.13 1 25.0 6.25 50.0 12.5 2 12.5 50.0 50.0 12.5 3 - 12.5 12.5 25.0 6.25 ■ 4th 25.0 12.5 25.0 12.5. 5 ^: 25.0 25.0 25.0 12.5 6th 6.25 25.0 25.0, 3.13. 7th 12.5 12.5 .12.5 ' 6.25 8th 0.78 25.0 . 6.25 / 0.39 9 1.57

The examples illustrate the invention.

4 0 9 82 2/1 1 7 0 BAD ORlGfNAt

1 example 1

A) ο - Br ο isb engy lbr oiui d

271 g of phosphorus tribromide are added dropwise to 187 g of o-bromobijicyl alcohol at room temperature and with stirring. After the addition has ended, the mixture is stirred for 3 hours at room temperature, then ^{heated to 90 to 100 °} C. for 3 hours and then poured into 6 kg of crushed ice. After hydrolysis, the mixture is extracted three times with 600 ml of dietary ethyl ether each time. The ether extract is washed, dried and 10 evaporated. -Man give the title compound, bp 130 .. _Γ bit 132 ° C.

^B ) o-Brpn iphenyIacetonitril ■

A suspension of 220 g of sodium cyanide in 265 ml of water and 380 ιπΓ ethanol is mixed with a solution of 911 g of o-bronbenzyl bromide in 911 ml of ethanol while stirring. An exothermic reaction ensues. Finally, the mixture is refluxed for about 30 minutes, then cooled in an ice bath and filtered. The filter residue is washed with diethyl ether, the filtrate evaporated and the residue suspended in 300 ml v / water and extracted three times with 500 ml diethyl ether each time. The ether extract is washed, dried and evaporated. The residue is distilled. Yield 730 g of the title compound from bp. ₁₂ 141 to 142 ° C,

C) o-Sromphenylacetic acid ethyl ester

A cooled solution of 730 g of o-bromophenylacetonitrile in 2.9 liters of anhydrous ethanol is added dropwise within about

2 hours and with stirring with 740 ml of concentrated sulfur- j v-: c 409822/1170

acid added. After that, the reaction time is under for g hours

• Heated to reflux, then poured into ice water and with 2.5 liters of diethyl ether extracted. The ether extract is gov: a ~ see, dried and evaporated, the residue is distilled.

Yield 780 g of the title compound forward Ep _{Z [115} to 117 ⁰ C; - ■. ⁶ ng 1.5434. ■■ ..- ■ -

• D) ο-3rοmphenäthyIaikoh o1.

A suspension of 106 g of lithium aluminum hydride in 3.7 liters of anhydrous diethyl ether is added dropwise and with stirring with a solution of 780 g'o-bromophenylacetic acid ethyl ester in 3.1 liters of anhydrous diethyl ether. When the addition is complete, the reaction mixture is stirred for about 3 hours and then heated under reflux for about 5 hours * The mixture is then cooled and 800 ml of tbsp / ie 1.5 liters of 10 percent hydrochloric acid are added dropwise. The ether solution is washed, dried and evaporated. The residue is distilled. Yield 554 g of o-bromophenethyl alcohol with a boiling point of ₈ 130 to 132 ° C .; n | ° 1.5760. .

20 -

E) ο-bromophenethyl bromide

550 g of o-bromophenethyl alcohol are added dropwise with stirring mixed with 375 g of phosphorus tribromide. After the addition is complete

• The mixture was stirred for 3 hours at room temperature and then

Heated on a steam bath for 3 hours. The mixture is then Poured into 6 kg of crushed ice, three times with, 600 ml each time and extracted twice with 200 ml of diethyl ether each time. the combined ether extracts are washed, dried and evaporated. The residue is distilled. Yield 531g. ^

40982 2/1170

BADORIGIWAL

V o-bromophenyl bromide of b.p. _Q g 86 Ms 88 ⁰ C; n ^ 1.5922.

