KR820001336B1 - Method for preparation of azabicycle hexane derivatives - Google Patents

Abstract

Optically active or racemic azabicyclohexanes [I; R = halogen, C1-6 alkyl, alkoxy, CF3, NO2, amino, acetamido, OH; X = H, C1-8 alkyl, CnH2nR1(n = 1-3; R1 = phenyl, p-fluorobenzoyl) and their pharmaceutically acceptable salts, useful as analgesics, were prepd. by reaction of II and hydride reducting agent at -70˜-125≰C. Thus, diethyl 1-(P-chlorophenyl)-cis-1,2-cyclopropane dicarboxylic acid was heated with urea to give the cyclic imide, which was reduced with sodium bis(2-methoxyethoxy)aluminium hydride to give I(R = 4-Cl; X = H).

Description

Manufacturing method of azabicyclohexane

The present invention relates to the preparation of azabicyclohexanes. The first compound according to the present invention is represented by an optically active compound having the following structural formula, a racemic mixture thereof, a colon thereof, and a nontoxic pharmacologically acceptable salt thereof. .

Wherein the phenyl group is unsubstituted or mono- in the group consisting of halogen, straight C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, trifluoromethyl, nitro, amino, acet amido and hydroxy, etc. Or de-substituted.

X consists of hydrogen, straight chain C ₁ -C ₈ alkyl and groups of the structure CnH ₂ nR ₁ , where n is an integer of 1-3 and R ₁ is selected from the group consisting of phenyl, P-fluorobenzoyl and the like It is selected from the group to become.

Preferred forms of the first compound are di-substituted from the group in which the phenyl group is composed of halogen, straight-chain C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, trifluoromethyl, nitro, amino, acetamido, hydroxy and the like. And also X is defined as described above.

A second preferred form of the first compound is a phenyl group unsubstituted or composed of halogen, straight chain C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, trifluoromethyl, nitro, amino, acetamido, hydroxy and the like. It consists of a compound which is mono-substituted from the group to which X is defined and X is defined as described above.

Preferred embodiments of the second aspect are composed of compounds wherein X is selected from the group consisting of hydrogen and straight chain C ₁ -C ₈ alkyl and the like.

More preferred embodiments consist of compounds wherein the phenyl group is para or meta substituted from the group consisting of straight-chain C ₁ -C ₆ alkyl, halogen, trifluoromethyl and the like and X is defined as described above.

More preferred embodiments consist of compounds wherein the phenyl group is pyra or meta substituted from the group consisting of methyl, ethyl, chloro, fluoro, bromo and trifluoro methyl and the like and X is defined as described above.

Most preferred embodiments consist of compounds wherein the phenyl group is substituted as described above and further X is selected from the group consisting of hydrogen, methyl and the like.

The second compound of the present invention is represented by an optically active compound of the following structure, a racemic mixture thereof, a colon thereof, and a nontoxic pharmacologically acceptable salt thereof.

Here, the phenyl group is mono- or di-substituted from the group consisting of phenyl, halophenyl, C ₁ -C ₆ alkoxy methyl, C ₃ -C ₆ cycloalkyl and the like.

X is hydrogen, a straight chain C ₁ -C ₈ alkyl and a group of the structure CnH ₂ nR ₁ , where n is an integer of 1-3 and R ₁ is selected from the group consisting of halophenyl, bis-halophenyl, aminophenyl and the like It is selected from the group consisting of.

Preferred forms of the second compound consist of compounds in which the phenyl group is di-substituted from the group consisting of phenyl, halophenyl, C ₁ -C ₆ alkoxy methyl, C ₃ -C ₆ cycloalkyl and the like, X is defined as described above do.

A second preferred form of the second compound is that the phenyl group is mono-substituted from the group consisting of phenyl, halophenyl, C ₁ -C ₆ alkoxy methyl, C ₃ -C ₆ cycloalkyl and the like, wherein X is defined as described above. It consists of a compound.

Preferred embodiments of the second aspect are composed of compounds wherein X is selected from the group consisting of hydrogen, straight chain C ₁ -C ₈ alkyl and the like.

More preferred embodiments consist of compounds wherein the phenyl group is para or metasubstituted from the group consisting of phenyl, halophenyl, C ₁ -C ₆ alkoxy methyl and the like and X is defined as described above.

More preferred embodiments consist of compounds wherein the phenyl group is para or metasubstituted from the group consisting of phenyl, mono-chlorophenyl, di-chlorophenyl, methoxymethyl, ethoxymethyl and the like and X is defined as described above.

Most preferred embodiments consist of compounds wherein the phenyl group is substituted as described above and X is selected from the group consisting of hydrogen, methyl and the like.

The third compound of the present invention is represented by an optically active compound of the following structure, a racemic mixture thereof, a colon thereof, and a nontoxic pharmacologically acceptable salt thereof.

Wherein the phenyl group is mono- or di-substituted from the group consisting of halogen, straight-chain C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, trifluoromethyl, nitro, amino, acet amido, hydroxy and the like, X Is selected from the group consisting of C ₃ -C ₆ cycloalkylmethyl, C ₃ -C ₆ alkenyl, C ₃ -C ₆ alkynyl and the like.

Preferred forms of the third compound are di-substituted from the group in which the phenyl group is composed of halogen, straight-chain C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, trifluoromethyl, nitro, amino, acetamido and hydroxy, etc. And X is composed of a compound defined as described above.

A second preferred form of the third compound is a phenyl group unsubstituted or composed of halogen, straight chain C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, trifluoromethyl, nitro, amino, acetamido, hydroxy and the like. It consists of a compound which is mono substituted from the group and X is defined as described above.

Preferred embodiments of the second aspect consist of compounds wherein X is selected from the group consisting of cyclopropyl methyl, cyclobutyl methyl, cyclopentylmethyl, allyl, butenyl, dimethylallyl, propargyl and the like.

More preferred embodiments consist of compounds wherein the phenyl group is para or meta substituted from the group consisting of straight chain C ₁ -C ₆ alkyl, halogen, trifluoromethyl and the like and X is defined as described above.

More preferred embodiments consist of compounds wherein the phenyl group is para or meta substituted from the group consisting of methyl, ethyl, chloro, fluoro, bromo and trifluoro methyl and the like and X is as defined above.

Most preferred embodiments are those in which a phenyl group is defined as described above and X is selected from the group consisting of cyclopropyl methyl, allyl, propargyl and the like.

The fourth compound of the present invention is represented by an optically active compound of the following structure, a racemic mixture thereof, a colon thereof, and a nontoxic pharmacologically acceptable salt thereof.

Wherein the phenyl group is mono- or di-substituted from the group consisting of unsubstituted or halogen, straight C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, trifluoromethyl, nitro, amino, acet amido and hydroxy It is replaced.

X is hydrogen, straight chain C ₁ -C ₈ alkyl, C ₃ -C ₆ cycloalkylmethyl, C ₃ -C ₆ alkenyl, C ₃ -C ₆ alkynyl and the structure of CnH ₂ nR ₁ where n is 1-3 Integer and R ₁ is selected from the group consisting of phenyl, P-fluorobenzoyl and the like. R is selected from the group consisting of hydrogen and C ₁ -C ₃ alkyl and the like and at least one R is selected from the group consisting of C ₁ -C ₃ alkyl groups.

Preferred forms of the fourth compound are di-substituted from the group in which the phenyl group consists of halogen, straight-chain C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, trifluoromethyl, nitro, amino, acetamido, hydroxy and the like. And R and X are composed of compounds as defined above.

A second preferred form of the fourth compound is a phenyl group unsubstituted or composed of halogen, straight chain C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, trifluoromethyl, nitro, amino, acetamido, hydroxy and the like. And mono-substituted from the group consisting of R and X are defined as described above.

Preferred embodiments of the second aspect consist of a mixture wherein X is selected from the group consisting of hydrogen, straight-chain C ₁ -C ₆ alkyl and the like and R is defined as described above.

More preferred embodiments consist of compounds wherein the phenyl group is para or metasubstituted from the group consisting of straight chain C ₁ -C ₆ alkyl, halogen, trifluoromethyl and the like and R and X are defined as described above.

More preferred embodiments are those wherein the phenyl group is para- or meta-substituted from the group consisting of methyl, ethyl, chloro, fluoro, bromo and trifluoromethyl and the like, X is as described above and R is carbon 2-or And mono-substituted compounds at the carbon 4-position.

Most preferred embodiments are composed of compounds wherein the phenyl group is substituted as described above, X is selected from the group consisting of hydrogen, methyl and the like, and R is defined as described above.

The fifth compound of the present invention is represented by the optically active compound of the following structural formula.

Wherein the phenyl group is mono-substituted from the group consisting of C ₁ -C ₆ alkyl. X is selected from the group consisting of hydrogen, C ₁ -C ₆ alkyl and the like. Preferred embodiments of the fifth compound consist of compounds wherein the phenyl group is mono-substituted from the group consisting of C ₁ -C ₆ alkyl and X is selected from the group consisting of hydrogen, C ₁ -C ₃ alkyl and the like.

More preferred embodiments consist of compounds wherein the phenyl group is mono-substituted in the para-position with a compound selected from the group consisting of methyl, ethyl and the like, and X is selected from the group consisting of hydrogen, methyl and the like.

The sixth compound of the present invention is represented by an optically active compound of the formula

Wherein the phenyl group is mono-substituted from the group consisting of C ₁ -C ₆ alkyl.

R ₁ is selected from the group consisting of hydrogen, C ₁ -C ₆ alkyl and the like.

Preferred embodiments of the sixth compound consist of compounds wherein the phenyl group is mono-substituted from the group consisting of C ₁ -C ₆ alkyl and R ₁ is selected from the group consisting of hydrogen and C ₁ -C ₃ alkyl.

More preferred embodiments consist of compounds wherein the phenyl group is mono-substituted in the para-position with a compound selected from the group consisting of methyl, ethyl and the like, and R ₁ is selected from the group consisting of hydrogen, methyl and ethyl and the like.

The seventh compound of the present invention is represented by the optically active compound of the following structural formula.

Wherein the phenyl group is mono-substituted from the group consisting of halogen, straight C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, trifluoromethyl, nitro, amino, acetamido, hydroxy and the like.

W is selected from the group consisting of leaving groups of electronegativity.

Preferred embodiments of the seventh compound consist of compounds wherein the phenyl group is mono-substituted as described above and W is selected from the group consisting of methanesulfonyl, toluenesulfonyl, chloride, iodine, bromine and the like.

More preferred embodiments consist of compounds wherein the phenyl group is mono-substituted in the para-position from the group consisting of methyl, ethyl, chloro, fluoro, bromo and trifluoromethyl and the like, and X is methanesulfonyl. Among the salts are, for example, hydrochloride, bromate, iodide, sulfate, nitrate, phosphate, maleate, succinate and the like.

Compounds of the present invention are prepared by the following reaction.

Where R and X are defined as described above.

The compound of formula (I) is dissolved in a solvent such as benzene, toluene, ether, tetrahydrofuran, and sodium bis (2) for 1-4 hours at a temperature of 0 ° -125 ° C, more preferably 25 ° -80 ° C. React with a reducing agent such as -methoxyethoxy) aluminum hydride. The reaction mixture is cooled and a strong base such as potassium hydroxide is added. The organic layer is concentrated and the product is collected by filtration.

The starting material of formula (I) is prepared as follows.

Where R and X are defined as described above.

The reaction component is heated in a neutral solvent such as xylene for 6-24 hours and the solvent is evaporated to recover the product.

Various other hydride reducing agents, such as diborane or lithium aluminum hydride, can be used to prepare the compounds of formula II. In this case, the compound of formula (I) is suspended in tetrahydrofuran, a reducing agent is added, and the reaction is carried out at 0 ° -80 ° C for 1-4 hours. The reaction mixture is cooled and acidified with an acid such as hydrochloric acid, the aqueous layer is separated and a strong base such as potassium hydroxide is added to liberate the product. Alternatively, the compound of the present invention of formula (II) is

또는

or

Of the lactams in a neutral solvent such as ether, benzene or tetrahydrofuran with a suitable reducing agent such as lithium aluminum hydride, diborane, sodium bis (2-methoxyethoxy) aluminum hydride and a temperature of 0 ° -80 ° C. Prepared by reacting for 1-6 hours. Compounds of formula (II) are separated as described above by reducing the imide of the corresponding formula (I).

The reduction is carried out using a limited amount of the above-mentioned reducing agent, where R is as described above, and when X is hydrogen, the following structural formula

또는

or

If an intermediate product of is obtained and X is not hydrogen,

또는

or

You can obtain the intermediate product of. These compounds can then be reduced to the compounds of the invention of formula (II) by the methods described above.

Alternatively, the compound of formula II may be prepared from a compound of the following formula under the same conditions.

Wherein R is defined as above and R ₅ is selected from the group consisting of C ₁ -C ₆ alkyl, hydrogen, C ₃ -C ₆ cyclo alkyl, phenyl and the like.

The compound of formula II is also represented by

Wherein R is defined as described above and W is a suitable leaving group such as bromide, chloride, iodide, methanesulfonyloxy or P-toluene sulfonyloxy, etc. in a solvent such as ethanol or methanol When R is hydrogen, it is prepared by cyclization with a sodamide or with a compound of formula XNH ₂ (where X is defined above) at a temperature of 0 ° -150 ° C. Acid binders such as sodium carbonate, ethyldiisopropylamine, etc. It is common to use.

The compound of formula III is

Is prepared by reacting di of (where R is as described above) with phosphorus pentabromide, hydrogen bromide, hydrogen iodide, hydrogen chloride-zinc chloride, thionyl chloride, methanesulfonyl chloride or P-toluene sulfonyl chloride.

