HU177531B - Process for producing azabicyclohexanes - Google Patents

Abstract

The Earfindunq relates to a process for the preparation of optically active azabicycloalkanes. For example, (-) - (p'-chlorophenyl) -3-azabicyclo [3.1.0] hexane hydrochloride is prepared by dissolving a solution of sodium bis (2-methoxyethoxy) a luminous anhydride at room temperature under nitrogen Solution of (~) -1- (p-chlorophenyl) -1,2-cyclopropanedicarboximide, and then this solution is heated, treated with 5N sodium hydroxide solution and diluted with water, followed by extraction with chloroform and drying over magnesium sulfate

Description

The present invention relates to novel azabicyclohexane derivatives. More particularly, the present invention provides novel racemic or optically active azabicyclohexane derivatives of formula I: wherein:

R ₀ is halogen, straight or branched chain alkyl having 1-6 carbon atoms, alkoxy of 1-4 carbon atoms, trifluoromethyl, nitro, amino, hydroxy, phenyl or (1-4C tartalmazójalkoxi-methyl , m is 0, 1, 2 or 3,

X is hydrogen or straight-chained C 1-8 -alkyl, adamantylmethyl, (C 3-6 -cycloalkylmethyl, C 3-6 -alkenyl, omega-bis (halophenyl) - (1) -C 6 H) alkyl or -C _n H 2 _n R 1, whereby n is 1, 2 or 3 and R 1 is phenyl, halophenyl or 4-fluorobenzoyl;

R ₂ and R _{3 are} hydrogen or C 1-4 alkyl, and pharmaceutically acceptable acid addition salts thereof, and for the preparation of a medicament containing an analgesic as an active ingredient.

Of the compounds of formula I, compounds of formula Ia are preferred. In formula la R, _o is halogen or straight chain alkyl having 1-6 carbon atoms, alkoxy of 1-4 carbon atoms, trifluoromethyl, nitro, amino, 177,531, or hydroxy, m is zero, 1 or 2; X is hydrogen, straight-chained C 1 -C 8 alkyl, or -C n H 1 -R 1 where n is 1, 2 or 3 and R 1 is hydrogen. phenyl or 4-fluoro-5-benzoyl.

Also preferred among the compounds of formula Ia are those in which the phenyl group is halogen, straight-chain alkyl of 1-6 carbon atoms, alkoxy of 1-4 carbon atoms, trifluoromethyl, 0 nitro, amino, acetamido or hydroxy. disubstituted, while X is as defined in formula Ia.

Further preferred compounds of formula Ia are those wherein the phenyl group is unsubstituted or monosubstituted with halogen, straight-chained C 1-6 alkyl, C 1-4 alkoxy, trifluoromethyl, nitro, amino or hydroxy. , while X is as defined in formula Ia) Of the latter compounds, those which are preferred are those wherein X is hydrogen or straight-chained alkyl having from 1 to 8 carbon atoms, with the latter being particularly preferred where the phenyl ring is or substituted in the 4-position 5 with a linear alkyl group containing from 1 to 6 carbon atoms, a halogen atom or a trifluoromethyl group. Particularly preferred compounds substituted at the 3- or 4-position on the phenyl are those which are methyl in one of these positions. ethyl) or a trifluoromethyl group, or a chlorine, bromine or fluorine 177531 atom, or those which, in this type of substitution of the phenyl ring, carry X or a hydrogen atom or a methyl group.

A preferred group of compounds of Formula I is the compound of Formula 1b wherein R _h is phenyl or (1-4C) alkoxymethyl, m is 1 or 2, X 'is hydrogen, C 1-8 straight chain. alkyl or -C _n H _2n R 1, wherein n is 1, 2 or 3 and R 1 is halophenyl or bis-halophenyl.

Of the compounds of formula Ib, we also prefer those compounds wherein the phenyl ring is disubstituted by phenyl or (1-4C) alkoxymethyl and X 'is as defined in formula 1b.

Of the compounds of formula Ib, we also prefer those compounds wherein the phenyl ring is monosubstituted by phenyl or (1-4C) alkoxymethyl and X 'is as defined in formula 1b.

Most preferred of the compounds of formula Ib are those in which X 'is hydrogen or straight-chain alkyl of 1 to 8 carbon atoms. Of these compounds, we prefer those in which the phenyl ring at the 3- or 4-position is phenyl or ( Substituted by 1 to 4 carbon atoms with alkoxymethyl, and of the latter compounds which are substituted in the 3 or 4 position by phenyl, methoxymethyl or ethoxymethyl, are particularly preferred. X 'is hydrogen or methyl.

A preferred group of compounds of formula I is the compound of formula Ic wherein R _h is halogen or straight-chain alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 4 carbon atoms, trifluoromethyl, nitro, amino or hydroxy. , m is 1 or 2, and X '' represents a (3-6 carbon atoms) cycloalkylmethyl or C 3-6 alkenyl.

Among the compounds of formula Ic, we prefer those in which the phenyl ring is disubstituted with one of the substituents listed above or X '' has the meaning given above. Even more preferred, however, are those compounds of formula Ic wherein the phenyl ring is monosubstituted with one of the substituents listed above and X '' is as defined above.

Particularly preferred are compounds of formula Ic wherein X '' is cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, allyl, butenyl or dimethylallyl. Of these latter compounds, those in which the phenyl ring is substituted in the para or meta position with a halogen atom or a linear alkyl or trifluoromethyl group containing from 1 to 6 carbon atoms are particularly preferred. Of the latter highly preferred compounds, those in which the phenyl ring is substituted with a methyl or trifluoromethyl group, or a chlorine, fluorine or bromine atom, or X '' is cyclopropylmethyl or allyl are particularly preferred.

Another particular group of preferred compounds of formula I are the racemic or optically active compounds of formula ld where R _o is a halogen atom or straight chain alkyl having 1-6 carbon atoms, alkoxy of 1-4 carbon atoms, trifluoromethyl, nitro -, amino or hydroxyl group, m is 0, 1 or 2, X ^1V are the same meanings of X, with the proviso that the omega-bis (halophenyl) -alkilcsoporttól and R ₂ 'and R 3' are the same R ₂ and R ₃ with the proviso that at least one of R ₂ 'and R ₃ ' is alkyl having 1 to 3 carbon atoms and pharmaceutically acceptable acid addition salts thereof.

Preferred compounds of formula Id are those which are disubstituted on the phenyl ring with halogen or straight-chain alkyl of 1 to 6 carbon atoms, alkoxy, 1 to 4 carbon atoms, trifluoromethyl, nitro, amino or hydroxy, while the other substituents are as defined above.

Further preferred compounds of formula Id are those that are monosubstituted or unsubstituted on the phenyl ring with one of the above-mentioned substituents.

Regardless of the substituents on the phenyl ring, compounds of formula Id wherein X ^iv is hydrogen or straight-chain alkyl of 1-6 carbon atoms are preferred.

Particularly preferred are compounds of formula I wherein the phenyl ring is substituted in the para or meta position with a halogen atom or a straight-chain alkyl or trifluoromethyl group containing from 1 to 6 carbon atoms.

Particularly preferred are compounds of formula Id wherein the phenyl ring is substituted in the para or meta position with a methyl or trifluoromethyl group or a chlorine, fluorine or bromine atom, X ^iv is as defined above, and R ₂ 'or R ₃ ' contains 1 to 3 carbon atoms. and the other substituents on the azabicyclohexyl ring represent hydrogen. Most preferred of these compounds are those wherein X ^iv is hydrogen or methyl.

The compounds of formula I according to the invention are prepared by:

a) forming down narrower group of the compounds of the formula I compounds - where R _2, R _3, R _lo 'and m are as defined above, X ^v is X above, respectively, with the proviso that R is alkenilcsoporttól - preparing a reacting a racemic or optically active compound of formula II wherein R ₂ , R ₃ , R, _o , m and X ^v are as defined above and R 'is oxygen, with a hydride reducing agent in an inert aprotic solvent at -70 ° C and + 125 ° C. ° C, or

b) X is cycloalkylmethyl (C 3-6), adamantylmethyl, C 2-7 alkyl, or -C _n H _2n R 1; a compound of formula I having a benzyl group as a group - wherein R 1, R 1 -. R '' and m are as defined above, a racemic or optically active compound of formula III wherein X 'is hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, adamantyl or phenyl, and R ₂ , R 1, R ₁₀ and m are as defined above, by reaction with a hydride-type reducing agent in an inert aprotic solvent at a temperature between 70 ° C and + 125 ° C, or

c) X is an atom of hydrogen, compounds of formula I - wherein R _2, R _3, R, _p and m are as defined above - for preparing a compound of formula IV, racemic or optically active - wherein R _2nd R "R _m and m are as defined above, while W is a leaving group, preferably methanesulfonylfloxy, is reacted with sodium amide in a solvent in the presence of an acid binder at a temperature of 0 ° C to 150 ° C and optionally a free base of formula I and converting it into a pharmaceutically acceptable acid addition salt.

Pharmaceutically acceptable acid addition salts of compounds of Formula I include, for example, salts with hydrochloric acid, hydrobromic acid, hydrogen iodide, sulfuric acid, nitric acid, phosphorus, maleic acid or succinic acid.

Thus, the compounds of formula le may be prepared, for example, as depicted in Scheme A. In particular, this reaction is accomplished by reducing a compound of formula II after dissolving it in, for example, benzene, toluene, diethyl ether or tetrahydrofuran, for example using sodium bis (2-methoxyethoxy) anhymium hydride as the reducing agent. 0 ° C to about 125 ° C, preferably about 25 ° C to about 80 ° C for about 1-4 hours. After completion of the reduction, the reaction mixture is cooled and a strong base such as potassium hydroxide is added. The organic phase is then separated, concentrated and the resulting product is isolated by filtration.

The compounds of formula II used as starting materials are generally compounds of formula V, wherein R ₂ and R ₂ are as defined above, while R 1 is hydrogen or C 1-6 alkyl, or the phenyl ring may be substituted as described above, preferably and can be prepared from compounds of formula Va, which are a narrower group of the latter, as shown in Scheme B. In carrying out this reaction, the two reagents are prepared in an aprotic solvent such as xylene.

After heating for 6-24 hours, the product is isolated by evaporation of the solvent.

Otherwise, in addition to said hydride, a variety of other hydride-type reducing agents, such as diborant or lithium aluminum hydride, may be used to carry out the reduction step of process variant a) or b). For example, when using the latter, a compound of formula IIb is suspended in tetrahydrofuran and the reducing agent is added to the suspension and the reaction mixture is kept at 0 to 80 for 1-4 hours. The reaction mixture is cooled and acidified with a suitable acid such as hydrochloric acid, the aqueous phase is separated off and the product is isolated from the acid addition salt by liberating it with a strong base such as potassium hydroxide.

For carrying out process variant c), for example, methanol or ethanol is used as a solvent, while sodium carbonate, ethyldiisopropylamine and the like are used as acid binders. can be used.

Compounds of formula IV used as starting materials in the latter process variant can be prepared by reacting a corresponding diol of formula VIII with phosphorus pentabromide, hydrogen bromide, hydrogen iodide, hydrogen chloride and zinc chloride, thionyl chloride, phosphorus pentachloride, methanesulfone. chloride! or with p-toluenesulfonyl chloride.

Compounds of Formula VIII are compounds of Formula IX, wherein R _{8 is} hydrogen or C 1-6 alkyl, with diborane, lithium altaluminum hydride, or sodium bis (2-methoxy).

They may be prepared by reduction with ethoxy) aluminum hydride by reduction in an aprotic solvent such as diethyl ether, benzene or tetrahydrofuran at a temperature of about 0 ° C to about 80 ° C for about 1-6 hours. The reaction mixture is then cooled and the product is liberated from the resulting compound using acids or bases in a manner known per se.

The cyclopropane-1,2-dicarboxylic acid esters of formula IX may also be used in other ways. For example, after saponification, they can be used in the preparation of starting materials of formula II as shown in Scheme B, or in the resolution steps described in more detail below.

The diesters of formula IX wherein R _g is C 1-6 alkyl are prepared by reacting a compound of formula X wherein R _s is C 1-6 alkyl _and R _s and m are as defined above with R _2. The acrylic acid ester of the formula CH = CR ₃ COOR ₃ , wherein R ₈ is as defined herein, while R ₂ and R ₂ are as defined above, is reacted with a suitable base such as lithium hydride, sodium hydride, sodium methylate or potassium tertiary in the presence of butylate in a suitable aprotic solvent such as diethyl ether, benzene or tetrahydrofuran as described in U.S. Patent 3,344,026. The more preferred cis isomers are generally the major component of the product formed by this reaction.

Certain cis-dicarboxylic acids of formula IX, i.e., compounds of formula Va, may also be prepared by reacting a compound of formula XII, wherein U and V, with the same or different meanings, are cyano or a group of formula -CO, R " group, _R9 represents a hydrogen atom or a C1-6 alkyl group - with a suitable base such as sodium or potassium hydroxide in a suitable solvent such as methanol, ethanol or water, at temperatures between about 30 ° C to about 100 ^J C for about 3 hours to about After heating for 18 hours, the free dicarboxylic acid is liberated by treatment with a suitable mineral acid such as hydrochloric acid or sulfuric acid.

Compounds of formula XII, wherein U is cyano and V is -CO ₂ R _{9, can} be prepared by reacting a compound of formula XIII with an acrylonitrile of formula R, HC-CR, CN as described for the preparation of diesters of formula IX. In addition, compounds having U, -CO ₂ R, and V being cyano may be prepared by reacting a bromophenylacetonitrile of formula XIV with an appropriate acrylic acid ester, as described above.

Are hydrogen, R ₂ and Rl is difluorobenzoyl compounds can also be prepared by reacting an XVII 3-phenyl-3-pyrroline derivative (CH2I2) was reacted with diiodomethane in the Simmons-Smith reaction [Kawabuton, N. et al ; Chem. Soc., 98, 2676 (1976)].

Another alternative route is that compounds of the formula wherein R 1 and R 1 are alkyl may be prepared by alkylation of the corresponding compounds R 1 and R 2 where H is alkyl by alkylation with a halogenating agent R ₆ CH, W where W and R ₆ is as defined above, except that the latter may also be 4-fluorobenzoylethyl or 4,4-bis (4-fluorophenyl) propyl 177531 pil, in a suitable solvent such as methanol, ethanol or water. about 25% in the presence of an acid scavenger such as sodium carbonate

At a temperature of from about C to about 80 for about 1-18 hours.

In yet another alternative, before carrying out the alkylation described in the preceding paragraph, the compound of formula R 1 and R 1, wherein H is hydrogen, are reacted with a strong non-nucleophilic base such as sodium hydroxide or potassium tert-butylate in a solvent, e.g. N, N-dimethylformamide, and only then the alkylating agent is used. When alkylated in this way, in addition to the alkylating agents of the formula R ₆ CH ₂ W, an alkylating agent of the formula R ₆ CHWR ₁₀ , wherein R ₆ and W are as defined above and R _{10 is C} 1-6 alkyl, may be employed.

