CH637929A5 - Process for the preparation of optically active azabicycloalkanes - Google Patents

Description

The invention thus relates to a process for the preparation of new azabicycloalkanes which are active analgesic drugs.

The new, optically active azabicycloalkanes obtainable according to the invention have the general formula:

fjrO

x wherein the phenyl radical is unsubstituted or mono- or disubstituted with halogen atoms, straight-chain alkyl groups with 1 to 6 carbon atoms, mono-branched alkyl groups with 1 to 5 carbon atoms, alkoxy groups with 1 to 6 carbon atoms, trifluoromethyl groups, nitro groups, amino groups, acetamido groups and / or hydroxyl groups is and

X is a hydrogen atom, a straight-chain alkyl group having 1 to 8 carbon atoms or a group of the general formula CnH: nRi,

in which n stands for an integer with a value from 1 to 3 and Ri for a phenyl group or a p-fluorobenzoyl group,

means.

The invention also relates to the preparation of racemic mixtures of these compounds, their mirror isomers and the non-toxic, pharmaceutically acceptable salts of these compounds.

Preferred among the compounds obtainable according to the invention are those in which the phenyl radical is unsubstituted or by a halogen atom, a straight-chain alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, a trifluoromethyl group, a nitro group, an amino group, one Acetami-dogruppe or a hydroxy group is monosubstituted and X has the meanings given above.

Among these, those in which X represents a hydrogen atom or a straight-chain alkyl group having 1 to 8 carbon atoms are further preferred.

Among the latter, those compounds are further preferred in which the phenyl radical in the para or meta position is substituted by a straight-chain alkyl group having 1 to 6 carbon atoms, a halogen atom or a trifluoromethyl group and X has the meanings given above.

Among the latter, those compounds are further preferred in which the phenyl radical is substituted in the para or meta position by a methyl group, an ethyl group, a chlorine atom, a fluorine atom, a bromine atom or a trifluoromethyl group and X has the meanings given above.

Among the latter, those compounds in which the phenyl radical substituted in the above manner represents a hydrogen atom or a methyl group are further preferred.

The salts of the new compounds can be, for example, the hydrochlorides, the hydrobromides, the hydroiodides, the sulfates, the nitrates, the phosphates, the maleates, the succinates and the like.

According to the invention, the compounds of the formula I and the racemic mixtures, mirror isomers and pharmaceutically acceptable salts of these compounds are prepared by using a compound of the general formula:

wherein the phenyl radical is unsubstituted or substituted as above, X has the meaning given above, one R represents an oxo group or a hydroxyl group and the other R represents a hydrogen atom or also an oxo group or hydroxyl group, at a temperature of -70 ° C to 125 ° C is reacted with a hydride reducing agent in an inert, aprotic solvent and the compound obtained is optionally split into its mirror isomers and / or converted into its pharmaceutically acceptable salts.

According to a particular embodiment of the invention, the compounds of general formula II are dissolved in a solvent, such as benzene, toluene, ether, tetrahydrofuran and the like, and with a reducing agent, such as sodium bis (2-methoxyethoxy) aluminum hydride , at a temperature from about 0 to about 125 ° C, preferably from 25 to about 80 ° C, for a period of 1 to 4 hours. The reaction mixture is cooled and a strong base such as potassium hydroxide is added. Then the organic layer is concentrated and the product is obtained by filtration.

A large number of other hydride reducing agents, such as diborane or lithium aluminum hydride, can be used to prepare the compounds of the general formula I. In this case, the compounds of the general formula I are suspended in tetrahydrofuran, the reducing agent is added and the reaction is carried out at 0 to 80 ° C. for 1 to 4 hours. The reaction mixture is then cooled, acidified with an acid such as hydrochloric acid, the aqueous layer is separated off and the product is released by adding a strong base such as potassium hydroxide.

For example, the compounds of the general formula I above can be prepared by adding a lactam of the following general formulas x

or S

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4th

/ \

N / ns

0

wherein X has the meanings given above, with a suitable reducing agent, such as lithium aluminum hydride, diborane, sodium bis (2-methoxyethoxy) aluminum hydride, in an aprotic solvent, such as ether, benzene or tetrahydrofuran, at a temperature of 0 to s 80 ° C for 1 to 6 hours. The compound of general formula I is isolated in the manner described for the reduction of the corresponding imides of general formula II.

The above reaction can be carried out using a limited amount of the reducing agents mentioned, so that if X represents a hydrogen atom, the intermediates of the following general formulas or are obtained, while if X is not a hydrogen atom, the intermediates of the following general formulas or receives.

The compounds are then reduced to the compounds of the general formula I in the manner described above.

The compounds of the general formula II above, in which both R are oxo groups, used from starting materials can be prepared according to the following reaction equation:

+ XWHCONHX-

COOH C00H

/ \

n / A

o ^ v o

I.

X

(IIa)

wherein X has the meanings given above.

For this purpose, the starting materials are heated in an aprotic solvent, such as xylene, for 6 to 24 hours, and the product is then obtained by evaporating the solvent.

Certain cis-dicarboxylic acids of the following general formula:

CL

u in which U and V, which may be the same or different, groups of the general formula -CO2R4, in which R4 represents an alkyl group having 1 to 6 carbon atoms, or Cya-50 no groups, with a suitable base, such as sodium hydroxide or potassium hydroxide , in a suitable solvent, such as methanol, ethanol or water, heated to a temperature of about 30 to about 100 ° C. for about 3 to about 18 hours and then the free acid is released with a suitable mineral acid, such as hydrochloric acid or sulfuric acid.

The compounds of the above general formula, in which U represents a cyano group and V stands for a group of the formula -CO2R4, can be prepared by reacting a bromine ester 60 of the general formula by preparing a compound of the following general formula:

hc02r4

in which R4 has the meanings given above, with

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an acrylonitrile of the general formula RHC = CRCN, in the manner described for the preparation of the diesters. The compounds of the above general formula in which U is a group of the general formula -CO2R4 and V is a cyano group can be reacted with a bromophenylacetonitrile of the general formula

: hcn

Br using an acrylic acid ester described above. The lactams of the following general formula can be derived from the above-described cyanoesters of the general formula cn in which Ri represents a hydrogen atom or a Ct-Cs-alkyl group, by reduction with diborane in a solvent such as tetrahydrofuran, for about 1 to about 3 hours a temperature of about 0 ° to about 60 ° C and reacting the intermediate formed with a mineral acid such as 6N hydrochloric acid.

Similarly, the lactams of the following general formula in which R has the meanings given above can be prepared by reducing a cyanoester of the following general formula c02r3 cn in which R3 has the meanings given above in the manner described above.

The compounds which can be prepared according to the invention are in the form of optical isomers, that is to say the left-handed shape, the right-handed shape and the racemate, the manufacture of which is the subject of the invention. The optical isomers of the compounds of formula I can be prepared by using a variety of methods to split them into the optical isomers.

First, one can start from optically active starting products of formula II and apply the method according to the invention to them.

According to one method, a cis-dicarboxylic acid of the following general formula:

with an optically active amine, for example (-) - a- (l-naphthyl) ethylamine, in a suitable solvent such as methanol, ethanol, acetone, tetrahydrofuran or acetonitrile, to form a salt which is 1 molar equivalent of (+) - Dicarboxylic acid and 1 mole equivalent of the above (-) - amine contains. In certain cases, and in particular when the phenyl radical is substituted by one or more alkyl groups, and in particular when the aryl radical is the p-tolyl group, it is advantageous to use a mixture of tetrahydrofuran and ether as the solvent.

The racemic dicarboxylic acid described above can also be reacted with (-) - 2-amino-1-butanol in a suitable solvent, as described above, to give a salt which contains the (+) - dicarboxylic acid as the acid residue. The salts formed in this way can be converted into the corresponding (H -) - dicarboxylic acid by treating them with a suitable base, such as sodium hydroxide, potassium hydroxide, ammonium hydroxide or potassium carbonate, and then the aqueous solution with a suitable acid, such as hydrochloric acid or sulfuric acid , acidified. To form the (-) - dicarboxylic acid, a cis-dicarboxylic acid of the following general formula with an optically active amine, such as brucine or (+) - a- (l-naphthyl) ethylamine or (+) - 2-amino-1 -butanol in a suitable solvent, as described above, to a salt which contains the (- ^ dicarboxylic acid as an acid residue.

These salts can be converted into the corresponding (-) - dicarboxylic acid in the manner described above. The (+) - or (-) - dicarboxylic acids described above can be converted into the (+) - or (- ^ compounds of the following general formula:

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IS

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in which X has the meanings given above, implement. These imides can then be reduced in the manner described above, so that the optically active left-handed or right-handed forms of the compounds of the formula I are obtained.

Alternatively, you can a racemic compound of formula I with an optically active acid such as (+) - or (-) - mandelic acid, (+) - or (-) - tartaric acid, (+) - or (-) - di-O -benzoyltartaric acid or (+) - or (-) - di-O- (p-toluoyl) -tartaric acid in a suitable solvent, such as methanol, ethanol, acetone, acetonitrile or tetrahydrofuran, to the corresponding salt. By reacting the salt formed with a suitable acid, such as hydrochloric acid or sulfuric acid, and then making the aqueous solution alkaline with a base, such as sodium hydroxide, potassium hydroxide, ammonium hydroxide or sodium carbonate, the compounds of the formula I are obtained in optically active form.

The following are particularly preferred azabi-cyclohexanes obtainable according to the invention:

1 - (p-chlorophenyl) -3-azabicyclo [3.1.0] hexane, 1 -phenyl-3-azabicyclo [3.1. Ojhexane, 3-methyl-l-phenyl-3-azabicyclo [3.1.0] hexane, l- (m-chlorophenyl) -3-azabicyclo [3.1.0] hexane, l- (m-fluorophenyl) -3-azabicyclo [3.1.0] hexane, l- (p-chlorophenyl) -3-methyl-3-azabicyclo [ 3.1.0] hexane, 3-benzyl-l-phenyl-3-azabicyclo [3.1.Ojhexane, 3-phenethyl-l-phenyl-3-azabicyclo [3.1.Ojhexane, 1 - (p-trifluoromethylphenyl) -3-azabicyclo [ 3.1 .Ojhexane, 3-ethyl-l-phenyl-3-azabicyclo [3.1.Ojhexane, l- (p-methoxyphenyl) -3-azabicyclo [3.1.0] hexane, 3-ethyl-l- (p-aminophenyl) - 3-azabicyclo [3.1.0] hexane, l- (3,4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane, l- (m-methoxyphenyl) -3-methyl-3-azabicyclo [3.1.Ojhexane, (+) - Phenyl-3-methyl-3-azabicyclo [3.1. Ojhexane, 1 - (4-chloro-a, a, a-trifluoro-m-tolyl) -3-azabicyclo [3.1. Ojhexane, l- (p -Acetamidophenyl) -3-ethyl-3-azabicyclo [3.1.0] hexane,

I - (m-Hydroxyphenyl) -3-methyl-3-azabicyclo [3.1. Ojhexane, l- (p-nitrophenyl) -3-azabicyclo [3.1. Ojhexane, l- (p-tolyl) -3-azabicyclo [3.1. OJhexane hydrochloride, l- (o-chlorophenyl) -3-azabicyclo [3.1.Ojhexane.