The diol has the structure

Wherein R is defined as described above, and R ₃ is selected from the group consisting of hydrogen, C ₁ -C ₆ alkyl, and the like, diborane, lithium in a neutral solvent such as ether, benzene or tetrahydrofuran Prepared by reacting aluminum hydride or sodium bis (2-methoxyethoxy) aluminum hydride for 1-6 hours at a temperature of 0 ° -80 ° C. The product is liberated by cooling the reaction mixture and hydrolyzing it by known methods using acids or bases.

These cyclopropane-1,2-dicarboxyl esters are also useful intermediate products in other methods of preparing the compounds of the present invention. For example, once saponified with cyclopropane-1,2-dicarboxylic acid, they are useful for making cyclopropane-1,2-dicarboxyboximide (I) as described above, and cyclopropane-1,2-dicarboxylic acid is also useful. It is useful for the division process described later.

The diester, wherein R ₃ is C ₁ -C ₆ alkyl, has the structure

Bromoester of R ₃ is as described above in a suitable neutral solvent such as ester, benzene or tetrahydrofuran in a suitable base such as lithium hydride, sodium hydride, sodium methoxide or potassium tert-butoxide. Can be prepared by reacting with an acrylic ester of the structural formula RCH = CRCOOR ₃ . In this reaction, the desired cis-isomer is the dominant product.

Next structural formula

Some cis-diacids of the following structural formula

A compound of (where R is selected from consisting of a defined as described above, U and V are the same or different, -CO ₂ R ₄ (wherein R ₄ is C ₁ -C ₆ alkyl), and cyano group, etc.) In a suitable solvent such as methanol, ethanol or water with a suitable base such as sodium or potassium hydroxide for 3-18 hours at a temperature of 30 ° -100 ° C. and then liberating the diacid with a suitable inorganic acid such as hydrochloric or sulfuric acid. Are manufactured.

The compound of the above formula wherein U is cyano and V is -CO ₂ R ₄ is a structural formula

It is prepared by reacting the bromoester of and acrylonitrile of the structural formula RHC-CRCN with the diester production method described above. The compound of the above formula wherein U is -CO ₂ R ₄ and V is cyano is

It is prepared by reacting bromo phenyl acetonitrile with an acrylic ester by the above-described method.

Next structural formula

The lactam is of the following structural formula

Is prepared by reducing the aforementioned cyano ester of to diborane at 0 ° -60 ° C. for 1-3 hours in a solvent such as tetrahydrofuran and then reacting the reduced intermediate with an inorganic acid such as 6N hydrochloric acid. Similarly, the following structural formula

The lactam is of the following structural formula

It is prepared by reducing the cyano ester of by the above-described method.

As another method, the compound of the present invention of formula (II), wherein R is hydrogen,

3-phenyl-3-pyrroline is prepared by reacting with a compound of formula CH ₂ I ₂ . Also, the following structural formula

Wherein the R and X are as described above and R ₇ is selected from the group consisting of C ₁ -C ₃ alkyl, but the phenyl group may not be substituted with hydroxy, acet amido, or amino The compound is represented by the following structural formula

It is prepared by reacting lactam with an organometallic compound such as methyl lithium and then reacting the intermediate product enamine with sodium borohydride. Similarly the following structural formula

The compound of

It is prepared from the compound of.

The lactams as defined above, wherein X is not hydrogen, are prepared by alkylating a lactang bond with the corresponding alkali method of the imide with a corresponding lactam wherein X is hydrogen.

Alternatively, the compound of formula (I) is reacted with a Grignard reagent such as methylmagnesium iodide or ethyl magnesium bromide in a neutral solvent such as ether, benzene or tetrahydrofuran at a temperature of 1-18 ° C. After reacting for a time, the reaction product is hydrolyzed with water,

Hydroxy lactam is obtained. The hydroxy lactam is reduced by the method described above to form a compound of the present invention of formula (IV).

Next structural formula

The amide of is converted to a compound of formula (II) wherein R is hydrogen at a temperature of 0 ° -80 ° C. using an acid binder such as sodium hydroxide, triethyleneamine, or sodium carbonate in a suitable solvent such as React with a halogenated acid of the formula R ₅ COX (where X is chlorine, bromine or imidazolyl) for 30 minutes-18 hours or an anhydride of the formula (R ₅ CO) ₂ O (where R ₅ is as described above) It is prepared by reacting with.

Alternatively, the new compounds of the present invention of formula (II), wherein R is not hydrogen, are defined as described above, in which a compound of formula (II) wherein R is hydrogen, such as sodium carbonate in a solvent such as methanol, ethanol or ether R ₅ CH ₂ W (wherein R ₅ is as defined above or a P-fluorobenzoylethyl group or 4,4-bis (P-fluorine) for 1-18 hours at a temperature of 25 ° -80 ° C using an acid binder Rophenyl) propyl group).

Alternatively, the imide of formula (I) wherein R is hydrogen can be alkylated with a compound of formula R ₅ CH ₂ W, wherein the imide is sodium hydroxide in a solvent such as N, N-dimethylformamide. Or by reacting with a nonnucleophilic strong base such as potassium tert-butoxide and then combining with an alkylating agent. As alkylating agents may also be used compounds of the formula R ₅ CHWR ₆ , wherein R ₅ and W are as described above and R ₆ is selected from the group consisting of C ₁ -C ₆ alkyl.

The novel compounds of the present invention exist as optical isomers and include the preferential and leciotic racemic forms. The present invention includes all such forms of isomers. Optical isomers of the compounds of the present invention are prepared by various cleavage methods. According to one method,

When combined with an optically active amine such as (-)-α- (1-naphthyl) ethylamine in a suitable solvent such as cis-diacid, methanol, ethanol, acetone, tetrahydrofuran or acetonitonitrile, A salt comprising (+) diacid and one molecule equivalent of said (-)-amine is obtained.

In some cases, it is advantageous to use tetrahydrofuran-ether mixtures as solvents, especially when the phenyl group is substituted with one or more alkyl groups, and also when the aryl group is a P-tolyl group and both R are hydrogen.

The racemic diacid can also be combined with (-)-2-amino-1-butanol in a suitable solvent as described above to obtain a salt whose acid value is (+)-diacid. The salts can be converted to the corresponding (+)-diacids by combining with a suitable base such as sodium hydroxide, potassium hydroxide, ammonium hydroxide or potassium carbonate and then acidifying with an aqueous solution of a suitable acid such as hydrochloric acid or sulfuric acid.

For (-)-diacid, the following structural formula

Optically active amines such as brucin, (+)-α- (1-naphthyl) -ethyl amine or (+)-2-amino-1-butanol in a suitable solvent as described above When combined as described above, a salt is obtained in which the acid group is (-)-diacid.

These salts can be converted to the corresponding (-)-diacids by the method described above. The above-mentioned (+) or (-) diacid is represented by the following formula

Is converted to a compound of. These imides are reduced by the method described above to give the following structural formula

To obtain an optically active form of the compound of the invention.

As another method, the following structural formula

The racemic compounds of are either (+) or (-) mandelic acid, (+) or (-) tartanic acid, (+) or (-) in a suitable solvent such as methanol, ethanol, acetone, acetonitrile, or tetrahydrofuran. Salts are obtained by combining with an optically active acid such as) -di-O-benzoyltartanic acid, or (+) or (-)-di-O- (p-toluoyl) tartanic acid. The salt is combined with a suitable acid, such as hydrochloric acid or sulfuric acid, and then the aqueous solution is basified with a base such as sodium hydroxide, potassium hydroxide, ammonium hydroxide, or sodium carbonate.

Compounds of the invention are obtained in optically active form.

Azibicyclohexane which belongs to the range of this invention has the following.

The compounds of the present invention are useful as analgesics in warm-blooded animals and their efficacy has been confirmed by various tests. One method is that of Randall and Celito [Arch. Int. Pharmacodyn. 111 409 (1957). This experiment measured the onset of pain in rats whose soles were pressure-sensitive by injecting a 0.1 ml suspension of a 20% aqueous solution of brewing yeast on the left hind paw surface. Apply increasing force (16 g / sec) to the swollen foot. If there is no reaction at 250 g of force, break the pressure. Control rats treated with starch carrier respond at about 30 g. The onset of pressure-pain is recorded one to several hours after oral administration of the test compound at a dose of up to 200 mg / kg.

2.0)Yeast is administered 2 hours before the onset of pain. Calculate the ratio of the test (T) / control (C), and use this ratio to determine the screening action, calculate the efficacy with the dose response experiment, and / or measure the analgesic effect (ie, T / The higher the C ratio, the greater the analgesic effect). For example, if the test compound delays the onset of pain by 100% (T / C

2.0)

Such compounds can be considered to be active (important relative to controls). Activity screening results were repeated at the same dose for confirmation; Testing at smaller dosages; Determine duration and maximum effect time; Dose-response calculations for efficacy; One or more of the experiments may be added, such as determining the upper limit of effect (maximum T / C) using an experimental protocol.

Representative compounds of the present invention also exhibit analgesic effects when measured by modifying the method of Atkinson and Coban (Palm, Pharmacol. 26 722 (1974)).

In this experiment, a 20-hour white star of Royalheart Farms' Vista-white male, weighing 120-150 g, is used. 0.25 ml of a 40% yeast suspension in physiological saline is injected into the sole of the left hind paw of each rat.

After 3 hours, which is the time of pain in the injected foot, the gait before dosing of each rat is evaluated by the following scoring.

0 = I continue using normal gait, sole even if there is the foot of the severe pain.

0.5 = as described above, but sometimes limping slightly.

1.0 = Ham continuously. But the soles continue to use

1.5 = limberly tricycles or toes with soles.

2.0 = Continuous walk or just toe tip. Do not use soles.

Prior to administration of the test compound, at least 95% of the rats scored 2 steps. The compound is mixed with a suitable carrier and orally administered at a dose of 0.5 ml per 100 g of body weight. After an hour or two, the gait after dosing is evaluated as described above. Post-dose reception is measured and compared with pre-dose scores. This result is used to determine the screening action and to calculate the dose-response of efficacy. For example, when a screening experiment is conducted using three animals per dose, if the pre-dose score is 6 (2.0 × 3) and the post-dose score is 4 (about 3 dogs), it may be considered an important action beyond the standard amount. For the calculation of dose-response, it can be considered that there is an analgesic effect if there is a recovery of more than 50% in the abnormal step score for individual rats, i.e., if the post-dose score is less than 1.0 after predose score 2.0.

Another method of measuring the action of the compounds of the present invention is based on a reduction in the number of writhing following peritoneal injection of 1 mg of phenyl-p-quinone per kg of body weight in 18-25 g male mice. These symptoms are characterized by irregular contractions of the abdomen, torsion of the torso and extension of the hind legs, which occur 3-5 minutes after the injection of phenyl-p-quinone. Thirty minutes before the injection of phenyl-p-quinone, two groups of mice each are administered orally with the indicated doses of the test compound. Begin 15 minutes after phenyl-p-quinone injection and record the total wriggling numbers for each group at 3 minute intervals. If the total number of compounds wriggling is reduced from the baseline of 30 per animal to less than 18, the compound can be considered to be working.

Representative compounds of the invention are tested with one or more of the test methods described above and the results are summarized in the following table.

TABLE 1a

Screening of Pain Killers

TABLE 1b

TABLE 1c

Effective (mg / kg oral, at indicated doses)

Azabicyclohexane of the present invention can be administered orally, for example, with an inert diluent or edible assimilar carrier, and can also be enclosed in gelatin capsules or compressed into tablets or incorporated directly into food. At the time of oral administration for treatment, the active compound of the present invention may be mixed with other ingredients to be used in the form of tablets, troches, capsules, elixirs, suspensions, syrups, oblates and the like. Such compositions and preparations should contain at least 0.1% of active compound. Of course, the percentage of composition and preparation can be varied and can be as much as 5% -75% of the weight of the dosage unit. The amount of active compound in such compositions and preparations should be such that an appropriate dosage will be obtained. Preferred compositions and preparations according to the invention are prepared such that oral dosage units contain 10-400 mg of active compound. Particularly preferred compositions are those in which the oral dosage unit contains 50-250 mg of the active compound.

Tablets, troches, pills, capsules, and the like may also contain the following. Binders such as gum tragacanth, acacia, corn starch or gelatin; Excipients such as dicalcium phosphate; Disintegrating agents such as corn starch, potato starch, alginic acid and the like; Lubricants such as magnesium stearate; Sweeteners such as sucrose, lactose or saccharin; Fragrances, such as mint, winter green oil, and fragrance | flavor fragrance | flavor, can be added. If the dosage unit is in the form of a capsule, in addition to the above-mentioned substances, it may contain a liquid carrier such as fatty oil. Various other materials can be used to coat the dosage unit or to change to another physical form. For example, tablets, pills, or capsules may contain the active compound and fragrances such as methyl and propyl parabens, dyes, cherries or tangerine scents as sweeteners and sweeteners as sweeteners and the like. Of course, any substance used to prepare dosage unit forms must be pharmacologically pure and non-toxic.

Compositions having the purity, stability and applicability desired for local use can be obtained by dissolving 0.10-10.0% by weight of azabicyclohexane in a carrier of a mixture of nonvolatile liquid polyethylene glycols. The polyethylene glycol is soluble in water and organic liquid and has a molecular weight of about 200-1500. Such polyethylene glycol mixtures are commercially available and are usually obtained by condensation of glycols with ethylene oxide. The amount of azabicyclo hexane dissolved in the carrier can be varied in the range of 0.10-10.0% by weight, but the preferred amount of use is about 3.0-9.0% by weight. Although various mixtures of the aforementioned nonvolatile polyethylene glycols can be used, it is preferable to use mixtures of nonvolatile polyethylene glycols having an average molecular weight of about 400. This mixture is commonly called polyethylene glycol 400. A preferred embodiment is a clear solution in which about 3.0-9.0% by weight of azabicyclohexane is dissolved in an aqueous solution of polyethylene glycol 400. In addition to azabicyclo hexane, the topical solution may contain various preservatives to prevent infection and chemical degradation of bacteria and fungi.