As mentioned, the compounds of formula I exist in the form of optical isomers which, in turn, are racemic mixtures of the left and right forms respectively. It will be appreciated by those skilled in the art that all such optically active forms are within the scope of the invention. The individual optical isomers may be separated by resolution techniques known per se.

For example, one method involves reacting a cis-dicarboxylic acid of formula Va with an optically active amine such as (-) -? - (1-naphthyl) ethylamine in a suitable solvent such as methanol, ethanol, acetone, tetrahydrofuran or acetonitrile. to form a salt consisting of one molar equivalent of (+) - dicarboxylic acid and one molar equivalent of the above - (-) - amine. In certain cases, and particularly when the phenyl ring is substituted with one or more alkyl groups, or, where the substituted phenyl are p-tolyl group, and R ₂ and R is hydrogen, it is preferred to use a solvent mixture composed of tetrahydrofuran and diethyl ether.

A racemic dicarboxylic acid of formula Va can also be reacted with (-) - 2-amino-1-butanol in a suitable solvent as described above to give a salt having the acid component of (+) -dicarboxylic acid.

From these salts, the free (+) - dicarboxylic acid can be liberated by treatment with a suitable base such as sodium hydroxide, potassium hydroxide, ammonium hydroxide or potassium carbonate followed by treatment with a suitable acid such as hydrochloric acid or sulfuric acid.

In order to isolate the (-) - dicarboxylic acid, a racemic cis-dicarboxylic acid of formula Va is reacted with an optically active amine in a solvent as described above, such as brucine. (+) - α- (1-Naphthyl) ethylamine or (+) -2-amino-1-butane

The salts thus obtained can then be converted to the corresponding (-) - dicarbonate blind as described above.

The (+) or (-) dicarboxylic acids thus prepared can then be converted into the corresponding (+) or (-) - isomers of the compounds of formula II as described above, and these compounds are the final (+) - compounds of formula le. or (-) - isomers thereof, as described above.

Alternatively, a racemic le compound may be reacted with an optically active acid such as (+) - or (-) - mandelic acid, (-Ej or (-) - tartaric acid, (+) - or (-) - di-O-benzoyl tartaric acid or (+) - or (-) - di-O- (p-toluoyl) tartaric acid in a suitable solvent such as methanol, ethanol, acetone, acetonitrile or tetrahydrofuran to give a salt. the salt is then treated with a suitable acid (e.g. hydrochloric acid or sulfuric acid) followed by an aqueous solution of a suitable base (e.g. sodium hydroxide, potassium hydroxide, ammonium hydroxide or sodium carbonate) to form the optically active form, i.e. (+) - or ( The (-) - isomer is a compound of formula le.

Among the azabicyclohexanes of Formula I that can be prepared by the process of the present invention, the following are noted for their advantageous effect:

- (4-Chloro-phenyl) -3-aza-bicyclo (3.1.0) hexane, 1-Phenyl-3-aza-bicyclo (3.1.0) hexane, 3-Methyl-1-phenyl-3-aza-bicyclo (3.1 .0) hexane.

- (3-Chloro-phenyl) -3-aza-bicyclo (3.1.1] -hexane, 1- (3-Fluoro-phenyl) -3-aza-bicyclo (3.1.1 -hexane, 1- (4-chloro-phenyl) -3 -methyl-3-azabicyclo [3.1.1] hexane, 3-benzyl-1-phenyl-3-azabicyclo (3.1.0] hexane, 3-cyclopropylmethyl-1-phenyl-3-azabicyclo (3.1. Phenethyl-1-phenyl-3-aza-bicyclo (3.1.1] -hexane, 3-isopropyl-1-phenyl-3-aza-bicyclo (3.1. 0 -hexane, 1- (4-trifluoromethyl-phenyl) -3-aza-bicyclo) (3.1. Ohexane, 3- (4-Chlorobenzyl) -1- (4-chlorophenyl) -3-azabicyclo (3.1. Ohexane,

3-Allyl-1-phenyl-3-aza-bicyclo (3.1-Ohexane, 3-Ethyl-1-methyl-3-aza-bicyclo (3.1.1-Ohexane, 3-Cyclohexylmethyl-1-phenyl-3-aza-bicyclo) 3.1 Ojohexane, 1- (4-Methoxyphenyl) -3-azabicyclo (3.1.1) hexane, 1- (4-Chlorophenyl) -3- (2-fluorobenzyl) -3-azabicyclo (3.1). Ohexane, 1-Phenyl-5-methyl-3-azabicyclo (3.1. Ohexane,

3-Methyl-1- (3,4,5-trimethoxyphenyl) -3-azabicyclo (3.1.1] hexane, 1- (p-Tolyl) -3,6-dimethyl-3-azabicyclo (3.1. Ohexane, 3- (2-Naphthylmethyl) -1- (4-chlorophenyl) -3-azabicyclo [3.1.1] hexane,

3- (5-Norbornen-2-ylmethyl) -1- (4-chlorophenyl) -3-azabicyclo (3.1.1) hexane,

3-Ethyl-1- (4-aminophenyl) -3-azabicyclo [3.1.1] hexane.

3- (4-Fluorobenzoyl) -1-phenyl-3-azabicyclo (3.1.1] hexane 3- (3-Fluorobenzoyl) -1-phenyl-3-azabicyclo (3.1.1) hexane,

3,4-Dichloro-phenyl-3-azabicyclo (3.1.Ojhexán,

- (3-Methoxyphenyl) -3-methyl-3-azabicyclo (3.1.1] hexane, (+) - 1-Phenyl-3-methyl-3-azabicyclo (3.1.0) hexane, 1- (4-) K. chloro-3-trifluoromethylphenyl) -3-azabicyclo [3.1.1] hexane,

3,6-Dimethyl-l-phenyl-3-azabicyclo (3.1.0) hexane,

1- (4-Acetamido-phenyl) -3-ethyl-3-aza-bicyclo (3.1-olhexane, 1- (3-Hydroxy-phenyl) -3-methyl-3-aza-bicyclo (3.1.1) -hexane, 1- (4-Nitrophenyl) -3-azabicyclo (3.1.0] hexane, 1- (p-Tolyl) -3-azabicyclo (3.1.0) hexane hydrochloride, and 1- (2-Chloro) phenyl) -3-azabicyclo (3.1.

The compounds of the present invention are useful as analgesics in warm-blooded patients, as will be apparent from the following pharmacological experiments.

One method for investigating the analgesic effect is the method of Randall and Selitto [Arch. Int. Pharmacodyn., Hl 409 (1957)]. In this method, the pain perception threshold of rats whose paw is pressurized by injecting 0.1 ml of a 20% aqueous suspension of brewer's yeast under the skin is injected into the left hind paw. The treated and swollen paws were then subjected to a continuously increasing force [16 g / sec] using an Ugo Basile analgesimeter (i.e., a painkiller). At 250 g, the pressure is released when there is no reaction (jerk or loudness). The control and starch treated rats show a reaction at a force of about 30 g. The pressure-induced pain sensitivity threshold is observed between 1 hour and a few hours (at the time of peak effect) after administration of a test compound of up to 200 mg / kg at 10 oral doses. Brewer's yeast is injected two hours before the start of the measurement. The ratio of the effect observed (T) in treated animals to that observed in control animals (C) is calculated and utilized to select the active compounds, determine the efficacy by responding to each dose and / or measure the analgesic efficacy (e.g. for example, the higher the T / C 20 ratio, the greater the analgesic efficacy), for example, the test compounds are considered to be significantly effective when compared to the parallel control when the pain detection threshold is increased by 100% [i.e., greater than or equal to T / C to 2.0]. Positive results obtained with the assays may be followed by one or more of the following experiments: repeated testing at the same dose for control purposes; lower dose study; determining the time and duration of the onset of the peak effect; estimating the dose-dependency of efficacy; and determining the maximum efficiency (i.e., the maximum T / C value) by methods well known to those skilled in the art.

The analgesic effects of some important compounds of Formula I are those of Atkinson, D.C. and Cowan, A. [J. Pharm. PharmacoL, 26, 727 (1974)].

In this study, male albino Wistar rats of Royalhart culture, weighing 120-150 g, were fasted for nearly 20 hours and then treated with 0.25 ml of brine yeast physiological saline under the foot of the left hind paw of each of 40 rats. injection. Three hours later (during which time the injected paw develops inflammation), the pre-45 gait pattern of each rat is examined and evaluated using the following system:

= normal gait in the presence of a severely inflamed paw; Continuous use of the sole while walking 50

0.5 = as above, but not constant, with slight limping

1,0 = constant limp but continuous use of sole

1.5 = strabby occasionally walking three feet (the treated sole does not touch the ground) or occasionally using the fingers in combination with the sole

2,0 = continuous walking on three feet and / or only finger tips touching the walking surface; the sole does not touch the ground at all.

Prior to administration of the test compound, more than 95% of the rats had a gait rating of 2. The test compounds were administered orally with a suitable vehicle at a dose of 0.5 ml / 100 kg body weight. One and / or two hours after administration, the gait pattern is reassessed as described above. The results obtained are again limited to screening the active compounds, determining efficacy, etc. utilized. For example, if the experiments were conducted in three animals per dose and had a gait value of 6 (three times 2.0) prior to drug treatment and 4 (three animals) after drug treatment, the test compound was considered to be significantly effective in comparison with the parallel control. . For the study of dose-response efficacy in a single animal, a pre-treatment gait value of 2.0 is reduced by at least 50%, i.e., less than or equal to 1.0.

A further method of measuring the analgesic effect of the compounds of the present invention is the so-called jerk syndrome test, described by Siegmund et al., Proc. Exp. Bioi, and Med., 1957, 95, 729], with minor modifications as follows: The essence of this method is that an analgesic compound is male albino Swiss mice (weighing 18- 25 g) phenyl-p-quinone at a dose of 1 mg / kg body weight ^; and the number of these jolts. The syndrome is characterized by occasional contraction of the abdomen, twitching and rotation of the torso, and extension of the hind legs 3 to 5 minutes after injection of phenyl-p-quinone. The test compounds were orally administered 30 minutes prior to the administration of phenyl-p-quinone to the experimental groups of 2 to 2 mice at the indicated doses. The total number of jerks performed by each group within 15 minutes of phenyl p-quinone administration is recorded. A test compound is considered effective when it reduces the total number of convulsions from a control of nearly 30 per pair to 18 or less.

The results are shown below !. table.

Table I Test for analgesic activity of compounds of formula Ia

Experimental method

(Ia) Substitute for a phenyl ring X correction of abnormal rat gait to reduce the number of jerks in the mouse reduction of pain in rat inflamed leg p-Cl H The (100) In (50) 0 A (100) ¹ ' p-Cl H, (-) - isomer The (100) p-Cl H, (+) - isomer A (50) The (100) A (50) H H The (150) The (100) The (200) H methyl The (150) The (100) The (200)

Continuation of Table I

Experimental method

(Ia) Substitute for a phenyl ring X correction of abnormal rat gait to reduce the number of jerks in the mouse reduction of pain in rat inflamed leg m-Cl H A (50) The (200) A (50) m-F H The (100) A (50) H H, (-) - isomer The (100) A (50) H Methyl, (-) - isomer A (50) p-Cl Methyl, (-) - isomer The (100) p-Cl Methyl, (-E) -isomer The (150) The (100) p-Cl methyl The (100) H benzyl The (200) H phenethyl The (100) fo-CF H The (I50) The (N5) H ethyl The (200) p-methoxybenzaldehyde H The (100) A (50) H H, (+) - isomer The (200) A (50) A (50) 3,4-Di-Cl H The (200) p-Ethyl H A (25) A (50) m-methyl H A (50) A (25) A (50) p-Br H The (200) P-F H The (100) A (50) A (50) p-Br benzyl The (200) m-methoxyphenyl methyl The (100) A (50) A (50) H Methyl +) isomer The (200) 4-Cl-3-CF ₃ Η φ The (200) _p -NO ₂ H The (200) p-methylphenyl H The (200) A (60) A (50) m-CF ₃ H A (25) A (50) 3-Br-4-methoxy H ' The (200) p-methylphenyl H, (+) - isomer A (50) A (25) The (N5) p-methylphenyl H, (-) - isomer The (100) A (50) p-methylphenyl Methyl The (100) A (50) p-OH H The (200) A (50) p-ethoxy H A (50) p-Cl Ethyl The (100) H 4,4-bis (4-fluorophenyl) butyl The (200) p-Cl 4,4-bis (4-fluorophenyl) butyl The (200) H 3- (4-fluorobenzoyl) propyl The (200) m-methoxyphenyl H The (200) 1) effective (at the indicated oral dose in mg / kg)

The azabicyclohexanes of the invention may be administered orally, for example, with an inert pharmaceutically acceptable carrier or carrier, or filled into hard or soft shell gelatin capsules, or may be mixed directly with the food. For oral pharmaceutical administration, the active compounds of the invention may be formulated together with customary carriers and / or excipients, for example, in the form of tablets, cachets, capsules, elixirs, suspensions, syrups or lozenges. Such pharmaceutical compositions comprise at least 0.1 wt _o active ingredient, although the amount of active agent and the additives vary widely, such as the amount of active agent 60 is usually between about 5% to about 75% by weight or even more. Of course, the amount of active ingredient in such pharmaceutical compositions is selected such that the dosage unit is administered. appropriate therapeutic effect. Pharmaceutical compositions ⁶⁵ containing from 10 mg to 400 mg of active ingredient are preferred, and oral compositions containing from about 50 mg to about 250 mg of active ingredient are particularly preferred.

In addition to the active ingredient, said pharmaceutical compositions may also contain, for example, a binder (e.g. gum tragacanth, gum arabic, corn starch or gelatin), a special pharmaceutical binder (e.g. dicalcium phosphate), a disintegrant (e.g. corn or potato starch), magnesium stearate), a sweetening agent (e.g., sucrose, lactose or saccharin) and a flavoring agent (e.g., mint, gaulteria oil or sour cherry extract). If the dosage unit form is a capsule, the latter may contain, in addition to materials of the above type, a liquid carrier such as a fatty oil. A variety of materials may also be used as coatings or otherwise to modify the physical form of the pharmaceutical composition. For example, the pills, tablets or capsules may contain, in addition to the active ingredient, sucrose as a sweetening agent, methyl and propylparaben as a preservative, a coloring agent and, for example, sour cherry or orange flavor. Of course, any material used in the preparation of any pharmaceutical composition, in the amount used, must be pharmaceutically acceptable and non-toxic.