The compounds obtainable according to the invention are useful analgesic agents for warm-blooded animals, which has been shown in corresponding pharmacological studies. An investigation method is a modification of the method of Randall and Selitto [Arch. Int. Pharmacodyn.,

II (1957) 409J. This study examines the pain threshold of rats whose paws have been made sensitive to pressure by injecting 0.1 ml of a 20% aqueous suspension of brewer's yeast into the sole skin of the left rear paw. Then you apply a constantly increasing pressure (16 g / sec) to the swollen paw using an analgesia meter (Analgesy Meter, Ugo Basile). The pressure is interrupted at a force of 250 g if there is no reaction (free fighting or screaming). Control rats that have only been treated with the starch carrier material respond at a pressure of approximately 30 g. The pressure-pain threshold values are determined several hours after the administration of the compound to be examined (with the estimated maximum effect) at doses of up to 200 mg / kg which are given orally. The brewing yeast is administered two hours before the pain threshold values are measured. The ratios of the values of the treated animals (T) and the control animals (C) are calculated and used to determine the activity and the potency via dose-response.

tion experiments and / or to determine the analgesic efficacy (which is higher the greater the T / C ratio). For example, the compounds examined can be described as active (in a significant way compared to control examinations) if they lead to an increase in the pain threshold of 100% (T / C ^ 2.0). If results are obtained which show activity, one or more of the following tests can be carried out: repeated test at the same dose for confirmation; Examination at a lower dose; Determination of the duration and the time of the maximum effect; Dose-response estimates of potency; Determination of the maximum effectiveness (maximum value of T / C), for which one uses known test methods.

Representative representatives of the compounds (I) also show an analgesic effect when examined by a method which is a modification of the method by D. C. Atkinson and A. Cowan [J. Pharm, phar-macol. 26 (1974) 727J.

In this study, male albino rats of the Wistar strain from the Royalhart farms weighing 120 to 150 g were fasted for about 20 hours. A 40% suspension of brewing yeast in physiological saline at a concentration of 0.25 ml / rat is then injected into the sole surface of the left hind paw of each rat. Three hours later, after which time the inflammation of the injected paw has developed, the running ability of the rat is assessed before the administration of the active substance to be investigated using the following evaluation scale:

0 = normal gait in the presence of a severely inflamed paw. The sole of the foot is used continuously.

0.5 = as above for temporary weak limping. 1.0 = constant limping, but constant use of the sole of the foot.

1.5 = limp with a partially three-legged gait (raising the paw) or with intermittent use of the toes in combination with the sole of the foot. 2.0 = constant gait on three paws and / or the tips of the toes that touch the surface of the floor, whereby the sole of the foot is not used.

More than 95% of the rats show a gait rating of 2 before administration of the compound to be examined. The compounds are then administered orally in a suitable carrier material via a probe in a volume of 0.5 ml / 100 g of body weight. Then, in the manner described above, one and / or two hours later, the gait evaluation after administration of the active ingredient is examined. The determined evaluation number is then compared with the evaluation number before administration of the active ingredient. The results obtained are used to determine activity, estimate dose response, potency, etc. If, for example, overview examinations are carried out in which three animals are used per dose, an evaluation number before the treatment with the active ingredient of 6 (2.0 × 3) and an evaluation number after the treatment with the active ingredient of 4 (for 3 animals) as a significant effect over control. To estimate the dose response, it can be assumed that a single animal will have an analgesic effect if the gait score improves the gait score by ^ 50% prior to drug administration (2.0) will (what an evaluator6

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number after administration of the active ingredient corresponds to ^ 1.0).

Another method for determining the action of the compounds of the formula I is the “convulsive syndrome” test by Siegmund et al [Proc. Soc. Exp. Biol. And Med. 95 (1957) 729], which is modified in a certain way. This method is based on the reduction in the number of convulsive movements which occur after the intraperitoneal injection of 1 mg phenyl-p-quinone per kg of body weight in male albino mice of the Swiss strain with a weight of 18 to 25 g. The syndrome is characterized by characteristic intermittent contractions of the abdomen, twisting and twisting of the trunk and stretching of the hind paws, which occurs 3 to 5 minutes after the phenyl-p-quinone injection. The compounds to be investigated are administered orally in the specified dosage to groups of two mice 30 minutes before the injection of the phenyl-p-quinone. The total number of spasms observed in each group of mice is examined over a 3 minute period, which time period begins 15 minutes after the phenyl-p-quinone injection. A compound is considered active if it reduces the total number of convulsions in two under-10 mice sought from a control cast of approximately 30 per pair to a value of 18 or less.

The results obtained with representative compounds of the formula I in one or more of the tests described above are summarized in Tables 15 I and II below.

Table I

Investigation of the analgesic effect

X

Examination method

Phenyl

X

Restoring the effect against

Pain sensation of the

Substituent

normal gait (rat) convulsions (mouse)

inflamed paw (rat)

p-Cl

H

A (100) *

A (50) *

A (100) *

p-Cl

H (-) - isomer

A (100)

p-Cl

H (+) - isomer

A (50)

A (100)

A (50)

H

H

A (150)

A (100)

A (200)

H

Me

A (150)

A (100)

A (200)

m-Cl

H

A (50)

A (200)

A (50)

m-F

H

A (100)

A (50)

H

H (-) - isomer

A (100)

A (50)

H

Me (-) - isomer

A (50)

p-Cl

Me (-) - isomer

A (100)

p-Cl

Me (+) - isomer

A (150)

A (100)

p-Cl H

Me

-CH2- <£ ^

A (200)

A (100)

«

H

-CH: CH2_ <f ^

A (100)

p-CFs

H W

A (150)

A (50)

H

Et

A (200)

p-MeO

H

A (100)

A (50)

H

H (+) - isomer

A (200)

A (50)

A (50)

3,4-di-cl

H

A (200)

p-Et

H

A (25)

A (50)

m-me

H

A (50)

A (25)

A (50)

p-Br

H

A (200)

p-F

H

A (100)

A (50)

A (50)

p-Br

-ch2- <2>

A (200)

m-MeO

Me

A (100)

A (50)

A (50)

H

Me (+) - Isom.

A (200)

4-C1-3-CF3

H

A (200)

p-NO:

H

A (200)

p-me

H

A (200)

A (60)

A (50)

m-CF3

H

A (25)

A (50)

3-Br-4-MeO

H

A (200)

p-me

H (+) - Isom.

A (50)

A (25)

A (50)

p-me

H (-) - Isom.

A (100)

A (50)

p-me

Me

A (100)

A (50)

* Active (at the specified dose in mg / kg given orally). Me = methyl; Et - ethyl

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Investigation of the analgesic effect

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Table I (continued)

'N

Phenyl substituent

Examination method

X

Restoration of normal gait (rat)

Effect against pain sensation of the

Cramping movements (mouse) inflamed paw (rat)

p-OH p-EtO p-Cl H

m-MeO

H A (200)

H A (50)

Et ^

- (CH2> CO p A (200)

H A (200)

A (50)

A (100)

Me = methyl; Et = ethyl

The azabicyclohexanes of formula I can be administered orally, for example using an inert diluent or an assimilable, edible carrier, or they can be placed in hard or soft gelatin capsules, compressed into tablets or administered directly with the food or feed. For oral therapeutic administration, the active ingredients can be incorporated into customary auxiliaries and used in the form of tablets, lozenges, capsules, elixirs, suspensions, syrups, wafers and the like. These preparations and preparations should contain at least 0.1% of the active compound. The percentage of these compounds in the formulations and preparations can, of course, vary and suitably make up about 5 to about 75% or more of the weight of the unit dose. The amount of the active ingredient in such therapeutically useful preparations or preparations is so large that a suitable dosage is achieved. The preferred preparations or preparations are prepared such that the unit dosage form to be administered orally contains 10 to 400 mg of the active ingredient. A most preferred embodiment of the drug is an oral dosage form containing about 50 to about 250 mg of the active ingredient.

The tablets, troches, pills, capsules and the like may further contain the following: a binder such as tragacanth, acacia, corn starch or gelatin; a carrier material such as dicalcium phosphate; a tablet disintegrating agent such as corn starch, potato starch, alginic acid and the like; a lubricant such as magnesium stearate; and a sweetener such as sucrose, lactose or saccharin; as well as flavorings such as peppermint, wintergreen oil or cherry aroma. When the dosage form is a capsule, it may contain liquid carriers such as a fatty oil in addition to the materials of the above type. Various other materials may also be present, such as coatings or similar products, to modify the physical form of the dosage unit; for example, the tablets, pills or capsules can contain the active ingredients, sucrose as a sweetener, methyl and propyl paraben as a preservative, a colorant and a flavoring such as cherry or orange. Of course, the materials administered to produce any unit dosage forms should be pharmaceutically pure and essentially non-toxic in the amounts used.

Preparations with the desired clarity, stability and suitability for parenteral use are obtained by dissolving 0.10% to 10.0% by weight of the azabicyclohexane in a carrier material which is a mixture of non-volatile, normally liquid Polyethylene glycols that are soluble in water and organic liquids and have a molecular weight of about 200 to about 1500. Such mixtures of polyethylene glycols are commercially available and are generally formed by condensing glycol with ethylene oxide. Although the amount of azabicyclohexane dissolved in the above carrier material can vary from 0.10 to 10.0% by weight, the amount used should preferably be about 3.0 to about 9.0% by weight. Although various mixtures of the non-volatile polyethylene glycols mentioned above can be used, a mixture of non-volatile polyethylene glycols which have an average molecular weight of about 400 is preferably used. Such a mixture is generally referred to as polyethylene glycol-400. A preferred embodiment comprises a clear solution which contains about 3.0 to about 9.0% by weight of azabicyclohexane dissolved in an aqueous solution of polyethylene glycol-400. In addition to azabicyclohexane, the solutions to be administered parenterally may additionally contain various preservatives which can be used to prevent bacterial and fungal contamination or chemical decomposition of the preparation.