F) 2-Amino-1- (o-bromophenethyl) pyridinium bromide A solution of 212 g of O-bromophenethyl bromide in 400 ml of anhydrous xylene is mixed with a solution of 120 g of 2-aminopyridine in 400 ml of anhydrous xylene. The mixture is refluxed for about 3 hours, then cooled and the xylene solution is decanted from the solid which has crystallized out. The crystals are digested with -300 ml of isopropanol, filtered off and dried. Yield 138 g of the title compound. The xylene solution is refluxed again for 16 hours and then worked up in the same way. A further 43 g of the title compound are obtained. The product (181 g.) Is recrystallized from isopropanol. Yield 170 g of the title compound

15 dung from F. 195 to 197 ⁰ C

G-) 11,12-Dihvdror> yrido / 2,1 -b.7 / j-3_ / benzodiazepine

A solution of 9.0 g of 2-amino-1- (o-bromophenethyl) pyridinium bromide in 55 ml of dimethylformamide is mixed with 10.3 g of finely powdered anhydrous potassium carbonate and 0.5 g. ^{Copper bronze crosslinked, heated to 100 °} C. for about 3 hours under nitrogen as protective gas and with stirring and then filtered while still hot. The filtrate is evaporated to dryness under reduced pressure. 8.6 g of a residue are obtained, which is extracted twice with 125 ml of boiling diisopropyl ether each time. The diisopropyl ether solution is treated with activated charcoal, filtered and evaporated to about 40 ml. 7.2 g of the titre crystallize on cooling. Oil connection with a temperature of 120 to 122 ° C.

^L 409822/1170

Example 2 '11, 12 - Dih y droOvri ^/ l o _i / 2,1 -Τ? ; 7 / ϊ,? _ / Ben7odiazepine A) 1- (o "Drompben äihyl) -2-iainopyridin

(a) HaOGII-; in methanol

10.8 g of the product from Example 1 (F) are added to a solution of 3.3 g of sodium methylate in 120 ml of anhydrous methanol, and the mixture is heated and stirred for 5 hours under nitrogen as a protective gas under reflux. The yellow solution obtained is evaporated to dryness under reduced pressure and the residue is partitioned between 250 ml of diethyl ether and 30 ml of water. The ether solution is separated off, washed, dried and evaporated C. After recrystallization from hexane, 6.8 g of the title compound with a melting point of 64 ° to 66 ° C. are obtained.

■■ '; · ■

(b) K ₀ CO ^ in hydrous n-propanol

A mixture of 18 "g of the product from Example 1 (F), 13.8 g of potassium carbonate, 200 ml of water and 100 ml of n-propanol is refluxed for 4 hours ml removed, cooled and diluted with A 20 ml diethyl ether. The ether solution is "separated" and worked up. Yield 2.1 g of the title compound with a melting point of 64 to 66 ° C. · Which is identical to the compound obtained in (a).

^B ) 11,12-DihydropyridoZ2,1-b / Zt, 3-7benzodiazepine (a) K _o C0- < in hydrous n-propanol "" .. ·

"~ * i_" D ■ '- I Il Il M lh-lflll L .... 1 Il l' .111

The remaining reaction mixture from Example 2 (b) is 0.3 g Copper bronze added and 3 hours under nitrogen as a protective gas heated under reflux and stirred. Then the 'Ge j

■ ^ Kwo c 'Ii - ^ o 9 8 2 2 i 117 0 ^ original

Γ "I.

Cooled mixed and diluted with 350 ml Bi ätlry Lather. The ether solution is separated off and worked up in the usual '"" ice. Yield 8.9 g of a yellow solid. The solid is dissolved in 250 ml of diethyl ether, the ether solution decolored with activated charcoal, filtered with diatomaceous earth as a filter aid and the filtrate evaporated to dryness are 7.6 g of a crystalline product melting at 119 leuehtendgelben get to 122 ° C. After recrystallization from 150 ml Diisopropylather be 5.9 g of the title compound, melting at 120 to 122 ⁰ C obtained -with in example 1 ( CJ) obtained compound is identical.

(b) KoCO ^ in anhydrous; n-premenol
■ A mixture of 6.0 g of the product of Example 1 (F), 4.6 g of anhydrous potassium carbonate, 0.2 g of copper bronze and 180 ml of anhydrous! n-Propanol is refluxed and stirred for 9 hours. After working up, 2.7 g of the Titeiverbin are obtained with a temperature of 120 to 122 ° C., which is identical to the compound obtained in (a).

20 '(c) NaOCH ^ in vmsser-free ethanol .

