JPS6232188B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a process for preparing 2-cyano-3-azabicyclo[3.1.0]hexane and certain derivatives thereof.

2-carboxy-3-azabicyclo [3.1.0]
Hexane and certain of its salts and esters have useful biological properties and are capable of sterilizing the stamens of plants. Therefore, the methods for producing these compounds are of considerable importance. However, the available manufacturing methods have proven to be relatively complex. One possible synthetic route involves hydrolysis of the corresponding 2-cyano compound, but hitherto this cyano compound could not be easily synthesized.

European Patent Application No. 79200096 has 2-cyano-3
-Azabicyclo[3.1.0]hexane and certain substituted derivatives thereof may be prepared by reacting the corresponding 2-cyano-4-oxo compound with trialkyl oxonium fluoroborate and then with a reducing agent. This is disclosed. However, this reaction is a two-step process that requires the use of expensive reagents.

European Patent Application No. 79200034 has 2-cyano-3
-Disclosed that azabicyclo[3.1.0]hexane can be prepared by reacting 3-azabicyclo[3,1.0]hex-2-ene with an alkali metal bisulfite and then with an alkali metal cyanide. ing. This method is also a two-step method.

A method has now been found which allows the introduction of a cyano group into a bicyclohexane ring system in one step.

The present invention has the general formula: (In the formula, R ¹ is a hydrogen atom, or unsubstituted or 1
represents an alkyl group substituted with one or more alkoxy groups, and R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ may be the same or each represents a hydrogen atom or an alkyl, aryl, aralkyl or alkaryl group which is unsubstituted or substituted with one or more alkoxy groups, and (representing a trialkylsilyl group), the general formula: (wherein R ¹ to R ⁷ have the above-mentioned meanings) and/or its trimer are reacted with a cyanide of the general formula: XCN (wherein X has the above-mentioned meanings) provide a method to do so.

Compounds of the general formula in which X represents an organic acyl group or a trialkylsilyl group are novel, and the present invention therefore also provides these compounds themselves.

Preferably, R ¹ represents a hydrogen atom or an unsubstituted alkyl group having up to 6 carbon atoms, and
R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ are each independently a hydrogen atom or an unsubstituted alkyl group having up to 6 carbon atoms, or an unsubstituted aryl, alkaryl or alkyl group having up to 10 carbon atoms. Represents an alkyl group.

More preferably, R ¹ represents a hydrogen atom or an alkyl group having up to 4 carbon atoms, such as a methyl group, and R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ each independently represent a hydrogen atom or a carbon atom. It represents an alkyl group having up to 4 atoms, for example a methyl group.

Most preferably R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ each represent a hydrogen atom.

X is, for example, an alkanoyl group, such as an acetyl group,
or an aroyl group such as a benzoyl group. In the trialkylsilyl group X, two or three of the alkyl groups may be the same or different and each alkyl group preferably has up to 4, especially 1 or 2 carbon atoms. . A particularly preferred trialkylsilyl group is trimethylsilyl.

The process of the invention is suitably carried out in the presence of an inert solvent such as an alcohol, an ether such as diethyl ether, or a hydrocarbon or chlorinated hydrocarbon such as dichloromethane. Mixed solvents may also be used. The reaction temperature can range, for example, from 0 to 60°C, preferably from 10 to 30°C. For example, the reaction can be carried out at the reflux temperature of the solvent used. However, it is most convenient to carry out at room temperature.

In some cases it may be preferable, and indeed necessary, to carry out the reaction under moisture-free conditions. This is the case when acyl cyanides or especially trialkylsilyl cyanides are used as reagents.

The molar ratios of the reactants can vary over a wide range. Cyanide reactant in excess, e.g.
It is possible to use an excess of up to 2 times, preferably up to 3 times, in particular up to 1.5 times. However, it is desirable to use approximately stoichiometric amounts, especially when the cyanide reactant is benzoyl cyanide. This is because separation problems during post-processing are thereby avoided.