The following examples serve to explain the invention further and deal with the preparation of representative compounds of the formula I.

example 1

Production of racemic l- (p-chlorophenyl) -3-azabi-cyclo [3.1.0] hexane hydrochloride.

A solution of 2 g of l- (p-chlorophenyl) cis-60 1,2-cyclopropanedicarboxylic acid diethyl ester (US Pat. No. 3,344,026, Example 1) in 25 ml of ethanol is treated with 13.5 ml of an in potassium hydroxide solution. The reaction mixture is then heated to reflux for 3.5 hours and then left to stand at room temperature overnight. The ethanol is removed under reduced pressure and the aqueous solution is extracted with ether to remove a small amount of the mineral oil. The aqueous solution is treated with 13.5 ml of hydrochloric acid and 2 ml of 6N chlorwas30

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seric acid. The oil-water mixture is extracted four times with chloroform. The chloroform solution is dried, removed and concentrated under reduced pressure to give a yellow solid. By recrystallizing twice from an ethyl acetate / petroleum ether (30 ° to 70 ° C) mixture, 0.85 g of 1 - (p-chlorophenyl) -cis-1,2-cyclopropanedicarboxylic acid is obtained in the form of a white solid which is at 162 to 163 ° C melts.

5.7 g of the acid obtained in the above manner and 2.02 g of urea in 200 ml of xylene are heated to reflux for 22 hours, cooled, diluted with benzene and washed with water. The organic layer is diluted with chloroform, dried, concentrated under reduced pressure and recrystallized from ethyl acetate and petroleum ether to give l- (p-chlorophenyl) -1, 2-cyclopropanedicarboximide. is

To a stirred solution of 30 ml of sodium bis (2-methoxyethoxy) aluminum hydride (in the form of a 70% solution in benzene), a solution of 2.2 g is added dropwise over a period of 30 minutes at room temperature under a nitrogen atmosphere 1 - (p-chlorophenyl) -1,2-cyclo-20-propanedicarboximide in 100 ml of benzene. The reaction vessel is warmed slightly to keep the materials dissolved. The clear yellow solution is then heated under reflux for 1 hour under a nitrogen atmosphere. The solution is cooled and the excess reagent is decomposed with 5N sodium hydroxide solution. Water is added to the mixture and the benzene phase is separated off. The aqueous phase is extracted with ether, whereupon the ether extracts are combined with the benzene phase and dried over magnesium sulfate. This organic phase is evaporated under reduced pressure to a viscous liquid which crystallizes out to form a sticky, dirty-white solid, the racemic l- (p-chlorophenyl) -3-azabicyclo- [3.1.0] hexane in the form the base contains. This solid is dissolved in ethanol, made acidic with ethanolic hydrochloric acid solution and mixed with ether, whereby the hydrochloride is obtained in the form of dirty-white crystals. The hydrochloride is recrystallized from ethanol and dirty-white crystals with a melting point of 215 to 217 ° C. are obtained. 40

Example 2

Preparation of (-) - l- (p-chlorophenyl) -3-azabi-cyclo [3.1.0] hexane hydrochloride.

To a stirred solution of 30 ml of sodium bis (2-methoxyethoxy) aluminum hydride (in the form of a 70% solution in benzene), a solution of 6 is added dropwise over 3 hours at room temperature under nitrogen. 6 g (-) - l- (p-chlorophenyl) -l, 2-cyclopropanedicarboximide (US Pat. No. 3,892,772) in 500 ml of benzene. The yellow solution, which is so clear, is heated to reflux under nitrogen for 90 minutes and then kept at room temperature overnight. The excess hydride reagent is decomposed by carefully adding 25 ml of 5N sodium hydroxide solution. Then the mixture is diluted with 200 ml of pure water. The benzene phase is separated off, the aqueous phase is extracted with chloroform, the combined benzene and chloroform phases are dried over magnesium sulfate and concentrated under reduced pressure, giving (-) - l- (p-chlorophenyl) -3-azabicyclo [3.1 .0] hexane in the form of a yellow solid. This solid is dissolved in ethanol and made acidic with 10 ml of 2.3N ethanolic hydrochloric acid solution. By adding ether, the hydrochloride of this base precipitates in the form of a solid, which is separated off and dried to form white crystals. 65 F = 197 to 200 ° C.

[a] gHl0H = -67 ° C.

Example 3

Preparation of (+) - l- (p-chlorophenyl) -3-azabi-cyclo [3.1.0] hexane hydrochloride.

A mixture of 192.5 g of racemic cis-l- (p-chlorophenyl) -l, 2-cyclopropanedicarboxylic acid (US Pat. No. 3,892,772) and 142 g of (-) - 2-aminobutanol in 1600 ml of acetone is left in for 48 hours stand, filtered and washed the solid with acetone. The solid is dissolved in 460 ml of warm water and made acidic. The solid is filtered off and dried in air. A mixture of 107.5 g of this crude (+) - dicarboxylic acid and 79.3 g (-) - 2-aminobutanol in 892 ml of acetone is left to stand for several hours. The solid is then filtered off, dried, dissolved in 200 ml of warm water, acidified with concentrated hydrochloric acid, cooled and filtered. This solid is recrystallized from acetonitrile to give (-t -) - cis-l- (p-chlorophenyl) -l, 2-cyclopropanedicarboxylic acid.

[cc] gH) 0H = + 180 ° C.

10.5 g of this (+) - dicarboxylic acid and 3.9 g of urea are stirred in 325 ml of xylene, then heated to reflux for 7.5 hours and then left to stand overnight. By distilling off the xylene, cooling and filtering, a white solid is obtained, which is recrystallized from ethanol to give (+) - l- (p-chlorophenyl) -l, 2-cyclo-propanedicarboximide.

[a] gHj0H = + 63 ° C.

To a stirred solution of 30 ml of sodium bis (2-methoxyethoxy) aluminum hydride (in the form of a 70% solution in benzene) is added dropwise a solution of 4 in the course of 45 minutes with stirring at room temperature and under nitrogen. 5 g (+) - l- (p-chlorophenyl) -l, 2-cyclo-propanedicarboximide in 400 ml benzene. The clear yellow solution is heated to reflux under nitrogen for 90 minutes and then kept at room temperature overnight. The excess hydride reagent is decomposed by carefully adding 25 ml of 5N sodium hydroxide solution. The mixture is then diluted with 200 ml of water and the benzene phase is separated off. The aqueous phase is extracted with chloroform, the combined benzene and chloroform phases are dried over magnesium sulfate and concentrated under reduced pressure, giving (+) - l- (p-chlorophenyl) -3-azabicyclo [3.1.0] hexane in the form of a sticky yellow solid. This solid is dissolved in ethanol and acidified with 20 ml of 2.3N ethanolic hydrochloric acid solution. 200 ml of ether are added, crystals forming, which are recrystallized from acetonitrile, so that the hydrochloride is obtained in the form of white crystals with a melting point of 190 to 192 ° C.

[a] gHs0H = + 63 ° C.

Example 4

Production of racemic l-phenyl-3-azabi-cyclo [3.1.0] hexane hydrochloride.

A solution of 6.6 g is added dropwise to a stirred solution of 30 ml of sodium bis (2-methoxyethoxy) aluminum hydride (in the form of a 70% solution in benzene) over the course of 1 hour at room temperature and under nitrogen 1-phenyl-1,2-cyclopropanedicarboximide (U.S. Patent 3,166,571, Example 8) in 400 ml of benzene. The reaction mixture is then heated to reflux under nitrogen for 90 minutes. The excess hydride reagent is decomposed by carefully adding 25 ml 10N sodium hydroxide solution. The mixture is diluted with 200 ml of water, the benzene phase is separated off, the aqueous phase is extracted with chloroform and the combined organic phases are dried over magnesium sulfate. The solution is then concentrated under reduced pressure and a brown liquid is obtained which is dissolved in ethanol

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10th

and acidified with 5 ml of 2.3N ethanolic hydrochloric acid. The addition of ether leads to the precipitation of a solid which is recrystallized from acetonitrile to form white crystals. F = 166 ° to 168 ° C.

Example 5

Production of racemic 3-methyl-1-phenyl-3-azabi-cyclo [3.1.0] hexane hydrochloride.

To a stirred solution of 30 ml of sodium bis (2-methoxyethoxy) aluminum hydride (in the form of a 70% solution in benzene), a solution of 5.5 g of N is added dropwise over a period of 1 hour at room temperature under nitrogen -Methyl-l-phenyl-1,2-cyclopropanedicarboximide (US Pat. No. 3,166,571, Example 1) in 400 ml of benzene. The mixture is heated under reflux under nitrogen for 90 minutes. Then the excess hydride reagent is decomposed by carefully adding 25 ml of 10N sodium hydroxide solution and then diluted to 200 ml with water. Then the benzene phase is separated off, the aqueous phase is extracted with chloroform, the combined organic phases are dried over magnesium sulfate and concentrated under reduced pressure Formation of a liquid. The liquid is dissolved in ethanol and made acidic with 15 ml of 2.3N ethanolic hydrochloric acid solution. The addition of ether forms a solid, which is recrystallized from an isopropyl alcohol / hexane mixture to form white crystals. F158 to 160 ° C. *

Example 6

Preparation of I- (m-chlorophenyl) -3-azabi-cyclo [3.1.0] hexane hydrochloride.

While stirring with a metal stirrer made of a nickel-chromium alloy (nichrome), 53.6 g of ethyl m-chlorophenylacetate (which has been prepared by esterifying the corresponding acid), 51.5 g of N-bromosuccinimide and 1 g of benzoyl peroxide are heated in 1.25 liters of carbon tetrachloride at reflux for 20 hours. Then the mixture is cooled, filtered and concentrated to an orange oil. The product is obtained by distillation in vacuo, i.e. a-Bromo-m-chlorophenylacetic acid ethyl ester.