Pharmaceutical compositions suitable for parenteral administration, i.e., having the desired purity and stability, may be prepared by dissolving 0.1 to 10.0% by weight of an azabicyclohexane of the present invention in a mixture of non-volatile and usually liquid polyethylene glycols dissolved in water and organic liquids. They are soluble in 15 aranes and have a molecular weight of about 200 to about 500. Such polyethylene glycol mixtures are commercially available and are usually prepared by condensing glycol with ethylene oxide.

Although the amount of azabicyclohexane 20 in the liquid carrier may vary from 0.10 wt% to 10.0 wt%, it is preferably from about 3.0 to 9.0 wt%. As a liquid carrier, a mixture of said polyethylene glycols having an average molecular weight of about 400 is preferred. Such a mixture is commonly referred to in the literature as "polyethylene glycol 400". Thus, a pharmaceutical composition of about 3.0 to about 9.0% by weight of a solution of azabicyclohexane in 400 aqueous polyethylene glycol is preferred. In addition to the active ingredient, pharmaceutical compositions suitable for parenteral administration may contain a preservative such as bacterial or fungal contamination or chemical degradation. for prevention.

The following examples illustrate the invention. 35

Example 1

Preparation of racemic 1- (4-chlorophenyl) -3-azabicyclo (3.1.0) hexane hydrochloride 40 g of diethyl cis-1- (4-chlorophenyl) -1,2-cyclopropanedicarboxylate (US Patent No. 3344026, Example 1) To a solution of ethanol (25 ml) was added 13.5 ml of potassium hydroxide solution (N), and the resulting mixture was refluxed for 3.5 hours and then at room temperature overnight. The ethanol is then evaporated under reduced pressure and the residual aqueous solution is extracted with diethyl ether to remove a small amount of oily phase. To the aqueous solution was then added 13.5 ml of n-hydrochloric acid and 2 ml of 6N hydrochloric acid, and the resulting oil-water mixture was extracted four times with chloroform. The combined chloroform extract was dried, clarified and evaporated under reduced pressure to give a yellow precipitate. Recrystallization twice from a mixture of ethyl acetate and petroleum ether (b.p. 30-70 ° C) gave 0.85 g of cis-1- (4-chlorophenyl) -1,2- as a white solid, m.p. 162-163 ° C. cyclopropanedicarbonate is obtained. 60

A suspension of 5.7 g and 2.02 g of urea in 200 ml of xylene was refluxed for 22 hours, then cooled, diluted with benzene and treated with water. The organic layer was then diluted with chloroform and dried, concentrated under reduced pressure and the residue was finally recrystallized from ethyl acetate / petroleum ether to give 1- (4-chlorophenyl) -1,2-cyclopropanedicarboximide.

A solution of 1- (4-chlorophenyl) -1,2-cyclopropanedicarboximide (2.2 g) in 70 ml of a 70% solution of sodium bis (2-methoxyethoxy) aluminum hydride in benzene was added dropwise with stirring. of benzene (30 ml) over 30 minutes at room temperature under a nitrogen atmosphere, and the reaction vessel was gently heated until a clear solution was obtained. The clear yellow solution was then refluxed under nitrogen for 1 hour, cooled and the excess reducing agent decomposed by addition of 5N sodium hydroxide solution. Water was added to the reaction mixture, and the benzene phase was separated. The aqueous phase is extracted with diethyl ether and the ether extract is added to the benzene phase, and the combined organic phases are dried over magnesium sulfate and concentrated under reduced pressure to give a viscous liquid. This then crystallizes into a sticky-white precipitate which is nothing more than racemic 1- (4-chlorophenyl) -3-azabicyclo (3.1.0) hexane. This precipitate was then dissolved in ethanol and the resulting solution was acidified with ethanolic hydrogen chloride solution and diethyl ether was added to give off-white crystals of the title compound. The crystalline precipitate was finally recrystallized from ethanol to give off-white crystals, m.p. 215-217 ° C.

Reduction of the imides listed below with sodium bis (2-methoxyethoxy) aluminum hydride, as described above, also affords the following compounds of formula I according to the invention.

imide

-phenyl-2-methyl-1,2-cyclopropanedicarboximide +

N-Methyl-1- (3,4,5-trimethoxyphenyl) -1,2-cyclopropanedicarboximide + +

I would do reduced

-phenyl-5-methyl-3-aza-bicyclo (3.1.1-hexane hydrochloride, m.p. 161-163 ° C

3-methyl-1- (3,4,5-trimethoxyphenyl) -3-azabicyclo [3.1.1] hexane hydrochloride, m.p. 243-245 ° C.

Note: The compounds "+" and "++" may be prepared as described in Examples 15 and 4 of U.S. Patent 3,66571.

Example 2 Preparation of (-) - 1- (4-chlorophenyl) -3-azabicyclo (3.1.0) hexane hydrochloride

While stirring under a nitrogen atmosphere at room temperature, 6.6 g of (-) - 1- (4-) is added dropwise to 30 ml of a 70% solution of sodium bis (2-methoxyethoxy) aluminum hydride in benzene over 30 hours. chlorophenyl) -1,2-cyclopropanedicarboximide (see U.S. Patent No. 3,892,772) in 500 ml benzene. The resulting clear yellow solution was refluxed under nitrogen for 90 minutes and then allowed to stand at room temperature overnight. The excess reducing agent was then quenched by careful addition of 25 mL of 5N sodium hydroxide solution and the reaction mixture was diluted with 200 mL of water. The benzene phase is then separated and the aqueous phase is extracted with chloroform. The combined benzene and chloroform phases were dried over magnesium sulfate and concentrated under reduced pressure to give (-) - 1- (4-chlorophenyl) -3-azabicyclo (3.1.0) hexane as a yellow precipitate. This precipitate is dissolved in ethanol and the resulting solution is acidified with 10 ml of 2.3N ethanolic hydrogen chloride solution and then diethyl ether is added. The resulting precipitate was filtered off and dried to give the title compound as white crystals, mp 197-200 ° C. Specific rotation [α] ο ^Η · ^{, 0Η} = —67.

Example 3 Preparation of (+) - 1- (4-chlorophenyl) -3-azabicyclo (3.1.0) hexane hydrochloride

192.5 g of racemic cis-1- (4-chlorophenyl) -1,2-cyclopropanedicarboxylic acid (see U.S. Patent 3,892,772) and 142 g of (-) - 2-aminobutanol in 1600 ml. acetone was allowed to settle for 48 hours, then filtered and the precipitate was washed with acetone. The precipitate was then dissolved in 460 mL of warm water and the resulting aqueous solution was acidified. The precipitate thus formed was filtered off and air-dried. A solution of the crude (+) -dicarboxylic acid thus obtained in a solution of 107.5 g and 79.3 g of (-) -2-aminobutanol in 892 ml of acetone was allowed to stand for several hours, then the precipitate was filtered off, dried and dissolved in 200 ml of warm water. dissolved. The resulting solution was acidified with concentrated hydrochloric acid, then cooled and filtered. The resulting precipitate was recrystallized from acetonitrile to give (+) - cis-1- (4-chlorophenyl) -1,2-cyclopropanedicarboxylic acid having a specific rotation [α] ο ^Η ' ^θΗ = + 180 °.

A mixture of this compound (10.5 g and 3.9 g) in xylene (325 ml) was heated at reflux for 7.5 hours and allowed to stand overnight. Distillation of the xylene, cooling and filtration gave a white precipitate which was recrystallized from ethanol to give (+) - 1- (4-chlorophenyl) -1,2-cyclopropanedicarboximide having a specific rotation [a] p ^{H, 0 H} = + 63 °.

While stirring at room temperature under nitrogen atmosphere, 4.5 g of (+) - 1- (4-) is added dropwise to 30 ml of a 70% solution of sodium bis (2-methoxyethoxy) aluminum hydride in benzene over 30 minutes. chlorophenyl) -1,2-cyclopropanedicarboximide in 400 ml of benzene and the resulting clear yellow solution was also refluxed under nitrogen for 90 minutes and then allowed to stand at room temperature overnight. The unreacted reducing agent is then quenched by careful addition of 25 ml of 5N sodium hydroxide solution, the reaction mixture is diluted with 200 ml of water and the benzene phase is separated off. The aqueous phase is extracted with chloroform and the combined benzene and chloroform phases are dried over magnesium sulfate and concentrated under reduced pressure to give (+) - 1- (4-chlorophenyl) -3-azabicyclo (3.1.0) hexane. as a sticky yellow precipitate. This was then dissolved in ethanol, and to the resulting solution was added 20 ml of a 2.3N solution of hydrogen chloride in ethanol, followed by 200 ml of diethyl ether to form crystals. These crystals were finally recrystallized from acetonitrile to give the title compound as a white crystal, m.p. 190-192 ° C, [α] ^{D 20} = + 63 °.

Example 4

Preparation of racemic 1-phenyl-3-azabicyclo (3.1.0) hexane hydrochloride

While stirring at room temperature under nitrogen atmosphere, 6.6 g of 1-phenyl-1,2-cyclopropanedicarboximide are added dropwise over a period of one hour from a 70% solution of sodium bis (2-methoxyethoxy) aluminum hydride in 70% benzene. (see Example 8 of U.S. Patent No. 3,166,571) in benzene (400 mL) and the resulting reaction mixture was also refluxed for 90 minutes under nitrogen. The excess reducing agent was then quenched by careful addition of 25 mL of 10N sodium hydroxide solution, the reaction mixture was sprinkled with 200 mL of water and the benzene phase separated. The aqueous phase is then extracted with chloroform and the combined organic phases are dried over magnesium sulfate and concentrated under reduced pressure to give a brown liquid. This was then dissolved in ethanol and the resulting solution was acidified by addition of 5 ml of a 2.3N solution of hydrogen chloride in ethanol. Finally, the product is precipitated by the addition of diethyl ether and recrystallized from acetonitrile. This gives white crystals of the title compound, m.p. 166-168 ° C.

Example 5

Preparation of racemic 3-methyl-1-phenyl-3-azabicyclo (3.1.0) hexane hydrochloride

While stirring at room temperature under nitrogen atmosphere, 5.5 g of N-methyl-1-phenyl-1 was added dropwise to 30 ml of a 70% solution of sodium bis (2-methoxyethoxy) aluminum hydride in benzene over 1 hour. A solution of 2-cyclopropanedicarboximide (prepared in Example 1 of US 3166571) in benzene (400 ml) was added and the resulting mixture was refluxed under nitrogen for 90 minutes. The excess reducing agent was destroyed by careful addition of ₇ ml of 10 N sodium hydroxide solution 25 and then the reaction mixture was diluted with 200 mL of water. The benzene phase is then separated, and the aqueous phase is extracted with chloroform. The combined organic layers were dried over magnesium sulfate and evaporated under reduced pressure to give a liquid. This liquid was then dissolved in ethanol and the ethanolic solution was acidified with 15 ml of 2.3N ethanolic hydrogen chloride. The product was finally precipitated with diethyl ether and recrystallized from a mixture of isopropanol and hexane. 158-160 ° C crystals of the title compound are obtained.

Example 6

- Preparation of (3-chlorophenyl) -3-azabicyclo (3.1.0) hexane hydrochloride

While mixing with Nichrome type metal mixers

53.6 g of ethyl α- (3-chlorophenyl) acetic acid (prepared by esterification of the corresponding acid), 51.5 g of N-bromosuccinimide and 1 g of benzoyl peroxide are prepared with 1.25 liters of carbon tetrachloride. The mixture was refluxed for 20 hours, then cooled, filtered and the filtrate evaporated to give an orange oil. The latter is subjected to vacuum distillation to give the product a-bromo-α- (3-chlorophenyl) -acetic acid ethyl ester.

To a suspension of 4.4 g of sodium hydride in 500 ml of diethyl ether in a nitrogen atmosphere are added 0.5 ml of ethanol, followed by dropwise addition of 27.8 g, 10 g of ethyl acrylate and 1 ml of ethanol from the ester prepared in the previous paragraph, and the resulting reaction mixture was stirred at room temperature overnight. Ethanol was added to the reaction mixture to decompose the unreacted sodium hydride, and the reaction mixture was washed with water (100 mL), hydrochloric acid (50 mL), dilute sodium bicarbonate (3x) and water (100 mL). The reaction mixture was dried and concentrated under reduced pressure to give 1- (3-chlorophenyl) -1,2-cyclopropanedicarboxylic acid ethyl ester as a yellow liquid.

From this diester, a mixture of 22 g of 150 ml of ethanol and 150 ml of n-potassium hydroxide solution was used under reflux.

After boiling for 3.5 hours, allow to stand at room temperature overnight. The reaction mixture was concentrated and extracted with diethyl ether. The remaining aqueous phase was acidified with 1N hydrochloric acid and extracted three times with chloroform. The combined chloroform extract was dried and concentrated under reduced pressure to give a yellow oil. This was crystallized from ethyl acetate / petroleum ether to give a cis-1- (3-chlorophenyl) -1,2-cyclopropanedicarboxylic acid as a white precipitate.

A mixture of this acid (5.7 g and 2.02 g) in xylene (200 ml) was refluxed for 22 hours, cooled, diluted with benzene and washed with water. The organic phase is then diluted with chloroform, dried and concentrated under reduced pressure, and the residue is recrystallized from ethyl acetate / petroleum ether to give 1- (3-chlorophenyl) -1,2-cyclopropanedicarboximide.

With stirring at room temperature under nitrogen atmosphere, 4.0 g of a 70% solution of sodium bis (2-methoxyethoxy) aluminum 35-hydride in benzene are added dropwise over 1 hour to the dicarboximide prepared as described in the preceding paragraph. A solution of 400 ml of benzene was added and the reaction mixture was refluxed under a nitrogen atmosphere for 90 to 40 minutes. The excess hydride was then quenched by addition of 25 mL of 10 N sodium hydroxide solution and the reaction mixture was diluted with 200 mL of water. The benzene phase is separated and the aqueous phase is extracted with chloroform. The combined organic phases were dried over magnesium sulfate and evaporated under reduced pressure to give a viscous orange to brown oil. This was then dissolved in ethanol and the resulting solution was acidified by addition of a 2.3N solution of hydrogen chloride in ethanol. The product is finally precipitated by addition of diethyl ether and recrystallized from isopropanol. White crystals of the title compound are obtained, m.p. 182-184 ° C.

Example 7 ⁵⁵

- Preparation of (3-Fluorophenyl) -3-azabicyclo (3.1.1] hexane hydrochloride

1- (3-Fluorophenyl) acetic acid (46.2 g) was dissolved in ethanol (120 ml), sulfuric acid (12 ml) was added to the resulting solution, and the resulting mixture was heated under reflux for 4.5 hours and then at room temperature overnight. let it stand. The reaction mixture was added with water (400 mL), extracted three times with diethyl ether, and the combined extracts were dried over magnesium sulfate and concentrated in vacuo. The resulting liquid was finally subjected to vacuum distillation to give ethyl α- (3-fluorophenyl) acetic acid.