The following specific examples detail the preparation of representative compounds of the invention.

Example 1

Preparation of racemic 1- (p-chlorophenyl) -3-azabicyclo [3,1,0] hexane hydrochloride

A solution of 2 g of diethyl 1- (p-chlorophenyl) -cis-1,2-cyclopropane dicarboxylate in 25 ml of ethanol is treated with 13.5 ml of 1N potassium hydroxide solution. The reaction mixture is refluxed for 3.5 hours and then left at room temperature overnight. Ethanol is removed under reduced pressure, and the aqueous solution is extracted with ether to remove a small amount of mineral oil.

The aqueous solution is treated with 13.5 ml of 1N hydrochloric acid and 2 ml of 6n hydrochloric acid. The oily aqueous mixture is extracted four times with chloroform. The chloroform solution is dried, decolorized and concentrated under reduced pressure to give a yellow solid.

Recrystallization twice from ethyl acetate-petroleum ether (30 ° -70 ° C.) yields 0.85 g of white solid 1- (p-chlorophenyl) -cis-1,2-cyclopropanedicarboxylic acid. Melting point 162 ° -163 ° C.

A solution of 5.7 g of the acid and 2.02 g of urea dissolved in 200 ml of xylene is refluxed for 22 hours, cooled, diluted with benzene and washed with water. The organic layer is diluted with chloroform, dried and concentrated under reduced pressure, and then recrystallized from ethyl acetate and petroleum ether to give 1- (p-chlorophenyl) -1,2-cyclopropane dicarboximide.

While stirring 30 ml of sodium bis (2-methoxyethoxy) aluminum hydride (70% benzene solution), 2.2 g of 1- (p-chlorophenyl) -1,2-cyclopropanedicarboxylate in 100 ml of benzene The solution in which the mead is dissolved is added dropwise over 30 minutes at room temperature under a nitrogen atmosphere. Slightly warm the reaction vessel to maintain the solution. The clear yellow solution is heated to reflux for 1 hour under nitrogen atmosphere. Cool the solution and decompose excess reagent with 5N sodium hydroxide. Water is added to the mixture and the benzene phase is separated. The aqueous phase is extracted with ether and the ether extract is combined with the benzene phase and dried over magnesium sulfate. The organic phase is evaporated under reduced pressure to give a viscous liquid, which when crystallized gives 1- (p-chlorophenyl) -3-azabicyclo [3,1,0] hexane of racemic base as a light gray sticky solid. This solid is dissolved in ethanol, acidified with hydrogen chloride ethanol solution and ether is added to give hydrochloride as light gray crystals. Recrystallization of this from ethanol yields a light gray crystal. Melting point 215-217 ° C.

In a similar manner, the next imide is reduced with sodium bis- (2-methoxyethoxy) aluminum hydride to yield the corresponding reduction product.

Example 2

Preparation of (-)-1- (p-chlorophenyl) -3-azabicyclo [3,1,0] hexanehydrochloride

While stirring 30 ml of sodium bis (2-methoxyethoxy) aluminum hydride (70% benzene solution), 6.6 g of (-)-1- (p-chlorophenyl) -1,2-cyclo in 500 ml of benzene A solution in which propanedicarboximide is dissolved is added dropwise over 3 hours at room temperature under nitrogen. The clear yellow solution is heated to reflux for 90 minutes under nitrogen and then left overnight at room temperature. Carefully add 25 ml of 5N sodium hydroxide to decompose the excess hydride reagent. The mixture is then diluted with 200 ml of water. The benzene phase is separated and the aqueous phase is extracted with chloroform. The benzene and chloroform phases are combined, dried over magnesium sulfate and concentrated under reduced pressure to afford (-)-1- (p-chlorophenyl) -3-azabicyclo [3,1,0] hexane as a yellow solid. This solid is dissolved in ethanol and acidified with 10 ml of 2,3N ethanol hydrogen chloride. Ether is added to precipitate the hydrochloride of this base into a solid which is collected and dried to give white crystals. Melting point 197 ° -200 ° C.

Example 3

Preparation of (+)-1- (p-chlorophenyl) -3-azabicyclo [3,1,0] hexane hydrochloride

A solution of 192.5 g of racemic cis-1- (p-chlorophenyl) -1,2-cyclopropanedicarboxylic acid and 142 g of (-)-2-aminobutanol solution in 1600 ml of acetone was placed for 48 hours. Leave, filtered and washed with acetone to give a solid. This solid is dissolved in 460 ml of hot water and acidified. The solid is filtered off and air dried. A solution dissolved in 107.5 g of azoze (+)-diacid and 79.3 g of (-)-2-amino butanol in 892 ml of acetone is left for several hours. The solid is filtered and dried, dissolved in 200 ml of hot water, acidified with concentrated hydrochloric acid, cooled and filtered.

This solid is recrystallized from acetonitrile to obtain (+)-cis-1- (p-chlorophenyl) -1,2-cyclopropanedicarboxylic acid.

A solution of 10.5 g of the above (+)-diacid and 3.9 g of urea dissolved in 325 ml of xylene was stirred, refluxed for 7 hours and a half and then left overnight. The xylene is distilled off, cooled and filtered to yield a white solid which is recrystallized from ethanol to give (+)-1- (p-chlorophenyl) -1,2-cyclopropanedicarboximide.

30 ml of sodium bis (2-methoxyethoxy) aluminum hydride (70% benzene solution) is stirred and 4.5 g of (+)-1- (p-chlorophenyl) 1,2-cycloprop in 400 ml of benzene The solution in which Pandicarboximide is dissolved is added dropwise for 45 minutes while stirring at room temperature under nitrogen. The clear yellow solution is heated to reflux under nitrogen for 90 minutes and left overnight at room temperature. Carefully add 25 ml of 5N sodium hydroxide to decompose the excess hydride reagent. The mixture is diluted with 200 ml of water and the benzene phase is removed. The aqueous phase is extracted with chloroform. The benzene and chloroform phases are combined, dried over magnesium sulfate and concentrated under reduced pressure to afford (+)-1- (p-chlorophenyl) -3-azabicyclo [3,1,0] hexane as a sticky yellow solid. This solid is dissolved in ethanol and acidified with 20 ml of 23N ethanol hydrogen chloride. 200 ml of ether is added to form crystals. These are recrystallized from acetonitrile to obtain hydrochloride as white crystals. Melting point 190 ° -192 ℃,

Example 4

Preparation of racemic 1-phenyl-3-azabicyclo [3,1,0] hexane hydrochloride

30 ml of sodium bis (2-methoxyethoxy) aluminum hydride (70% benzene solution) was stirred and 6.6 g of 1-phenyl-1,2-cyclopropanedicarboximide was dissolved in 400 ml of benzene. Is added dropwise at room temperature under nitrogen for 1 hour. The reaction mixture is heated to reflux for 90 minutes. Carefully add 25 ml of 10N sodium hydroxide to digest excess hydride reagent. The mixture is diluted with 200 ml of water and the benzene phase is separated. The aqueous phase is extracted with chloroform and the organic extracts are combined and dried over magnesium sulfate. The solution is concentrated under reduced pressure to give a brown liquid which is dissolved in ethanol and acidified with 5 ml of 2,3N ethanol hydrogen chloride. The addition of ether precipitates a solid which is recrystallized from acetonitrile to give white crystals. Melting point 166 ° -168 ° C.

Example 5

Preparation of racemic 3-methyl-1-phenyl-3-azabicyclo [3,1,0] hexane hydrochloride

30 ml of sodium bis (2-methoxyethoxy) aluminum hydride (70% benzene solution) is stirred and 5.5 g of N-methyl-1-phenyl-1,2-cyclopropanedicarboximide in 400 ml of benzene The dissolved solution is added dropwise at room temperature under nitrogen for 1 hour. The mixture is heated to reflux for 90 minutes under nitrogen. Carefully add 25 ml of 10N sodium hydroxide to dissolve the excess hydride reagent and dilute with 200 ml of water. The benzene phase is separated and the aqueous phase is extracted with chloroform.

The combined organic phases are dried over magnesium sulfate and concentrated under reduced pressure to give a liquid. This liquid is dissolved in ethanol and acidified with 15 ml of 2,3Nethanol hydrogen chloride. Ether is added to form a solid, which is recrystallized from isopropyl alcohol-hexane to give white crystals. Melting point 158 ° 160 ° C.

Example 6

Preparation of 1- (m-chlorophenyl) -3-azabicyclo [3,1,0] hexane hydrochloride

Nichrome was prepared by dissolving 53.6 g of ethyl m-chlorophenyl acetate (prepared by esterifying the corresponding acid), 51.5 g of N-bromosuccinimide and 1 g of benzoyl peroxide in 1.25 L of carbon tetrachloride. Stir with a metal stirrer and reflux for 20 hours. The mixture is cooled, filtered and concentrated to give an orange oil. Vacuum distillation affords the product ethyl α-bromo-m-chlorophenylacetate.

In 500 ml of ether a suspension containing 4.4 g of sodium hydride is stirred under nitrogen and 0.5 ml of ethanol is added. A mixture of 27.8 g of the ester, 10 g of ethyl acrylate, and 1 ml of ethanol is stirred overnight at room temperature. Ethanol is added to decompose the unreacted sodium hydride, and the mixture is washed with 100 ml of water, 50 ml of 1N hydrochloric acid, three dilute solutions of sodium bicarbonate, and finally 100 ml of water. The product is dried and concentrated under reduced pressure to give 1- (m-chlorophenyl) -1,2-cyclopropanedicarboxylic acid diethyl ester as a yellow liquid.

A solution containing 22 g of the diester in 150 ml of ethanol and 150 ml of 1N potassium hydroxide is refluxed for 3.5 hours and left overnight at room temperature. The mixture is concentrated and extracted with ether. The aqueous phase is acidified with 1N hydrochloric acid, extracted three times with chloroform, dried and concentrated under reduced pressure to give a yellow oil which is determined from ethyl acetate-petroleum ether to give cis-1- (m-chlorophenyl)- 1,2-cyclopropanedicarboxylic acid is obtained as a white solid.

A solution containing 5.7 g of the acid and 2.02 g of urea in 200 ml of xylene is refluxed for 22 hours, cooled, diluted with benzene and washed with water. The organic layer is diluted with chloroform, dried and concentrated under reduced pressure and recrystallized from ethyl acetate and petroleum ether to give 1- (m-chlorophenyl) -1,2-cyclopropanedicarboximide.

30 ml of sodium bis (2-methoxyethoxy) aluminum hydride (70% benzene solution) is stirred and 4.0 g of 1- (m-chlorophenyl) -1,2-cyclopropanedicarboxylate in 400 ml of benzene The solution in which the mead is dissolved is added dropwise at room temperature under nitrogen for 1 hour. The reaction mixture is heated to reflux for 90 minutes under nitrogen. Dilute excess hydride reagent with 25 ml of 10N sodium hydroxide and dilute the mixture with 200 ml of water. The benzene phase is removed and the aqueous phase is extracted with chloroform. The combined organic phases are dried over magnesium sulfate and concentrated under reduced pressure to give a viscous yellowish brown liquid. This liquid is dissolved in ethanol and acidified with 2.3 N ethanol hydrogen chloride. The addition of ether gives a solid, which is recrystallized from isopropanol to give 1- (m-chlorophenyl) -3-azabicyclo [3,1,0] hexane hydrochloride as white crystals. Melting Point 182 ° -184 ℃

Example 7

Preparation of 1- (m-fluorophenyl) -3-azabicyclo [3,1,0] hexane hydrochloride

Dissolve 46.2 g of 1- (m-fluorofluoro) acetic acid in 120 ml of ethanol. 12 ml of sulfuric acid are added and the mixture is refluxed for 4.5 hours and left overnight at room temperature. 400 ml of water are added, the mixture is extracted three times with ether, dried over magnesium sulfate and concentrated under reduced pressure to give a liquid. Vacuum distillation yields ethyl 1- (m-fluorophenyl) acetate.

A mixture containing 49.3 g of ethyl 1- (m-fluorophenyl) acetate, 53 g of N-bromosuccinimide and 0.95 g of benzoyl peroxide in 1.6 L of carbon tetrachloride was refluxed for 24 hours with a nichrome metal stirrer. After stirring and concentrating, an orange oil is obtained, and vacuum distillation gives ethyl α-bromo-1- (m-fluorophenyl) acetate.

65 g of ethyl α-bromo-1- (m-fluorophenyl) acetate, 25 g of ethyl acrylate, 2 ml of ethanol, etc. while stirring a suspension containing 11 g of sodium hydride in mineral oil in 1 liter of ether under nitrogen One drop of the mixture is added. The temperature is maintained at 25 ° -29 ° C. with stirring overnight. The mixture is cooled and several ml of ethanol are added to decompose the unreacted sodium hydride, and then the mixture is washed sequentially with water, 1N hydrochloric acid, dilute sodium bicarbonate and saturated sodium chloride solution and concentrated to give a liquid. Vacuum distillation of this liquid yields a diethyl ester of 1- (m-fluorophenyl) -1,2-cyclopropanedicarboxylic acid.

A mixture containing 20.5 g of the diester and 160 ml of 1N potassium hydroxide in 150 ml of ethanol is refluxed and concentrated for 3.5 hours. The mixture is acidified with 1N hydrochloric acid, extracted three times with chloroform, dried and concentrated under reduced pressure to give a solid. Recrystallization of the solid from ethyl acetate-petroleum ether twice gives cis-1- (m-fluorophenyl) -1,2-cyclopropanedicarboxylic acid.