The cyanide reactant is optionally added in situ.
(in situ) can be manufactured and used. Trialkylsilyl cyanide is prepared by combining trialkylsilyl chloride and potassium cyanide, optionally in the presence of zinc iodide, in Journal of Organic Chemistry (J.Org.Chem.) 39 , No. 7 (1974). ),
It can be produced by the reaction method described on page 916. Whether the resulting trialkylsilyl cyanide is isolated or used in situ, it is appropriate to keep it protected from moisture.

Hydrogen cyanide can be generated in situ, for example by the action of an alkali metal cyanide with a strong mineral acid or by using cyanohydrin under alkaline conditions, but preferably it is a gas as such. , in solution in the reaction solvent or preferably in liquid form, to the compound of the general formula and/or its trimer.

Compounds of the general formula and/or trimers thereof are, for example, of the general formula: (wherein R ¹ to R ⁷ have the meanings given in the general formula) can be produced by direct oxidation of a compound. Manganese dioxide is a suitable reagent and the oxidation can be carried out simply by stirring the compound of general formula and manganese dioxide in the presence of a suitable solvent such as benzene or a hydrocarbon such as gas oil, conveniently at room temperature. can.

In addition, the compound of the general formula and/or its trimer is of the general formula: (wherein R ¹ to R ⁷ each have the meaning given in the general formula, and Hal represents a chlorine or bromine atom) can also be produced by dehydrohalogenation of a compound.

Dehydrohalogenation can be carried out using any suitable dehydrohalogenating agent, such as a strong organic base such as triethylamine or pyridine in a non-aqueous solution, or a strong inorganic base such as sodium hydroxide in an aqueous or non-aqueous solution. can also be done. Suitable polar solvents are, for example, ethers, alcohols or water. The reaction is preferably carried out at a temperature of up to 150°C,
It is preferably carried out at a temperature in the range of 20 to 80°C. The process can conveniently be carried out at the reflux temperature of the solvent used.

The advantage of carrying out the dehydrohalogenation in a non-aqueous reaction medium is that the resulting solution can optionally be used directly in situ in the cyanide addition step of the invention, even when using moisture-sensitive cyanide reagents. This is something that can be done. On the other hand, if an aqueous reaction medium is used, the reaction times required are generally shorter; however, in this case the desired compound must be isolated so that the subsequent cyanide addition can proceed in the absence of moisture. Sometimes.

It is believed that this dehydrohalogenation step results in a solution consisting mostly of monomers of the general formula. Removal of the solvent produces a solid with a complex NMR spectrum, and this is a trimer: (wherein substituents R ² to R ⁷ are omitted) is believed to be. Redissolving the solid trimer produces a solution in which the trimer is in equilibrium with the monomer;
The concentration of each species depends on the dilution of the solution.
The process of the invention can be carried out regardless of the relative proportions of monomer and trimer in the reaction solution.

Compounds of the general formula may be prepared, for example, by N-chlorination or N-bromination of compounds of the general formula. Any suitable chlorinating or brominating agent may be used, such as N-halo compounds such as N-bromo- or especially N-chloro-succinimide, or inorganic hypolites such as sodium hypochlorite. Sodium hypochlorite may be conveniently used in the form of sodium hydroxide plus chlorine. The process is suitably carried out by mixing a slight excess of halogenating agent with a compound of the general formula. Any suitable solvent may be used, such as ether. The reaction can be carried out, for example, at room temperature.

The invention thus provides for converting a compound of the general formula into a compound of the general formula and/or a trimer thereof, and converting at least a portion of said compound into a compound of the formula XCN
Also provided is a method for preparing a compound of the general formula, which comprises reacting the compound with a compound of the general formula.

Compounds of the general formula in which R ¹ , R ⁶ and R ⁷ each represent a hydrogen atom have the general formula: (wherein R ² , R ³ , R ⁴ and R ⁵ each have the meanings given above) or its mono- or di-acyl halide or mono- or di-ester or anhydride with ammonia and optionally is reacted with water and the resulting product is cyclized by heating to give the general formula: (wherein R ² , R ³ , R ⁴ and R ⁵ each have the meanings given above) and 2 of the compound of the general formula
and the carbonyl group at position 4, for example, by reduction using lithium aluminum hydride. Compounds of the general formula in which R ¹ , R ⁶ and/or R ⁷ represent groups other than hydrogen atoms may be prepared by introducing these groups in a manner similar to that known in the art.