A mixture of 49.3 g of 53 g of N-bromosuccinimide, 0.95 g of benzoyl peroxide and 1.6 liters of carbon tetrachloride is refluxed for 24 hours and then concentrated to an orange oil, which is concentrated to an orange oil. and vacuum distillation to give ethyl α-bromo-α- (3-fluorophenyl) acetic acid.

Under a nitrogen atmosphere, a suspension of 11 g of sodium hydride (used as a mineral oil dispersion) in 1 liter of diethyl ether is added dropwise with a mixture of the ester obtained in the preceding paragraph, 65 g, 25 g of ethyl acrylate and 2 ml of ethanol. Store at 29 ° C. The reaction mixture was cooled, and a few ml of ethanol was added to decompose the excess sodium hydride, followed by washing successively with water, n hydrochloric acid, dilute sodium bicarbonate solution and saturated sodium chloride solution. The resulting liquid is subjected to vacuum distillation to give 1- (3-fluorophenyl) -1,2-cyclopropanedioic acid diethyl ester.

From this diester, a mixture of 20.5 g of 160 ml of n-potassium hydroxide solution and 150 ml of ethanol was used under reflux.

Boil for 3.5 hours and then concentrate. The concentrate was acidified with n hydrochloric acid, extracted three times with chloroform, and the combined extracts were dried and evaporated to dryness under reduced pressure. The resulting precipitate was recrystallized twice from ethyl acetate / petroleum ether to give cis-1- (3-fluorophenyl) -1,2-cyclopropanedioic acid.

8.0 g of the dicarboxylic acid thus obtained were stirred and

A mixture of 2.6 g of urea in 500 ml of xylene is refluxed for 22 hours, and the resulting solution is diluted with benzene, washed with water and dried over magnesium sulfate. The organic phase is then concentrated under reduced pressure to give 1- (3-fluorophenyl) -1,2-cyclopropanedicarboximide as an off-white precipitate.

While stirring at room temperature under nitrogen atmosphere, 5.6 g of the dicarboximide described in the previous paragraph are added dropwise to 30 ml of a 70% solution of sodium bis (2-methoxyethoxy) aluminum hydride in 70% benzene over 90 minutes. and the reaction mixture is refluxed under nitrogen for 90 minutes. The excess hydride was then quenched by careful addition of 25 mL of 10 N sodium hydroxide solution and the reaction mixture was diluted with 200 mL of water. The benzene phase is then separated and the aqueous phase is extracted with chloroform. The combined organic layers were dried over magnesium sulfate and evaporated under reduced pressure to give a mixture of an oily precipitate and a viscous liquid. This mixture was then dissolved in ethanol and the resulting ethanolic solution was acidified with ethanolic hydrogen chloride solution. Finally, the product is precipitated by addition of diethyl ether and recrystallized from acetonitrile to give the title compound as gray crystals, m.p. 140-146 ° C.

Example 8 Preparation of (-) - 1-Phenyl-3-azabicyclo (3.1.0) hexane hydrochloride

With stirring under a nitrogen atmosphere, a suspension of (-) - 1-phenyl-1,2-cyclopropanedicarboximide (18.7 g) in benzene (500 mL) was treated with 70% sodium bis (2-methoxyethoxy) aluminum hydride over 10 minutes. 150 ml of a benzene solution are added and the reaction mixture is stirred at room temperature for 2 hours, then refluxed for 4 hours and then allowed to stand at room temperature for 20 hours. Thereafter, 150 ml of 10N sodium hydroxide solution were carefully added with stirring, and the organic phase was separated, washed with water, dried over magnesium sulfate and concentrated under reduced pressure to give a yellow oil. This was then dissolved in diethyl ether (300 mL) and dry hydrogen chloride gas was bubbled through the resulting solution until a precipitate formed. The reaction mixture was filtered to give colorless crystals which were then recrystallized from acetonitrile. The title compound is obtained in the form of light brown crystals, m.p. 170-172 ° C.

Example 9

Preparation of racemic 1-phenyl-3-azabicyclo (3.1.0) hexane

If I-phenyl-1,2-cyclopropanedicarboximide can be prepared as described in Example 8 of US-A-3 166 571, starting from the procedure described in Example 8, but treatment with hydrogen chloride gas is omitted, then 15 mm Hg at 130-133 ° C to give the hot title compound.

Example 10 Preparation of (-) - 3-Methyl-1-phenyl-3-azabicyclo (3.1.0) hexane hydrochloride

To a solution of 18.7 g of (-) -1-phenyl-1,2-cyclopropanecarboximide in 100 ml of anhydrous dimethylformamide was added 5 g of sodium hydride (as a 54% dispersion in mineral oil) over 15 minutes, and the resulting mixture was stirred for 30 minutes. and 10 ml of methyl iodide are then added over 5 minutes. The reaction mixture was allowed to stand for 15 minutes, heated in a water bath for 15 minutes, cooled and poured into 250 ml of water. The aqueous mixture was filtered and the filtered crystals were washed with petroleum ether and air dried to give (-) - N-methyl-1-phenyl-1,2-cyclopropanecarboximide.

Under nitrogen, while stirring, to a solution of 5.0 g of the compound obtained in the preceding paragraph in 125 ml of benzene, 30 ml of a 70% solution of sodium bis (2-methoxyethoxy) aluminum hydride in benzene are added over 10 minutes, followed by The resulting mixture was refluxed for 5 hours, cooled and carefully added with 60 ml of 10N sodium hydroxide solution. After separation of the organic phase, it is washed with water, dried over magnesium sulfate and concentrated under reduced pressure to give an amber oil. This was then dissolved in diethyl ether (250 mL), and the resulting solution was saturated with hydrogen chloride gas and then filtered to give colorless crystals. These crystals were recrystallized from acetonitrile to give the title compound as colorless crystals, m.p. 194-196 ° C, with a specific rotation = -73 °.

Example 11 Preparation of (-) - 1- (4-chlorophenyl) -3-methyl-3-azabicyclo (3.1.0) hexane hydrochloride

To a solution of (-) -1- (4-chlorophemyl) -1,2-cyclopropanecarboximide (22.1 g) in anhydrous dimethylformamide (100 ml) was added 5.0 g of sodium hydride (as a 54% dispersion in mineral oil) over 15 minutes. ), the resulting mixture was stirred for 30 minutes and then 10 ml of methyl iodide was added over 5 minutes. The reaction mixture was allowed to stand for 15 minutes, heated in a water bath for 15 minutes, cooled and poured into 250 ml of water. The precipitated crystals are filtered off, washed with petroleum ether and air-dried to give (-) - N-methyl-1- (4-chlorophenyl) -1,2-cyclopropanecarboximide as colorless crystals.

To a stirred solution of 11.8 g of the compound obtained in the preceding paragraph in 250 ml of benzo, under a nitrogen atmosphere, 60 ml of a 70% solution of sodium bis (2-methoxyethoxy) aluminum hydride in benzene are added over a period of 10 minutes. The reaction mixture was refluxed for 5 hours, then cooled and carefully added with 60 ml of 10N sodium hydroxide solution. The organic layer was separated, washed with water, dried over magnesium sulfate and concentrated under reduced pressure to give an amber oil. This was then dissolved in 250 ml of diethyl ether and the resulting solution was saturated with hydrogen chloride and filtered to give colorless crystals. Recrystallization from acetonitrile gave the title compound as colorless crystals, m.p. 211-212 ° C, with a specific rotation = -68 °.

Example 12 Preparation of (+) - 1- (4-Chlorophenyl) -3-methyl-3-azabicyclo (3.1.0) hexane hydrochloride

To a stirred solution of (+) -1- (4-chlorophenyl) -1,2-cyclopropanecarboximide (11.08 g) in anhydrous dimethylformamide (50 mL) was added 2.5 g of sodium hydride (54 mL) over 15 minutes with stirring under nitrogen. % mineral oil dispersion). The resulting mixture was stirred for 30 minutes and then 5 ml of iodomethane was added over 5 minutes. The reaction mixture was allowed to stand for 15 minutes, heated in a water bath for 15 minutes, cooled and poured into 125 ml of water. The resulting aqueous mixture was filtered, washed with petroleum ether and dried to give (+) - N-methyl-1- (4-chlorophenyl) -1,2-cyclopropanecarboximide as colorless crystals.

To a solution of (+) - N-methyl-1- (4-chlorophenyl) -1,2-cyclopropanecarboximide (3.92 g) in benzene (100 ml) was added sodium bis (2-methoxyethoxy) solution over 10 minutes under a nitrogen atmosphere. 20 ml of a 70% solution of aluminum hydride in benzene and the resulting mixture is stirred for 2 hours at room temperature and then refluxed for 2 hours. Then, 10 ml of sodium hydroxide solution (10 ml) was added carefully, the benzene layer was separated, washed with water, dried over magnesium sulfate and concentrated under reduced pressure to give an oil. This was then dissolved in diethyl ether (200 mL) and the resulting solution was saturated with dry hydrogen chloride gas to give a colorless crystalline cake after filtration of the solution. This is then crystallized from acetonitrile to give the title compound as pale brown crystals, m.p. 209-210 ° C. The product has a specific rotation [α] ο ^Η '° ^Η = - + 67 °.

Example 13

Preparation of racemic 1- (4-chlorophenyl) -3-methyl-3-azabicyclo (3.1.0) hexane hydrochloride

To a stirred solution of 44.2 g of racemic 1- (4-chlorophenyl) -1,2-cyclopropanecarboximide in 200 ml of anhydrous dimethylformamide is added 10 g of sodium hydride (as a 50% dispersion in mineral oil) over 5 minutes, and then 20 ml of methyl iodide are added slowly over 5 minutes. The reaction mixture was then heated in a water bath for 30 minutes, cooled and poured into 500 ml of water. The precipitate was filtered off and recrystallized from a mixture of heptane and ethyl acetate to give racemic N-methyl-1- (4-chlorophenyl) -1,2-cyclopropanecarboximide.

While stirring under a nitrogen atmosphere, 60 ml of a 70% solution of sodium bis (2-methoxyethoxy) aluminum hydride in 70% benzene are added over a period of 10 minutes to a solution of the compound obtained in the preceding paragraph in 250 ml of benzene. After allowing the reaction mixture to stand for 16 hours, it was refluxed for 4 hours, then cooled and carefully added with 60 ml of 10N sodium hydroxide solution. After separation of the organic phase, it is dried over sodium sulfate and then with magnesium sulfate, filtered and concentrated under reduced pressure to give the free base as a pale yellow oil. The oil was then dissolved in diethyl ether (200 mL) and the resulting solution was saturated with dry hydrogen chloride gas. The resulting precipitate was filtered off and then crystallized from acetonitrile to give the title compound as pale brown disc crystals, mp 180-182 ° C.

Example 14

Preparation of 3-Benzyl-1-phenyl-3-azabicyclo (3.1.0) hexane hydrochloride

To a stirred solution of 1-phenyl-1,2-cyclopropanedicarboximide (37.4 g) in anhydrous dimethylformamide (200 ml) was added 10 g of sodium hydride (as a 50% dispersion in mineral oil) followed by 25.4 ml of benzyl chloride and 20 mg potassium iodide is added. The reaction mixture was stirred at room temperature for 2 hours and then poured into 1 liter of water. The resulting viscous precipitate was treated with petroleum ether to give N-benzyl-1-phenyl-1,2-cyclopropanedicarboxynide as pale yellow crystals.

While stirring under nitrogen atmosphere, 60 ml of a 70% solution of sodium bis (2-methoxyethoxy) aluminum hydride in 70% benzene are added over 10 minutes to a solution of the compound obtained in the preceding paragraph in 250 ml of benzene, the resulting mixture was refluxed for 5 hours, then cooled and carefully added with 60 ml of 10N sodium hydroxide solution. After separation of the benzene phase, it is washed with water, dried over magnesium sulfate and concentrated under reduced pressure to give an amber oil. This was then dissolved in diethyl ether and the resulting solution was saturated with dry hydrogen chloride gas. The resulting precipitate was filtered off and recrystallized from isopropanol to give colorless crystals, m.p. 194-196 ^° C.

Example 15

Preparation of 3-Cyclopropylmethyl-1-phenyl-3-azabicyclo (3.1.0) hexane hydrochloride

With stirring under nitrogen atmosphere, a suspension of 61.2 g of 1-phenyl-1,2-cyclopropanecarboximide (prepared in Example 8 of U.S. Patent No. 3,166,571) in 2 liters of benzene was treated with sodium bis (2-methoxyethoxy). 400 ml of a 70% solution of aluminum hydride in benzene are added, and the resulting mixture is stirred at room temperature for 2 hours, then refluxed for 4 hours and finally stirred at room temperature for 20 hours. Subsequently, 400 ml of 10N sodium hydroxide solution was carefully added with stirring. After separation of the organic phase, the mixture was washed twice with dilute sodium hydroxide solution, then with water, dried over magnesium sulfate and evaporated to give an amber oil. This solution was diluted with dilute hydrochloric acid and the resulting solution was washed with diethyl ether, filtered and the filtrate basified with sodium hydroxide. The alkaline filtrate was then extracted with benzene and the extract was dried over magnesium sulfate, filtered and evaporated to give an amber oil. azabicyclo (3.1.0) hexane is obtained. To a solution of this compound (15.9 g) in benzene (100 ml) was added triethylamine (20 ml) and a solution of cyclopropanecarbonyl chloride (11.0 g) in benzene (20 ml) was added over 5 minutes. The resulting reaction mixture was stirred for 30 minutes and water (50 mL) was added. After separation of the benzene phase, the mixture is extracted with dilute sodium bicarbonate solution, dilute hydrochloric acid and water, dried over magnesium sulfate and concentrated to give 3-cyclopropylcarbonyl-1-phenyl-3-azabicyclo (3.1.0) as a brown oil. ) hexane was obtained.

While stirring, a solution of 11.35 g of the compound obtained in the preceding paragraph in 100 ml of benzene was added 25 ml of a 70% solution of sodium bis (2-methoxyethoxy) aluminum hydride in benzene, and the resulting mixture was stirred for 18 hours. After standing for 2 hours, reflux for 2 hours, cool and slowly add 25 ml of 10N sodium hydroxide solution. After separation of the organic phase, it is washed with saturated sodium chloride solution, dried over magnesium sulfate and concentrated to a brown oil. This oil was dissolved in diethyl ether and the resulting solution was bubbled through with dry hydrogen chloride gas to give pink crystals. After filtration, these crystals were recrystallized from isopropanol to give the title compound as pink crystals, m.p. 164-165 ° C.

Reaction of 1- (p-tolyl) -3-azabicyclo (3.1.0) -hexane with cyclopropanecarbonyl chloride, which can be prepared as described in Example 36 below, yields 3-cyclopropanecarbonyl-1- (p-tolyl) - Reduce 3-azabicyclo (3.1.0) hexane as colorless crystals, m.p. 180-182 ° C, as described above.