A mixture containing 8.0 g of the diacid and 2.6 g of urea in 500 ml of xylene is heated under reflux for 22 hours. The solution is diluted with benzene, washed with water and dried over magnesium sulfate. The organic layer is concentrated under reduced pressure and 1- (m-fluorophenyl) -1,2-cyclopropanedicarboximide is obtained as a light gray solid.

After stirring 30 ml of sodium bis (2-methoxy ethoxy) aluminum hydride solution, 5.6 g of 1- (m-fluorophenyl) -1,2-cyclopropanedicarboximide was dissolved in 400 ml of benzene. The prepared solution is added dropwise at room temperature under nitrogen for 90 minutes. The reaction mixture is heated to reflux for 90 minutes under nitrogen. Carefully add 25 ml of 10N sodium hydroxide to dissolve the excess hydride reagent, then dilute the mixture with 20 ml of water. The benzene phase is removed and the aqueous phase is extracted with chloroform. The combined organic phases are dried over magnesium sulfate and concentrated under reduced pressure to give a mixture of oily solids and viscous liquids. This mixture is dissolved in ethanol and acidified with ethanol hydrogen chloride. Addition of ether gives a precipitate, which is recrystallized with acetonitrile to give 1- (m-fluorophenyl) -3-azabicyclo [3,1,0] hexane hydrochloride as gray crystals.

Melting point 140 ° 146 ° C.

Example 8

Preparation of (-)-1-phenyl-3-azabicyclo [3,1,0] hexane hydrochloride

A slurry containing 18.7 g of (-)-1--phenyl-1,2-cyclopropane dicarboximide in 500 ml of benzene was stirred under nitrogen and 150 ml of sodium bis (2-methoxyethoxy) aluminum hydride Ride (70% benzene solution) is added over 10 minutes. The mixture is stirred at room temperature for 2 hours, refluxed for 4 hours and left at room temperature for 20 hours. 150 ml of 10N sodium hydroxide is added carefully while stirring. The organic layer is washed with water, dried over magnesium sulfate and evaporated under reduced pressure to give a yellow oil.

This oil is dissolved in 300 ml of ether. Dry hydrogen chloride gas is passed through the bubble until precipitation stops, and the mixture is filtered to give colorless crystals. When this is recrystallized from acetonitrile, light brown crystals are obtained. Melting point 170 ° -172 ° C.

Example 9

Preparation of racemic 1-phenyl-3-azabicyclo [3,1,0] hexane

Example 1 with 1-phenyl-1,2-cyclopropanedicarboxylate and without addition of hydrogen chloride gas gave racemic 1-phenyl-3-azibacyclo [3,1,0] hexane. Get Melting point 130 ° -133 ° C. (15 mm).

Example 10

Preparation of (-)-3-methyl-1-phenyl-3-azabicyclo [3,1,0] hexane hydrochloride

In a solution of 18.7 g of (-)-1-phenyl-1,2-cyclopropanedicarboximide dissolved in 100 ml of anhydrous dimethylformamide, 5.0 g of sodium hydride (54% in mineral oil) was added over 15 minutes. Add. The mixture is stirred for 30 minutes and then 10 ml of iodomethane is added over 5 minutes. The mixture is stirred for 30 minutes and then 10 ml of iodomethane is added over 5 minutes. The mixture is left for 15 minutes, then heated in a steam bath for 15 minutes, cooled and poured into 250 ml of water. The mixture is filtered and the crystals washed with petroleum ether and then air dried to afford (-)-N-methyl-1-phenyl-1,2-cyclopropane dicarboximide.

A solution of 5.0 g of (-)-N-methyl-1-phenyl-1,2-cyclopropanedicarboximide dissolved in 125 ml of benzene was stirred under nitrogen, and 30 ml of sodium bis (2-methoxy ethoxy) was added. Aluminum hydride (70% benzene solution) is added over 10 minutes. The mixture is refluxed for 5 hours, cooled and carefully added 60 ml of 10N sodium hydroxide. The organic layer is washed with water, dried over magnesium sulfate and evaporated under reduced pressure to give amber oil.

This oil is dissolved in 250 ml of ether, saturated with hydrogen chloride and filtered to give colorless crystals. Recrystallization of this crystal from acetonitrile produces colorless crystals. Melting Point: 194 ° -196 ° C.

Example 11

Preparation of (-)-1- (P-chlorophenyl) -3-methyl-3-azabicyclo [3,1,0] -hexane hydrochloride.

5.0 g of sodium hydride (54% in mineral oil) in a solution in which 22.1 g of (-)-1 (P-chlorophenyl) -1,2-cyclopropanedicarboximide was dissolved in 100 ml of anhydrous dimethylformamide. Add over 15 minutes.

The mixture is stirred for 30 minutes and then 10 ml of iodomethane is added over 5 minutes. The mixture is left for 15 minutes, heated in a steam bath for 15 minutes, cooled and poured into 250 ml of water. The precipitate is filtered off, washed with petroleum ether and air dried to give (-)-N-methyl-1- (P-chlorophenyl) -1,2-cyclopropanedicarboximide as colorless crystals.

A solution of 11.8 g of this product in 250 ml of benzene was stirred under nitrogen and 60 ml of sodium bis (2-methoxyethoxy) aluminum hydride (70% benzene solution) was added over 10 minutes. The mixture is refluxed for 5 minutes, cooled and carefully added 60 ml of 10N sodium hydroxide. The organic layer is washed with water, dried over magnesium sulfate and evaporated under reduced pressure to give amber oil. This oil is dissolved in 250 ml of ether, saturated with hydrogen chloride and filtered to give colorless crystals. Recrystallization from acetonitrile gives colorless crystals.

Melting Point: 211 ° -212 ℃

Example 12

Preparation of (+)-1- (P-chlorophenyl) -3-methyl-3-azabicyclo [3,1,0] hexane hydrochloride.

A solution of 11.08 g of (+)-1- (P-chlorophenyl) -1,2-cyclopandicarboximide dissolved in 50 ml of anhydrous dimethylformamide was stirred, followed by 2.5 g of sodium hydride (in mineral oil). 54%) is added under nitrogen over 15 minutes. The mixture is stirred for 30 minutes and 5 ml of iodomethane is added over 5 minutes. The mixture is left for 15 minutes, heated in a steam bath for 15 minutes, cooled and poured into 125 ml of water. The mixture is filtered, washed with petroleum ether and dried to give (+)-N-methyl-1- (P-chlorophenyl) -1,2-cyclopropanedicarboximide as colorless crystals.

A solution of 3.92 g of (+)-N-methyl-1- (P-chlorophenyl) -1,2-cyclopropanedicarboximide dissolved in 100 ml of benzene was stirred under nitrogen and 20 ml of sodium bis (2- Methoxyethoxy) aluminum hydride (70% benzene solution) is added for 10 minutes. The mixture is stirred at room temperature for 2 hours and refluxed for 2 hours. Carefully add 20 ml of 10N sodium hydroxide. The benzene layer is washed with water, dried over magnesium sulfate and evaporated under reduced pressure to obtain oil. This oil was dissolved in 200 ml of ether and wrapped with dry hydrogen chloride to give a cake of colorless crystals, which was recrystallized from acetonitrile to give (+)-1- (P-chlorophenyl) -3-methyl-3-azabicyclo [3,1,0] hexane hydrochloride is obtained as light brown crystals. Melting point: 209 ° -210 ° C.

Example 13

Preparation of racemic 1- (P-chlorophenyl) -3-methyl-3-azabicyclo [3,1,0] hexane hydrochloride.

A solution of 44.2 g of racemic 1- (P-chlorophenyl) -1,2-cyclopandicarboximide dissolved in 200 ml of anhydrous dimethylformamide was stirred and 10.0 g of sodium hydride (50% in mineral oil) ) Over 5 minutes. 20 ml of uridomethane is slowly added over 5 minutes. The mixture is heated for 30 minutes, cooled and poured into 500 ml of water. The solids were collected by filtration and recrystallized from heptane-ethyl acetate to yield racemic N-methyl-1- (P-chlorophenyl) -1,2-cyclopropanedicarboximide as colorless crystals.

Stir the solution containing 11.8 g of this product in 250 ml of benzene, and add 60 ml of sodium bis (2-methoxyethoxy) aluminum hydride (70% benzene solution) over 10 minutes under nitrogen. Leave for 16 hours, reflux the mixture for 4 hours, cool and carefully add 60 ml of 10N sodium hydroxide. The organic layer is successively dried over sodium sulfate and magnesium sulfate, filtered and evaporated under reduced pressure to give the free base as a pale yellow oil. This oil is dissolved in 200 ml of ether and saturated with dry brine gas. The solid is recovered and crystallized from acetonitrile to give a light brown plate shape. Melting point: 180 ° -182 ° C.

Example 14

Preparation of 3-benzyl-1-phenyl-3-azabicyclo [3,1,0] -hexane hydrochloride.

To 200 ml of anhydrous dimethylformamide is added 10 g of sodium hydride (50% in mineral oil) to a solution containing 37.4 g of 1-phenyl-1,2-cyclopropanedicarboximide with stirring. 25.4 ml of benzyl chloride are added dropwise. 20 mg of potassium iodide is added. The mixture was stirred at room temperature for 2 hours and then poured into 1 liter of water to obtain a residue in the form of a gum which was treated with petroleum ether to give N-benzyl-1-phenyl-1,2-cyclopropanedicarboximide. Obtained as light yellow crystals.

A solution of 13.87 g of the product dissolved in 250 ml of benzene is stirred and 60 ml of sodium bis (2-methoxyethoxy) aluminum hydride (70% benzene solution) is added over 10 minutes under nitrogen. The mixture is refluxed for 5 hours, then cooled and carefully added 60 ml of 10N sodium hydroxide. The benzene layer is washed with water, dried over magnesium sulfate and evaporated under reduced pressure to give a pale yellow oil. This oil is dissolved in ether, followed by dry hydrogen chloride gas, and the solid is recovered and recrystallized from isopropyl alcohol to give colorless crystals.

Melting Point: 194 ° -196 ° C.

Example 15

Preparation of 3-cyclopropylmethyl-1-phenyl-3-azabicyclo [3,1,0] hexane hydrochloride.

A slurry containing 61.2 g of 1-phenyl-1,2-cyclopropanedicarboximide was stirred in 2 L of benzene and 400 ml of sodium bis (2-methoxyethoxy) aluminum hydride (70% benzene) under nitrogen. Solution).

The mixture is stirred at room temperature for 2 hours, refluxed for 4 hours and then at room temperature for 20 hours. Carefully add 400 ml of 10N sodium hydroxide while stirring. The organic layer is washed twice with dilute sodium hydroxide, then with water, dried over magnesium sulfate and evaporated to give a pale yellow oil. This oil is dissolved in dilute hydrochloric acid, washed with ether and filtered, and the filtrate is made basic with sodium hydroxide. The basic filtrate is extracted with benzene, dried over magnesium sulfate, filtered and evaporated to give 1-phenyl-3-azabicyclo [3,1,0] hexane as pale yellow oil. 11.0 g of cyclopropanecarboxylic acid dissolved in 20 ml of benzene in a solution of 15.9 g of 1-phenyl-3-azabicyclo [3,1,0] hexane dissolved in 100 ml of benzene and 20 ml of triethylamine. Is added over 5 minutes. The mixture is stirred for 30 minutes and 50 ml of water are added. The benzene layer was extracted with dilute sodium bicarbonate, then extracted with dilute hydrochloric acid and water, dried over magnesium sulfate and evaporated to yield the product 3-cyclopropylcarboyl-1-phenyl-3-azabicyclo [3,1,0] hexane Gets into brown oil. 25 ml of sodium bis (2-methoxyethoxy) aluminum hydride in a solution of 11.35 g of 3-cyclopropyl carboyl-1-phenyl-3-azabicyclo [3,1,0] hexane in 100 ml of benzene (70% benzene solution) is added with stirring. The mixture is left for 18 hours, refluxed for 2 hours, cooled and slowly added 25 ml of 10N sodium hydroxide. The organic layer is washed with saturated sodium chloride, dried over magnesium sulfate and evaporated to give a brown oil.

This oil is dissolved in ether and dried hydrogen chloride gas is bubbled to give pink crystals. This crystal is recrystallized from isopropyl alcohol to give pink crystals. Melting point: 164 ° -165 ° C.

In the same manner, 3-cyclopropane carboyl-1- (P-tolyl is reacted by reacting 1- (P-tolyl) -3-azabicyclo [3,1,0] hexane (Example 36) with cyclopropane carboylchloride. ) -3-azabicyclo [3,1,0] hexane was obtained and reduced as described above to yield 3-cyclopropylmethyl-1- (Ptolyl) -3-azabicyclo [3,1,0] hexane hydro Chloride is obtained as colorless crystals. Melting point: 180 ° -182 ° C.

Example 16

Preparation of 3-phenethyl-1-phenyl-3-azabicyclo [3,1,0] hexane hydrochloride.

A solution of 9.35 g of 1-phenyl-1,2-cyclopropanedicarboximide dissolved in 50 ml of dimethylformamide is stirred, and 2.5 g of sodium hydride (50% in mineral oil) is added over 5 minutes. . The mixture is warmed and stirred for 1/2 hour to add 0.1 g of potassium iodide followed by 9.25 g of phenethyl bromide. The mixture is stirred for 1/2 hour, heated for 15 minutes in a steam bath and then stirred for 15 minutes at room temperature and poured into 1 liter of water acidified with acetic acid. The mixture is extracted with methylene chloride and the solution is combined with 50 g of magnesium silicate and evaporated under reduced pressure. The remaining powder was applied to a magnesium silicate column, eluted with 1 L of petroleum ether, 500 ml of methylene chloride, 1 L of chloroform and evaporated to give N-phenethyl-1-phenyl-1,2-cyclopropanedicarboximide as colorless. Gets into oil.