Compounds of the general formula are formed by hydrolysis into the general formula: (wherein R ¹ to R ⁷ have the above-mentioned meanings). Such compounds have interesting pollen-suppressing and plant growth regulating effects. Hydrolysis may be carried out, for example, by refluxing a compound of the general formula in the presence of an aqueous acid. This hydrolysis can produce acid addition salts of compounds of general formula. Refluxing a compound of general formula in the presence of an alcohol and dry hydrogen chloride produces an ester of the compound of general formula or its HCl salt.

Thus, the present invention also provides a method for producing a compound of the general formula or a salt and/or ester thereof, which comprises hydrolyzing or alcoholysing the compound of the general formula produced by the method of the present invention.

When X in a compound of the general formula represents a trialkylsilyl group, the compound can be partially hydrolyzed to a compound of the general formula in which X represents a hydrogen atom by carefully controlling the reaction conditions. This is generally not possible with compounds of the general formula in which X represents an acyl group. Mild reaction conditions can be used for this partial hydrolysis, such as stirring the silyl compound with water at room temperature.

In the compound of the general formula, the 2-cyano group is
It can be cis or trans to the CR ⁴ R ⁵ group, and in addition, for each of these geometric isomers there is a pair of optical isomers based on the chirality of the 2-carbon atom. Furthermore, R ⁴ , R ⁵ , R ⁶ and R ⁷
Other geometric and/or optical isomers may exist depending on the meaning of . In some applications of the process of the invention, certain isomers are exclusively produced; e.g.
When R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ each represent a hydrogen atom and the cyanide reagent is hydrogen cyanide, the process of the invention will generally be exclusively trans-2-cyano -Produces 3-azabicyclo[3.1.0]hexane.

As mentioned above, compounds of the general formula can be converted to the corresponding 2-carboxylic acids, for example by treatment with strong acids. For example, trans(D,L)2-cyano-3-azabicyclo[3.1.0]hexane is hydrolyzed into trans(D,L)2-carboxy-
It can be 3-azabicyclo[3.1.0]hexane. The production of this single geometric isomer is extremely useful. This is because, in general, the two geometric isomers have different physical properties, and mixtures of geometric isomers pose manufacturing and formulation problems.

The method of the present invention is directed to the trans 2-carboxy-3
- Of particular importance in the production of azabicyclo[3.1.0]hexane or its salts and/or esters.

Thus, the preferred routes for the production of trans-2-carboxy-3-azabicyclo[3.1.0]hexane are (i) 3-azabicyclo[3.1.0]hexane, for example by direct oxidation, or by N-chlorination or N- (ii) conversion to 3-azabicyclo[3.1.0]hex-2-ene and/or its trimer by bromination followed by dehydrohalogenation; (ii) trans by reaction of the product from (i) with hydrogen cyanide; Preparation of 2-cyano-3-azabicyclo[3.1.0]hexane and (iii) 2-carboxy-3-azabicyclo[3.1.0]hexane or salts thereof by hydrolysis or alcoholysis of the product from (ii) and/or the production of esters.

However, in some cases, direct hydrolysis of a compound of the general formula containing inorganic impurities to the free acid of the general formula or an acid addition salt thereof can be quite costly to carry out on a large scale. The free acid is an amino acid that cannot be distilled and is soluble in both acidic and basic solutions. Therefore, in order to obtain a product free of inorganic impurities, it is preferred to purify the product by passing it through an ion exchange column using a series of aqueous eluents. Although this method is perfectly suitable in the laboratory, it is rather expensive to perform on a large scale given the large amounts of deionized water required to elute the product.

The need for elution is met by alcoholysis of the compound of the general formula obtained by the process of the invention using a lower alkanol in the presence of a non-aqueous acid catalyst, suitably dry hydrogen chloride, to obtain the acid of the general formula. This can be avoided by converting to the corresponding lower alkyl ester. Alkanols having 1 to 3 carbon atoms are suitable. The resulting esters, unlike the free acids, can be distilled and therefore purified by distillation.
The ester may then be hydrolyzed to produce the free acid using water which may optionally contain small amounts of mineral acid or aqueous ammonia. Alkaline hydrolysis is undesirable because it introduces inorganic ions into the reaction mixture that must be removed with an ion exchange column.