0.5 ml of ethanol is added to a stirred suspension of 4.4 g of sodium in 500 ml of ether under nitrogen. A mixture of 27.8 g of the ester formed in the above manner and 10 g of ethyl acrylate in 1 ml of ethanol is then added dropwise and the mixture is stirred overnight at room temperature. To decompose the unreacted sodium hydride, ethanol is added, the mixture is washed with 100 ml of water, 50 ml in hydrochloric acid, three times with dilute sodium bicarbonate solution and finally with 100 ml of water, whereupon the product is dried and recrystallized under reduced pressure to a yellow liquid which consists of the l- (m-chlorophenyl) -l, 2-cyclopropandicar-bonsäurediäthylester.

22 g of this diester are heated in 150 ml of ethanol and 150 ml in potassium hydroxide solution at reflux for 3.5 hours and then left to stand at room temperature overnight. The mixture is concentrated and extracted with ether. The aqueous phase is made acidic in hydrochloric acid solution, extracted three times with chloroform, dried and concentrated under reduced pressure to give a yellow oil which is recrystallized from an ethyl acetate / petroleum ether mixture, the cis-l- (m-chlorophenyl) -1, 2-cyclopropanedicarboxylic acid in the form of a white solid.

5.7 g of this acid and 2.02 g of urea in 200 ml of xylene are refluxed for 22 hours, cooled, diluted with benzene and washed with water. Then the organic layer is diluted with chloroform, dried, concentrated under reduced pressure and recrystallized from ethyl acetate and benzene ether to give l- (m-chlorophenyl) -l, 2-cyclopropanedicarboximide.

A solution of 4.0 g is added dropwise over a period of one hour at room temperature and under nitrogen to a stirred solution of 30 ml of sodium bis (2-methoxyethoxy) aluminum hydride (in the form of a 70% solution in benzene) l- (m-chlorophenyl) -l, 2-cyclopropanedicar-boximide in 400 ml of benzene. The reaction mixture is heated to reflux under nitrogen for 90 minutes. Then the excess hydride reagent is decomposed by adding 25 ml of 10N sodium hydroxide solution and the mixture is diluted with 200 ml of water. The benzene phase is separated off, the aqueous phase is extracted with chloroform, the combined organic phases are dried over magnesium sulfate and concentrated under reduced pressure to form a viscous, orange-brown liquid.

This liquid is dissolved in ethanol and made acidic with 2.3N ethanolic hydrochloric acid solution. The addition of ether precipitates another solid, which is recrystallized from isopropyl alcohol to form l- (m-chlorophenyl) -3-azabicyclo [3.1.0] hexane hydrochloride in the form of white crystals. F182 to 184 ° C.

Example 7

Preparation of 1 - (m-fluorophenyl) -3-azabi-cyclo [3.1.0] hexane hydrochloride.

46.2 g of l- (m-fluorophenyl) acetic acid are dissolved in 120 ml of ethanol, 12 ml of sulfuric acid are added, the mixture is heated to reflux for 4.5 hours and then left to stand at room temperature overnight. Then 400 ml of water are added, the mixture is extracted three times with ether, dried over magnesium sulfate and concentrated to a liquid under reduced pressure. The l- (m-fluorophenyl) acetic acid ethyl ester is obtained by distillation in vacuo.

While stirring with a metal stirrer made of a nickel-chromium alloy (nichrome), a mixture of 49.3 g of ethyl l- (m-fluorophenyl) -acetate, 53 g of N-bromosuccinimide and 0.95 g of benzoyl peroxide in 1 is heated. 6 liters of carbon tetrachloride at reflux for 24 hours, concentrated to an orange oil and distilled in vacuo to give the ethyl a-bromo-l- (m-fluorophenyl) acetic acid.

A mixture of 65 g of ethyl a-bromo-l- (m-fluorophenyl) -acetate, 25 g of ethyl acrylate and 2 ml of ethanol is added dropwise to a suspension of 11 g of sodium hydride in mineral oil in 1 liter of ether under nitrogen. The mixture is stirred overnight at a temperature of 25 to 29 ° C. Then the mixture is cooled, a few ml of ethanol are added to decompose the unreacted sodium hydride, the mixture is washed successively with water, with in hydrochloric acid solution, dilute sodium bicarbonate solution and saturated sodium chloride solution, then concentrated to a liquid which is distilled in vacuo, with receives the 1 - (m-fluorophenyl) -1,2-cyclopropanedicarboxylic acid diethyl ester.

A mixture of 20.5 g of the above diester and 160 ml in potassium hydroxide solution in 150 ml of ethanol is heated under reflux for 3.5 hours and then concentrated. The mixture is then acidified with hydrochloric acid solution, extracted three times with chloroform, dried and concentrated to a solid under reduced pressure. The solid is recrystallized twice from an ethyl acetate / petroleum ether mixture, giving the cis-1- (m-fluorophenyl) -1, 2-cyclopropanedicarboxylic acid.

A mixture of 8.0 g of the above dicarbonate is heated

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IS

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35

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65

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acid and 2.6 g of urea in 500 ml of xylene with stirring at reflux for 22 hours. The solution is diluted with benzene, washed with water and dried over magnesium sulfate. The organic layer is concentrated under reduced pressure and 1 - (m-fluorophenyl) -1,2-s cyclopropanedicarboximide is obtained in the form of a dirty-white solid.

A solution of 5.6 g of 1- (m-fluorophenyl) -1.2 is added dropwise to a stirred solution of 30 ml of sodium bis (2-methoxyethoxy) aluminum hydride over 90 minutes under nitrogen at room temperature -cy cl opropandi-carboximide in 400 ml of benzene. The reaction mixture is heated to reflux under nitrogen for 90 minutes. Then the excess hydride reagent is decomposed by carefully adding 25 ml of 10N sodium hydroxide solution and the mixture is then diluted with 200 ml of water. The benzene phase is separated off and the aqueous phase is extracted with chloroform. The combined organic solutions are dried over magnesium sulfate and concentrated under reduced pressure to a mixture of an oily solid and a viscous liquid. This mixture is dissolved in ethanol and made acidic with ethanolic hydrochloric acid solution. The addition of ether leads to a precipitation which is recrystallized from acetonitrile, 1 - (m-fluorophenyl) -3-azabicyclo [3.1.0] hexane-25 hydrochloride being obtained in the form of gray crystals.

F 140 to 146 ° C.

Example 8

Preparation of (-) - l-phenyl-3-azabicyclo [3.1.0] hexane-30 hydrochloride.

To a stirred slurry of 18.7 g of (-) - l-phenyl-l, 2-cyclopropanedicarboximide in 500 ml of benzene, 150 ml of sodium bis (2-methoxyethoxy) aluminum hydride (in the form 35 a 70% solution in benzene). The mixture is stirred at room temperature for 2 hours, heated to reflux for 4 hours and then left to stand at room temperature for 20 hours. Then 150 ml of 10N sodium hydroxide solution are carefully added with stirring. 40 The organic layer is washed with water, dried over magnesium sulfate and evaporated to a yellow oil under reduced pressure. This oil is dissolved in 300 ml of ether.

Dry hydrogen chloride gas is then passed through until precipitation no longer occurs and the mixture is then filtered 45 to form colorless crystals. These crystals are recrystallized from acetonitrile and give light yellow-brown crystals with a melting point of 170 to 172 ° C.

Example 9 50

Preparation of racemic 1-phenyl-3-azabi-cyclo [3.1.0] hexane.

If, in the process of Example 8, l-phenyl-1,2-cyclopropanedicarboximide (US Pat. No. 3,166,571, Example 8) is used and no gaseous hydrogen chloride is added, racemic l-phenyl-3-azabicyclo [3.1. Ojhexane. Kp.is = 130 to 133 ° C.

Example 10

Preparation of (-) - 3-methyl-1-phenyl-3-azabi-60

cyclo [3.1 .OJhexane hydrochloride.

5.0 g of sodium hydride (54% in mineral oil) are added to a solution of 18.7 g of (-) - l-phenyl-l, 2-cyclopropane-dicarboximide in 100 ml of anhydrous dimethylformamide in the course of 15 minutes. The mixture is stirred for 30 6 seconds and then 10 ml of iodomethane are added over the course of 5 minutes. The mixture is left to stand for 15 minutes, heated on a steam bath for 15 minutes,

cools and poured into 250 ml of water. The mixture is filtered, the crystals are washed with benzene ether, dried in air and (-) - N-methyl-1-phenyl-1, 2-cyclopro-pandicarboximide is obtained.

30 ml of sodium bis (2-methoxyethoxy) - are added to a stirred solution of 5.0 g of (-) - N-methyl-l-phenyl-l, 2-cyclopropanedicarboximide in 125 ml of benzene over the course of 10 minutes. aluminum hydride (in the form of a 70% solution in benzene). The mixture is heated to reflux for 5 hours, cooled and carefully added 60 ml 10N sodium hydroxide solution. The organic layer is washed with water, dried over magnesium sulfate and evaporated to an amber oil under reduced pressure. This oil is dissolved in 250 ml of ether, saturated with hydrogen chloride and the colorless crystals are filtered off. These crystals are recrystallized from acetonitrile, giving colorless crystals with a melting point of 194 to 196 ° C. [ct] gHl0H = -73 ° C.

Example 11

Preparation of (~) -l- (p-chlorophenyl) -3-methyl-3-azabi-cyclo [3.1.OJhexane hydrochloride.

5.0 g of sodium hydride (54% in mineral oil) are added to a solution of 22.1 g of (-) - l- (p-chlorophenyl) -l, 2-cyclopropanedicarboximide in 100 ml of anhydrous dimethylformamide in the course of 15 minutes. The mixture is stirred for 30 minutes and then 10 ml of iodomethane are added over the course of 5 minutes. The mixture is left to stand for 15 minutes, heated on a steam bath for 15 minutes, cooled and poured into 250 ml of water. The crystals are filtered off, washed with petroleum ether and dried in air, giving (-) - N-methyl-l- (p-chlorophenyl) -l, 2-cyclopropanedicarboximide in the form of colorless crystals.

60 ml of sodium bis (2-methoxyethoxy) aluminum hydride (in the form of a 70% strength solution in benzene) are added to a stirred solution of 11.8 g of the above product in 250 ml of benzene in the course of 10 minutes. The mixture is heated to reflux for 5 hours, cooled and carefully added 60 ml 10N sodium hydroxide solution. The organic layer is washed with water, dried over magnesium sulfate and evaporated to an amber oil under reduced pressure. The oil is dissolved in 250 ml of ether, saturated with hydrogen chloride and the colorless crystals are filtered off. Recrystallization from acetonitrile gives colorless crystals with a melting point of 211 to 212 ° C. [a] gH) OH = - 68 ° C.