To a solution of 5.80 g of the compound dissolved in 50 ml of benzene is added with stirring 10 ml of sodium bis (2-methoxyethoxy) aluminum hydride (70% benzene solution). The mixture is left for 18 hours, refluxed for 2 hours, cooled and treated with 10 ml of 10N sodium hydroxide by the method described in Example 15 to obtain crystalline product. Melting point: 207 ° -209 ° C.

Example 17

3-isopropyl-1-phenyl-3-azabicyclo [3,1,0] hexane hydrochloride.

A mixture containing 20.6 g of 1-phenyl-1,2-cyclopropanedicarboxylic acid and 15 g of 1,3-diisopropyl urea in 500 ml of xylene was refluxed for 6 hours, filtered and the solvent removed under reduced pressure. Get oil. This oil is absorbed onto 500 ml of magnesium silicate in methylene chloride. The evaporation of the solvent leaves a powder.

This powder is added to magnesium silicate on a Buchner funnel and eluted sequentially with 500 ml of petroleum ether and 1 liter of methylene chloride. When methylene chloride evaporates, N-isopropyl-1-phenyl-1,2-cyclopropanedicarboximide is obtained as a colorless oil.

20 ml of sodium bis (2-methoxyethoxy) aluminum hydride (70% benzene solution) is added to a solution in which 9.17 g of the product is dissolved in 100 ml of benzene. The mixture is left for 18 hours, refluxed for 2 hours, cooled, slowly adding 20 ml of 10N sodium hydroxide, and again 30 ml of 5N sodium hydroxide. The organic layer is extracted with dilute hydrochloric acid. The aqueous extract is made basic with sodium hydroxide, extracted with ether, dried over magnesium sulfate, bubbled with dry hydrogen chloride gas, and passed through to obtain a gum. The gum is triturated with ether and determined from acetone to give brown crystals. Melting point: 141 ° -144 ° C.

In a similar manner, N, 1-diphenyl-1,2-cyclopropanedicarboximide is obtained from 1- (P-chlorophenyl) -1,2-cyclopropanedicarboxylic acid and 1,3-diphenylurea. This was reduced with sodium bis (2-methoxyethoxy) aluminum hydride (70% benzene solution) to give 1,3-diphenyl-3-azabicyclo [3,1,0] hexane.

Example 18

Preparation of 1- (P-trifluoromethylphenyl) -3-azabicyclo [3,1,0] hexane hydrochloride.

Ethyl P- (trifluoromethyl) phenyl acetate was converted to ethyl α-bromo-P- (trifluoromethyl) phenyl acetate (melting point: 92 ° -95 ° C.) (0.4 mm) using the method of Example 6. Converted to ethyl acrylate-sodium hydride to react with diethyl 1- (P-trifluoromethylphenyl) -1,2-cyclopropanedicarboxylate (melting point: 108 ° -110 ° C (0.2 mm)) Get Hydrolysis with 1N potassium hydroxide yields cis-1- (P-trifluoromethylphenyl) -1,2-cyclopropanedicarboxylic acid as colorless crystals. Melting point: 161 ° -162 ° C.

This diacid is then reacted with urea to give 1- (P-trifluoromethylphenyl) -1,2-cyclopropanedicarboximide as colorless crystals. Melting point: 164 ° -165 ° C.

20 ml of sodium bis (2-methoxyethoxy) aluminum hydride (70% benzene solution) is added to a urine solution in which 3.5 g of the imide is dissolved in 75 ml of benzene. It is refluxed for 1 hour, cooled to room temperature and the excess hydride reagent is digested with 20 ml of 10N sodium hydroxide. The benzene layer is washed with water, dried over magnesium sulfate and evaporated under reduced pressure to give a pale yellow oil. This oil is dissolved in ether and dry hydrogen chloride gas is bubbled through the solution. The resulting precipitate is collected by filtration and recrystallized from isopropyl alcohol to give the product. Melting point: 249 ° -251 ° C.

Example 19

Preparation of 3- (P-chlorobenzyl) -1- (P-chlorophenyl) -3-azabicyclo [3,1,0] hexane.

19.35 g of 1- (P-chlorobenzyl) -1- (P-chlorophenyl) -3-azabicyclo [3,1,0] hexane, 10.59 g sodium carbonate and 17.5 g P-chlorobenzoyl chloride in benzene React in Benzene is evaporated, the dark purple residue is dissolved in 200 ml of chloroform, washed sequentially with 5% sodium carbonate, 0.5N hydrochloric acid and water, and dried over magnesium sulfate to give a dark purple oil. The addition of ether gives the product 3- (P-chlorobenzyl) -1- (P-chlorophenyl) -3-azabicyclo [3,1,0] hexane as gray crystals. Melting point: 98 ° -100 ° C.

16.60 g of 3- (P-chlorobenzoyl) -1- (P-chlorophenyl) -3-azabicyclo [3,1,0] hexane is dissolved in 160 ml of benzene and 55.5 g of sodium bis (2-meth) Add methoxyethoxy) aluminum hydride (70% benzene solution) drop by drop. The mixture is refluxed for 2 hours, cooled and slowly cooled with 10N sodium hydroxide. Water is added, the organic layer is separated, washed three times with water and dried over magnesium sulfate. Removal of the solvent gives a light gray solid. Melting point: 88 ° -92 ° C.

In the same manner the following amide is reduced with sodium bis (2-methoxyethoxy) aluminum hydride to give the corresponding reduction product.

The intermediates A, B and D are prepared by acylating the corresponding 3-azabicyclo [3,1,0] hexanes with the appropriate acid chlorides as in Example 19.

The intermediate C is prepared by acetylating 1- (P-nitrophenyl) -3-azabicyclo [3,1,0] hexane (Example 34) and then reducing it to palladium on charcoal in tetrahydrofuran.

Example 20

Preparation of 3- (1-adamantylmethyl) -1- (P-chlorophenyl) -3-azabicyclo [3,1,0] hexane.

19.35 g of 1-P-chlorophenyl-3-azabicyclo [3,1,0] hexane, 10.59 g of sodium carbonate and 19.87 g of 1-adamantanecarboxylic acid chloride were reacted as in Example 36 to obtain the product. 3- (1-adamantylcaaboyl) -1- (P-chlorophenyl) -3-azabicyclo [3,1,0] hexane is obtained as a white solid. Melting point: 163 ° -165 ° C.

17.77 g of 3- (1-adamantylcaraboyl) -1- (P-chlorophenyl) -3-azabicyclo [3,1,0] hexane were treated as in Example 19 to obtain yellow oil. If left, it is determined to be a white solid. Melting point: 72 ° -75 ° C.

Example 21

Preparation of 3-allyl-1-phenyl-3-azabicyclo [3,1,0] hexane hydrochloride.

5 g of sodium hydride (50% in mineral oil) is added to a solution of 18.7 g of 1-phenyl-1,2-cyclopropane dicarboximide dissolved in 100 ml of dimethylform amide. The mixture is heated in a steam bath and 5 ml of allyl bromide are added over 5 minutes with stirring. The mixture is heated in a steam bath for 1/2 hour and then left at room temperature for 2 hours, poured into 1 liter of water and extracted with methylene chloride. The organic phase is mixed with 50 g of magnesium silicate and evaporated with a rotary evaporator. This mixture is added to 200 g of magnesium silicate on a Buchner funnel and eluted sequentially with 1 liter of petroleum ether and 1 liter of chloroform. Evaporation of the chloroform fractions under reduced pressure yields N-allyl-1-phenyl-1,2-cyclopropanedicarboxyboximide as a colorless oil.

To a solution of 8.0 g of the above product dissolved in 70 ml of benzene is added 17.5 ml of sodium bis (2-methoxyethoxy) aluminum hydride (70% Benze solution). The mixture is refluxed for 2 hours and stirred at room temperature for 2 hours.

The method of example 19 is followed to yield the desired product. Melting point: 124 ° -128 ° C.

In a similar manner, when 1- (P-tolyl) -1,2-cyclopropanedicarboximide is reacted with allyl bromide, N-allyl-1- (P-tolyl) -1,2-cyclopropanedicarboximide And reduction as described above yields 3-allyl-1- (P-tolyl) -3-azabicyclo [3,1,0] -hexane hydrochloride as a colorless binder. Melting point: 165 ° -167 ° C.

In a similar manner, when 1- (P-tolyl) -1,2-cyclopropanedicarboximide (Example 36) is reacted with brominated propargyl, N-propargyl-1- (P-tolyl) -1 Obtain, 2-azacyclopropanedicarboximid and reduce it as described above to yield 3-propargyl-1- (P-tolyl) -3-azabicyclo [3, ㅇ 1,0] -hexane hydrochloride Get

Example 22

Preparation of 3-ethyl-1-phenyl-3-azabicyclo [3,1,0] hexane hydrochloride.

20 ml of acetic anhydride is added to a solution containing 15.9 g of 1-phenyl-3-azabicyclo [3,1,0] hexane in 20 ml of pyridine. The mixture is left overnight at room temperature and then evaporated to yield oil. This oil is dissolved in a mixture of ether and methylene chloride, washed sequentially with dilute hydrochloric acid and sodium bicarbonate, dried over magnesium sulfate and evaporated to give a light amber liquid. This liquid was determined from hexane to give the product 3-acetyl-1-phenyl-3-azabicyclo [3,1,0] hexane. Melting point: 63 ° -65 ° C.

A solution containing 10.0 g of 3-acetyl-1-phenyl-3-azabicyclo [3,1,0] hexane in 100 ml of benzene was added to 25 ml of sodium bis (2-methoxyethoxy) aluminum hydride (70% Benzene solution) as in Example 19 to give brown crystals. Melting point: 148 ° -152 ° C.

Example 23

Preparation of 3- (cyclohexylmethyl) -1-phenylazabicyclo [3,1,0] hexane hydrochloride.

To 60 ml of benzene add 6.4 g of 1-phenyl-3-azabicyclo [3,1,0] hexane. A solution of 4.2 g of sodium carbonate dissolved in 400 ml of water is added with stirring. To 40 ml of benzene is added a solution of 5.9 g of cyclohexylcarbonylchloride dissolved and the mixture is stirred overnight. The oily solid in the aqueous layer is extracted with chloroform. The extract is washed with water and dilute hydrochloric acid, dried over magnesium sulfate, filtered and evaporated. Extraction of the residue, such as oil, with ether gives the product 3-cyclohexylcaraboyl-1-phenyl-3-azabicyclo [3,1,0] hexane as a white solid. Melting point 81 ° -82 ° C.

To 50 ml of benzene, 13 ml of sodium bis (2-methoxyethoxy) was dissolved in a solution of 3-cyclohexylcarbonyl-1-phenyl-3-azabicyclo [3,1,0] hexane dissolved in 7.0 g of the stomach. Treatment with aluminum hydride (70% benzene solution) and 13 ml of 10N sodium hydroxide as in Example 19 yields hydrochloride as colorless crystals.

Melting point: 215 ° -218 ° C.

Example 24

Preparation of 1- (P-methoxyphenyl) -3-azabicyclo [3,1,0] hexane hydrochloride.

2.6 g diethyl-1- (P-methoxyphenyl) -1,2-cyclopropanedicarboxylate (prepared from the method of Example 6 from ethyl-P-methoxyphenylacetate), 20 ml of 1N potassium hydroxide And 20 ml of ethanol was refluxed for 3.5 hours, and the ethanol was removed by concentration. 20 ml of 1N hydrochloric acid is added, and the acid is added little by little until the pH reaches 1. The mixture was extracted three times with chloroform, dried and concentrated to yield a yellow solid. Recrystallization of this solid from ethyl acetate-hexane affords cis-1- (P-methoxyphenyl) -1,2-cyclopropanedicarboxylic acid as a light yellow solid.

6.6 g of this diacid and 2.4 g of urea and 300 ml of xylene are refluxed and stirred for 24 hours. The mixture was cooled, diluted with 25 ml of benzene, washed with water, dried and concentrated under reduced pressure to give a solid which was recrystallized from ethyl acetate-hexane to give 1- (P-methoxyphenyl) -1,2-cyclopropane Obtain dicarboximid.

3.0 g of the product is mixed with 70 ml of benzene and 20 ml of sodium bis (2-methoxyethoxy) aluminum hydride (70% benzene solution) is added with stirring over 5 minutes. After stirring for 1/2 hour and refluxing for 1 hour, the mixture is cooled and 20 ml of 10N sodium hydroxide is added followed by saturated sodium chloride again. The organic layer is dried over magnesium sulfate, filtered and evaporated to give an oil.

The oil is dissolved in ether and hydrogen chloride gas is added to create a bubble. Recrystallization of the solid formed from isopropyl alcohol yields a pale pink platy organism. Melting point: 174 ° -175 ° C.

Example 25

Preparation of (+)-1-phenyl-3-azabicyclo [3,1,0] hexane hydrochloride.

A slurry containing 10 g of (+)-1-phenyl-1,2-cyclopropanedicarboximide in 300 ml of benzene was stirred under nitrogen, and 80 ml of sodium bis (2-methoxyethoxy) aluminum hydride ( 70% benzene solution) is added. The mixture is stirred at room temperature for 2 hours, refluxed for 4 hours, stirred at room temperature for 20 hours and then slowly added while stirring 80 ml of 10N sodium hydroxide.