A solution of 5 kg of sodium methylate in 220 ml _f which serf reieni Bfethanol is ntit 18 g of the product of Example 1 (F) and 0.3 g of copper bronze are added and refluxed for 3 hours ER • hitzt and stirred. After working up, $> Q g of the title compound νοώ F. 120 to 122 ° C are obtained, which is identical in terms of the compounds obtained in (a) and (b) * ■ "-""■

409822/1170 BAD Cff « ⁰ ^

(d) K aOlI in v / a; v nerhsI ^ -e -. \. Methanol ~ ■

. ' An aliquot of 5 NC ml of a solution (c) produced in accordance v / ith with 25 rnl water was added and diluted kit 0.07 g Kupferbronze- _$ and Genisch is refluxed for 3 1/2 hours under reflux and stirred, and then worked up "yield 1 , 6 g of the title compound with a melting point of 120 to 122 ° C, which is identical in every respect with the products of (a), (ρ) and (c).

Example 3 Iff 11.1 2 - Diiiydrop yridp / §., 1 _r ^ / ^ _K ^ le n-q6 ± a zepiri ^ i ^ o_olilöT ± d

A solution of 1.5 g 11 ·, 12 ~ dihydr “opyrido / 2 _i 1 - b7 / i» 37benzodiaze “pin in 10 ml · anhydrous methanol is mixed with 5 oil of a 3.3 η.“ (0 , 0175 Hol) solution of hydrogen chloride in Xther.

The resulting solution vrird with v, ^r-H asserfreie diethyl ether Ver ~ thinned until at room temperature remains turbidity.

The solution is then cooled to ^{0 ° C.} The crystals formed are filtered off . _f geti-ocknet and üiiikristallisierti from 20 ml isopropanoli Yield 1 _f 2 g of the Hydro Ohio r-ids F, 205.0 to ZQGi ^ ³ C,

Example 4

(a) 2-

ZIB g {Qt77 Köi) 2-bromo-4-cM0rbenzylbroffiid C% » _ö . ^ 9S to iQ4 '° Gi ιϊ | ^ 1 ^ 1 * 262) i are at least 220 si 95 perzeMigßm Itjbäiiöl" dissolved and intieriiäiB 20 Hinutön mrbeT Feet of 45 g (0 ^ 92 Hai} Katriuzyaiiid in 55 ml of water and 50 percent etiiau oil added: oils tetape "temperature of the mixture rises

SpöEttäij - \ mn 23 to 46 ⁰ G an * Bias öeftiiscfi becomes 1 $ minutes under _r - 409822 / 117® _Μ original

Γ

Heated to reflux, then .filtered and the filter return: r, tar_d with Washed 300 ml of diethyl ether. The combined filtrates are evaporated to dryness. The residue is between 500 ml of diethyl ether and 150 ml of water distributed. The ether solution is separated, dried and evaporated. Yield 171 g of 2 - bromo-4-chlorophenylacetonitrile.

(b) 2-BrOn- 4 - chi ο rphenyl essi />; acid ath vl ester

171 g of the product from (a) are dissolved in 760 ml of anhydrous, üthano-1 dissolved and added dropwise and with stirring with 190 ml concentrated sulfuric acid. The mixture is 1 hour stirred at room temperature and then refluxed for 3 hours. After cooling, the mixture becomes 2.5 kg Poured crushed ice and extracted the product with ether. The ether extract is evaporated. Yield 204 g of the title compound.

(c) 2-bromo-4-chi ο rphenyl ess i ρ; acid e

204 g of the ester from (b), 3500 ml of 95 percent ethanol and 64 S (1.0 mol) of 85 percent potassium hydroxide in 640 ml of water are refluxed for 5 hours, then under reduced pressure The pressure is evaporated to dryness, and 1.5 liters of water are added to the residue. The aqueous solution is cooled j extracted with diethyl ether and the aqueous solution on a. i> K ~ V / ert of 2 set. The precipitated crystals - are · filtered off., dried and from a ·. Mixture of

200 ml of benzene and 300 ml of hexane recrystallized. Yield; 'SP, 3 £ 2-bromo-4-chloropheny! .Acetic acid from F. 1g7. up to 129 ° C.