Example 12

Preparation of (+) - l- (p-chlorophenyl) -3-methyl-3-azabi-cyclo [3.1 .OJhexane hydrochloride.

To a stirred solution of 11.08 g of (+) - l- (p-chlorophenyl) -l, 2-cyclopropanedicarboximide in 50 ml of anhydrous dimethylformamide, 2.5 g of sodium hydride (54% in mineral oil). The mixture is stirred for 30 minutes, then 5 ml of iodomethane are added in the course of 5 minutes, the mixture is left to stand for 15 minutes, heated on a steam bath for 15 minutes, cooled and poured into 125 ml of water. The mixture is filtered, washed with petroleum ether and dried and (+) - N-methyl-1 - (p-chlorophenyl) -1,2-cyclopropanedicarboximide is obtained in the form of colorless crystals.

To a stirred solution of 3.92 g (+) - N-methyl-l- (p-chlorophenyl) -l, 2-cyclopropanedicarboximide in 100 ml of benzene, 20 ml of sodium bis (2 -methoxyethoxy) aluminum hydride (in the form of a 70% solution in benzene). The mixture is stirred

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12

for 2 hours at room temperature, then heated to boiling under reflux for 2 hours, carefully added 20 ml 10N sodium hydroxide solution, washed the benzene layer with water, dried over magnesium sulfate and evaporated to an oil under reduced pressure. The oil is dissolved in 200 ml of ether, saturated with dry hydrogen chloride and a colorless crystal cake is obtained, which is recrystallized from acetonitrile, where (+) - l- (p-chlorophenyl) -3-methyl-3-azabicyclo [3.1.0] hexane hydrochloride is obtained in the form of weakly colored crystals. F 209 to 210 ° C.

[a] gH'0H = + 67 ° C.

Example 13

Preparation of racemic l- (p-chlorophenyl) -3-methyl-3-azabicyclo [3.1.0] hexane hydrochloride.

10.0 g of sodium hydride (50% in mineral oil) are added to a stirred solution of 44.2 g of racemic l- (p-chlorophenyl) -1, 2-cyclopropanedicarboximide in 200 ml of anhydrous dimethylformamide in the course of 5 minutes. Then 20 ml of iodomethane are slowly added with stirring over the course of 5 minutes. The mixture is heated on a steam bath for 30 minutes, cooled and poured into 500 ml of water. The solid is filtered off and recrystallized from a heptane / ethyl acetate mixture, resulting in racemic N -methyl-1 - (p-chlorophenyl) -1,2-cyclopropanedicarboximide in the form of colorless crystals.

60 ml of sodium bis (2-methoxyethoxy) aluminum hydride (in the form of a 70% strength solution) are added to a stirred solution of 11.8 g of the product formed in the above manner in 250 ml of benzene over the course of 10 minutes Benzene). After standing for 16 hours, the mixture is heated to reflux for 4 hours, cooled and carefully added 60 ml of 10N sodium hydroxide solution. The organic layer is dried over sodium sulfate and then over magnesium sulfate, filtered and evaporated under reduced pressure to give the free base in the form of a light yellow oil. The oil is dissolved in 200 ml of ether and saturated with dry hydrogen chloride gas. The solid is separated off and recrystallized from acetonitrile to form pale yellow-brown colored platelets. F180 to 182 ° C.

Example 14

Preparation of 3-benzyl-1-phenyl-3-azabi-cyclo [3.1 .OJhexane hydrochloride.

10 g of sodium hydride (50% in mineral oil) are added to 37.4 g of l-phenyl-1,2-cyclopropanedicarboximide in 200 ml of anhydrous dimethylformamide. Then 25.4 ml of benzyl chloride are added dropwise, 20 mg of potassium iodide are added, the mixture is stirred for 2 hours at room temperature and then poured into 11 water to form a resinous residue, which is treated with petroleum ether, giving N-benzyl-1 -phenyl-l, 2-cyclopropane-dicarboximide in the form of light yellow crystals.

60 ml of sodium bis (2-methoxyethoxy) aluminum hydride (in the form of a 70% strength solution) are added to a stirred solution of 13.87 g of the product formed in the above manner in 250 ml of benzene over the course of 10 minutes Benzene). The mixture is heated to boiling under reflux for 5 hours, cooled and carefully added 60 ml of 1 on sodium hydroxide solution. The benzene layer is washed with water, dried over magnesium sulfate and evaporated to an amber oil under reduced pressure. The oil is dissolved in ether, dry hydrogen chloride gas is added, the solid is separated off and recrystallized from isopropyl alcohol to form white crystals. F194 to 196 ° C.

Example 15

Preparation of 1-pheny l-3-azabicyclo [3.1.OJhexane hydrochloride.

400 ml of a 70% solution of sodium bis (2-methoxyethoxy) are added under nitrogen to a stirred slurry of 61.2 g of 1-phenyl-1, 2-cyclopropanedicarboximide (US Pat. No. 3 166 571, Example 8) in 21 benzene. aluminum hydride in benzene. The mixture is stirred for 2 hours at room temperature, refluxed for 4 hours and then stirred for 20 hours at room temperature. Then 400 ml of 10N sodium hydroxide solution are carefully added with stirring, the organic layer is washed twice with dilute sodium hydroxide solution and then with water, dried over magnesium sulfate and evaporated to an amber oil. This oil is dissolved in dilute hydrochloric acid, washed with ether, filtered and the filtrate made basic with sodium hydroxide. The basic filtrate is extracted with benzene, dried over magnesium sulfate, filtered off and evaporated to give 20 l-phenyl-3-azabicyclo [3.1.0] hexane in the form of an amber oil.

Example 16

Preparation of 3-phenethyl-l-phenyl-3-azabi-2s cyclo [3.1.0] hexane hydrochloride.

2.5 g of sodium hydride (50% in mineral oil) are added to a stirred solution of 9.35 g of l-phenyl-1,2-cyclo-propanedicarboximide in 50 ml of dimethylformamide in the course of 5 minutes. The mixture is warmed, stirred for 30 hours, 0.1 g of potassium iodide is added and then 9.25 g of phen-ethyl bromide are added. The mixture is stirred for half an hour, heated on a steam bath for 15 minutes, stirred at room temperature for 15 minutes and then poured into 11 water which has been acidified with acetic acid. The mixture is extracted with methylene chloride, this solution is combined with 50 g of magnesium silicate and evaporated under reduced pressure. The powder obtained is applied to a column filled with magnesium silicate and eluted with 11 petroleum ether, 500 ml of methylene chloride, 11 chloroform and 40 is obtained by evaporating the eluted fraction N-phenethyl-1-phenyl-l, 2-cyclopropanedicarboximide in the form of a colorless oil .

To a solution of 5.80 g of the compound obtained in this way in 50 ml of benzene, 10 ml of 45 sodium bis (2-methoxyethoxy) aluminum hydride (in the form of a 70% solution in benzene) are added with stirring. The mixture is left to stand for 18 hours, heated to reflux for 2 hours, cooled and treated with 10 ml of 10N sodium hydroxide solution as described in Example 15 to give the product in the form of crystals which Melt at 207 to 209 ° C.

Example 17

Preparation of l- (p-trifluoromethylphenyl) -3-azabi-55 cyclo [3.1 .OJhexane hydrochloride.

Using the method of Example 6, manp- (trifluoromethylphenyl) phenyl-acetic acid ethyl ester is converted into a-bromo-p- (trifluoromethyl) -phenylacetic acid ethyl ester (bp.o.4 = 92 to 95 ° C), which is treated with ethyl acrylate / natri -60 umhydrid in l- (p-trifluoromethylphenyl) -l, 2-cyclopropandi-carboxylic acid diethyl ester converted (bp o, 2 = 108 to 110 ° C). Hydrolysis with in potassium hydroxide solution gives ice-1 - (p-trifluoromethylphenyl) -1,2-cyclopropane dicarboxylic acid in the form of colorless crystals, F161 to 162 ° C. 65 This dicarboxylic acid is then reacted with urea to give 1 - (p-trifluoromethylphenyl) -1,2-cyclopropanedicarboximide, which is obtained in the form of colorless crystals with a melting point of 164 to 165 ° C.

13

637 929

20 ml of sodium bis (2-methoxyethoxy) aluminum hydride (in the form of a 70% solution in benzene) are added to a solution of 3.5 g of this imide in 75 ml of benzene. The reaction mixture is heated to boiling under reflux for 1 hour, cooled to room temperature and the excess hydride reagent is decomposed by adding 20 ml of 10N sodium hydroxide solution. The benzene layer is washed with water, dried over magnesium sulfate and evaporated to an amber oil under reduced pressure. This oil is dissolved in ether, after which dry hydrogen chloride gas is introduced into the solution, the precipitate formed is filtered off and recrystallized from isopropyl alcohol, giving the product which melts at 249 to 251 ° C.

Example 18

Preparation of l- (p-methoxyphenyl) -3-azabi-cyclo [3.1.0] hexane hydrochloride.

A mixture of 2.6 g of diethyl l- (p-methoxyphenyl) -1,2-cyclopropanedicarboxylate (which was prepared from ethyl p-methoxyphenylacetate by the method of Example 6), 20 ml of potassium hydroxide solution and 20 ml of ethanol are heated during 3.5 hours at reflux, after which the ethanol is removed by evaporation. Then add 20 ml in hydrochloric acid solution in individual portions until the pH is 1. Then the mixture is extracted three times with chloroform, dried and concentrated to a yellow solid. This solid is recrystallized from an ethyl acetate / hexane mixture, whereby cis-l- (p-methoxyphenyl) -l, 2-cyclopropandicarboxylic acid is obtained in the form of a light yellow solid.

6.6 g of this dicarboxylic acid, 2.4 g of urea and 300 ml of xylene are heated to reflux with stirring for 24 hours. The mixture is then cooled, diluted with 25 ml of benzene, washed with water, dried, concentrated under reduced pressure and a solid is obtained, which is recrystallized from an ethyl acetate / hexane mixture, 1 - (p-methoxyphenyl) - 1,2-cyclopropanedicarboximide obtained.

