WO2012049688A1

WO2012049688A1 - An improved process for the preparation of racemic 6, 6- dimethyl-3-azabicyclo-[3.1.0]-hexane and its salts, a key raw material for hcv inhibitor.

Info

Publication number: WO2012049688A1
Application number: PCT/IN2011/000428
Authority: WO
Inventors: Anant Dharma Shinde; Bapu Atmaram Chaudari; Ganesh Gurpur Pai; Arun Kanti Mandal
Original assignee: Arch Pharmalabs Ltd
Current assignee: Arch Pharmalabs Ltd
Priority date: 2010-10-12
Filing date: 2011-06-28
Publication date: 2012-04-19
Anticipated expiration: 2013-04-12
Also published as: WO2012049688A8

Abstract

The present invention discloses an efficient and economical process for the preparation of racemic 6, 6-dimethyl-3-azabicyclo-[3.1.0]-hexane of formula I and its salts. The invention relates to the compounds of formulae I and II. The compound of formula I is a key raw material for the preparation of a key intermediate (1R, 2S, 5S) - methyl 6,6-dimethyl -3-azabicyclo [3.1.0] hexane-2 carboxylic acid and ester and salts of formula III for a class of inhibitors of the protease of the formula PI. Among the compounds provided herein, compounds those inhibit HCV NS3/NS4a serine protease activity are preferred.

Description

TITLE: An improved process for the preparation of racemic 6, 6- dimethyl-3-azabicyclo-[3.1.0]-hexane and its salts, a key raw material for HCV inhibitor.

TECHNICAL FIELD OF THE INVENTION: The present invention discloses an efficient and economical process for the preparation of racemic 6, 6-dimethyl-3-azabicyclo-[3.1.0]-hexane of formula I and its salts. The invention relates to the compounds of formulae I and II. The compound of formula I is a key raw material for the preparation of a key intermediate (1R, 2S, 5S) - methyl 6,6-dimethyl -3-azabicyclo [3.1.0] hexane-2 carboxylic acid and ester and salts of formula III for a class of inhibitors of the protease of the formula PI. Among the compounds provided herein, compounds those inhibit HCV NS3/NS4a serine protease activity are preferred.

Formula I

Formula II

Rl is hydrogen ,aralkyl, substituted

aralkyl or alkenyl prefereably Rl is

selected from hydrogen and benzyl

Formula III

R is, for example alkyl, aryl,

aralkyl, cycloalkyl, cycloalkylalkyl

PI

Wherein Rl is H, OR8, NR9R10 or CHR9R10, wherein R8, R9 and RIO can be the same or different, each being independently selected from the group consisting of H, alkyl-, alkenyl-, alkynyl- , aryl-, heteroalkyl-, hetroaryl-, cyclalkyl-, heterocyclyl-, aryl-, heteroalkyl, heteroaryl-, cycloalkyl-, heterocyclyl- arylalkyl- and heteroarylalkyl;

A and M can be the same or different, each being independently selected from R, OR, NHR, NRR',SR, SO2R and halo; or A and M are connected to each other such that the moiety:

A

E

shown above in the formula PI forms either a three, four, six, seven or eight member cycloalkyl, a four to eight membered heterocyclyl, a six to ten membered aryl, or a five to ten membered heteroaryl; E is C (H) or C(R);

L is C (H),C(R), CH2C(R) or C(R)CH2;

R, R\ R2. R3 can be the same or different, each being independently selected from the group consisting of H, alkyl-, alkenyl-, alkynyl- , aryl-, heteroalkyl-, hetroaryl-, cycloalkyl-, heterocyclyl-, aryl-, heteroalkyl, heteroaryl-, (cycloalkyl) alkyl-, (heterocyclyl) alkyl- arylalkyl- and heteroarylalkyl; or alternately R and R' in NRR' are connected to each other such that NRR' forms a four to eight membered heterocyclyl

And Y is selected from the following moieties:

Wherein G is NH or O; and R15, R16, R17, R17 and R18 can be the same or different, each being independently selected from the group consisting of H, alkyl-, alkenyl-, alkynyl- , aryl-, heteroalkyl-, heteroalkenyl, cycloalkyl, , alkynyl, cyclalkyl, heterocyclyl, arylalkyl, heteroarylalkyl or alternately, (i) R15 and R16 ar connected to each other to form a four to eight membered cyclic structure , and (ii) likewise, independently R17 and R18 are connected to each other to form a three to eight membered cycloalkyl or heterocyclyl; wherein each of said alkyl, aryl, heteroaryl, cycloalkyl or heterocyclyl can be unsubstituted or optionally independently substituted with one or more moieties selected from the group consisting hydroxy, alkoxy, aryloxy, thio, alkylthio, arylthio, amino, amido, alkylamino, arylamino, alkylsulfonyl, arylsulfonyl, sulfonamido, alkylsulfonamido, arylsulfonamido, alkyl, aryl, heteroaryl, keto, carboxy, carbalkoxy, carboxamido, alkoxycarbonylamino, alkoxycarbonyloxy, alkylureido, arylureido, halo, cyano and nitro.