■ _ 409822/1 170 ' ^BftD ° ^RIQ ' ^NAL ^

¹ (c! ·) 2-Bro ;? ~ 4 ~ chlorine:; henaethol

A solution of 11.5 g of lithium aluminum hydride in 300 ml of anhydrous diethyl ether is added to a solution of 52 g (0.21 mol) of the product from (c) in 500 ml of anhydrous diethyl ether in the course of 90 minutes while stirring and under nitrogen as protective gas . After the addition is complete, the mixture is refluxed for 40 minutes, then cooled, treated with 20 ml of AtLy1 acetate and then poured into 1.5 kg of crushed ice. After adding 200 ml of 20 percent hydrochloric acid, the product is extracted with ether and the ether solution is evaporated. Yield 44.3 g of the title compound as a light yellow oil; n ^ ⁴ 1.5714.

(e) 2-bromine --- 4-chloro ''' ^t henäthylbror; ild

on _o
44.2 g of the product from (d) are cooled / OC and treated with 26 g of phosphorus tribronide over the course of 20 minutes. After complete addition, the Geraisch 75 is Minuten.auf heated 100 ⁰ C, then cooled "and in 1 kg of crushed ice poured. The product is extracted with diethyl ether 'and the ether extract evaporated. The residue is distilled. Yield 55.8 g of the title compound as a viscous oil from Kp.q / 95-102 ⁰ C; ng ² 1.5838.

Example 5 3-chloro-11,12-dihydro-oryrido / 2,1 -b // i, l7benzodiaz.epin -

(a) 2-Amino-1- (2-bromo-4-chlorophenethyl) -pyri'diniumbromid A solution of 10.4 g (0.11 mol). 2-aminopyridine and 20.9 g (0.07 mol) of 2-bromo-A-chlorophenyl bromide in 150 ml of anhydrous xylene are refluxed for about 10 hours. Then _j

"409822/1170

■ - 21 -

the mixture cooled and chlorine supernatant from the solid product

-o ^v

decanted. The solid is filtered off, dried and recrystallized from 150 ml of isopropanol. Yield 17.6 g of the title compound, melting at 191 ⁰ C 189bis
5

(t>) 3 - chloro -1 1,12-di hvdropyriri.o / 2.1 X>] β, ~ i cU 7benzo azepin 'A mixture of 6 g of the product of a game is 5 (a), 6 g ■■ anhydrous potassium carbonate, 0.2 g copper bronze and 220 ml n ~ propanol is refluxed and stirred for 12 hours. After working up and recrystallization from cyclohexane, 2.3 g of the title compound are obtained in deep yellow crystals with a melting point of 165 to 167 ° C.

.Example - 3-chloro-H, 12-dihydro- pyrido ^, ib / Zi »^ Jbeia ^ odiag.epln- hydrochloride ■.

A solution of 1 g of the product of Example 5 (b) in 10 ml of warm anhydrous methanol is added dropwise with 5 ml of a '3) 3 N solution of hydrogen chloride in diethyl ether added.

Then 200 ml of anhydrous diethyl ether are added. The crystalline precipitate of the hydrochloride is filtered off and recrystallized from 40 ml of isopropanol. Yield 1.0 g of the Ti ■ "t el connection from F .. 232-23 i ° C (dec.) ^Z.

B e i s ρ i e 1 7.

A) 2-bromo - ^ - ^{rftethylme'rcaptoben:::} ylbroinid 2-bromo-4-methylmercaptoben2ylalkohol is prepared as follows:
2-Bromo-4 «nitrobenzoic acid is treated with iron and hydrochloric acid in aq

409822/1170

. ■ "■ '- BAD ORIGINAL

Γ. <"1

in accordance with ethanol to 2-BrOm- ⁷ S-aminobinzoGsäur'e reduced. This compound is diazotized with sodium nitrite in aqueous sulfuric acid and the diazonium compound formed is reacted with sodium methyl nercaptide. The 2-bromo-4-methylcaptobenzoic acid obtained is refluxed with methanol and concentrated solvent. The methyl ester formed is extracted from the reaction mixture with diethyl ether. The animal extract is evaporated and the residue is distilled. The dietaryl ester is then reduced with lithium aluminum hydride. The 2-bron-4-methylraercaptobenzyl alcohol obtained is reacted with PBr ^ according to Example i (A) to give 2-brora-A ~ methylmercaptobenzyl bromide.