If it is necessary to produce a relatively pure trans compound, it is preferred to isolate or further react the trans 2-cyano compound as soon as possible after production.

Thus, the present invention provides alcoholysis of the compound of the general formula produced by the method of the present invention using an alkanol having 1 to 3 carbon atoms, purification of the resulting ester by distillation, and purification of the purified ester. There is also provided a process for producing acids of the general formula, which comprises hydrolyzing to the desired acid using water or aqueous ammonia which may contain a catalytic amount of a mineral acid. This method is particularly advantageous when the compound of general formula is trans-2-cyano-3-azabicyclo[3.1.0]hexane.
Because it is trans 2-carboxy-3-
This is because it provides a convenient method for producing azabicyclo[3.1.0]hexane.

The invention is further illustrated by the following examples.

Example 1 Preparation of trans-2-cyano-3-azabicyclo[3.1.0]hexane A slurry of 23.6 g (0.175 mol) of N-chlorosuccinimide in 500 ml of diethyl ether was stirred at room temperature under a blanket of nitrogen to form 3-azabicyclo. [3.1.0] 8.4 g (0.1 mol) of hexane was added.
The mixture was stirred at room temperature for 21/2 hours under a blanket of nitrogen and then filtered to remove the succinimide. The liquid was washed twice with 100 ml of water each time and once with 50 ml of saturated aqueous sodium chloride solution.

The combined liquids were dried over Na ₂ SO ₄ and concentrated on a rotary evaporator at 20-25° C. and a pressure of about 60 mm Hg to a volume of about 60 ml. Pour the remaining solution into absolute ethanol.
Added to 6.6 g of 85% potassium hydroxide in 50 ml at 5-10°C. An exothermic reaction occurred and the temperature rose to 30°C. The mixture was stirred at room temperature overnight under nitrogen atmosphere and then filtered. Add 5.4 g (0.2 mol) of liquid hydrogen cyanide to the solution and raise the temperature to 22℃ for 5 minutes.
The temperature rose from 29℃ to 29℃. The mixture was stirred at room temperature for 11/2 hours and then stripped on a rotary evaporator at 50°C to give an oily product containing some crystals.
I got g.

Distilled from an oil bath to trans-2-cyano-3-azabicyclo[3.1.0]hexane (boiling point 56℃/0.1mm
Hg) was obtained. Yield: 65%.

Example 2 Preparation of trans-2-carboxy-3-azabicyclo[3.1.0]hexane A slurry of 159 g (1.2 moles) of N-chlorosuccinimide in 500 ml of diethyl ether was stirred at 20°C to produce 3-azabicyclo[3.1.0]. ]Hexane 83
g (1.0 mol) was added over 30 minutes. The mixture was stirred for an additional 1.5 hours and then filtered to remove the succinimide. The filter pad was washed twice with 50 ml each time of diethyl ether, and the liquids were combined.

48g of sodium hydroxide in 300ml of methanol
(1.2 mol) was added to the above diethyl ether solution of N-chloro-3-azabicyclo[3.1.0]hexane and the mixture was stirred and refluxed overnight (16 hours) once the initial exothermic reaction had subsided. After cooling to 20℃, this 3-azabicyclo[3.1.0]hexyl
An excess of liquid hydrogen cyanide (40
g) was added and the mixture was stirred for 1 hour.

Add 800ml of 6N hydrochloric acid to the obtained trans-2-cyano-3-azabicyclo[3.1.0]hexane solution,
The reaction mixture was then heated at 100° C. for 3 hours, during which time diethyl ether and methanol were distilled off to leave an acidic aqueous solution, which was then treated on an ion exchange resin in the H ⁺ form using aqueous ammonia as the eluent. . Recrystallization from aqueous isopropyl alcohol gave 77.7 g of white crystalline material (mp 248-250°C, decomposed). The analysis result shows that this product is 98.3
% chemical purity of isomerically pure trans(D,L)2-carboxy-3-azabicyclo[3.1.0]hexane. Overall yield from 3-azabicyclo[3.1.0]hexane: 61.2
%.