The organic layer is washed with saturated sodium chloride and water, dried over magnesium sulfate and filtered. The filtrate is evaporated, ether is added, and dry hydrogen chloride gas is bubbled.

Recrystallization from filtration and acetonitrile gives a colorless needle-like product. Melting point: 169 ° -171 ° C.

Example 26

Preparation of 1- (P-chlorophenyl) -3- (0-fluorobenzyl) -3-azabicyclo [3,1,0] hexane hydrochloride.

19.53 g of 1- (P-chlorophenyl) -3-azabicyclo [3,1,0] hexane, 10.59 g of sodium carbonate and 15.8 g of 0-fluorobenzoyl chloride were reacted to produce the product 3- (0-fluoro Robenzoyl) -1- (P-chlorophenyl) -3-azabicyclo [3,1,0] hexane is obtained as a brown gum.

13.9 g of 3- (0-fluorobenzoyl) -1- (P-chlorophenyl) -3-azabicyclo [3,1,0] hexane was added to 50 ml of sodium bis (2-methoxy by the method of Example 19. Reaction with ethoxy) aluminum hydride (70% benzene solution) yields a pale yellow oil. This base is treated with ethanol hydrochloric acid and ether to give hydrochloride as a white solid. Melting point: 204 ° -206 ° C.

In a similar manner, 3- (P-fluorobenzoyl) -1-phenyl-3-azabicyclo [3,1,0] hexane is reduced to sodium bis (2-methoxyethoxy) aluminum hydride to give 3- ( P-fluorobenzyl) -1-phenyl-3-azabicyclo [3,1,0] hexane is obtained.

Likewise, 3- (m-fluorobenzoyl) -1-phenyl-3-azabicyclo [3,1,0] hexane is replaced with 3- (m-fluorobenzyl) -1-phenyl-3-azabicyclo [3, 1,0] hexane.

Example 27

Preparation of 1- (3,4-dichlorophenyl) -3-azabicyclo [3,1,0] hexane.

A solution of 59.5 g of 3,4-dichloro phenylacetic acid dissolved in 500 ml of anhydrous ethanol is saturated with anhydrous hydrogen chloride, heated at reflux for 2 hours, and refluxed. The mixture is concentrated under reduced pressure to 200 ml, diluted with 200 ml of water and neutralized with concentrated ammonium hydroxide. This aqueous mixture is extracted three times with chloroform. Concentration and decolorization of the chloroform extract yields ethyl 3,4-dichlorophenylacetate as a yellow oil.

In a three necked flask equipped with a nichrome stirrer and a mixed condenser, add 7.0 g of ethyl 3,4-dichlorophenyl acetate, 5.9 g of N-bromosuccinimide, 0.1 g of benzoyl peroxide, and 150 ml of carbon tetrachloride. . The reaction mixture is heated to reflux for 18 hours, cooled and filtered. The carbon tetrachloride filtrate is concentrated under reduced pressure to give a dark orange liquid. Vacuum distillation at 115 ° -120 ° C. (0.5 mm) yields ethyl α-bromo-3,4-dichlorophenylacetate as a pale yellow liquid.

This product was obtained from J.A.C.S. … 80 65 68 (1958)] is converted to diethyl cis-1- (3,4-dichlorophenyl) -1,2-cyclopropanedicarboxylate.

A mixture containing 150 g of the diester and 66 g of 85% KOH in 500 ml of water and 500 ml of ethanol is refluxed for 6 hours and cooled in ice.

The oily material is extracted with ether and the aqueous layer is made acidic with 100 ml of 12N hydrochloric acid. The lower layer, like oil, slowly crystallizes into a colorless crystalline cake.

This is recrystallized from a mixture of ethanol and ethyl acetate to give 1- (3,4-dichlorophenyl) -1,2-cyclopropanedicarboxylic acid as colorless crystals.

A mixture containing 30.3 g of the diacid and 12.6 g of urea in 1 L of xylene is refluxed for 6 hours. The solvent is removed under reduced pressure and the crystalline residue is slurried with water. The colorless crystals were collected by filtration, washed with water and air dried to afford 1- (3,4-dichlorophenyl) -1,2-cyclopropanedicarboximide.

While stirring 40 ml of 1 molar borane-tetrahydrofuran at 0 ° C. under nitrogen, a solution of 2.56 g of the imide dissolved in 50 ml of tetrahydrofuran is added over 15 minutes. The solution is heated in a steam bath for 1 hour, cooled in ice, 20 ml of 6N hydrochloric acid is added and the tetrahydrofuran is removed under reduced pressure. The residue is basified with 75 ml of 5N sodium hydroxide and extracted with ether. The extract is dried over magnesium sulfate, filtered and the filtrate is saturated with hydrogen chloride. The precipitated crystals are collected by filtration and recrystallized from isopropyl alcohol to give 1.70 g of 1- (3,4-dichlorophenyl) -3-azabicyclo [3,1,0] hexane hydrochloride as colorless crystals. Melting point 180 ° -181 ° C.

The next imide prepared by the process described above is likewise reduced to the corresponding 3-azabicyclo [3,1,0] hexane.

N-benzoyl-1- (p-bromophenyl) -1,2 made by reacting 1- (p-bromophenyl) -1,2-cyclopropanedicarboximide with benzyl chloride as in Example 14 -Cyclopropanedicarboximide is converted to 3-benzyl-1- (p-bromophenyl) -3-azabicyclo [3,1,0] hexane in the manner described above. Melting Point 69 ° -70 ℃

Example 28

Preparation of 1- (m-methoxyphenyl) -3-methyl-3-azabicyclo [3,1,0] hexane hydrochloride

92.3 g of m-anisidine is dissolved in 225 ml of concentrated hydrochloric acid, 150 ml of water and 150 g of ice and cooled to 0 ° C. The mixture is carefully diazotized with a solution of 52.5 g of sodium nitrile dissolved in 120 ml of water, with vigorous stirring at 0 ° -5 ° C.

This mixture is added to a solution in which 83.25 g of N-methylmaleimide is dissolved in 225 ml of acetone at 0 ° C. The pH is adjusted to 3.0, 25.5 g of cupric chloride anhydride are added at once, followed by 200 ml of acetone with stirring. The acetone is evaporated off and the aqueous layer is left, leaving a black residue, which is boiled with 1 L of benzene, dried over magnesium sulfate and filtered through a funnel containing 50 g of active magnesium silicate. The residue is boiled with 1 L of benzene and filtered through activated magnesium silicate. The dark filtrate is evaporated under reduced pressure and dehydrochlorinated by heating with 100 ml of 2,6-rutinin for 10 minutes.

The solution is combined with 500 ml of water and 400 ml of pyridine and filtered. Press crystalline cake to remove dark oil and boil with 500 ml of 90% ethanol. Cooling and filtration of this give 2- (m-methoxyphenyl) -N-methylmaleimide as orange crystals. Melting point 138 ° -146 ℃

The product was obtained from J. Org.chem. 28,1713 (1963)] to 1- (m-methoxyphenyl) -N-methyl-1,2-cyclopropanedicarboxyboximide.

20 ml of sodium bis (2-methoxyethoxy) aluminum hydride (70% benzene solution) was added to the mixture containing 3.0 g of the imide in 70 ml of benzene over 5 minutes with stirring under nitrogen. The mixture is stirred for 30 minutes, refluxed for 1 hour and then cooled, and 20 ml of 10N sodium hydroxide and saturated sodium chloride are added. The organic layer is dried over magnesium sulfate, filtered and evaporated to give crystals which are recrystallized from ether. Reaction with hydrogen chloride gas and recrystallization from isopropyl alcohol yields crystalline product 1- (m-methoxyphenyl) -3-methyl-3-azabicyclo [3,1,0] hexane hydrochloride. Melting point 148 ° -150 ° C.

Example 29

Preparation of (+)-1-phenyl-3-methyl-3-azabicyclo [3,1,0] hexane hydrochloride

A mixture of 10 g of (+)-1-phenyl-1,2-cyclopropanedicarboximide, 2.67 g of sodium hydride (50% in mineral oil), 50 ml of dimethylformamide and 5 ml of methyl iodide was reacted Pour in 500 ml of water. The mixture is extracted with methylene chloride, washed with water, dried over magnesium sulfate and evaporated.

The residue is taken up on activated magnesium silicate in a Buchner funnel and washed with 250 ml of benzene. The eluate is washed with 500 ml of methylene chloride and evaporated to yield green crystals (+)-1-phenyl-N-methyl-1,2-cyclopropanedicarboximide.

A solution containing 3.0 g of the imide in 0 ml of anhydrous benzene is reacted with 20 ml of sodium bis (2-methoxyethoxy) aluminum hydride (70% benzene solution). The mixture is stirred at room temperature for 15 minutes and then heated in a steam bath for 15 minutes.

The reaction mixture was cooled and then treated by the method of Example 12 to give (+)-1-phenyl-3-methyl-3-azabicyclo [3,1,0] hexane hydrochloride as crystals. Melting Point 188 ° -190 ℃

Example 30

Prepared with 1- (4-chloro-α, α, α-trifluoro-m-tolyl) -3-azabicyclo [3,1,0] hexane hydrochloride

Methyl (4-chloro-α, α, α-trifluoro-m-tolyl) acetate was prepared using the method of Example 6 with methyl (4-chloro-α, α, α-trifluoro-m-tolyl). It is converted to acetate and reacted with methylacrylate-sodium hydride to give dimethyl 1- (4-chloro-α, α, α-trifluoro-m-tolyl) cyclopropanedicarboxylate. Hydrolysis with 1N potassium hydroxide yields cis-1- (4-chloro-α, α, α-trifluoro-m-tolyl) -1,2-cyclopropanedicarboxylic acid as colorless crystals. Melting Point 167 ° -169 ℃

This diacid is reacted with urea to give 1- (4-chloro-α, α, α-trifluoro-m-tolyl) -1,2-cyclopropanedicarboximide as colorless crystals. Melting point 123 ° -124 ℃

1 ml of sodium bis (2-methoxyethoxy) in a solution of 0.28 g of 1- (4-chloro-α, α, α-trifluoro-m-tolyl) cyclopropanedicarboximide dissolved in 10 ml of benzene ) Aluminum hydride (70% benzene solution) is added. It is refluxed for 1 hour, cooled to ambient temperature and then the excess hydride reagent is decomposed with 1 ml of 10N sodium hydroxide. The benzene layer is washed with water, dried over magnesium sulfate and evaporated under reduced pressure to give a pale yellow oil. It is dissolved in ether and dried hydrogen chloride is bubbled through the solution. The resulting precipitate was recovered by filtration and recrystallized from isopropyl alcohol to give 1- (4-chloro-α, α, α-trifluoro-m-tolyl) -3-azabicyclo [3,1,0] hexane hydrochloride Get This hydrochloride is purified by recrystallization from acetonitrile to give colorless crystals. Melting Point 164 ° -166 ℃

Example 31

Preparation of 3,6-dimethyl-1-phenyl-3-azabicyclo [3,1,0] hexane hydrochloride

The solution of N, 3-dimethylcyclopropane-1,2-dicarboximide in benzene is stirred and sodium bis (2-methoxyethoxy) aluminum hydride (70% benzene solution) is added over several minutes. The solution is stirred for several hours at ambient temperature, refluxed for one hour, cooled and combined with sodium hydroxide and converted to hydrochloride as in Example 11 to give the title product.

Example 32

Preparation of 1- (p-acetamidophenyl) -3-ethyl-azabicyclo [3,1,0] hexane

Acetic anhydride is added to a suspension containing 3-ethyl-1- (p-acetamidophenyl) -3-azabicyclo [3,1,0] hexane (Example 19) in an aqueous sodium acetate solution. It is heated for several minutes in a steam bath and filtered to give the product.

Example 33

Preparation of 1- (m-hydroxyphenyl) -3-methyl-3-azabicyclo [3,1,0] hexane

A solution containing 1- (m-hydroxyphenyl) -3-methyl-3-azabicyclo [3,1,0] hexane in 48% bromic acid was refluxed for several hours, and the solution was made basic with sodium bicarbonate. Make. Filtration recovers the desired phenol.

Example 34

Preparation of 1- (p-nitrophenyl) -3-azabicyclo [3,1,0] hexane hydrochloride

To 25 ml concentrated sulfuric acid, a slurry containing 20.6 g of 1-phenylcyclopropane-1,2-dicarboxylic acid was stirred at 0 ° C. and 15 ml of concentrated nitric acid was added over 30 minutes. The resulting solution is stirred at ambient temperature for 30 minutes and then poured onto ice. The crystalline product is recrystallized from hexane-ethyl acetate to give 1- (p-nitrophenyl) -cyclopropane-1,2-dicarboxylic acid as colorless crystals. Melting point 138 ° -144 ℃

The diacid is converted to 1- (p-nitrophenyl) -1,2-cyclopropane-dicarboximide by the method of Example 6. Melting Point 171 ° -173 ℃

The imide solution in tetrahydrofuran is added to a 1 molar solution of borane-tetrahydrofuran at 0 ° C. under nitrogen. The solution is refluxed for 1 hour, cooled to 0 ° C. and 6N hydrochloric acid is added. Tetrahydrofuran is removed under reduced pressure and the residue is partitioned between ether and sodium hydroxide. The ether solution containing 1- (p-nitrophenyl) -3-azabicyclo [3,1,0] hexane was dried over magnesium sulfate, filtered, and hydrogen chloride was added to the filtrate to give the product as a brown solid. Melting Point 215 ° -217 ℃

Example 35

Preparation of 1- (0-chlorophenyl) -3-azabicyclo [3,1,0] hexane hydrochloride

In 500 ml of carbon tetrachloride, a mixture containing 36.9 g of methyl 0-chloroacetate, 36.0 g of N-bromosuccinimide, and 2 drops of 48% bromic acid is stirred, refluxed for 20 hours, and filtered through magnesium silicate. do. Evaporation under reduced pressure affords methyl α-bromo-0-chlorophenyl acetate as a straw colored liquid.