'B) of 3- (2-3roin - ^ - nic-rthylrner captophenyl) -1-p _i röpanol • A suspension of 25 g of magnesium turnings in a Lösung'von 0.5 g of iodine in 550 ml of anhydrous diethyl ether is washed with 5 ml a solution of 29β g of 2 ~ bromo-4-methylinercaptobenzyl bromide in .250 ml v / ate erfrei era diethyl ether added. The reaction is started by gentle warming. The remaining solution is then added dropwise so that the mixture is refluxed. When the addition is complete, the mixture is refluxed and stirred for 1 hour and then cooled to 10 ° C. Nitrogen, which has been passed through a container with 48 g of ethylene oxide, is introduced into the reaction mixture. The addition of the ethylene oxide takes 2 hours. The mixture is then allowed to warm to room temperature and stirred. The mixture is then stirred for 4 hours at room temperature and then poured into a mixture of 1 kg of ice and 55 g of ammonium chloride. The mixture is then extracted with diethyl ether and the ether extract is worked up.

A09822 / 1 170

The residue is distilled. Yield 210 ρ: the title compound

O,

dung from Kp. _n r 125 to 127 C.

C) 5- (2-bror /] -4- methylmercaptophenyl ) -; orop

To 49 g of the product from (A) v / earth, 27.1 g of phosphate bromide are added dropwise with stirring. The mixture is then stirred for 3 hours at room temperature and then heated ^{to 90 to 100 ° C. for 3 hours.} The reaction mixture is then poured into 1 kg of crushed ice. The mixture is extracted with diethyl ether, the extract is evaporated and the residue is distilled. Yield 52.7 g of the title compound with a boiling point of ^{100 to 102} ° ^c .

D) 2 ~ A? Nino ~ 1 - / B- (2-bron-4-met.hylmerca-o tophenyl) propyl / - 'T5 pyridinium bromide - -

A solution of 154 g of the compound obtained in (C) in 400 ml anhydrous xylene is mixed with a solution of 70 g of 2-aminopyridine in 300 ml of anhydrous xylene and about 1½ hours under Heated to reflux. After cooling, the XyIο11ösung of the precipitated crystals are decanted, the crystals are digested with 200 ml of isopropanol and filtered off. yield 117 g of crude product. Ground after recrystallization from isopropanol. 98 g of the title compound were obtained.

E) 12,13-dihydro-3-methylmercapto-11H-pyrido / 2,1 - b7 / ~ 1 «5 / - benzodiazocine

A solution of 8.1 g of the compound obtained in (D) in 50 ml of dimethylformamide is mixed with 10.3 g of once-powdered in vas se γι free potassium carbonate and 0.5 g of copper bronze. The GE- '40982271170

The mixture is heated for about 3 hours at 100 ° C. under nitrogen as a protective gas and with stirring. The mixture is then filtered while it is still hot. The filtrate is evaporated to dryness under reduced pressure. 9.0 g of a residue are obtained, which is extracted twice with 120 ml of boiling diisopropyl ether. The diisopropyl ether solution is treated with activated charcoal, filtered and evaporated to about 35 ml. After cooling, the crystals formed are filtered off. Yield h, 5 g of the title compound. · "■

Examples 8-22 According to Example 1 (A), but using an equivalent

• .. th amount of the substituted o-bromine listed in column 1 • benzyl alcohol ^, one obtains the corresponding one listed in column 2 o-bromophenethyl bromide. The implementation of this connection with 2-aminopyridine according to Example 1 (F) gives the in column 3 listed pyridinium compound. The implementation of this compound with KpCOp and copper bronze according to Example ΐ (G) provides that end product listed in column 4. ·,;

iO9 82 2 / '117O BAP original

JNJ

III / 11f§

CN

ίϋ

• Η ft co • Η Q) Ρ'-ί

C \]

ν-

'4 * 0982 2/1170

CN

HO) • Η ft CQ • Η (D

Λ 0 9 8 2 2 / 1.17 0

(M

■ M · CQ CM U do CQ U. CM CM W. do O OJ-) CM do. O U IC y I fe I PQ CM
O
ω

CM

CM CQ tö U O PQ U CM I. υ 3Ϊ 1 Yo) U fe

(D ■ H ft

• W • i-r ω pq

.

f-1 ö>

• Η P ₁ Ul

• Η

P-X

CO

40 9822/1170

CM

OJ ο CM ro CM CNl ta υ— -U-O

U ο Z ?, I. «Η ω • Η P ₁ • Γ-ί O

CM

C \! OJ

L

ν AO9822V 117 0

,. 32 -

CM

cm fNj cn WWW U — U — U

CN

cn cn η W W- W U— U - U.