3.0 g of the product obtained in the above manner are mixed with 70 ml of benzene and 20 ml of sodium bis (2-methoxy-ethoxy) aluminum hydride (in the form of a 70% strength solution in benzene) are added over the course of 5 minutes ) too. After stirring for half an hour and heating to reflux for 1 hour, the mixture is cooled, 20 ml of 10N sodium hydroxide solution and finally saturated sodium chloride solution are added. The organic layer is dried over magnesium sulfate, filtered and evaporated to an oil. The oil is dissolved in ether, after which hydrogen chloride gas is passed into the solution, a solid being formed which is recrystallized from isopropyl alcohol to form light pink plates.

F174 to 175 ° C.

Example 19

Preparation of (+) - l-phenyl-3-azabicyclo [3.1.0] hexane hydrochloride.

80 ml of sodium bis (2-methoxyethoxy) aluminum hydride (in the form of a 70% solution in benzene) are added to a stirred slurry of 10 g (+) - l-phenyl-l, 2-cyclopropanedicarboximide in 300 ml of benzene ). The mixture is stirred for 2 hours at room temperature, heated to reflux for 4 hours, stirred for 20 hours at room temperature and then 80 parts of sodium hydroxide solution are slowly added with stirring. The organic layer is washed with saturated sodium chloride solution and water, dried over magnesium sulfate and filtered. The filtrate is evaporated, whereupon the residue is mixed with ether and dry hydrogen chloride gas is introduced. The product is filtered off and recrystallized from acetonitrile, colorless needles having a melting point of 169 to 171 ° C. being obtained.

[a] gHi0H = + 68 ° C.

Example 20

Preparation of l- (3,4-dichlorophenyl) -3-azabi-cyclo [3.1.0] hexane.

A solution of 59.5 g of 3,4-dichlorophenyl acetic acid in 500 ml of absolute ethanol is saturated with anhydrous hydrogen chloride and then heated to reflux for 2 hours. The mixture is then concentrated to 200 ml under reduced pressure, diluted with 200 ml of water and neutralized with concentrated ammonium hydroxide solution. This aqueous mixture is extracted three times with chloroform. Concentration and decolorization of the chloroform extracts gives ethyl 3,4-dichlorophenylacetate in the form of a yellow oil.

A three-necked flask, which is equipped with a stirrer made of a nickel-chromium alloy (Nichrome) and a reflux condenser, is charged with 7.0 g of ethyl 3,4-dichlorophenylacetic acid, 5.9 g of N-bromosuccinimide, 0.1 g Benzoyl peroxide and 150 ml carbon tetrachloride. The mixture is heated to reflux for 18 hours, cooled and filtered. The carbon tetrachloride filtrate is concentrated under reduced pressure, giving a dark orange colored liquid. Distillation in vacuo at 115 to 120 ° C (0.5 mm Hg) gives ethyl a-bromo-3,4-dichlorophenylacetate in the form of a light yellow liquid.

The product is converted according to the method of L. L. McCoy [J. A.C. S. 80 (1958) 6568] into cis-1- (3,4-dichlorophenyl) -1,2-cyclopropanedicarboxylic acid diethyl ester.

A mixture of 150 g of this diester and 66 g of 85% potassium hydroxide solution in 500 ml of water and 500 ml of ethanol is refluxed for 6 hours and then cooled in ice. Then the oily material is extracted with ether and the aqueous ether is acidified with 100 ml of 12N hydrochloric acid solution. The lower oily layer crystallizes slowly and results in a colorless crystal cake. It is recrystallized from a mixture of ethanol and ethyl acetate and l- (3,4-dichlorophenyl) -1, 2-cyclopropanedicarboxylic acid is obtained in the form of colorless crystals.

A mixture of 30.3 g of this dicarboxylic acid and 12.6 g of urea in 11 xylene is heated to boiling under reflux for 6 hours. The solvent is then stripped off under reduced pressure and the crystalline residue is slurried in water. The colorless crystals are filtered off, washed with water and air-dried and give l- (3,4-dichlorophenyl) -l, 2-cyclopro-pandicarboximide.

A solution of 2.56 g of this imide in 50 ml of tetrahydrofuran is added to 40 ml of a 1 molar solution of borane in tetrahydrofuran with stirring and under nitrogen at 0CC over the course of 15 minutes. The mixture is heated on a steam bath for 1 hour, then cooled in ice, 20 ml of 6N hydrochloric acid solution are added and the tetrahydrofuran is stripped off under reduced pressure. The residue is made alkaline with 75 ml of 5N sodium hydroxide solution and extracted with ether. The extract is dried over magnesium sulfate and filtered, whereupon the filtrate is saturated with hydrogen chloride. The precipitated crystals are filtered off and recrystallized from isopropyl alcohol, giving 1.70 g of l- (3,4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane hydrochloride in the form of colorless crystals. F180 to 181 ° C.

The imides given below, which can be found in the s

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prepared above are similarly reduced to the corresponding 3-azabicyclo [3.1.0] hexanes.

Imid

Reduction product

1 - (p-ethylphenyl) -1,2-cyclo-propanedicarboximide, F102-104 ° C.

1 - (p-Hexylphenyl) -1,2-cyclo-propanedicarboximide, F115-117 ° C.

1 - (m-tolyl) -1, 2-cyclopropane-dicarboximide,

F164-166 ° C.

1 - (p-Bromophenyl) -l, 2-cyclo-propanedicarboximide, F150-151 ° C.

1 - (p-fluorophenyl) -1,2-cyclo-propanedicarboximide, F 146-148 ° C

1 - (p-ethylphenyl) -3-azabi-cyclo [3.1.O] hexane hydrochloride, F 207-209 ° C.

1 - (p-Hexylphenyl) -3-azabi-cyclo [3.1. Ojhexane hydrochloride, F 181-183 ° C.

1 - (m-T olyl) -3-azabi-cyclo [3.1.O] hexane hydrochloride, F 129-131 ° C.

1 - (p-Bromophenyl) -3-azabi-cyclo [3.1.O] hexane hydrochloride, F231-233 ° C.

1 - (p-fluorophenyl) -3-azabi-cyclo [3.1.O] hexane hydrochloride, F 170-172 ° C.

Example 21

Preparation of l- (m-methoxyphenyl) -3-methyl-3-azabi-cyclo [3.1. Ojhexane hydrochloride.

92.3 g of m-anisidine are dissolved in 225 ml of concentrated hydrochloric acid, 150 ml of water and 150 g of ice and the mixture is cooled to 0.degree. Then the mixture is carefully diazotized with vigorous stirring at 0 to 5 ° C. with 52.5 g of sodium nitrite in 120 ml of water. Then the mixture is added at 0 ° C. to 83.25 g of N-methyl-maleimide in 225 ml of acetone. The pH is adjusted to 3.0 and then 25.5 g of copper (I) chloride dihydrate are added in one portion with stirring, and finally 200 ml of acetone. Evaporation of the acetone and decanting off the aqueous layer gives a black residue, which is boiled with 11 benzene, dried over magnesium sulfate and filtered through a Buchner funnel containing 50 g of activated magnesium silicate. The residue is heated to boiling with 11 benzene, whereupon it is filtered through activated magnesium silicate. The dark filtrate is evaporated under reduced pressure and the residue is heated for 10 minutes with 100 ml of 2,6-lutidine to ensure dehydrochlorination. The solution obtained is combined with 500 ml of water and 400 ml of pyridine and filtered. A dark oil is pressed out of the crystal cake and the cake is boiled with 500 ml of 90% ethanol. The mixture is cooled and filtered and 2- (m-methoxyphenyl) -N-methylmaleimide is obtained in the form of orange crystals with a melting point of 138 to 146 ° C.

This product is manufactured according to the method of P. T. Izzo [J. Organic Chemistry, 28 (1963) 1713] converted to 1- (m-methoxy-phenyl) -N-methyl-1,2-cyclopropanedicarboximide.

20 ml of sodium bis (2-methoxyethoxy) aluminum hydride (in the form of a 70% strength solution in benzene) are added to a mixture of 3.0 g of this imide and 70 ml of benzene in the course of 5 minutes under nitrogen and with stirring ). The mixture is stirred for 30 minutes, refluxed for 1 hour, cooled, and then 20 ml of 10N sodium hydroxide solution and then saturated sodium chloride solution are added. The organic layer is dried over magnesium sulfate, filtered and evaporated,

whereby crystals are obtained which are recrystallized from ether. Reaction with hydrogen chloride gas and recrystallization from isopropyl alcohol gives l- (m-methoxy-phenyl) -3-methyl-3-azabicyclo [3.1.0] hexane hydrochloride in the form of a crystalline product which melts at 148 to 150 ° C. .

Example 22

Preparation of (+) - l'-phenyl-3-methyl-3-azabi-lo cyclo [3.1 .OJhexane hydrochloride.

A mixture of 10 g (+) - l-phenyl-l, 2-cyclo-propane carboximide, 2.67 g sodium hydride (50% in mineral oil), 50 ml dimethylformamide and 5 ml methyl iodide is reacted and the reaction mixture is poured into 500 ml Water. The mixture is extracted with methylene chloride, washed with water, dried over magnesium sulfate and evaporated. The residue is adsorbed on activated magnesium silicate in a Büchner funnel and washed with 250 ml of benzene. The eluate is washed with 250 ml of methylene chloride and evaporated to give (+) - 1-phenyl-N-methyl-1,2-cyclopropanedicarboximide in the form of green crystals.

3.0 g of this imide are reacted in 70 ml of dry benzene with 20 ml of sodium bis (2-methoxyethoxy) aluminum hydride (in the form of a 70% solution in benzene). The mixture is stirred for 15 minutes at room temperature and then for 15 minutes on a steam bath. After cooling, the reaction mixture is treated according to the procedure of Example 12, with (+) - l-phenyl-3-30 methyl-3-azabicyclo [3.1.OJhexane hydrochloride being obtained in the form of crystals which are at 188 to 190 ° C. melt.

[a] gHl0H = + 72 ° C.

35 Example 23

Preparation of l- (4-chloro-a, a, a-trifluoro-m-tolyl) -3-aza-bicyclo [3.1.0] hexane hydrochloride.