Stir the suspension containing 4.8 g of sodium hydride (50% in mineral oil) in 100 ml of benzene-N, N-dimethylformamide (1: 1), and 26.3 g of the bromoester and 8.69 g of methylacrylic The mixture of rates is added over 1/2 hour. The mixture is stirred at ambient temperature for 4 hours, the excess sodium hydride is decomposed with 2 ml of methanol, and the mixture is poured into 500 ml of water. The organic layer was washed with water, dried over magnesium sulfate and evaporated to yield dimethyl-1- (0-chlorophenyl) -1,2-cyclopropanedicarboxylic acid as brown oil.

The diester (17.35 g) and 200 ml of 1N potassium hydroxide were refluxed in 50 ml of ethanol for 6 hours. The solution is halved and acidified under reduced pressure to give 1- (0-chlorophenyl) -1,2-cyclopropanedicarboxylic acid as brown oil.

A mixture containing 10.0 g of the diacid and 3.4 g of urea in 500 ml of xylene is refluxed for 6 hours. The solution is washed with water and sodium bicarbonate and then dried over magnesium sulfate to give a brown solid. Recrystallization from ethanol yields 1- (0-chlorophenyl) -1,2-cyclopropanedicarboximide as colorless crystals.

Melting point 154 ° -156 ℃

To a solution containing 1.35 g of the imide in 30 ml of benzene, 9 ml of sodium bis (2-methoxyethoxy) aluminum hydride (70% benzene solution) was added over 2 minutes with stirring. The solution is stirred at ambient temperature for 15 minutes and then refluxed for 30 minutes. 10 ml of 10N sodium hydroxide is added to the cooled solution, and the benzene layer is washed with water, dried over magnesium sulfate and filtered. The filtrate is evaporated under reduced pressure, the residual oil is dissolved in ether, and anhydrous hydrogen chloride gas is added to this solution. Recrystallization of the precipitated product from isopropyl alcohol yields 1- (0-chlorophenyl) -3-azabicyclo [3,1,0] hexane hydrochloride as colorless crystals.

Melting Point 188 ° -190 ℃

Example 36

Preparation of 1- (P-tolyl) -3-azabicyclo [3,1,0] hexane hydrochloride

230 ml of thionyl chloride is added to 120 g of P-tolylacetic acid and the solution is left at room temperature for 2 hours and then heated to 60 ° C for 1 hour. To this solution is added 285 g of N-bromosuccinimide and 10 drops of 48% bromic acid and the mixture is refluxed in a 90 ° C. oil bath for 1 hour. 90 ml further thionyl chloride is added and refluxing is continued for 45 minutes. The mixture is distilled off under reduced pressure to remove 250 ml of thionyl chloride, and the remaining liquid is poured into 500 ml of cold methanol with stirring and cooled on ice for 15 minutes. Evaporation of the solution under reduced pressure gives a dark oil which is dissolved in 100 ml of chloroform. The solution is washed with 500 ml of water, dried over magnesium sulfate and filtered. The filtrate is evaporated under reduced pressure to give a dark oil which is distilled off to give 94 g of bromo ester as a pale yellow liquid. Boiling point 115 ° -120 ° C. (0.05 mm).

This light yellow liquid is reacted with methylacrylate-sodium hydride in ether (as in Example 6) to give dimethyl cis-1- (P-tolyl) -1,2-cyclopropane dicarboxylate. Melting Point 58 ° -59 ℃

Hydrolysis with 1N potassium hydroxide followed by acidification with hydrochloric acid (as in Example 6) yields cis-1- (P-tolyl) -1,2-cyclopropane dicarboxylic acid as colorless crystals. Melting Point 188 ° -190 ℃

Reaction of this diacid with urea (as in Example 6) yields 1- (P-tolyl) -1,2-cyclopropane dicarboximide as light yellow crystals. Melting point 82 ° -85 ℃

To 600 ml of benzene was added 160 ml of sodium bis (2-methoxyethoxy) aluminum hydride to a mixture containing 20.1 g of the imide and reacted as in Example 8, followed by excess reagent with 160 ml of 10N sodium hydroxide. Disassemble. The benzene layer is washed with water, dried over magnesium sulfate and filtered. The filtrate is evaporated under reduced pressure to give dark oil, which is dissolved in ether and dried hydrogen chloride is passed through the solution to form a bubble. The resulting precipitate is recovered by filtration and recrystallized from acetonitrile-methanol to give 12.1 g of 1- (P-tolyl) -3-azabicyclo [3,1,0] hexane hydrochloride in light brown plates.

Melting point 207 ° -208 ℃

1- (P-cumyl) -3-azabicyclo [3,1 to 1- (P-cumyl) -1,2-cyclopropanedicarboximide (melting point 147 ° -148 ° C.) by the method described in the above examples. Hexane hydrochloride (melting point 231 ° -232 ° C.) is obtained.

The imide is then reduced by the method described above to give the corresponding aminehydrochloride.

Example 37

Preparation of (+)-1- (P-tolyl) -3-azabicyclo [3,1,0] hexane hydrochloride

94.8 g of racemic 1- (P-tolyl) -1,2-cyclopropanedicarboxylic acid (Example 36) and 73.8 g of (-) α- (1-naphthyl) ethyl in 300 ml tetrahydrofuran The solution in which the amine is dissolved is diluted with 300 ml of ethyl ether and left at room temperature until crystals are completed. The mixture was filtered and the recovered crystals washed with cold tetrahydrofuran to afford 4.95 g of salt, which is equivalent to 1 molar equivalent of (+)-1- (P-tolyl) -1,2-cyclopropanedicarboxylic acid. And 1 molar equivalent of (-) α- (1-naphthyl) ethylamine. This salt is shaken with sodium hydroxide solution and ether. The aqueous phase is acidified with 12N hydrochloric acid and the product collected by filtration to give 26.0 g of (+)-1- (P-tolyl) -1,2-cyclopropanedicarboxylic acid as colorless crystals.

15.0 g of (+)-1- (P-tolyl) -1,2-cyclopropanedicarboxylic acid, 6.6 g of urea and 500 ml of xylene are refluxed and stirred for 5 hours. The reaction mixture was filtered while hot and the filtrate was evaporated under reduced pressure to afford (+)-1- (P-tolyl) -1,2-cyclopropanedicarboximide as colorless crystals. Melting Point 148 ° -155 ℃

14 g of this product are mixed with 420 ml of benzene and 112 ml of sodium bis (2-methoxyethoxy) aluminum hydride (70% benzene solution) is added over 15 minutes with stirring. After refluxing for 1.5 hours, the mixture is cooled and 160 ml of 10N sodium hydroxide is added. The organic layer is dried over sodium sulfate, filtered and evaporated to yield an oil. This oil is dissolved in ether and hydrogen chloride gas is bubbled. Recrystallization of the solid formed from acetonitrile affords (+)-1- (P-tolyl) -3-azabicyclo [3,1,0] hexane hydrochloride as colorless crystals. Melting Point 208 ° -210.5 ℃

The racemic diacid is combined with an equimolar amount of brookine in ethanol to form a salt which is equivalent to 1 molar equivalent of (-)-1- (P-tolyl) -1,2-cyclopropanedicarboxylic acid and 1 mole. Contains the equivalent of brucin.

Treatment of this salt as described above affords (-)-1- (P-tolyl) -1,2-cyclopropanedicarboxylic acid as colorless crystals.

(-)-1- (P-tolyl) -1,2-cyclopropanedicarboxylic acid is converted to (-)-1- (P-tolyl) -1,2-cyclopropanedicarboximide by the method described above. do. Melting Point 145 ° -148 ℃

Reduction of this imide as described above affords (-)-1- (P-tolyl) -3-azabicyclo [3,1,0] hexane hydrochloride as colorless crystals. Melting Point 204 ° -207 ℃

Example 38

Preparation of 3-methyl-1- (P-tolyl) -3-azabicyclo [3,1,0] hexane hydrochloride

4.19 g of 1- (P-tolyl) -3-azabicyclo [3,1,0] hexane hydrochloride and 20 ml of water are made basic with sodium hydroxide, which is extracted with ether and the ether is evaporated. Get oil. The oil is combined with 40 ml of 97% formic acid and 35 ml of 37% formaldehyde and the solution is heated in a steam bath for 2 hours. The solution is cooled, made basic with sodium hydroxide and extracted with ether. The extract is dried over magnesium sulfate and filtered, and the filtrate is saturated with hydrogen chloride. The precipitated crystals are collected and recrystallized from isopropyl alcohol to give 3-methyl-3-azabicyclo [3,1,0] hexane hydrochloride as colorless crystals. Melting Point 197 ° -198 ℃

The following amines can also be converted to N-methyl derivatives in this manner.

Example 39

1- (P-hydroxyphenyl) -3-azabicyclo [3,1,0] hexane hydrochloride

In a slurry containing 7.2 g (0.15 mol) of sodium hydride in 170 ml of N, N-dimethylformamide, a solution of 10.1 ml of ethanethiol dissolved in 85 ml of N, N-dimethylformamide was added to 0 ° -5. Add at 15 ° C. over 15 minutes. 3.16 g more sodium hydride is added followed by 14.4 g 1- (P-methoxyphenyl) -3-azabicyclo [3,1,0] hexane hydrochloride. After 40 ml of N, N-dimethylformamide is added, the mixture is refluxed for 4 hours and the solvent is removed. The residue is dissolved in 150 ml of water and the mineral oil is extracted with ether. The aqueous solution is made acidic with acetic acid and the precipitated crystals are collected by filtration to give 9.8 g of 3-formyl-1- (P-hydroxyphenyl) -3-azabicyclo [3,1,0] hexane as brown crystals. . Melting Point 166 ° -167 ℃

A solution of 4.50 g of the N-formyl derivative dissolved in 40 ml of 1.25 N sodium hydroxide is heated in a steam bath under nitrogen for 3 hours. The cooled solution is neutralized with acetic acid and filtered to give 3.30 g of amine as a brown powder. Melting Point 174 ° -177 ℃

It is dissolved in 20 ml of anhydrous ethanol and HCl gas is passed through the solution to create a bubble. Evaporation of the liquid yields 3.78 g of (P-hydroxyphenyl) -3-azabicyclo [3,1,0] hexane hydrochloride as brown crystals. Melting Point 195 ° -196 ℃

Example 40

Preparation of 1- (m-hydroxyphenyl) -3-azabicyclo [3,1,0] hexane hydrochloride

By the method of Example 39, 1- (m-methoxyphenyl) -3-azabicyclo [3,1,0] hexane hydrochloride was added to 3-formyl-1- (m-hydroxyphenyl) -3-azabi. Convert to cyclo [3,1,0] hexane. Melting Point 129 ° -130 ℃

Hydrolysis of this with sodium hydroxide as described above yields 1- (m-hydroxyphenyl) -3-azabicyclo [3,1,0] hexane hydrochloride as pale brown crystals. Melting Point 209 ° -210 ℃

Example 41

Preparation of 1- (P-ethoxyphenyl) -3-azabicyclo [3,1,0] hexane hydrochloride

In 25 ml of anhydrous ethanol, a mixture containing 1.0 g of 3-formyl-1- (P-hydroxyphenyl) -3-azabicyclo [3,1,0] hexane and 0.7 g of potassium carbonate was stirred and 10 ml To anhydrous ethanol was added a solution of 3.2 g of ethyl iodide dissolved. The mixture is refluxed for 2 hours, filtered and evaporated. The remaining mixture of crystals and liquid is combined with water, which is extracted with chloroform and the extract is dried over magnesium sulfate and evaporated to yield 1.0 g of a colorless viscous liquid which is left to crystallize. Recrystallization from hexane yields 0.31 g of 3-formyl-1- (P-ethoxyphenyl) -3-azabicyclo [3,1,0] hexane as colorless crystals. Melting Point 48 ° -51 ℃

A solution of 2.0 g of the compound dissolved in 50 ml of ethanol and 20 ml of 5N sodium hydroxide was heated in a steam bath for 30 minutes and then the ethanol was removed under reduced pressure. The residue is extracted with ether, the extract is dried over magnesium sulfate, filtered and evaporated to give 1- (P-ethoxyphenyl) -3-azabicyclo [3,1,0] hexane as colorless crystals. Melting Point 48 ° -49 ℃

Combine this with ethanol hydrogen chloride to give 1- (P-ethoxyphenyl) -3-azabicyclo [3,1,0] hexane hydrochloride as colorless crystals. Melting Point 192 ° -193 ℃

Example 42

Preparation of 1-phenyl-3-azabicyclo [3,1,0] hexane hydrochloride

A solution of 9.00 g of cis-1-phenyl-1,2-cyclopropanedi carboxylic acid dissolved in 100 ml of tetrahydrofuran is added to 180 ml of 1 molar borane-tetrahydrofuran at 0 ° C. over 15 minutes under nitrogen. . The solution is left at room temperature for 30 minutes and refluxed for 4 hours.

The reaction mixture is cooled on ice, 60 ml of 6N hydrochloric acid is added and then tetrahydrofuran is removed under reduced pressure. The aqueous residue is made basic with sodium hydroxide and then extracted with ester. The extract was dried over potassium carbonate and the filtered solution was evaporated to yield 7.7 g of cis-1-phenyl-1,2-cyclopropanedimethanol.