Example 3 Trans 2-carboxy-3- under acidic conditions
Preparation of Azabicyclo[3.1.0]hexane As in Example 1, 3-azabicyclo[3.1.0]hexane (0.15 mol) was treated with N-chlorosuccinimide and then with potassium hydroxide.
The resulting solution was treated with 20 ml of 10N HCl in ethanol. The temperature was kept below 10°C by cooling on an ice bath. The resulting mixture was then treated with 7.7 ml (0.2 mol) of liquid hydrogen cyanide at 10-13°C. The reaction mixture was then allowed to reach room temperature and stirred for 2 hours. The pH was approximately 2.

The mixture was then stripped of solvent on a rotary evaporator to obtain a very viscous orange oil, which was purified by distillation. The resulting product was hydrolyzed using 6N hydrochloric acid as in Example 2 to yield 2-carboxy-3-azabicyclo[3.1.0]hexane. ¹³ C NMR showed no cis isomer present.

Example 4 Trans 2-cyano-3 under alkaline conditions
-Preparation of azabicyclo[3.1.0]hexane The procedure of Example 3 was repeated, except that HCl was replaced with 1.5 ml of triethylamine. The pH of the reaction mixture after addition of hydrogen cyanide was 9-10.

¹³ C NMR shows that the product is trans-2-cyano-3
-Azabicyclo[3.1.0]hexane, showing the absence of cis isomer.

Example 5 Production of 2-cyano-3-trimethylsilyl-3-azabicyclo[3.1.0]hexane and its partial hydrolysis (a) 3-azabicyclo[3.1.0]hex-2-ene and its trimer Diethyl ether A solution of 8.3 g (0.1 mol) of 3-azabicyclo[3.1.0]hexane in 50 ml was added at room temperature to a suspension of 23.6 g of N-chlorosuccinimide in 150 ml of diethyl ether. The suspension was stirred at room temperature for 21/4 hours, then filtered and washed with water. The ether solution was dried with Na ₂ SO ₄ and
and under the vigreaux column.
It was concentrated to about 25 ml at 70°C. Add 50ml of methanol to the residue.
was added dropwise to a solution of 6.6 g (85%) of KOH in the solution at 5-10° C. with stirring. The suspension was stirred at 0-5°C for 2 hours and then left at room temperature overnight. Heat the mixture at 35°C for 18
Concentrate for 6 hours at a pressure of cmHg, then add 50 ml of water. The mixture was extracted successively with diethyl ether.

The diethyl ether was distilled off at atmospheric pressure and the residue was then distilled at atmospheric pressure. The first fraction obtained (boiling point
77-96℃) is 3g of colorless liquid, infrared and
The NMR spectrum showed that it was an aqueous solution of the monomer 3-azabicyclo[3.1.0]hex-2-ene.

The second fraction, boiling at 96-110°C, condenses to 3.8 g of an off-white solid (melting point 60-63°C), which infrared and NMR spectra show to be the trimer of this imine. It was done. Analysis of white solid: C H N C ₁₅ N ₃ H ₂₁ Calculated value 73.2 9.1 17.2 Measured value 74.0 8.7 17.3 (b) 2-cyano-3-trimethylsilyl-3-azabicyclo[3.1.0]hexane and its partially hydrated Decomposition To a solution of 7 g (28.8 mmol) of the imine trimer prepared above in (a) in 700 ml of dry CH ₂ Cl ₂ was added 16 ml (0.128 mol) of trimethylsilyl cyanide under a nitrogen atmosphere at room temperature with exclusion from moisture. was added.
This solution was stirred at room temperature for 24 hours to obtain 2-cyano-3.
A solution of -trimethylsilyl-3-azabicyclo[3.1.0]hexane was obtained. Add this solution to 1 part water.
pour over the bottle, stir at room temperature for 30 minutes, and
Extracted _{with CH2Cl2} . The extract was dried with Na ₂ SO ₄ and
Then, it was evaporated and boiled down to obtain 9.4 g of a yellow liquid.

This liquid was purified by distillation and 0.7mmHg
5.45 g of a distillate boiling at 72-74℃ at a pressure of
It was identified as 2-cyano-3-azabicyclo[3.1.0]hexane by NMR.