According to the procedure of Example 6, methyl (4-chloro-a, a, a-trifluoro-m-tolyl) -acetate is converted into 40 bromo- (4-chloro-a, a, a-trifluoro-m-tolyl) -acetic acid methyl ester um, which is converted with methyl acrylate / sodium hydride into the 1- (4-chloro-a, a, a-trifluoro-m-tolyl) -cyclopropanedicarboxylic acid di-methyl ester. Hydrolysis of this diester with in potassium hydroxide solution gives cis-l- (4-chloro-a, a, a-trifluoro-45 m-tolyI) -l, 2-cyclopropanedicarboxylic acid in the form of colorless crystals that melt at 167-169 ° C. The dicarboxylic acid is then reacted with urea to give l- (4-chloro-a, a, a-trifluoro-m-tolyl) -l, 2-cyclopropanedicarboximide, which is obtained in the form of colorless crystals at 123 to 124 ° C so melt.

To a solution of 0.28 g of l- (4-chloro-a, a, a-trifluoro-m-tolyl) cyclopropanedicarboximido in 10 ml of benzene is added 1.0 ml of sodium bis (2-methoxyethoxy) aluminum hydride ( in the form of a 70% solution in benzene). The ss reaction mixture is heated to boiling under reflux for 1 hour, cooled to room temperature and the excess hydride reagent is decomposed by adding 1 ml of 1 on sodium hydroxide solution. The benzene layer is washed with water, dried over magnesium sulfate and evaporated to an amber oil under such reduced pressure. The oil is dissolved in ether and dry hydrogen chloride is introduced into the solution. The precipitate formed is filtered off and recrystallized from isopropyl alcohol, giving 1 - (4-chloro-a, a, a-trifluoro-m-tolyl) -3-azabi-65 cyclo [3.1.0] hexane hydrochloride. The hydrochloride is purified by recrystallization from acetonitrile and gives colorless crystals with a melting point of 164 to 166 ° C.

15

637929

Example 24

Preparation of l- (p-nitrophenyl) -3-azabi-cyclo [3.1.OJhexane hydrochloride.

To a stirred slurry of 20.6 g of 1-phenyl-cyclopropane-l, 2-dicarboxylic acid in 25 ml of concentrated sulfuric acid, 15 ml of concentrated nitric acid are added over 30 minutes at 0 ° C. The solution obtained is stirred for 30 minutes at room temperature and then poured onto ice. The crystalline product is recrystallized from a hexane / ethyl acetate mixture and l- (p-nitrophenyl) -cyclopropane-1,2-dicarboxylic acid is obtained in the form of colorless crystals with a melting point of 138 to 144 ° C.

The above dicarboxylic acid is converted according to the procedure of Example 6 into 1- (p-nitrophenyl) -1, 2-cyclo-propane-dicarboximide. F171 to 173 ° C.

A solution of the imide formed in the above manner in tetrahydrofuran is added under nitrogen at 0 ° C. to an im solution of borane in tetrahydrofuran. The solution is heated to reflux for 1 hour, cooled to 0 ° C. and then 6N hydrochloric acid solution is added. The tetrahydrofuran is removed under reduced pressure and the remaining material is distributed between ether and sodium hydroxide solution. The ether solution containing l- (p-nitrophenyl) -3-aza-bicyclo [3.1.Ojhexane is dried over magnesium sulfate and filtered, after which the filtrate is mixed with hydrogen chloride and the product is obtained in the form of a brown solid. F 215 to 217 ° C.

Example 25

Preparation of l- (o-chlorophenyl) -3-azabi-cyclo [3.1 .OJhexane hydrochloride.

A stirred mixture of 36.9 g of o-chloro-phenyl-acetic acid methyl ester, 36.0 g of N-bromosuccinimide and 2 drops of 48% hydrobromic acid with 500 ml of carbon tetrachloride is boiled under reflux for 20 hours, then filtered through Magnesium silicate and obtained after evaporation under reduced pressure a-bromo-o-chlorophenyl-acetic acid methyl ester in the form of a straw-colored liquid.

A mixture of 26.3 g is added to a stirred suspension of 4.8 g of sodium hydride (50% in mineral oil) in 100 ml of a benzene / N, N-dimethylformamide mixture (1/1) over the course of 6 hours of the bromo ester prepared in the above manner and 8.69 g of methyl acrylate. The mixture is stirred for 4 hours at room temperature, then the excess sodium hydride is decomposed with 2 ml of methanol and the mixture is poured into 500 ml of water. The organic layer is washed with water, dried over gastric sodium sulfate and evaporated to give dimethyl l- (p-chlorophenyl) -1,2-cyclopropanedicarboxylate in the form of a brown oil.

17.35 g of the diester thus formed and 200 ml of potassium hydroxide solution in 50 ml of ethanol are heated to reflux for 6 hours. The solution is then concentrated to half the volume under reduced pressure and l- (o-chlorophenyl) -1, 2-cyclopropane-dicarboxylic acid is obtained in the form of a brown oil.

A mixture of 10.0 g of the dicarboxylic acid obtained in the above manner and 3.4 g of urea in 500 ml of xylene is heated under reflux for 6 hours. The solution is then washed with water and sodium bicarbonate solution, dried over magnesium sulfate and a yellow-brown solid is obtained. Recrystallization from ethanol gives l- (o-chlorophenyl) -l, 2-cyclopropanedi-carboximide in the form of colorless crystals. F 154 to 156 ° C.

To 1.35 g of the imide formed in the above manner in 30 ml

9 ml of sodium bis (2-methoxyethoxy) aluminum hydride (in the form of a 70% solution in benzene) are added to benzene over the course of 2 minutes with stirring. The solution is stirred for 15 minutes at room temperature and then heated to reflux for 30 minutes. 10 ml of 1% sodium hydroxide solution are added to the cooled solution, the benzene layer is washed with water, dried over magnesium sulfate and filtered. The filtrate is evaporated under reduced pressure, whereupon the residual oil is dissolved in ether and anhydrous hydrogen chloride gas is passed into this solution. The precipitated product is recrystallized from isopropyl alcohol and gives l- (o-chlorophenyl) -3-azabicyclo [3.1 .OJhexane hydrochloride in the form of colorless crystals. F188 to 190 ° C.

Example 26

Preparation of l- (p-tolyl) -3-azabicyclo [3.1.OJhexane hydrochloride.

230 ml of thionyl chloride are added to 120 g of p-tolylacetic acid, and the solution is left to stand at room temperature for 2 hours, after which it is heated to 60 ° C. for 1 hour. 285 g of N-bromosuccinimide and 10 drops of 48% hydrobromic acid are added to this solution, whereupon the mixture is refluxed for 1 hour on an oil bath kept at 90 ° C. Then another 90 ml of thionyl chloride are added and the reflux is continued for 45 minutes. The mixture is distilled under reduced pressure to distill off 250 ml of thionyl chloride, after which the remaining liquid is poured into 500 ml of cold methanol with stirring and cooled with ice for 15 minutes. The solution is evaporated under reduced pressure and a dark oil is obtained which is dissolved in 100 ml of chloroform. The solution is washed with 500 ml of water, dried over magnesium sulfate and filtered. The filtrate is evaporated under reduced pressure to give a dark oil which, when distilled, gives 94 g of the bromine ester in the form of a light yellow liquid. Kp.o.os = 115 to 120 ° C. The light yellow liquid is then (according to the procedure of Example 6) reacted with methyl acrylate / sodium hydride in ether and gives eis-1 - (p-Toly 1) -1,2-cyclopropanedicarboxylic acid dimethyl ester at 58 to 59 ° C. melts. Hydrolysis with in potassium hydroxide solution followed by acidification with hydrochloric acid (following the procedure of Example 6) gives cis-l- (p-tolyl) -l, 2-cyclopropanedicarboxylic acid in the form of colorless crystals. F 188 to 190 ° C. This dicarboxylic acid is then (according to the procedure of Example 6) reacted with urea and gives l- (p-tolyl) -1, 2-cyclopropanedicarboximide in the form of light yellow crystals. F 82 to 85 ° C.

160 ml of sodium bis (2-methoxyethoxy) aluminum hydride are added to a mixture of 20.1 g of this imide in 600 ml of benzene, the reaction is carried out according to the procedure of Example 8, and the excess reagent is then decomposed by adding 160 ml lOn sodium hydroxide solution. The benzene layer is washed with water, dried over magnesium sulfate and filtered. The filtrate is evaporated under reduced pressure to a dark oil, which is dissolved in ether, after which dry hydrogen chloride is introduced into the solution. The precipitate formed is filtered off and recrystallized from an acetonitrile / methanol mixture, giving 12.1 g of l- (p-tolyl) -3-azabicyclo [3.1.OJhexane hydrochloride in the form of pale yellow-brown colored platelets. F 207 to 208 ° C.

In the same way, the procedure of this example gives l- (p-cumyl) -1, 2-cyclopropanedicarboximide (F147 to 148 ° C) l- (p-cumyl) -3-azabicyclo [3.1.0Jhexane hydrochloride (F 231 up to 232 ° C).

s

10th

15

20th

25th

30th

35

40

45

50

55

60

65

637929

16

The following imides are reduced to the corresponding amine hydrochlorides in the above manner.

Imid

3-Azabicyclo [3.1.0] hexane

1 - (a, cc, a-trifluoro-m-tolyl) -1.2-1 - (a, cc, aT rifluor-m-tolyl) -3-cyclopropanedicarboximide, azabicyclo [3.1 .OJhexan-F 94-95, 5 ° C hydrochloride, F 146-148 ° C.

1 - (3-bromo-4-methoxyphenyl) - 1 - (3-bromo-4-methoxy-azacyclopropanedicarboximide, phenyl) -3-azabi-F184-186 ° C cyclo [3.1. Ojhexane hydrochloride, F108-211 ° C.

1 - (o-tolyl) -1,2-cyclopropanedi-1 - (o-tolyl) -3-azabi-carboximide cyclo [3.1.0] hexane hydro-

chloride.

Example 27

Preparation of (+) - l- (p-tolyl) -3-azabicyclo [3.1.0] hexane hydrochloride.

A solution of 94.8 g of racemic l- (p-tolyl) -l, 2-cyclopropanedicarboxylic acid (Example 26) and 73.8 g of (-) - a- (l-naphthyl) -ethylamine in 300 ml of tetrahydrofuran are diluted with 300 ml of ethyl ether and let the solution stand at room temperature until crystallization is complete. Then the mixture is filtered, the separated crystals are washed with cold tetrahydrofuran and 4.95 g of a salt of 1 molar equivalent (+) - l- (p-tolyl) -l, 2-cyclopro-pandicarboxylic acid and 1 molar equivalent are obtained (-) - a- (l-Naphthyl) ethylamine. The salt is shaken with a sodium hydroxide solution and ether. The aqueous phase is then acidified with 12N hydrochloric acid solution and the product is filtered off, giving 26.0 g of (+) - l- (p-tolyl) -1, 2-cyclo-propanedicarboxylic acid in the form of colorless crystals. [cc] gH'0H = + 192 ° C.