A solution of 6.00 g of the diol dissolved in 335 ml of dichloromethane and 14 ml of triethylamine was cooled to −10 ° C., and 8.45 g of methanesulfonyl chloride was added thereto over 15 minutes. It is stirred for 30 minutes at room temperature and washed sequentially with cold dilute hydrochloric acid, cold water and 10% sodium bicarbonate solution. The organic solution is dried over magnesium sulfate and the filtered solution is evaporated to yield 8.40 g of dimethane sulfonate as light yellow oil. The solution of the oil dissolved in 100 ml of tetrahydrofuran is combined with 1.0 g of sodamide, the mixture is refluxed and then filtered.

Evaporation of the solution yields 1-phenyl-3-azabicyclo [3,1,0] hexane as a colorless liquid.

This amine is treated with ethanol hydrogen chloride and converted to hydrochloride to give 1-phenyl-3-azabicyclo [3,1,0] hexane hydrochloride. Recrystallization from acetonitrile gives the product as colorless crystals. Melting Point 166 ° -167 ℃

Example 43

Preparation of 1- (m-chlorophenyl) -3-methyl-3-azabicyclo [3,1,0] hexane hydrochloride

1- (m-chlorophenyl) -N-methyl-1,2-cyclopropane prepared from 1- (m-chlorophenyl) -1,2-cyclopropanedicarboximide (Example 6) and methyl iodide Treatment of dicarboximide (melting point 72 ° -73 ° C.) by the method of Example 10 gave 1- (m-chlorophenyl) -3-methyl-3-azabicyclo [3,1,0] hexane hydrochloride colorless Get into the decision Melting Point 180 ° -182 ℃

Example 44

Preparation of 1- (p-chlorophenyl) -3-ethyl-3-azabicyclo [3,1,0] hexane

The reaction of 1- (p-chlorophenyl) -3-azabicyclo [3,1,0] hexane (Example 1) with acetyl chloride by the method of Example 19 gave 3-acetyl-1- (p-chlorophenyl) Obtain 3-azabicyclo [3,1,0] hexane and convert it to give 1- (p-chlorophenyl) -3-ethyl-3-azabicyclo [3,1,0] hexane as brown oil.

Example 45

Preparation of 3- [4,4-bis (p-fluorophenyl) butyl] -1phenyl-3-azabicyclo [3,1,0] hexane fumarate

The water mixture containing sodium hydride and 1-phenyl-1,2-cyclopropanedicarboximide in anhydrous N, N-dimethylformamide is stirred until hydrogen evolution ceases. To this was added 1-chloro-4,4-bis (4-fluorophenyl) butane and the mixture was stirred at room temperature for 20 hours and then heated briefly at 100 ° C. The mixture was combined with water and extracted with ether, and the extract was evaporated to give N- [4,4-bis (p-fluorophenyl) butyl] -1-phenyl-1,2-cyclopropanedicarboximide as colorless glass. Get

The compound was reduced as in Example 10 and this base combined with fumaric acid gave 3- [4,4-bis (p-fluorophenyl) butyl] -1-phenyl-3-azabicyclo [3,1,0 Hexane fumarate is obtained as colorless crystals.

Melting point 153 ° -155 ° C.

1- (p-chlorophenyl) -1,2-cyclopropanedicarboximide (US Pat. No. 3,344,026) was replaced with N- [4,4-bis (p-fluorophenyl) butyl] -1- ( p-chlorophenyl) -1,2-cyclopropanedicarboximide (melting point 98 ° -99 ° C.).

This compound is reduced as in Example 27, and this base is combined with fumaric acid to form 3- [4,4-bis (p-fluorophenyl) butyl] -1- (p-chlorophenyl) -3-azabicyclo [ 3,1,0] Hexane fumarate can be obtained as colorless crystals. Melting point 152 ° -154 ° C.

Example 46

Preparation of 3- [3- (p-fluorobenzoyl) propyl] -1-phenyl-3-azabicyclo [3,1,0] hexane hydrochloride

15.9 g of 1-phenyl-3-azabicyclo [3,1,0] hexane (Example 9) in 100 ml of toluene, 20.1 g of r-chloro-p-fluorobutyrophenone and 10 mg of potassium iodide This contained mixture is refluxed for 24 hours. Filtration yields 11.6 g of 1-phenyl-3-azabicyclo [3,1,0] hexane hydrochloride. Melting point 166 ° -167 ° C. Evaporation of the filtrate yields a brown oil, which is combined with 2N hydrochloric acid and chloroform. The crystals formed on the chloroform layer were collected by filtration and recrystallized from ethanol to give 3.10 g of 3- [3- (p-fluoro benzoyl) propyl] -1-phenyl-3-azabicyclo [3,1,0] hexane hydro The chloride is obtained as light brown crystals. Melting point 151 ° -153 ° C.

Example 47

Preparation of 1- (m-methoxyphenyl) -3-azabicyclo [3,1,0] hexane hydrochloride

When methyl-m-methoxymandedate is reacted with phosphorus tribromide and Veletsskaya (Zh. Obshch khim. 34, 321 (1964)), methyl bromo- (m-methoxyphenyl) acetate is light yellow. Obtained as a liquid, used as follows without further purification.

In the same way, the next mandelate ester can be converted to the corresponding bromo ester.

Prepared by the method of Example 6 from 37.0 g of dimethyl 1- (m-methoxyphenyl) -1,2-cyclopropanedi carboxylate (methyl bromo- (m-methoxyphenyl) acetate and methylacrylate ), 20 g of potassium hydroxide and 200 ml of 1: 1 water-methanol and the like are refluxed for 16 hours and the methanol is concentrated to remove. Concentrated hydrochloric acid is added little by little until pH is 1. The mixture is extracted three times with ether, dried and concentrated to give cis-1- (m-methoxyphenyl) -1,2-cyclopropanedicarboxylic acid as light yellow gum.

34.7 g of the diacid, 12 g of urea and 750 ml of xylene are refluxed and stirred for 5 hours. Cool the mixture and pour the clear solution above and filter through magnesium silicate, and concentrate the filtrate under reduced pressure to give a solid, which is recrystallized from ethanol to give 1- (m-methoxyphenyl) -1,2-cyclopropanedia Obtain a boximid. Melting point 125 ° -127 ° C.

3.0 g of this product are mixed with 75 ml of benzene and 20 ml of sodium bis (2-methoxyethoxy) aluminum hydride (70% benzene solution) is added over 5 minutes with stirring. After refluxing for 1/2 hour and stirring for 1 hour, the mixture is cooled, 20 ml of 10N sodium hydroxide is added followed by saturated sodium chloride. The organic layer is washed with water, dried over magnesium sulfate, filtered and evaporated to give an oil. The oil is dissolved in ether and hydrogen chloride gas is added to create a bubble. Recrystallization of the resulting solid from acetonitrile gives 1- (m-methoxyphenyl) -3-azabicyclo [3,1,0] hexane hydrochloride as colorless crystals. Melting Point 150 ° -152 ℃

Example 48

Preparation of 1- (m-hydroxyphenyl) -3-methyl-3-azabicyclo [3,1,0] hexane hydrochloride

Combined 1- (m-methoxyphenyl) -3-methyl-3-azabicyclo [3,1,0] hexane hydrochloride with ethanol in sodium hydride and N, N-dimethylformamide as in Example 40 Obtain 1- (m-hydroxyphenyl) -3-methyl-3-azabicyclo [3,1,0] hexane hydrochloride.

Example 49

Preparation of 1-[(p-methoxyphenyl) phenyl] -3-azabicyclo [3,1,0] hexane hydrochloride

2.48 g of cis-dimethyl-1- (p-tolyl) -1,2-cyclopropanedicarboxylate (Example 36), 1.78 g of N-bromosuccinimide and 5 mg in 50 ml of carbon tetrachloride. The mixture containing azabicisobutyronitrile is then rinsed with 500 watts of tungsten for 2 hours. Filtration and evaporation of the filtrate affords cis-dimethyl-1- (α-bromo-p-tolyl) -1,2-cyclopropanedicarboxylate as brown crystals which is used for the next conversion without further purification. .

The benzyl bromide is stirred with the methanol solution of sodium methoxide for 2 hours, refluxed for 3 hours and the methanol is evaporated. The residue was partitioned between water and dichloromethane and the organic solution was evaporated to afford cis-dimethyl-[(p-methoxyphenyl) phenyl] -1,2-cyclopropanedicarboxylate as a dark oil, which It is used for the next manufacturing without further purification.

Hydrolysis of the diester with ethanol potassium hydroxide as in Example 6 yields cis-1 [(p-methoxyphenyl) phenyl] -1,2-cyclopropanedicarboxylic acid as brown oil.

The dicarboxylic acid was refluxed with urea in xylene as in Example 6 to give [(p-methoxyphenyl) phenyl] -1,2-cyclopropanedicarboximide as colorless crystals. Melting point 122 ° -124 ° C.

Reduction of the imide with borane-tetrahydrofuran as in Example 27 yields 1-[(p-methoxyphenyl) phenyl] -3-azabicyclo [3,1,0] hexane hydrochloride.

Example 50

Preparation of 3- (n-hexyl) -1- (p-tolyl) -3-azabicyclo [3,1,0] hexane

Reduction alkylation of 1- (p-tolyl) -3-azabicyclo [3,1,0] hexane (Example 36) with sodium borohydride and hexanoic acid gave 3- (n-hexyl) -1- (p- Tolyl) -3-azabicyclo [3,1,0] hexane hydrochloride is obtained. Melting point 182 ° -184 ° C.

Example 51

Preparation of 1- (p-tolyl) -3-azabicyclo [3,1,0] hexan-2-one containing 350 g of ether and 0.5 ml of methanol with 5.0 g of sodium hydride (50% mineral oil dispersion) To the slurry, a solution of 24.0 g of methylbromo-p-tolyl acetate, 8.0 g of acrylonitrile and 1.0 ml of methanol was added at 20 ° -28 ° C. over half an hour.

After stirring for another hour, 10 ml of methanol are added and the ether solution is washed with water. The organic phase is dried over sodium sulfate and the filtered solution is evaporated to yield 5.5 g of transverse color crystals. Recrystallization from ethanol yields 3.50 g of cis-2-cyano-1-methoxycaraboyl-1- (p-tolyl) cyclopropane as colorless crystals.

Melting point 88 ° -91 ° C.

7.5 ml of 1 molar borane-tetrahydrofuran is added to a solution of 2.15 g of the cyanoester dissolved in 100 ml of anhydrous tetrahydrofuran at 0 ° C. The solution is refluxed for 30 minutes and then left at room temperature for 2 hours. 10 ml of 6N hydrochloric acid is added to the cooled solution, which is heated in a steam bath for 15 minutes and then evaporated. The residue is extracted with dichloromethane and the solution is evaporated to give 1- (p-tolyl) -3-azabicyclo [3,1,0] hexan-2-one as colorless oil. i.r. 5.90 micron.

Example 52

Preparation of 2-methyl-1- (p-tolyl) -3-azabicyclo [3,1,0] hexanehydrochloride

1- (p-tolyl) -3-azabicyclo [3,1,0] hexane-2-one is reacted with methyl lithium and again with sodium borohydride. Excess reagent is decomposed with methanol and then with 1N hydrochloric acid and 1N sodium hydroxide, the solution is evaporated to give a residue, which is dissolved in ether. The solution is dried over sodium sulphate and filtered and dry hydrogen chloride is added to the filtrate. Filtration of this suspension affords 2-methyl-1- (p-tolyl) -3-azabicyclo [3,1,0] hexane hydrochloride.

Example 53

Preparation of 1- (p-chlorophenyl) -4-ethyl-3-azabicyclo [3,1,0] hexane.

To a solution of 4.43 g of 1- (p-chlorophenyl) -1,2-cyclopropanedicarboxyboximide in 100 ml of ether is added 16.4 ml of 2 mol ethyl magnesium bromide. The mixture is left at room temperature for 18 hours and then combined with water. The ether solution was dried over sodium sulfate and evaporated to yield 4.05 g of pink semisolid. Recrystallization from ether-hexane affords 1- (p-chlorophenyl) -4-ethyl-4-hydroxy-3-azabicyclo [3,1,0] hexane-2-silver as colorless crystals. Melting point 154 ° -157 ° C.

Evaporating the mother liquor of the crystallized product yields 1- (p-chlorophenyl) -4-ethyl-4-hydroxy-3-azabicyclo [3,1,0] hexane-2-one as colorless crystals. Melting point 117 ° -124 ° C.

Reduction of the hydroxy lactams with melting points of 117 ° -124 ° C and 154 ° -157 ° C with sodium borohydride in methanol resulted in epimeric 1- (p-chlorophenyl) -4-ethyl-3-azabicyclo [3, 1,0] get hexane.

Example 54

Preparation of 1- (p-tolyl) -3-azabicyclo [3,1,0] hexane hydrochloride

A mixture of 3- (p-tolyl) -3-pyrroline, methylene iodide, and powdered copper in a molar ratio of 1: 2: 4 is heated in benzene for 50 hours. Filtration and evaporation of the solution gave 1- (p-tolyl) -3-azabicyclo [3,1,0] hexane.

Claims (1)

By reacting the compound of the following formula with a hydride reducing agent in an inert neutral solvent at a temperature of about -70 ° -125 ° C

A process for preparing a compound of the formula

Wherein the phenyl group is unsubstituted or halogen, straight-chain C ₁ -C ₆ alkyl, C ₁ -C | Mono- or di-substituted from the group consisting of ₆ alkoxy, trifluoromethyl, nitro, amino, acetamido and hydroxy; X is selected from the group consisting of hydrogen, straight chain C ₁ -C ₈ alkyl and the structure CnH _2n R ₁ , wherein n is an integer of 1-3 and R ₁ is selected from phenyl and P-fluorobenzoyl; r is selected from the group consisting of hydrogen and oxygen, at least one r must be oxygen.