Example 6 Preparation of 2-cyano-3-benzoyl-3-azabicyclo[3.1.0]hexane and its hydrolysis (a) Addition of benzoyl cyanide to imine trimer The above implementation in 700 ml of dry CH ₂ Cl ₂ 11.3 g (86.4 mmol) of benzoyl cyanide were added to a solution of 7 g (28.8 mmol) of the imine trimer prepared in Example 5(a). The solution was stirred at room temperature overnight and then boiled down. The resulting oil was heated to a temperature of 160℃ and 0.1mmHg.
and the distillate was treated with gasoline/ether and filtered.

The resulting compound, a solid with a melting point of 74-77°C, 4.8
g was identified as 2-cyano-3-benzoyl-3-azabicyclo[3.1.0]hexane by infrared and NMR spectra. The spectral data are as follows: IR: 1650cm ^-1 : C=O stretching 2240cm ^-1 : C=N stretching NMR: 0.2ppm1H (multiplet) 0.7ppm1H (multiplet) 1.7ppm2H (multiplet) 3.6ppm2H ( 5.1ppm1H (multiplet) 7.3ppm5H (singlet) (b) Production of 2-carboxy-3-azabicyclo[3.1.0]hexane 1 g of the compound produced in (a) above in 50 ml of CH ₂ Cl ₂
The solution was heated and stirred under reflux overnight. The suspension was cooled, washed with diethyl ether and the aqueous layer was evaporated to dryness. The residue was dissolved in water and passed through an acidic ion exchange column "DOWEX 50" (trademark). The ion exchange bed was washed with water and the product was eluted with 2N NH ₄ OH.

0.4 g of product was obtained. NMR shows that the product is 2-carboxy-3-azabicyclo[3.1.0] containing cis and trans isomers in a 1:1 ratio.
It was shown to be hexane.

Example 7 Preparation of trans 2-carboxy-3-azabicyclo[3.1.0]hexane via the corresponding ethyl ester 4.01 Kg (30 mol) of N-chlorosuccinimide are suspended in 12.5 kg of diethyl ether, and 3
- 2.08Kg (25mol) of azabicyclo[3.1.0]hexane was added over 80 minutes. Maintain the temperature within the range of 11 to 22°C during the addition and then 18 to 20°C.
The temperature was maintained within this range for an additional 2 hours. The reaction mixture is then filtered and added to a solution of 1.2 Kg (30 mol) of sodium hydroxide in ethanol for 10 min under a nitrogen blanket.
It was added in 2 hours at a temperature of .degree. The temperature rose to 23°C and in the next hour to 38°C. The mixture was then refluxed for 6 hours and cooled to 10°C.

844 g (31.25 moles) of liquid hydrogen cyanide were added over 30 minutes and stirring continued for a further hour at room temperature. The resulting mixture was filtered and then anhydrous hydrogen chloride maintained at a temperature of -10 to +2°C7.3
Kg (200 mol) of absolute ethanol 22.5 to 20
Added within minutes. At this stage, an additional batch of trans 2-cyano-3-azabicyclo[3.1.0]hexane solution prepared from 50 moles of 3-azabicyclo[3.1.0]hexane was also added to the reaction mixture. The ether was then distilled off and the mixture was refluxed for 4 hours and then cooled to -5°C. Anhydrous ammonia was passed through the reaction mixture for 2 hours to bring the pH to 10.0.
I made it.

The reaction mixture was filtered and the solvent was stripped off on a rotary evaporator.

5.42 Kg of 2-ethoxycarbonyl-3-azabicyclo[3.1.0]hexane were obtained, which was shown by NMR to be 99% chemically pure and to contain 96% trans isomer. This is based on 3-azabicyclo[3.1.0]hexane, and the through yield is
Indicates that it is 70%.

This production was repeated several times. 8.3 Kg (53.3 mol) of the prepared trans-2-ethoxycarbonyl-3-azabicyclo[3.1.0]hexane were added to 217 ml of concentrated hydrochloric acid in 83 ml of water under reflux for 1 hour. Heating was continued for an additional 21/2 hours, during which time the ethanol was distilled off. Water is then removed from the reaction mixture in a rotary evaporator.
Stripping was performed until crystals formed. Isopropyl alcohol was added and the resulting precipitate was filtered and the solid residue was washed with isopropyl alcohol then hexane and air dried.