3-Cyclopropylmethyl-1- (p-tolyl) -3-azabicyclo (3.1.0) hexane hydrochloride is obtained.

Example 16

Preparation of 3-phenethyl-1-phenyl-3-azabicyclo (3.1.0) hexane hydrochloride

To a stirred solution of 1-phenyl-1,2-cyclopropanedicarboximide (9.35 g) in dimethylformamide (50 ml) was added 2.5 g of sodium hydride (as a 50% dispersion in mineral oil) over 5 min. After stirring for 0.5 h, 0.1 g of potassium iodide and 9.25 g of phenethyl bromide are added. The reaction mixture was then heated for 0.5 hour on a water bath for 15 minutes, stirred at room temperature for another 15 minutes and finally poured into 1 liter of water acidified with acetic acid. The aqueous mixture was extracted with methylene chloride and the extract was added to 50 g of magnesium silicate and the mixture was concentrated to dryness under reduced pressure. The resultant powder was applied to a column of magnesium silicate, followed by addition of 1 liter of light petroleum. Elute with 500 ml of methylene chloride and 1 liter of chloroform. Evaporation of the eluate gave N-phenethyl-1-phenyl-1,2-cyclopropanedicarboximide as a colorless oil.

To a stirred solution of 5.8 g of this compound in 50 ml of benzene was added 10 ml of a 70% solution of sodium bis (2-methoxyethoxy) aluminum hydride in benzene, and the resulting mixture was allowed to stand for 18 hours. and then refluxed for 2 hours, cooled and treated with 10 ml of 10N sodium hydroxide solution as described in Example 15 to give the title compound as crystals, m.p. 207-209 ° C.

Example 17

Preparation of 3-isopropyl-1-phenyl-3-azabicyclo (3.1.0) hexane hydrochloride

A mixture of 20.6 g of 1-phenyl-1,2-cyclopropanedicarboxylic acid and 15 g of 1,3-diisopropylurea in 500 ml of xylene is refluxed for 6 hours, then filtered and the filtrate is concentrated under reduced pressure. when we get oil. The oil was then adsorbed on magnesium silicate in 500 mL of methylene chloride and the solvent was evaporated to leave a powder. This powder was added to the magnesium silicate in a Buchner funnel, eluted first with 500 ml of light petroleum and then with 1 liter of methylene chloride. The latter eluate was stripped of methylene chloride to give N-isopropyl-1-phenyl-1,2-cyclopropanedicarboximide as a colorless oil.

To a solution of this compound (9.17 g) in benzene (100 ml) was added 20 ml of a 70% solution of sodium bis (2-methoxyethoxy) aluminum hydride in benzene with stirring, and the resulting mixture was allowed to stand for 18 hours, it is refluxed for 2 hours, cooled, and then 20 ml of 10N sodium hydroxide solution are added slowly, followed by 30 ml of 5N sodium hydroxide solution. After separation, the organic phase is extracted with dilute hydrochloric acid. The aqueous extract was made basic with sodium hydroxide and then extracted with diethyl ether and, after drying over magnesium sulfate, the resulting extract was bubbled through with dry hydrogen chloride gas to give a resin. This was then triturated with diethyl ether and crystallized from acetone to give the title compound as tan crystals, m.p. 141-144 ° C.

Example 18 Preparation of 1- (4-Trifluoromethylphenyl) -3-azabicyclo (3.1.0) hexane hydrochloride

As in Example 6, ethyl 1- (4-trifluoromethyl-phenyl) -acetic acid was converted to ethyl α-bromo-α- (4-trifluoromethyl-phenyl) -acetic acid (boiling point at 0.4 mm Hg).

92-95 C) and the latter compound is reacted with ethyl acrylate and sodium hydride. yielding hot 1- (4-trifluoromethylphenyl) -1,2-cyclopropanedioic acid diethyl ester at 0.2 mm Hg at 108-110 ° C. Hydrolysis of this latter compound with n-potassium hydroxide gave cis-1- (4-trifluoromethylphenyl) -1,2-cyclopropanedicarboxylic acid as colorless crystals, m.p. 161-162 ° C. This compound was then reacted with urea to give 1- (4-trifluoromethylphenyl) -1,2-cyclopropanedicarboximide as colorless crystals, m.p. 164-165 ° C.

To a solution of this compound (3.5 g) in benzene (75 ml) was added 20 ml of a 70% solution of sodium bis (2-methoxyethoxy) aluminum hydride in benzene, and the resulting mixture was refluxed for 1 hour, it is then cooled and the excess hydride is decomposed by the addition of 20 ml of 10N sodium hydroxide solution. The benzene layer was washed with water, dried over magnesium sulfate and concentrated under reduced pressure to give an amber oil. This was then dissolved in diethyl ether and the resulting solution was bubbled through with dry hydrogen chloride gas. The resulting precipitate was finally filtered off and recrystallized from isopropanol to give the title compound, mp 249-251 ° C.

Example 19

Preparation of 3- (4-chlorobenzyl) -1- (4-chlorophenyl) -3-azabicyclo (3.1.0) hexane

19.35 g 1- (4-chlorophenyl) -3-azabicyclo (3.1.0) hexane 17.5 g

After treatment with 4-chlorobenzoyl chloride in benzene in the presence of 10.59 g of sodium carbonate, the benzene is distilled off and the dark purple residue is dissolved in 200 ml of chloroform. The resulting solution was washed thoroughly with 5% sodium carbonate solution, 0.5 N hydrochloric acid and water, then dried over sodium sulfate and evaporated to give a dark purple oil. Diethyl ether was added to this oil in the form of 98 to 100 ^J C melting gray crystals of 3- (4-chlorobenzoyl) -l- (4-chlorophenyl) -3-azabicyclo (3.l.Ojhexánt obtained.

To a solution of this compound (16.6 g) in benzene (160 mL) was added dropwise 55.5 g of a 70% solution of sodium bis (2-methoxyethoxy) aluminum hydride in benzene. the reaction mixture was refluxed for 2 hours, cooled and slowly quenched with 10N sodium hydroxide solution. Water was added to the reaction mixture, and the organic layer was separated and washed three times with water and then dried over a mixture of sodium sulfate and magnesium sulfate. Evaporation of the solvent gave the title compound as off-white crystals, mp 88-92 ° C.

Example 20

Preparation of 3- (1-Adamantylmethyl) -1- (4-chlorophenyl) -3-azabicyclo (3.1.0) hexane

In the same manner as in Example 33, 19.35 g of 1- (4-chlorophenyl) -3-azabicyclo (3.1.0) hexane are reacted with 19.87 g of 1-adamantanecarbonyl chloride in the presence of 10.59 g of sodium carbonate. m.p. 163-165 ° C giving 3- (1-adamantylcarbonyl) -1- (4-chlorophenyl) -3-azabicyclo (3.1.0) hexane.

17.7 g of this compound were reduced as described in Example 19 to give a yellow oil which crystallized on standing to a white precipitate, m.p. 72-75 ^° C.

Example 21 5

Preparation of 3-Allyl-1-phenyl-3-aza-bicyclo (3.1.1O) hexane hydrochloride

To a solution of 18.7 g of 1-phenyl-1,2-cyclopropanedicarboximide in 100 ml of dimethylformamide was added 5 g of sodium hydride 10 (as a 50% dispersion in mineral oil), followed by heating in a water bath and stirring for 5 minutes. allyl bromide (9 mL) was added. The reaction mixture was then heated in a water bath for 0.5 h, allowed to stand at room temperature, then poured into water (1 L) and the aqueous mixture was extracted with methylene chloride. The extract was mixed with 50 g of magnesium silicate and concentrated in a rotary evaporator. The resulting mixture was added to 200 g of magnesium silicate in a Buchner funnel and eluted with 1 liter of petroleum ether and then 1 liter of chloroform. The chloroform fraction was concentrated under reduced pressure to give N-allyl-1-phenyl-1,2-cyclopropanedicarboximide as a colorless oil.

To a solution of this compound (8.0 g) in benzene (70 ml) was added 17.5 ml (25%) of a solution of sodium bis (2-methoxyethoxy-aluminum hydride 25% in benzene) and the resulting mixture was refluxed for 2 hours. and then stirred at room temperature for 2 hours.

The reaction mixture was then worked up in the same manner as in Example 19 to give the title compound, mp 124-128 ° C.

When the 1- (p-tolyl) -1,2-cyclopropanedicarboximide described in Example 33, described below, is reacted with allyl bromide, the N-allyl-1- (p-tolyl) -1 is obtained. 2-Cyclopropanedicarboximide is reduced to give 3-allyl-1- (p-tolyl) -3-azabicyclo (3,1-ol) hexane hydrochloride, m.p. 165-167 ° C.

Example 22

Preparation of 3-Ethyl-1-phenyl-3-aza-bicyclo (3.1.1) hexane hydrochloride

To a solution of 15.9 g of 1-phenyl-3-azabicyclo (3.1.0) hexane in pyridine (20 ml) was added acetic anhydride (20 ml), the mixture was allowed to stand at room temperature overnight and then concentrated to give an oil. This oil was dissolved in diethyl ether and methylene chloride, and the resulting solution was washed with dilute hydrochloric acid and then with sodium bicarbonate solution, dried over magnesium sulfate and concentrated to give a pale amber oil. This was then crystallized from hexane to give 3-acetyl-1-phenyl-3-azabicyclo (3.1.0) hexane, m.p. 63-65 ° C. 55

To a solution of this compound (10.0 g) in benzene (100 ml) was added 25 ml of a 70% solution of sodium tri-bis (2-methoxyethoxy) aluminum hydride in benzene, following the procedure described in Example 19. Thus, the title compound is obtained in the form of tan crystals, m.p. 148-152 ° C.

Example 23

Preparation of 3-Cyclohexymethyl-1-phenyl-3-aza-bicyclo [3.1.1] hexane hydrochloride 65

To a stirred solution of 6.4 g of 1-phenyl-3-azabicyclo (3.1.0) hexane in 60 ml of benzene was added a solution of 4.2 g of sodium carbonate in 40 ml of water, followed by a solution of 5.9 g of cyclohexylcarbonyl chloride in 40 ml of benzene. and the reaction mixture was stirred overnight. The oily precipitate in the aqueous phase was extracted with chloroform and the extract was washed with water and dilute hydrochloric acid, dried over magnesium sulfate, filtered and evaporated. The oily residue was extracted with diethyl ether to give 3-cyclohexylcarbonyl-1-phenyl-3-azabicyclo (3.1.0) hexane as a white solid, m.p. 81-82 ° C.

A solution of this compound (7.0 g) in benzene (50 ml) was prepared as described in Example 19, first from a 70% solution of sodium bis (2-methoxyethoxy) aluminum hydride in benzene (13 ml) followed by 13 ml of 10N sodium hydroxide. solution to give the title compound as colorless crystals, mp 215-218 ° C.

Example 24 Preparation of 1- (4-Methoxyphenyl) -3-azabicyclo (3.1.1) hexane hydrochloride

2.6 g of 1- (4-methoxyphenyl) -1- (4-methoxyphenyl) -1,2-cyclopropanedicarboxylic acid diethyl ester prepared from the ethyl ester of α- (4-methoxyphenyl) acetic acid according to the procedure described in Example 6, 20 ml of 1N potassium of ethanol and 20 ml of ethanol are refluxed for 3.5 hours, the ethanol is evaporated off, and 20 ml of n-hydrochloric acid are added to the residue, followed by the addition of increasing amounts of acid until the pH of the reaction mixture is 1. After extraction three times with chloroform, the combined extracts were dried and evaporated to give a yellow solid which was recrystallized from ethyl acetate-hexane to give a pale yellow solid cis-1- (4-methoxyphenyl) -1,2-cyclopropanedioic acid.

A mixture of this compound (6.6 g, 2.4 g urea) and xylene (300 ml) was stirred at reflux for 24 hours, cooled, diluted with benzene (25 ml), washed with water, dried and evaporated under reduced pressure. The resulting precipitate was recrystallized from ethyl acetate-hexane to give 1- (4-methoxyphenyl) -1,2-cyclopropanedicarboximide.

To this mixture of 3.0 g of this compound in 70 ml of benzene was added 20 ml of a 70% solution of sodium bis (2-methoxyethoxy) aluminum hydride in benzene over 5 minutes with stirring. Stir for 5 hours and then reflux for 1 hour. After cooling, 20 ml of 10 N sodium hydroxide solution are added to the reaction mixture, followed by saturated sodium chloride solution. After separation of the organic phase, it is dried over magnesium sulfate, filtered and evaporated. The resulting oil was dissolved in diethyl ether and hydrogen chloride gas was bubbled through the resulting solution. The precipitate was recrystallized from isopropanol to give the title compound as pale pink crystals, m.p. 174-175 ° C.

Example 25 Preparation of (+) - 1-Phenyl-3-azabicyclo (3.1-Ohexane hydrochloride)

With stirring under nitrogen atmosphere, a suspension of 10 g of (+) - 1-phenyl-1,2-cyclopropanedicarboximide in 300 ml of benzene was treated with a solution of 70% sodium bis (2-methoxyethoxy) aluminum hydride in 80 ml of benzene. we give.

the resulting mixture was stirred at room temperature for 2 hours, then refluxed for 4 hours and then stirred at room temperature again for 20 hours. After cooling, 80 ml of 10N sodium hydroxide solution was slowly added to the reaction mixture with stirring, and the organic phase was separated and washed with brine, water, dried over magnesium sulfate and filtered. The filtrate was evaporated and the residue was dissolved in diethyl ether and a solution of dry hydrogen chloride gas was bubbled through the resulting solution. The precipitated product is filtered off and recrystallized from acetonitrile. This gives the title compound as colorless needles, m.p. 169-171 ° C. Specific rotation: [α] D ^H, ° ^H = + 68 °.

Example 26 Preparation of 1- (4-chlorophenyl) -3- (2-fluorobenzyl) -3-azabicyclo (3.1.0) hexane hydrochloride.

19.53 g of 1- (4-chlorophenyl) -3-azabicyclo (3.1.0) hexane in the presence of 10.59 g of sodium carbonate are reacted with 15.8 g of 2-fluorobenzoyl chloride to give a brown gum. 3- (2-Fluorobenzoyl) -1- (4-chlorophenyl) -3-azabicyclo (3.1.0) hexane is obtained. 2.5

13.9 g of this compound were reduced by 50 ml of a 70% solution of sodium bis (2-methoxyethoxy) aluminum hydride in benzene as described in Example 19 to give a pale yellow oil. This free base is then treated with ethanolic hydrochloric acid and diethyl ether to give the title compound as a precipitate, m.p. 204-206 ° C.