■ Η

I. Q r-l C \ J O) -.- I P. CO ■ <- \ Q) pn

C \ J

CAJ CAJ

40 98 2 2/1 170

^Γ <- 33 -

According to Example 1, but using that listed in column 1 substituted 2-aminopyridine is obtained in Spal te 2 listed quaternary salt. The implementation of this connection according to Example 1, the end product listed in column 3 is obtained.

^U BAD ORIGINAL J

409822/1170

365309

CM

Ρ9

E = Sj

_ * Β

Ρ «

il

P. ö

U-.

IT!

40Ü22 / 117P

Example-

27

28

OCH ₂ CH ₃

O].

NH,

CH ₃ CH ₂

¹ N

OCH ₂ CH ₃

Br

OCH ₀ CH,

Br

CH-, CH-

NH,

Br

Br

Br

Br

CH ₀ -CH
ζ

CH
CH-

N '

H ₃ C

^H 2 ^C

cn co ο

_ 36 _

Γ \]

co Co U CN «CN ο CN \ - U / Λ -ζ ■■ -

co CNJ W. ίΰ O CM m. υ

0) • Η P.

K!

(1) PT

O CJ

409822/1170

to

Example • No.

.B *

Br

Β3Γ

"Bar*

-JS-

• Η

409822/1170

c \]

C * J

S.
/ @ CJ U ■; el- Pi
(D
Cl to

Ο \

409822/1170

KJ Oi

Ui

Example-

Zl '

42

(CH,

Br

NH "

Br

.Br

· ^Ι; .Br

(CH ₂ ) ₆ CH ₃

■ CH _n -CH

T Example 43

1141 g- ^ Diliydrop'Yrldo / ä, 1-ΐ? / ΖΪ. ».IZhenzMiazemn

A solution of 18 g of 2-Araino-1 - = - (ö - l3rompiienäthyl) ^ pyf'liniuin - "brömid and 14.7 S potassium carbonate in 100 ml of il-Proprafiöl and 0.5 g of copper bronze is added to 2ÖÖ ml ¥ ¥ water and heated to 9Ö ° C for 2 1/2 hours under nitrogen as a protective gas and with stirring * The mixture is then cooled down three times each time. 10ö ml of diethyl ether extracted * Boron extract is washed, dried and evaporated * The residue is made from di- *

Or iso-propyl ether uffiltristailisiert, iiusbetite 10 g of the title verbiii ". Fertilized by F, 122 Ms ⁰

example

tS Sing solution of 3.3 g sodium methylate in 12 ifll wääs'erfreiffl methanol is mixed with 1, S g prepared according to Example 1 (G) 2 ^ iüöillö-i- (ö-l3i ^s ömphenätliyI) -pyf ⁱ idinillQTDrömid * The LÖ The mixture is stirred for 2 hours under nitrogen and then heated for 5 hours under liquid

2Q . The solution is diluted with reduced black and the residue is digested with 20 ml of anhydrous dietary ether. The ethereal solution is washed off gietfööknet and untei * vfrmiiidertem i evaporated * Sä Mnterbitlfoeä B ₁ B g eifttiS gelofü fgätttoffs, -dö'r after Ümkristallisatiön axxä KexSii % ύί 68 feis 7Ö ^ö ß söhfflilzt »

.,. BZbenzödlazeMft . -

5> 6 g of the compound obtained in (A) in 100 ml of xylene are mixed with 2.8 g of potassium carbonate and 0.5 g of copper brown and refluxed for three hours. The mixture is then fil- j

4018 tti HfO.

2365300 and the filtrate evaporated under reduced pressure. * The residue is crystallized from diisopropyl ether. Ausfaett * te _f 2 3 g of TitelverMridung mp 122 to 124 ° C.

'Examples 45 Ms 4?