The product was 5.08Kg (40mol) of 2-carboxy-3-azabicyclo[3.1.0]hexane, 98% of which
was the trans isomer. This is a 75% yield based on the corresponding ethyl ester.

An additional 1.20 kg of 2-carboxy-3-azabicyclo[3.1.0]hexane was obtained from the washing liquid and the liquid. It had a trans:cis ratio of 33:65.

Example 8 Preparation of 2-cyano-3-azabicyclo[3.1.0]hexane via oxidation of 3-azabicyclo[3.1.0]hexane 1 g of 3-azabicyclo[3.1.0]hexane
(0.012 mol), manganese dioxide 5g (0.057 mol)
and gasoline with a boiling range of 40-60°C was stirred at room temperature for 4 hours. Add sodium sulfate;
The mixture was then allowed to stand for a further 4 hours and then filtered. Thin layer chromatography showed the presence of a trimer of 3-azabicyclo[3.1.0]hex-2-ene.

Then 3 ml (0.024 mol) of trimethylsilyl cyanide were added and the mixture was stirred at room temperature under nitrogen atmosphere for 20 hours. The solution became cloudy and some solid precipitated. 10 ml of water was added and the mixture was stirred for 1 hour. The aqueous layer was separated and washed with diethyl ether, and the combined organic phases were dried over sodium sulfate, filtered, and boiled down. 1.05 g of straw colored oil was obtained. 80% of this product is 2
-cyano-3-azabicyclo[3.1.0]hexane, and 20% was unreacted 3-azabicyclo[3.1.0]hexane.

Claims (1)

[Claims] 1. General formula: (In the formula, R ¹ is a hydrogen atom, or unsubstituted or 1
represents an alkyl group substituted with one or more alkoxy groups, and R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ may be the same or each represents a hydrogen atom or an alkyl, aryl, aralkyl or alkaryl group, which may be different, and which is unsubstituted or substituted with one or more alkoxy groups, and X is a hydrogen atom, an organic acyl group or (representing a trialkylsilyl group), the general formula: (wherein R ¹ to R ⁷ have the abovementioned meanings) and/or its trimer are reacted with a cyanide of the general formula: XCN (wherein X has the abovementioned meanings). how to. 2. Process according to claim ¹ , characterized in that starting materials are used in which R 1 to R ⁷ each represent a hydrogen atom or an alkyl group having up to 4 carbon atoms. 3. Process according to claim 2, characterized in that starting materials are used in which R ¹ to R ⁷ each represent a hydrogen atom. 4.Cyanide reactants are used in which X represents a hydrogen atom, an alkanoyl or aroyl group, or a trialkylsilyl group having up to 4 carbon atoms in each alkyl group. - The method described in any of the paragraphs in Section 3. 5. Process according to claim 4, characterized in that a cyanide reactant is used in which 5 X represents a hydrogen atom, a benzoyl group or a trimethylsilyl group. 6. The method of claim 5, wherein the cyanide reactant is hydrogen cyanide. 7. The method according to any one of claims 1 to 6, wherein the reaction temperature is within the range of 0 to 60°C. 8. The method according to claim 7, characterized in that the reaction temperature is in the range of 10 to 30°C. 9 Claims 1 to 8 characterized in that the cyanide reactant is used in an excess of up to 5 times
The method described in any of the sections. 10 General formula (In the formula, R ¹ is a hydrogen atom, or unsubstituted or 1
represents an alkyl group substituted with one or more alkoxy groups, and R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ may be the same or each represents a hydrogen atom or an alkyl, aryl, aralkyl or alkaryl group unsubstituted or substituted with one or more alkoxy groups, and X is a hydrogen atom, an organic acyl group or (representing a trialkylsilyl group), the general formula: (wherein R ¹ to R ⁷ have the above-mentioned meanings) is directly oxidized or N-chlorinated or N-brominated and then dehydrohalogenated, and the general formula: A ^compound of the ^formula : A method characterized by causing a reaction.