Example 27 l- ^{(3,4-Dichloro-phenyl)} -3-azabicyclo (3.1.0) hexane solution of

A solution of 59.5 g of α- (3,4-dichlorophenyl) acetic acid in 500 ml of anhydrous ethanol is saturated with dry hydrogen chloride gas and refluxed for 2 hours. it is then concentrated under reduced pressure to a volume of 200 ml. The resulting concentrate was diluted with water (200 mL) and neutralized with concentrated ammonium hydroxide. This aqueous mixture was then extracted three times with chloroform, and the combined extracts were decolorized and concentrated to give the α- (3,4-dichlorophenyl) -acetic acid ethyl ester as a yellow oil.

7.0 g of 3,4-dichlorophenylacetic acid ethyl ester, 5.9 g of N-bromosuccinimide, 50 0.1 g of benzoyl peroxide and 150 ml of carbon tetrachloride are weighed into a three-necked round bottom flask equipped with a Nichrome stirrer and a reflux condenser the resulting reaction mixture was refluxed for 18 hours, then cooled and filtered. The filtrate was concentrated under reduced pressure to give an orange liquid. Subsequent vacuum distillation gave a pale yellow,? X -bromo-α- (3,4-dichlorophenyl) -cetsa-ethyl ester as a pale yellow liquid at a pressure of 0.5 mmHg at 115-120 ° C.

This compound is then converted to the diethyl ester of cis-60-1- (3,4-dichlorophenyl) -1,2-cyclopropanedioic acid by the method of McCoy, L. L. (1958, 80, 6568).

A mixture of 150 g, 66 g of 85% potassium hydroxide in 500 ml of water and 500 ml of ethanol was heated at reflux for 6 hours and then cooled in an ice-65 gel. The oily precipitate is extracted with diethyl ether and the aqueous phase is acidified by the addition of 100 ml of 12N hydrochloric acid. The then oily lower phase slowly crystallizes to give a colorless crystalline filter cake. This was then recrystallized from ethanol / ethyl acetate to give 1- (3,4-dichlorophenyl) -1,2-cyclopropanedioic acid as colorless crystals.

A mixture of 30.3 g and 12.6 g of urea in 1 liter of xylene is refluxed for 6 hours, then the solvent is evaporated off under reduced pressure and the crystalline residue is slurried with water. The precipitated colorless crystals are filtered off, washed with water and air-dried to give 1- (3,4-dichlorophenyl) -1,2-cyclopropanedicaloxylate.

Stirring under nitrogen atmosphere at 0 ° C 2.56 g of this compound in 50 ml of tetrahydrofuran are added to 40 ml of a 1 molar solution of borane in tetrahydrofuran and the reaction mixture is heated on a water bath for 1 hour and then cooled with ice (20 ml). n hydrochloric acid was added and the tetrahydrofuran was evaporated under reduced pressure. The residue was basified with 75 ml of 5N sodium hydroxide solution and extracted with diethyl ether. The extract was dried over magnesium sulfate, filtered and the filtrate was saturated with hydrogen chloride. The precipitated crystals were filtered off and recrystallized from isopropanol to give 1.7 g of the title compound as colorless crystals, m.p. 180-181 ° C.

In the same manner as described above, the imide compounds listed below can also be converted to the compounds of formula I listed below:

1- (4-Hexylphenyl) -3-azabicyclop: article> (3.1.0) Hexane Hydrochloride, m.p.

- (4-Ethylphenyl) -1,2-cyclopropanecarboximide, m.p. 102-104 ° C

- (4-Hexylphenyl) -? 2 -cyclopropanedicarboximide, 115-117 ° C

- (m-tolyl) -1,2-cyclopropanedicarboximide, m.p. 164-168 ° C

- (4-Bromophenyl) -1,2-cyclopropanedicarboximide, m.p. 150-151 ° C.

- (4-Fluorophenyl) -1,2-cyclopropanedicarbomixide, m.p. 146-148 ° C.

The final product of formula I

- (4-Ethylphenyl) -3-azabicyclo (3.1.0) hexane hydrochloride, m.p. 207-209 ° C (3.1.0) hexane hydrochloride, m.p. 129-131 ° C

- (4-Bromophenyl) -3-azabicyclo (3.1.0) hexane hydrochloride, m.p. 231-233 ° C

- (4-Fluorophenyl) -3-azabicyclo (3.1.0) hexane hydrochloride m.p. 170-172 ° C

As described above, N-benzoyl-1- (4-bromophenyl) -1,2-cyclopropanedicarboximide prepared from 1- (4-bromophenyl) -1,2-cyclopropanedicarboximide and benzoyl chloride was prepared as described in Example 14. 69-70 ° C can be converted to 3-benzyl-1- (4-bromophenyl) -3-azabicyclo (3.1.0) hexane.

Example 28 Preparation of 1- (3-methoxyphenyl) -3-methyl-3-azabicyclo (3.1.0) hexane hydrochloride

In a mixture of 225 ml of concentrated hydrochloric acid, 150 ml of water and 150 g of ice, 92.3 g of m-anizidine are dissolved, the resulting mixture is cooled to 0 ° C and then stirred at 0-5 ° C with 52.5 g of sodium diazotize by adding a solution of nitrite in 120 ml of water. The resulting mixture is circled 14

17753!

is added dropwise at 0 C to a solution of 83.25 g of N-methyl maleimide in 225 ml of acetone, and the reaction mixture is adjusted to pH 3.0 with 25.5 g of copper (I) chloride dihydrate in one portion, followed by stirring. and 200 ml of aeetone are added. After evaporation of the acetone and decantation of the aqueous phase, a black residue remains, which is boiled with 1 liter of benzene, dried over magnesium sulfate and filtered through a Buchner funnel containing 50 g of activated magnesium silicate. The dark filtrate was concentrated under reduced pressure and the residue was refluxed with 100 ml of 2,6-lutidine for 10 minutes to effect dehydrochlorination. To the resulting solution was added water (500 mL) and pyridine (400 mL), and the resulting mixture was filtered. From the filtered crystalline filter cake, the dark oil was squeezed and refluxed with 500 ml of 90% ethanol. The ethanol mixture was then cooled and filtered

138-146 ° C, 2- (3-methoxyphenyl) -N-methyl maleimide is obtained as orange crystals.

E Compound Bulb, Ρ. T. [J. Organic Chemistry, 28, 1713 (1963)] can be converted to 1- (3-methoxyphenyl) -N-methyl-1,2-cyclopropanedicarboximide.

To a mixture of the latter compound (3.0 g) in benzene (70 ml) was added 20 ml of a 70% solution of sodium bis (2-methoxyethoxy) aluminum hydride in benzene under stirring for 5 minutes under a nitrogen atmosphere, followed by stirring. The reaction mixture was stirred for 30 minutes, then refluxed for 1 hour, cooled, and treated with 10N sodium hydroxide solution (20 mL) followed by saturated sodium chloride solution. After separation of the organic phase, it is dried over magnesium sulfate, filtered and evaporated to give crystals which are recrystallized from diethyl ether. Reaction with hydrogen chloride gas and recrystallization from isopropanol gave the crystalline title compound, mp 148-150 ° C.

Example 29 Preparation of (+) - 1-Phenyl-3-methyl-3-azabicyclo (3.1.0) hexane hydrochloride in g (+) - 1-phenyl-1,2-cyclopropanedicarboximide in 50 ml of dimethylformamide. After treatment with 67 g of sodium hydride (as a 50% dispersion in mineral oil) and 5 ml of methyl iodide, the reaction mixture is poured into 500 ml of water. The aqueous mixture was extracted with methylene chloride and the extract was washed with water, dried over magnesium sulfate and evaporated. The residue was adsorbed on a Buchner funnel of activated magnesium silicate and eluted with 250 ml of benzene. The eluate was washed with methylene chloride (500 mL) and evaporated to give green crystals of (+) -1-phenyl-N-methyl-1,2-cyclopropanedicarboximide.

To a solution of 3.0 g of this compound in 70 ml of anhydrous benzene was added 20 ml of a 70% solution of sodium bis (2-methoxyethoxy) aluminum hydride in benzene, and the resulting mixture was stirred for 15 minutes at room temperature and then for 15 minutes. stir in a water bath. After cooling, the reaction mixture was worked up as described in Example 12 to give the title compound as a crystal, mp 188-190 ° C, having a specific rotation [α} ο ^{Η, ηκ} - + 72 '.

Example 30

- Preparation of (4-chloro-3-trifluoromethylphenyl) -3-azabicyclo (3.1.0) hexane hydrochloride

In the same manner as in Example 6, the methyl s- (4-chloro-3-trifluoromethylphenyl) acetic acid was converted to the methyl ester of α-bromo-α- (4-chloro-3-trifluoromethylphenylacetic acid). acrylate and sodium hydride to give dimethyl ester of 1- (4-chloro-3-trifluoromethylphenyl) -1,2-cyclopropanedioic acid, when hydrolyzed with 1 N potassium hydroxide, m.p. 167-169 ° C. crystals of 1- (4-chloro-3-trifluoromethylphenyl) -1,2-cyclopropanedicarboxylic acid are obtained by reacting the latter with 1- (4-chloro-3-trifluoromethylphenyl) as colorless crystals, m.p. -1,2-cyclopropanedicarboximide is obtained.

A solution of this compound (0.28 g) in benzene (10 mL) was treated with a solution of sodium bis (2-methoxyethoxy) aluminum hydride (70 mL) in benzene, followed by 1.0 mL. the resulting mixture is refluxed for 1 hour. it is cooled to room temperature and the excess hydride is decomposed by addition of 1 ml of 10N sodium hydroxide solution. After separation, the benzene phase is washed with water, dried over magnesium sulfate and concentrated under reduced pressure. The resulting amber oil was dissolved in diethyl ether and bubbled dry hydrogen chloride gas through the resulting solution. The precipitate was filtered off and recrystallized from isopropanol. yielding the title compound. Recrystallization from acetonitrile gave colorless crystals, m.p. 164-166 ° C.

Example 31

- Preparation of (4-Nitrophenyl) -3-azabicyclo (3,1.0) hexane hydrochloride:

To a suspension of 20.6 g of 1-phenyl-1,2-cyclopropanedioic acid in 25 ml of concentrated sulfuric acid was added 15 ml of concentrated nitric acid over 30 minutes with stirring, and the resulting solution was stirred at room temperature for 30 minutes and then poured onto ice. The precipitated crystalline product is recrystallized from a mixture of hexane and ethyl acetate to give 1- (4-nitrophenyl) -1,2-cyclopropanedicarboxylic acid as colorless crystals, m.p. 138-144 ° C.

This dicarboxylic acid can be converted to 1- (4-nitrophenyl) -1,2-cyclopropanedicarboximide, m.p. 171-173 C, as described in Example 6.

A solution of the latter compound in tetrahydrofuran was added under nitrogen at 0 ° C to a 1M solution of borane in THF and the resulting solution was refluxed for 1 hour, then cooled to 0 ° C and 6N hydrochloric acid was added. The tetrahydrofuran was then evaporated under reduced pressure and the residue partitioned between diethyl ether and sodium hydroxide solution. The diethyl ether phase containing the appropriate free base was dried over magnesium sulfate and filtered, and the filtrate was triturated with hydrogen chloride gas to give the title compound as a brown precipitate, m.p.

Example 32 Preparation of 1- (2-chlorophenyl) -3-azabicyclo (3.1.0) hexane hydrochloride:

While stirring, 36.9 g of methyl α- (2-chlorophenyl) acetic acid, 36.0 g of N-bromosuccinimide. A mixture of 2 drops of 48% hydrobromic acid solution and 500 ml of carbon tetrachloride was refluxed for 20 hours and then filtered through magnesium silicate. Concentration of the filtrate under reduced pressure afforded a-bromo-α- (2-chlorophenyl) -acetic acid methyl ester as a straw-colored liquid.

To a stirred suspension of 4.8 g of sodium hydride (50% in mineral oil 5) in 100 ml of a 1: 1 mixture of benzene and N, N-dimethylformamide is added over 0.5 hour. of the ester (26.3 g) and methyl methacrylate (8.69 g) were stirred at room temperature for 4 hours and then the excess hydride was quenched by the addition of 2 ml of methanol. The reaction mixture was poured into 500 ml of water and the organic layer was separated, washed with water, dried over magnesium sulfate and evaporated to give 1- (2-chlorophenyl) -1,2-cyclopropanecarboxylic acid dimethyl ester as a brown oil. .

A mixture of this compound (17.35 g, 200 ml) in potassium hydroxide solution (200 ml) and ethanol (50 ml) was refluxed for 6 hours, then concentrated under reduced pressure to half its volume and then acidified to give 1- (2) as a brown oil. -chlorophenyl) -1,2-cyclopropanedioic acid.

A solution of this compound (10.0 g and 3.4 g) in xylene (500 ml) was heated at reflux for 6 hours, and the resulting solution was washed with water and sodium bicarbonate solution, dried over magnesium sulfate and evaporated. . The resulting tan solid was recrystallized from ethanol to give 1- (2-chlorophenyl) -1,2-cyclopropanedicarboximide as colorless crystals, m.p. 154-156 ° C. 30

To a solution of this compound (1.35 g) in benzene (30 ml) was added with stirring, 9 ml of a 70% solution of sodium bis (2-methoxyethoxy) aluminum hydride in benzene over 2 minutes, and the resulting solution was stirred at room temperature for 15 minutes. After stirring for one minute, it is refluxed for 30 minutes, and after cooling, 10 ml of 10N sodium hydroxide solution are added. The benzene layer was then separated, washed with water, dried over magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure. The resulting oil is dissolved in diethyl ether and anhydrous hydrogen chloride gas is passed through the resulting solution. The precipitated product is recrystallized from isopropanol. The title compound is obtained in the form of colorless crystals, m.p. 188-190 ° C. 45

Example 33 Preparation of 1- (p-Tolyl) -3-azabicyclo (3.1.0) hexane hydrochloride:

To 120 g of? - (p-tolyl) acetic acid was added 230 ml of thionyl chloride and the resulting solution was allowed to stand at room temperature for 2 hours and then at 60 ° C for 1 hour. To the solution was then added 285 g of N-bromosuccinimide and 10 drops of a 48% hydrobromic acid solution, and the resulting mixture was heated at reflux in a 90 ° C oil bath for 1 hour. Thionyl chloride (90 mL) was added and reflux was continued for 45 minutes. The reaction mixture was then distilled under reduced pressure to remove 250 mL of thionyl chloride. The resulting liquid was poured into cold methanol (500 mL) and the resulting mixture was stirred under ice-cooling for 15 minutes. The mixture was then concentrated under reduced pressure to give a dark oil which was dissolved in 100 ml of 65 chloroform. The chloroform solution was washed with water (500 mL), dried over magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to give a dark oil which was subjected to vacuum distillation. This gives methyl α-bromo-α- (p-tolyl) acetic acid as a hot pale yellow liquid at a pressure of 0.05 mmHg at 115-120 ° C. Amethyl was reacted with methyl acrylate in diethyl ether as in Example 6 and reacted with sodium hydride to give cis-1- (p-tolyl) -1,2-cyclopropanedioic acid dimethyl ester, m.p. 58-59 ° C. . The latter compound was hydrolyzed with n-potassium hydroxide as described in Example 6 and then acidified to give cis-1- (p-tolyl) -1,2-cyclopropanedioic acid as colorless crystals, m.p. 188-190 ° C. This compound is also a

Reaction with carbatide as described in Example 6 gives 1- (p-diethyl) -1,2-cyclopentopyridic acid trifuran in the form of pale yellow crystals, m.p. 82-85 ° C. .