According to example Ί (Β) Ms (G), but using the fertilizer in • Iföfbindüngen listed in column 1 in stage (b) and using of the 2-amino pyridines listed in column 2 in stage (F) are the pyridine compounds listed in column 3 and from this the benzodiazocines listed in column 4 are prepared. ~.

9022/1170

κ \

OJ

PQ U CM PQ U CM it! υ

m U CM CQ υ CN W. υ

CM

CO CM CM

ill K O

U — CJ -!?; - to

CN]

ro CN] CM M. m ι α O CQ U-C 3-ω M. CQ CM U CM O

C)

• H ω fQ

in vn

4098.2-2 / 1 170

evr

η cn υ — υ—

I. φ • Η Pi co u φ

L--

4098 2 2/1170

236S303

1 ; Examples 40 Ms 55 '

According to Example I _7, however, dividing the 2 xainopyridines listed in column 1, the pyridinium compounds listed in column 2 are obtained.

FQ

Φ ' U PQ

Φ k

PQ.

(N

Φ Ή

Gr PQ

409822/1170

_ 47

ti

CM

in Eü

ω • Η P. to century • Η Iu ω PA

CAJ in

ΙΓ \

4098 22/1170

ro

O / ro Φ Φ « 5-1 U CQ m

(M

- ■ *

CM

φ Ig ρ- *

(V

tr}

CN

- «κ

CN

(0

\ / S

ro

CN

/
U ■ Ό " ro Lf \ J T-I - (U • rl P, · a f •H ; .: / j) PI

Lf \

0 9 8 2 2/117 0 BAD ORIGINAL

1 . . ■ Examples 5G bi-; 67

According to 1 (B) to 1 (G), but using the information in column 1 listed: connections and using the in column 2 The aminopyridines listed are obtained in column 3 Pyridinium compounds and from these the benzodiazepines listed in column 4.

4 0 9 8 2 2/117 0 BAD ORiGINAi

IO

c / i

to

example

■ Ο eat CO

BrCH ₂ CH ₂ -

56

Br I

57

BrCH-CH

Br

rCH ₂ CH,

Br

NS-

H ₃ C

CH-

of TO] ■:

Br I

(CH ₂ ),

.Br

NS-

H ₃ C

Y ^^

X ^

N.

NS-

CD

CQ

α CN H! U U m Λ H Φ • Η · P-: £ < ΟΛ toi-; ΙΓ \ • Η ω -

CN

O V.)

AO3822 / 1 170

U (N

do

ν-VO

Lf ",

H OJ

• rl -

Vl O)

vo

• r ^ m: -m.

| if \

170

(N ■ VO M. ic
ο m Vv) m CM CNJ
5U υ ρ H m PQ t- VO

4 0 9 8 2 2/1170

BATH

Γ 54 "T

1 -example 6s _

Herst ell u?] R siner. Medicinal product in Ka ^ aelform }? Es'. "; - and - :: o" ⁱ ~ -r ^:. mg / capsule ■ '"

11,12-Dih3'dropyrido / 2.1 // b i, 3_ / benzodiazepine 400, ^Jc: strength 80

■ 5

The drug, the starch and the magnesium stearate are mutually exclusive mixed. The mixture becomes more suitable in hard gelatin capsules Size up to a filling weight of 485 mg / capsule

filled. · '"

Example 69 ''

, Manufactu! - ·; -; of a medicinal product in tablet form Components mgc / tablet

12,13-dihydro-3-diethylmercapto-11H-pyrido /// i7d

300

Lactose '. :. 200

Corn starch (to mix) ■ - 50-

Corn starch (for paste production). 50

Ilagnesium stearate 6. "■■ -...

The medicinal substance, the lactose and the corn starch (for mixing) are mixed together. The corn starch for paste production is dissolved in water in an amount of 10 _; g / βθ ml Viasser suspended and heated with stirring until a paste forms. This paste is used to granulate the Pulvergem.lsch.es. · The moist granulate is passed through a sieve min the clear .Maschenweite 2.33 and dried at 50 ⁰ C. Thereafter

L-,. J

- ^: ". · .... ....-.- 409822/1170 BADORiGINAL

^Γ _ 55 _

7365309 the moist granulate is passed through a Zxeb dor clear! Ιει ^ ν-ον v'eite 1,0 rnrri. The mixture is mixed with I-Jag ^ f ^ iiinstoara as a lubricant and compressed in a tabletting machine s; u tablets- Each tablet reveals 500 ;;> g of the Arr-.noj

5 ßoffs.