15.0 g of (+) - l- (p-tolyl) l, 2-cyclopropanedicarboxylic acid, 6.6 g of urea and 500 ml of xylene are heated to boiling under reflux for 5 hours. The reaction mixture is then filtered while hot and the filtrate is evaporated under reduced pressure to give (+) - l- (p-tolyl) -l, 2-cyclopropanedicarboximide in the form of colorless crystals. F148 to 155 ° C.

14 g of the product obtained in this way are mixed with 420 ml of benzene and 112 ml of sodium bis (2-methoxyethoxy) aluminum hydride (in the form of a 70% strength solution in benzene) are added over the course of 15 minutes. After heating for 1 1/2 hours, the mixture is cooled and 160 ml of 10N sodium hydroxide solution are added. The organic layer is dried over sodium sulfate, filtered and evaporated to an oil. The oil is dissolved in ether, after which hydrogen chloride gas is introduced into the solution. The solid which forms is recrystallized from acetonitrile and gives (+) - l- (p-tolyl) -3-azabi-cyclo [3.1.0] hexane hydrochloride in the form of colorless crystals. F 208 and 210.5 ° C. [a] gHj0H = + 64.5 ° C.

The above recurrent dicarboxylic acid is combined with the equivalent amount of brucine in ethanol and a salt is obtained which consists of 1 mole equivalent (-) - l- (p-tolyl) -1, 2-cyclopropane-dicarboxylic acid and 1 mole equivalent of brucine . [a] gH, OH = -46 ° C.

Treatment of this salt in the manner described above provides (-) - l- (p-tolyl) -l, 2-cyclopropanedicarboxylic acid in the form of colorless crystals. [a] gHl0H = - 189 ° C.

In the above manner, one converts (-) - l- (p-tolyl) -l, 2-cyclopropanedicarboxylic acid into (-) - l- (p-tolyl) -l, 2-cyclopro-pandicarboximide (F145 to 148 ° C, [a] gHl0H = -74 ° C), which compound is then described in the above

Reduced to (-) - l- (p-tolyl) -3-azabicyclo [3.1.0] hexane-hydrochloride, which is obtained in the form of colorless crystals.

. F 204 to 207 ° C, [<x] gH, 0H = -64 ° C.

"s Example 28

Preparation of l- (m-chlorophenyl) -3-methyl-3-azabi-cyclo [3.1.0] hexane hydrochloride.

According to the procedure of Example 10, 1- (m-chlorophenyl) -N-methyl-1,2-cyclopropanedicarboximide io (F72 to 73 ° C.) is obtained from l- (m-chlorophenyl) -l, 2- cyclo-propanedicarboximide (Example 6) and methyl iodide has prepared 1 - (m-chlorophenyl) -3-methyl-3-azabicyclo [3.1.0] hexane hydrochloride in the form of colorless crystals. F180 to 182 ° C.

15

Example 29

Preparation of l- (m-methoxyphenyl) -3-azabi-cyclo [3.1.0] hexane hydrochloride.

Methyl m-methoxymandelic acid is used according to the 20 method of I. P. Beletskaya [Zh. Obshch. Khim. 34 (1964) 321] with phosphorus tribromide to give bromo (m-methoxyphenyl) acetic acid ethyl ester, which is obtained in the form of a light yellow liquid and is used in the next step without further purification.

25 In a similar manner, the following mandelic acid esters can be converted into the corresponding bromoesters:

Almond acid

Bromester

30th

35

40

p-Hexyl-mandelic acid ethyl ester p-isopropyl-mandelic acid ethyl ester m-methyl-mandelic acid methyl ester o-methyl-mandelic acid methyl ester

Bromo (p-hexylphenyl) acetic acid ethyl ester

Bromo- (p-cumyl) -acetic acid ethyl ester

Bromomethyl (m-tolyl) acetic acid

Bromo- (o-tolyl) acetic acid methyl ester

A mixture of 37.0 g of dimethyl l- (m-methoxy-phenyl) -1,2-cyclopropanedicarboxylate is heated [the 45 of methyl bromo- (m-methoxyphenyl) -acetic acid and methyl acrylate according to the procedure of Example 6 has produced], 20 g of potassium hydroxide and 200 ml of a water / methanol mixture (1/1) for 16 hours at reflux, after which the methanol is removed by concentration. Then concentrated hydrochloric acid is added in portions until the pH is 1. The mixture is extracted three times with ether, dried and concentrated,

whereby cis-l- (m-methoxyphenyl) -l, 2-cyclopropanedicarboxylic acid is obtained in the form of a light yellow resin. 55 A mixture of 34.7 g of this dicarboxylic acid, 12 g of urea and 750 ml of xylene is heated to reflux with stirring for 5 hours. The mixture is cooled, the supernatant solution is decanted off, filtered through magnesium silicate and the filtrate is concentrated under reduced pressure to a solid which is recrystallized from ethanol, l- (m-methoxyphenyl) -l, 2- cyclo-propanedicarboximide receives. F125 to 127 ° C.

3.0 g of the product obtained in this way are mixed with 75 ml of benzene and 20 ml of sodium bis (2-methoxyethoxy) aluminum hydride (in the form of a 70% solution) are added over the course of 5 minutes Benzene). After stirring for half an hour and heating the mixture to reflux for 1 hour

one gives off, 20 ml 10N sodium hydroxide solution and finally a saturated sodium chloride solution. The organic layer is washed with water, dried over magnesium sulfate, filtered and evaporated to an oil. The oil is dissolved in ether and hydrogen chloride gas is introduced into the solution. The solid which forms is recrystallized from acetonitrile and gives l- (m-methoxyphenyl) -3-azabi-cyclo [3.1.OJhexane hydrochloride in the form of colorless crystals. F150 to 152 ° C.

Example 30

Using the procedures given in the preceding examples, the following is obtained in an analogous manner:

17 637929

3-ethyl-1-phenyl-3-azabicyclo [3.1 .Ojhexane hydrochloride: yellow-brown colored crystals with a melting point of 148 to 152 ° C;

3-benzyl-1 - (p-bromophenyl) -3-azabicyclo [3.1. Ojhexane: 5 F 69 to 70 ° C;

3-methyl-l- (p-tolyl) -3-azabicyclo [3.1 .OJhexane hydrochloride: colorless crystals, F197 to 198 ° C;

3- [3- (p-fluorobenzoyl) propylj-1-phenyl-3-azabi-10 cyclo [3.1.Ojhexane hydrochloride: light brown-yellow crystals, F151 to 153 ° C;

3- (n-Hexyl) -1 - (p-tolyl) -3-azabicyclo [3.1 .OJhexane hydrochloride: F182 to 184 ° C.

B

Claims (3)

637929 2. The method according to claim 1, characterized in that the hydride reducing agent used is sodium bis (2-methoxy-oxyoxy) aluminum hydride, lithium aluminum hydride and / or diborane, benzene, tetrahydrofuran, ether and / or toluene are used as the inert, aprotic solvent and works at a temperature of 0 to 120 ° C. 3. The method according to claim 2, characterized in that sodium bis (2-methoxy-oxyoxy) aluminum hydride is used as the hydride reducing agent and benzene is used as the inert, aprotic solvent, and the temperature is from 25 to 80 ° C. 4. The method according to claim 3, characterized in that (+) - l- (p-tolyl) -3-azabicyclo [3.1.0] hexane from (+) - l- (p-tolyl) -l, 2- cyclopropane dicarboximide produces. 5. The method according to claim 3, characterized in that (-) - l- (p-tolyl) -3-azabicyclo [3.1.0] hexane from (-) - l- (p-tolyl) -1,2- cyclopropane dicarboximide produces. 6. The method according to claim 1, characterized in that obtained compounds are split into their mirror image isomers. 30th (II) wherein the phenyl radical is unsubstituted or substituted as above Various compounds having an azabicyclo-alkane structure, such as Compound 1 [J. Med. Chem. 20 (1977), 221], or with a phenylpyrrolidine structure, such as the compound called Pro-fadol 2 [Chem. Ind. (London) 1969, 1077], has been reported to be analgesics with mixed agoistic-antagonistic properties. The common features of these compounds that are responsible for the significant activity are apparently the m-hydroxyphenyl group and the 1-methyl or 1-alkyl substituent. On the other hand, compound 3 was the subject of research in the patentee's laboratories as a possible anxiolytic agent. Now the reduction of this compound gave the l- (4-chlorophenyl) -3-azabicyclo [3.1.0] hexane of the formula 4a: 2nd PATENT CLAIMS 1. Process for the preparation of optically active azabicycloalkanes of the general formula: / X (I) 4. P x N ' l X in which the phenyl radical is unsubstituted or mono- or with halogen, straight-chain alkyl groups with 1 to 6 carbon atoms, mono-branched alkyl groups with 1 to 5 carbon atoms, alkoxy groups with 1 to 6 carbon atoms, trifluoromethyl groups, nitro groups, amino groups, acetamido groups and / or hydroxyl groups is disubstituted and X is a hydrogen atom, a straight-chain alkyl group having 1 to 8 carbon atoms or a group of the general formula CnH2nRi, in which n stands for an integer with a value from 1 to 3 and Ri for a phenyl group or a p-fluorobenzoyl group, means the racemic mixtures of these compounds, their mirror image isomers and the pharmaceutically acceptable salts of these compounds, characterized in that a compound of the general formula: 10th 20th 25th X is as defined above, one R represents an oxo group or a hydroxyl group and the other R represents a hydrogen atom or also an oxo group or hydroxyl group, at a temperature of -70 ° C to 125 ° C with a hydride reducing agent in an inert , aprotic solvent and optionally converting the compound obtained into a pharmaceutically acceptable salt. 3rd 637929 which had analgesic effects in the rat. A number of new l-phenyl-3-azabicyclo [3.1.0] hexanes were then prepared, including the p-methylphenyl analog 4b, also called bicifadine [J. At the. Med. Assoc. 242 (1979), 1912], has been shown to be analgesic in rats and mice. These compounds differ from the ones mentioned above (such as 1 and 2) not only from a structural point of view, but their analgesic effects on rats and mice are also not of the narcotic type.