To a solution of this compound (20.1 g) in benzene (600 ml) was added 160 ml of a 70% solution of sodium bis (2-methoxyethoxy) aluminum hydride in benzene, and the reaction was quenched with

The excess reducing agent was decomposed by addition of 160 ml of a 10 N sodium oxide solution. After separation of the benzene phase, it is washed with water, dried over magnesium sulfate and filtered. The filtrate was evaporated under reduced pressure to give a dark oil, which was dissolved in diethyl ether and bubbled with dry hydrogen chloride gas. The precipitate was filtered off and recrystallized from a mixture of acetonitrile and methanol. 12.1 g of the title compound are obtained in the form of pale-bama pale crystals, m.p. 207-208 ° C.

1- (4-Isopropylphenyl) -1,2-cyclopropanedicarboximide, m.p. 147-148 ° C, was prepared as described above, m.p. 1- (4-isopropylphenyl) -3-azabicyclo (3.1) m.p. 231-232 ° C. .0) convertible to hexane hydrochloride.

Reduction of the imides listed below as described above also gives the compounds of Formula I listed below in the form of the free base or the hydrochloride salt.

Imide compound

- (3-Trifluoromethylphenyl) -1,2-cyclopropanedicarboximide, m.p. _: From 94 to 95.5 = C

- (3-Bromo-4-methoxyphenyl) -1,2-cyclopropanedicarboximide, m.p. 184-186 ° C.

- (4-Biphenyl) -1,2-cyclopropanedicarboximide

- (4-aminophenyl) -1,2-ciklopropándikarboximid

Compound of Formula I

- (3-Trifluoromethylphenyl) -3-azabicyclo (3.1.0) hexane hydrochloride, m.p.

146-148 ° C

- (3-Bromo-4-methoxyphenyl) -3-azabicyclo (3.1.0) hexane hydrochloride, m.p.

1- (4-biphenylyl) -3-azabicyclo (3.1.0) hexane hydrochloride, m.p. 268-270 ° C

1- (4-Aminophenyl) -3-azabicyclo (3.1.0) hexane hydrochloride, m.p. 208-210 ° C.

Example 34 Preparation of (+) -1- (p-Tolyl) -3-azabicyclo (3.1.0) hexane hydrochloride:

Example 33 can be prepared from 9-racemic 1- (p-tolyl) -1,2-cyclopropanedioic acid 94.8 g of (-) -? - (1-naphthyl) ethylamine. A solution of tetrahydrofuran (3 mL) was diluted with diethyl ether (300 mL) and the resulting mixture was allowed to stand at room temperature until crystallization was complete. The mixture is then filtered and the filtered crystals are washed with tetrahydrofuran to give 49.5 g of a salt of one molar equivalent of (+) - 1- (p-tolyl) -1,2-cyclopropanedioic acid and one molar equivalent of (-) -. It consists of (1-naphthyl) ethylamine. This salt is then shaken with a mixture of sodium hydroxide solution and diethyl ether, the aqueous phase is separated, after separation, acidified with 12N hydrochloric acid and the precipitated product is filtered off. 26.0 g of (+) - 1- (p-tolyl) -1,2-cyclopropanedicarboxylic acid are obtained in the form of colorless crystals having a specific rotation of _[a] ™, OH_ _+).

A mixture of this compound (15.0 g, 6.6 g of urea) and xylene (500 ml) was refluxed for 5 hours and then filtered while hot and the filtrate was concentrated under reduced pressure to a melting point of 148-155 ° C as colorless crystals. (+) - 1- (p-tolyl) -1,2-cyclopropanedicarboximide was obtained.

To a mixture of this compound (14 g) in benzene (420 ml) was added 112 ml of a 70% solution of sodium bis (2-methoxyethoxy) aluminum hydride in benzene over 15 minutes with stirring, and the resulting mixture was refluxed. After refluxing for 1.5 hours, the reaction mixture was cooled and 160 ml of 10N sodium hydroxide solution was added. After separation of the organic phase, it is dried over sodium sulfate, filtered and evaporated. The resulting oil was dissolved in diethyl ether and hydrogen chloride gas was bubbled through the resulting solution. The precipitate was recrystallized from acetonitrile to yield the title compound, melting at 208 to 210.5 as colorless crystals, having a specific rotation of _[a] S ^(H _{= 64 + 5} =.

Reaction of the aforementioned racemic dicarboxylic acid with ethanol with an equimolar amount of brucine yields a salt consisting of one molar equivalent of (-) - (p-tolyl) -1,2-cyclopropanedicarboxylic acid and one molar equivalent of brucine. The specific rotation of this salt is [α] d ^H, µ ^{, H} = - 46 °. This salt is treated as described above to give (-) - 1- (p-tolyl) -1,2-cyclopropanedioic acid in the form of colorless crystals having a specific rotation [?] D ^{H, OH} = -189 °.

The specific rotation of (-) - 1- (p-tolyl) -1,2-cyclopropanedicarboximide, m.p. 145-148 ° C, as described above [α] ^ΗιΟΗ = -74 ° -, which is reduced by (-) ) -1- (p-tolyl) -3-azabicyclo (3.1.0) hexane hydrochloride. Colorless crystals of the latter end product having a melting point of 204-207 ° C and a specific rotation of [ ^α ] ^{D 20 H} = -64.

Example 35

Preparation of 3-Ethyl-1- (p-tolyl) -3-azabicyclo (3.1.0) hexane hydrochloride

A mixture of 4.19 g of 1- (p-tolyl) -3-azabicyclo (3.1.0) hexane hydrochloride and 20 nd of water is made basic with sodium hydroxide, extracted with diethyl ether and the ether extract is evaporated to give an oil. To the oil was added 40 haogyasaw and 35 ml of a 37% formaldehyde solution, and the reaction mixture was heated on a water bath for 2 hours. The resulting solution was then cooled, made basic with hydroxide and extracted with diethyl ether. The extract was dried over magnesium sulfate, filtered and the filtrate was saturated with hydrogen chloride gas.

The precipitated crystals were collected and recrystallized from isopropanol. The title compound was obtained

197-198 ° C in the form of colorless crystals.

Example 36

Preparation of 1- (4-Hydroxyphenyl) -3-azabicyclo [3.1.1] hexane hydrochloride:

To a suspension of 7.2 g (0.15 mol) of sodium hydride (as a 50% dispersion in mineral oil) at 0-5 C in 170 ml of Ν, amid-dimethylformamide is added 10.1 ml of ethanediol over 85 minutes. A solution of Ν, Ν-dimethylformamide was added, followed by the addition of sodium hydride (3.16g), followed by addition of 14.4g of 1- (4-methoxyphenyl) -3-azabicyclo (3.1.0) hexane hydrochloride. After addition of 40 ml of Ν, Ν-dimethylformamide, the reaction mixture was refluxed for 4 hours and the solvent was evaporated. The residue was dissolved in water (150 ml) and the oily phase was extracted with diethyl ether. The aqueous phase is acidified with acetic acid and the precipitated crystals are filtered off. 9.8 g of 3-formyl-1- (4-hydroxyphenyl) -3-azabicyclo (3.1.0) hexane are obtained in the form of tan crystals, m.p. 166-167 ° C.

Under nitrogen atmosphere, a solution of 4.5 g of the latter compound in 40 ml of 1.25 N sodium hydroxide solution was heated in a water bath for 3 hours, and the cooled solution was neutralized with acetic acid to give 3.3 g of the free base of the title compound. The free base is then dissolved in 20 ml of anhydrous ethanol, and hydrogen chloride gas is bubbled through the resulting solution. Evaporation of the saturated solution gave the title compound (3.78 g) as tan crystals, m.p. 195-196 ° C.

Example 37 Preparation of 1- (3-hydroxyphenyl) -3-azabicyclo (3.1.0) hexane hydrochloride

As in Example 39, 1- (3-methoxyphenyl) -3-azabicyclo (3.1.0) hexane hydrochloride, m.p. 129-130 ° C. 3-Azabicyclo (3.1.0) can be converted to hexane. If the latter compound is also hydrolyzed with sodium hydroxide in the same manner as in Example 39 and the resulting free base is obtained to give the hydrochloride, the title compound is obtained in the form of tan crystals, m.p. 209-210 ° C.

Example 38 Preparation of 1- (4-Ethoxyphenyl) -3-azabicyclo (3.1.0) hexane hydrochloride:

To a stirred mixture of 1.0 g of 3-formyl-1- (4-hydroxyphenyl) -3-azabicyclo (3.1.0) hexane and 0.7 g of potassium carbonate in 25 ml of anhydrous ethanol was added 3.2 g of ethyl acetate. A solution of iodide in 10 ml of anhydrous ethanol was added and the reaction mixture was refluxed for 2 hours, then filtered and evaporated. The residue, which consists of a mixture of crystals and liquid, is mixed with water and the resulting aqueous mixture is extracted with chloroform. The extract was dried over magnesium sulfate and evaporated to give 1.0 g of a colorless viscous liquid which crystallized on standing. Recrystallization of the precipitated crystals from hexane gave 0.31 g of 3-formyl-1- (4-ethoxyphenyl) -3-azabicyclo (3.1.0) hexane as colorless crystals, m.p. 48-51 ° C.

A solution of this compound (2.0 g) in ethanol (50 ml) and 5N sodium hydroxide (20 ml) was heated in a water bath for 30 minutes and the ethanol was evaporated under reduced pressure. The residue was extracted with diethyl ether and the extract was dried over magnesium sulfate, filtered and evaporated. This gives the free base of the title compound as colorless crystals, m.p. 48-49 ° C. Treatment of the latter with ethanolic hydrochloric acid gave colorless crystals of the title compound, m.p. 192-193 ° C.

Example 39 Preparation of 1-Phenyl-3-azabicyclo (3.1.0) hexane hydrochloride:

A solution of 9.0 g of cis-1-phenyl-1,2-cyclopropanedicarboxylic acid in 100 ml of tetrahydrofuran is added over 15 minutes under nitrogen atmosphere at 0 C to 180 ml of a 1M solution of borane in THF and the reaction mixture is kept at room temperature for 30 minutes. it is then refluxed for 4 hours. After cooling with ice, 6N hydrochloric acid (60 ml) was added to the reaction mixture, and the tetrahydrofuran was evaporated under reduced pressure. The aqueous residue was made basic with sodium hydroxide and extracted with diethyl ether. The extract was dried over potassium carbonate, filtered and evaporated to give 7.7 g of cis-1-phenyl-1,2-bis-hydroxymethyl-cyclopropane.

A solution of this compound (6.0 g) in dichloromethane (335 ml) and triethylamine (14 ml) was cooled to -10 ° C and methanesulfonyl chloride (8.45 g) was added over 15 minutes. After stirring at room temperature for 30 minutes, the reaction mixture was washed with cold dilute hydrochloric acid, cold water and finally with 10% sodium bicarbonate solution, dried over magnesium sulfate, filtered and evaporated to give the title compound as a pale yellow oil (8.4 g). dimethylsulfonate is obtained. To a solution of this oil in 100 ml of tetrahydrofuran was added 1.0 g of sodium amide, and the reaction mixture was refluxed, filtered and the filtrate was evaporated to give the free base of the title compound as a colorless liquid. The latter was converted to the title compound with ethanolic hydrogen chloride, which, after recrystallization from acetonitrile, gave colorless crystals, m.p. 166-167 ° C.

Example 40 Preparation of 1- (3-chlorophenyl) -3-methyl-3-azabicyclo (3.10.O) hexane hydrochloride:

In the same manner as in Example 10, 1- (3-chlorophenyl) -1- (3-chlorophenyl) -1- (3-chlorophenyl) -1- (3-chlorophenyl) -1- (3-chlorophenyl) -1- By reaction of 2-cyclopropanedicarboximide with methyl iodide, colorless crystals of the title compound are obtained, m.p. 180-182 ° C.

Example 41

Preparation of 3- (4,4-bis-) 4-fluorophenyl (butyl) -1-phenyl-3-azabicyclo (3.1.0) hexane fumarate:

A mixture of sodium hydride and 1-phenyl-1,2-cyclopropanedicarboximide (prepared in U.S. Patent 3,166,571) is stirred with anhydrous N, N-dimethylformamide until the evolution of hydrogen gas ceases. The reaction mixture was then treated with 1-chloro-4,4-bis (4-fluorophenyl) butane, stirred for 20 hours at room temperature and then briefly heated to 100 ° C. The reaction mixture was diluted with water, extracted with diethyl ether liver, and the extract was evaporated to give N- [4,4-bis (4-fluorophenyl) butyl] -1-phenyl-1,2-cyclopropanedicarboximide as a colorless glassy resin. we get.

This compound is then reduced as described in Example 10 and the resulting free base is treated with fumaric acid to give the title compound as colorless crystals, m.p. 153-155 ° C.

As described above, 1- (4-chlorophenyl) -1,2-cyclopropanedicarboximide described in U.S. Patent 3,344,026, m.p. 98-99 DEG C., is prepared from N- [4,4-bis (4-fluoro). -phenyl) -butyl] -1- (4-chlorophenyl) -1,2-cyclopropanedicarboximide. If the latter compound is reduced as described in Example 27 and the resulting free base is treated with fumaric acid, 3- [4,4-bis (4-fluorophenyl) butyl], m.p. 152-154 ° C. 1- (4-Chlorophenyl) -3-azabicyclo (3.1.0) hexane fumarate is obtained.

Example 42

Preparation of 3- [3- (4-Fluorobenzoyl) -propyl] -1-phenyl-3-azabicyclo (3.1.0) hexane hydrochloride:

A mixture of 15.9 g of the 1-phenyl-3-azabicyclo (3.1.0) hexane mentioned in Example 9, 20.1 g of γ-chloro-4-fluorobutyrophenone, 10 mg of potassium iodide and 100 ml of toluene was added. reflux for 24 hours and filter. At

11.6 g of 1-phenyl-3-azabicyclo (3.1.0) hexane hydrochloride, m.p. 166-167 ° C, are filtered off. The filtrate was evaporated to give a brown oil, to which was added 2N hydrochloric acid and chloroform. The crystals in the chloroform phase are then filtered off and recrystallized from ethanol. The title compound is obtained in the form of light brown crystals, m.p. 151-153 ° C.