At -ε ρ ie 1 70 Eerste "! Ιυ'αρ; of a remedy" yes Fon: nines .'Jirv.Dg

■ ° ml 150 ag 90 mg 10 mg 10 rag 50 mg 100 ml

. 11,1.2 - dihydropyrido / 2,1 -b // i, 27benzod; .a ™ epin; 500 ng

Sorbitol solution (70 percent N.F.) sodium benzoate

Sucaryl

Saccharin. . "

15 red dye (F.D. & C. No. 2) cherry flavor

distilled water ad

The sorbitol solution is added to 40 ml of distilled water, and the drug is suspended in this solution. Thereafter v / ground sucaryl, saccharin, sodium benzoate, cherry ar-ia and the red dye dissolved in the solution. The volume of v.'ircl is made up to 100 ml with distilled water.

In this medicinal product, other components can also be used instead of the aforementioned components. For example, a suspending agent such as Bentonitnagma, tragacanth, or I-CarboxymQthylcellulose Ietliyloellulose Vej ^r .-; Ondet v / ground.

Piinsphate, Citrate or Tartrate can be used as Pufforsubctanr.on

.-: 409822/1170

BATH ORIGINAL

1 verv / on-ί · '■ · "'" --- ' -.- ■ order, v-j ο other arc- ".: ■

_ 56 _
■■ .οC "-r;: V = · λ" όοπ1χ: "'' ode

The inventive pyridinium compounds of the general Formula I and II -

(CH ₂ J ₁ .

(D

(II)

are valuable intermediates for the production of dihydro pyridobensodiazepines and -benzodicizocines of the general Formula Ia

(Ia)

In which R, R ', m and η have the above meaning, by' Condensation in a solvent with a base and. against- ■ · War of copper as a catalyst and optionally converting the compound obtained with an inorganic or organic one . Acid in their salt.

-40 9 82Z / 1 1 7 0

Claims (6)

1 Pate n tansprüche V 1,2-dihydro-2-iminopyriüinderivate of the general formula (H) _m -i- ^ / r * ¹ (II) in u.er R is the same or different and a ``. an alkyl mercapto radical with "1 to 4 carbon atoms, a benzyl, phenethyl, ^ henyl, Pliehy! mercapto or one with a fluorine, chlorine, bromine or iodine atom, an alkyl radical with 1 to 4 carbon atoms, an alkoxy group having Ί to 4 carbon atoms or a trifluoromethyl group mono-substituted phenyl 'group, and R is in the 3- and / or 5-position, v. hen ^r R a Plalogenatoia, R' represents a hydrogen, fluorine, chlorine -, bromine or iodine atom, an alkyl radical with 1 to 9 carbon atoms, an alkoxy radical with 1 to 4 carbon atoms, an alkyloercapto radical with 1 to 4 carbon atoms, an alkylsulfonyl radical with 1 to 4 carbon atoms, a phenyl, phenylο χγ , sulfanoyl or Dialkylamidosulfonyl group with 1 to 4 carbon atoms in each alkyl radical, a trifluoromethyl or a fluorine, chlorine, bromine or iodine atom, an alkyl radical with 1 to 4 carbon atoms, an alkoxy radical with 1 to 4 carbon atoms or a trifluoromethyl r group denotes a monosubstituted phenyl or phenyloxy group, m denotes 1 or 2 and η denotes 2 or 3. L - ■ 4 09822/1170 2. '1,? «Dihydro-2 ~ iniiriD-1- (o ~ bro] i! Ph'r ⁱ näthYl) - pyridine. 3. Compound til the general formula I. .Br (D NH Br in the R, Il ^! , ra and n, the meaning given in claim 1 '. to have. 4. 2-An; iiio-'1- (o - bromophenethyl) ~ pyrj.diniumbro: ßid. 5. 2-Amino-1 - / 3- (2-bromo-4-ffiethylmercaptophenyl) propyl / pyridine bromide. - 6.. Use of the compounds according to Claim 1 as bactericides. BATH ORIGINAL 409822/11