Example 43

- Preparation of (3-methoxyphenyl) -3-azabicyclo (3.1.0) hexane hydrochloride:

Beleckaya, I. P. [Zs. Obscsej Kim., 34, 321 (1964)] is reacted with 3-methoxy-mandelic acid methyl ester with phosphorus tribromide to give a-bromo-α- (3-methoxyphenyl) acetic acid methyl ester as a pale yellow liquid. without further purification).

Similarly, the following brominated esters can be prepared from the following manduic acid esters.

Brominated ester ethyl ethyl α-bromo-α- (4-hexylphenyl) acetic acid α-bromo-α- (4-isopropylphenyl) acetic acid ethyl ester 5 α-bromo-α- (m-tolyl) acetic acid ethyl ester

177531 -.

Mandelic acid ester Hexyl mandelic acid ethyl ester

4-isopropyl-mandelic acid ethyl ester

3-methyl-mandelic acid methyl ester

2-Methyl-mandelic acid methyl ester α-bromo-α- (0-tolyl) acetic acid 10

ethyl ester

37.0 g of 1- (3-methoxyphenyl) -1,2-cyclopropanedicarboxylic acid dimethyl ester [a] bromo-α- (3-methoxyphenyl) acetic acid methyl ester and methyl 15 - according to the procedure described in Example 6. acrylate], a mixture of 20 g of potassium hydroxide and 200 ml of a 1: 1 mixture of water / methanol was refluxed for 16 hours and the methanol was evaporated. The residue was treated with increasing amounts of concentrated hydrochloric acid until pH = 1. . At this time, the reaction mixture was extracted three times with diethyl ether, and the combined extracts were dried and evaporated. This gives cis-1- (3-methoxyphenyl) -1,2-cyclopropanedioic acid as a pale yellow resin.

A mixture of 34.7 g of 12 g of urea and 750 ml of xylene is refluxed for 5 hours, cooled and the supernatant liquid is decanted. It was then filtered through magnesium silicate and the filtrate was concentrated under reduced pressure to give a precipitate which was recrystallized from ethanol. There is thus obtained 1- (3-methoxyphenyl) -1,2-cyclopropanedicarboximide, m.p. 125-127 ° C.

To this mixture of 3.0 g of this compound in 75 ml of benzene was added 20 ml of a 70% solution of sodium bis (2-methoxyethoxy) aluminum hydride in benzene over 5 minutes, followed by stirring. After stirring for 0.5 hour, the reaction mixture was refluxed for 1 hour, cooled and treated with 10N sodium hydroxide solution (20 mL) and saturated sodium chloride solution. After separation, the organic phase is washed with water, dried over magnesium sulfate, filtered and evaporated to give an oil. This was then dissolved in diethyl ether and hydrogen chloride gas was bubbled through the resulting solution. The precipitate was finally recrystallized from acetonitrile. The title compound is obtained in the form of colorless crystals, m.p. 45-150-152 ° C.

Example 44

- Preparation of (3-Hydroxyphenyl) -3-methyl-3-azabicyclo (3.1.0) hexane-50-hydrochloride:

When 1- (3-methoxyphenyl) -3-methyl-3-azabicyclo (3.1.0) hexane hydrochloride in N, N-dimethylformamide, as described in Example 37, is reacted with sodium hydride and ethanediol. yield the title compound. 55

Example 45 Preparation of 1- (4-methoxymethylphenyl) -3-azabicyclo (3.1.0) hexane hydrochloride.

2.48 g of dimethyl ester of cis-1- (p-tolyl) -1,2-cyclopropahydroxycarboxylic acid, mentioned in Example 33, 1.78 g of N-biosuccinimide, 5 mg of azobis-isobutyronitrile and 50 ml of The tetrachloride mixture was irradiated with a 500 watt tungsten lamp for 2 hours, then the mixture was filtered and the filtrate was evaporated. This affords cis-1- (α-bromo-p-tolyl) -1,2-cyclopropanedioic acid dimethyl ester as yellowish crystals which is used directly in the next step without purification.

Thus, this compound was stirred with a solution of sodium methylate in methanol for 2 hours, then refluxed for 3 hours and then the methanol was evaporated. The residue was partitioned between water and dichloromethane, and the organic phase was evaporated to give cis-1- (4-methoxymethylphenyl) -1,2-cyclopropanedicarboxylic acid methyl ester as a dark oil which was used in the next step without further purification. .

Thus, this compound was treated with a solution of potassium hydroxide in ethanol a

Hydrolyze as described in Example 6 to give cis-1- (4-methoxymethylphenyl) -1,2-propanedicarboxylic acid as a brown oil.

This compound is refluxed with urea in xylene as described in Example 6 to give 1- (4-methoxymethyl) -1,2-cyclopropanedicarboximide in the form of unsalted crystals, m.p. 122-124 ° C.

This compound was reduced as described in Example 27 with a borane solution in tetrahydrofuran to give the title compound as slurry crystals, m.p. 169-171 ° C.

Example 46

Preparation of 3- (n-Hexyl) -1- (p-tolyl) -3-azabicyclo (3.1.0) hexane:

When the 1- (p-tolyl) -3-azabicyclo (3.10.0) hexane mentioned in Example 33 is reacted with sodium borohydride and hexanoic acid, the reductive alkylation method of Gribble, GW et al., 1975, Synthesis, 702. ], the title compound is obtained, m.p. 182-184 ° C.

Example 47

- Preparation of (p-tolyl) -3-azabicyclo (3.1.0) hexan-2-one:

To a suspension of 5.0 g of sodium hydride (as a 50% dispersion in mineral oil) in 350 ml of diethyl ether and 0.5 ml of methanol are added 24.0 g of α-bromo-carbon at 0.5 to 28 ° C over 0.5 hour. Methyl a-p-tolylacetic acid, a mixture of 8.0 g of acrylonitrile and 1.0 ml of methanol, and after stirring for 1 hour, 10 ml of methanol were added to the reaction mixture and the resulting diethyl ether solution was washed with water. The organic phase is then dried over sodium sulfate, filtered and evaporated to give 5.5 g of yellow crystals. 3.5 g, m.p. 88-91 ^Q colorless crystals of cis-2-cyano-l- (p-tolyl) -1-methoxycarbonyl-cyclopropane was obtained after recrystallisation from ethanol.

To a solution of the compound obtained in the preceding paragraph in 2.15 g in 100 ml of anhydrous tetrahydrofuran at 0 ° C

7.5 ml of a 1M solution of borane in tetrahydrofuran are added and the resulting solution is refluxed for 0.5 hour and then kept at room temperature for 2 hours. To the cooled solution was added 10 ml of 6N hydrochloric acid, the resulting mixture was heated in a water bath for 15 minutes and then concentrated. The residue was extracted with dichloromethane and the extract was evaporated to give the title compound as a colorless oil. Its infrared spectrum exhibits a characteristic absorption band at 5.9 microns.

Claims (9)

Patent claims A process for the preparation of racemic or optically active azabicyclohexanes of the formula I in the formula _I0 R represents a halogen atom, a linear or branched chain alkyl having 1-6 carbon atoms, alkoxy of I to 4 carbon atoms, trifluoromethyl, nitro, amino or hydroxy, m is 0, 1, 2 or 3, X is hydrogen or straight-chained alkyl of 1-8 carbon atoms. adamaníil-methyl. Cycloalkylmethyl (C 3-6), alkenyl (C 3-6), omega-bis (halophenyl) - (C 1-6) alkyl or -C "H _2n R 1", wherein in the latter group, n is 1, 2 or 3 and R, phenyl or 4-fluorobenzoyl; R 1 and R 1 are hydrogen or C 1 -C 4 alkyl - and their pharmaceutically acceptable acid addition salts, characterized in that a) for the preparation of compounds of formula I which form a narrower group of compounds of the formula I, wherein R 1, R 9, R ₁₀ and m are as defined above, X ^v is the same as X above, with the proviso that it is not alkenyl; reacting an optically active compound of formula 11 wherein R 1, R ₃ , R ₁₀ , m and X ^v are as defined above with a hydride-type reducing agent in an inert aprotic solvent at a temperature of -70 ° C to + 125 ° C, or (b) Compounds of formula I wherein X is (C 3-6) cycloalkylmethyl, adamantylmethyl, C 2-7 alkyl, or CnHinR, benzyl as R _? , R "R _in and m are as defined above, a racemic or optically active compound of formula III wherein X 'is hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, adamantyl or phenyl; R ₂ , R ₁ , R ₁₀ and m are as defined above, by reaction with a hydride-type reducing agent in an inert aprotic solvent at a temperature between 70 ° C and + 125 ° C, or c) for the preparation of a compound of formula I wherein X is hydrogen, wherein R ₂ , R ₁ , R _{t ()} and m are as defined above, a racemic or optically active compound of formula IV, wherein R 1. R _"ln and m are, preferably metánszulfoniloxicsoportot as defined above and W is a leaving group - sodium amide in a solvent a pharmaceutically acceptable free base of Formula I in a known manner at a temperature between 0 C and 150 C and optionally an acid acceptor in the presence of acid addition salt We converted. (Priority: September 1977 14.) 2. A process for the preparation of racemic or optically active azabicyclohexanes of the formula I in the formula R _l0 is a halogen atom, a linear or branched chain alkyl of 1 to 6 carbon atoms, alkoxy of 1-4 carbon atoms, trifluoromethyl, nitro, amino or hydroxyl group, m is 0, 1 or 2; X is hydrogen or straight-chained alkyl of 1-8 carbon atoms, adamantylmethyl. Cycloalkylmethyl (C3-6), alkenyl (C3-6) or -CrfhnRi (C3-C6) and n in the latter group 1, 2 or 3 and R 1 is phenyl or 4-fluorobenzoyl; R 1 and R 1 are alkyl or hydrogen having from 1 to 4 carbon atoms - and pharmaceutically acceptable acid addition salts thereof, characterized in that a) compounds of the general formula I, wherein R ₂ , R ₃ , R ₁₀ and m have the same meaning as X, X ^v has the same meaning as X with the proviso that it is not alkenyl; - reacting a racemic or optically active compound of formula II, wherein R ₂ , R ₃ , R _w , Pi and X ^v are as defined herein, with a hydride-reducing agent in an inert aprotic solvent at a temperature of -70 ° C to + 125 ° C, or b) Compounds of formula I wherein X is (C 3-6) cycloalkylmethyl, adamantylmethyl, C 2-7 alkyl, or benzyl as -CnHinRj - wherein R ₂ , R ₃ , R ₁₀ and m is as defined herein for a racemic or optically active compound of formula III wherein X 'is hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, adamantyl or phenyl, and R ₂ , R _{3, i0} R and m are as defined above - at a temperature between 70 ° C and +125 ° C, or - is reacted with a hydride reducing agent in an inert aprotic solvent c) for the preparation of a compound of formula I wherein X is hydrogen, wherein R ₂ , R ₃ , R ₁₀ and m are as defined herein, a racemic or optically active compound of formula IV wherein R ₂ , R ₃ , R ₁₀ and m wherein W is a leaving group, preferably methanesulfonyloxy, is reacted with sodium amide in a solvent in the presence of an acid scavenger at a temperature of 0 ° C to 150 ° C and optionally converting a free base of formula I into a pharmaceutically acceptable acid addition salt thereof. . (Priority: June 23, 1977) 3. A process for preparing the azabicyclohexanes of formula I in the formula R ₁₀ is halogen, C 1-4 alkoxy, C 1-6 alkyl, trifluoromethyl, nitro, amino, or hydroxy. m is 0, 1 or 2, X is hydrogen, C2-7 alkyl, benzyl, adamantylmethyl or C3-6 cycloalkylmethyl. I < 2 &gt; and R &lt; 3 &gt; independently represent hydrogen or C 1-4 alkyl - and pharmaceutically acceptable acid addition salts thereof, wherein: a) reacting a compound of formula II wherein R ₂ , R ₃ , R 1 'and m are as defined herein, and X ^v is as defined in X, in a hydride-type reducing agent at 30 ° C and 100 ° C. ° C, or b) Compounds of formula X where X is (C 3-6 -cycloalkylmethyl, C 2-7 -alkyl, adamantylmethyl or benzyl) wherein R ₂ , R ₁ , R ₁₀ and m is a racemic or optically active compound of formula III wherein X 'is hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, adamantyl or phenyl, and R 1, R " R _lu and m are as defined in the foregoing reaction with a hydride-type reducing agent in an inert aprotic solvent at a temperature of -70 ° C to + 125 ° C. and optionally converting the resulting free base of formula 1 into a pharmaceutically acceptable acid addition salt in a manner known per se. (Priority: December 10, 1976) 4. A process according to claim 1 or 2, wherein the hydride reducing agent is sodium bis (2-methoxyethoxy) aluminum hydride, lithium aluminum hydride or 15 diborane and benzene, tetrahydrofuran, diethyl ether or toluene are used as inert aprotic solvents and the reduction is carried out at 0 to 120 ° C. (Priority: June 23, 1977) 5. A process according to claim 3 or 4 wherein the hydride reducing agent is sodium bis (2-methoxyethoxy) aluminum hydride and benzene is used as the inert aprotic solvent at 30 ° C and 80 ° C. C. 25 (Priority: September 15, 1976) 6. A process according to claim 1 or 2, wherein the solvent is an alkanol having from 1 to 6 carbon atoms. and the acid binder is sodium carbonate or ethyl diisopropylamine. (Priority: June 23, 1977) 7. A process for the preparation of a pharmaceutical composition containing azabicyclohexanes of the formula I as claimed in claim 1, characterized in that an azabicyclohexane of the formula I, wherein R 1, R 1, R ₁₀ , m and X are as defined in claim 1, and / or a pharmaceutically acceptable acid addition salt thereof, in admixture with carriers or excipients conventionally used in the manufacture of a medicament to form a pharmaceutical composition. (Priority: September 14, 1977) 8. The process of claim 2 for the preparation of a pharmaceutical composition containing azabicyclohexanes of formula I wherein the azabicyclohexane of formula I is a compound of formula I wherein R 1, R 1. _L0 R, m and X are as defined in claim 2 - or and pharmaceutically acceptable acid addition salt thereof in admixture with carriers and / or excipients commonly used in pharmaceutical manufacturing a pharmaceutical composition. (Priority: June 23, 1977) 9. The process of claim 3 for the preparation of a pharmaceutical composition comprising azabicyclohexanes of formula I wherein an azabicyclohexane of formula I wherein R 1, R 1, R ₁₀ , m and X are as defined in claim 3 and / or a pharmaceutically acceptable acid addition salt thereof, in admixture with excipients and / or excipients commonly used in the manufacture of pharmaceuticals, to form a pharmaceutical composition. (Priority: September 15, 1976) The Director of Economic and Legal Publishing is responsible for the publication 82.6680.6Ó-42 Great Plain Printing House. Debrecen-- Chief Executive Officer: István Benkö Director