The statement alternately, (i) R15 and R16 are connected to each other to form a four to eight membered cyclic structure and (ii) likewise independently R17 and R18 are connected to form a three to eight membered cycloalkyl or heterocyclyl means the following possibilities: (i) R15 and R16 are connected to form a cyclic structure while R17 and R18 are not, (ii) rl7 and R18 are connected to form a cyclic structure while R15 and R16 are not and (iii) R15 and R16 are connected to form a cyclic structure and R17 and R 18 are also connected to form a cyclic structure . These possibilities can occur independent of one another.

In the above noted definitions of R, R', R2 and R3, preferred alkyl is made of one to ten carbon atoms, preferred alkenyl or alkynyl is made of two to ten carbon atoms; and preferred heteroalkyl, heteroaryl or heterocyclalkyl has one to six oxygen, nitrogen, sulphur or phosphorus atoms.

The compounds represented by formula PI, by themselves or in combination with one or more other suitable agents disclosed herein can be useful for treating diseases such as HCV, HIV and related disorders as well as for modulating the activity of hepatitis C virus (HCV) protease, preventing HCV or ameliorating one or more symptoms of hepatitis C. Without being limited to theory, it is believed that the HCV protease may be NS3 or NS4a protease.

Thus the efficient and economical process for the preparation of the compound of formula I contributes significantly towards the safe and economical preparation of compound of formula PI at industrial scale.

BACKGROUND OF THE INVENTION: The invention discloses an improved and economical process for the preparation of racemic 6,6- dimethyl-3-azabicyclo-[3.1.0]-hexane of formula I and its corresponding salts in high yield and good purity. This compound is a key raw material for the preparation of (1R, 2S, and 5S) - methyl 6,6-dimethyl -3- azabicyclo [3.1.0] hexane-2 carboxylic acid and ester of formula III and salts thereof. Esters of 6,6-dimethyl -3-azabicyclo [3.1.0] hexane-2 carboxylic acid are useful as intermediates in the synthesis of the compounds that have a utility, for example (1R, 2S, and 5S) - 6,6- dimethyl -3-azabicyclo [3.1.0] hexane-2 carboxylic acid methyl ester hydrochloride is a key intermediate used in the preparation of serine protease inhibitor of the general formula PI.

Compound of formula PI is useful for treating hepatitis C and related disorders, specifically, the HCV NS₃/NS_4a serine protease.

Various methods are known in the art to make esters of 6,6-dimethyl -3- azabicyclo [3.1.0] hexane-2 carboxylic acid of the formula III. The general scheme for the preparation of esters of 6,6-dimethyl -3- azabicyclo [3.1.0] hexane-2 carboxylic acid of the formula III via racemic 6,6-dimethyl-3-azabicyclo-[3.1.0]-hexane using caronic anhydride can be represented as follows:

However there are very limited processes for the preparation of racemic 6,6-dimethyl-3-azabicyclo-[3.1.0]-hexane and its corresponding salts of formula I a key raw material for the preparation of 6,6-dimethyl -3- azabicyclo [3.1.0] hexane-2 carboxylic acid esters.

The present invention discloses an efficient and economical process for the preparation of racemic 6, 6-dimethyl-3-azabicyclo-[3.1.0]-hexane of the formula I as shown below:

RI is hydrogen

The efficient and economical process comprises the reduction of the compound of the formula II wherein Rl is hydrogen using alkali metal borohydride as a reducing agent in the presence of an acid yielding the compound of formula I.

Another aspect of the invention is the improved process for the conversion of the compound of the formula II into compound of formula I as shown below:

The efficient and economical process relates to the reduction of the compound of the formula II wherein Rl is benzyl group using alkali metal borohydride as a reducing agent in the presence of an acid yielding the compound of formula V followed by its debenzylation using palladium hydroxide replacing palladium/C(known in the prior art) or chloroformates like 1-chlorethylchloroformate yielding the compound of formula I.

WO2008082508 discloses the process for the preparation of the compound of formula I comprising two steps of reduction, first is to deoxygenate the compound of formula IV using lithium aluminium hydride to obtain the compound of formula V, second reduction is hydrogenation using palladium /charcoal yielding compound of formula I.

IV V

WO2007075790A1 discloses use of lithium aluminium hydride as reducing agent for the preparation of the compound of formula I. The yield reported is 88%, but there is no mention of the purity. The compound of formula was further converted into its hydrochloride by purging dry HC1 at -23°C to -20°C.

WO2009/73380A1 also discloses use of lithium aluminium hydride as reducing agent for the preparation of the compound of formula I. The yield reported is 88%, but there is no mention of the purity.

US7723531 (hereinafter referred as '531) discloses both the possible routes as shown below. It also discloses the use of reducing agent selected from the group consisting of lithium aluminium hydride, lithium borohydride, vitride chemically named as sodium bis(2- methoxyethoxy) aluminium hydride and borane. The inventors of '531 have broadened the scope of claim by also including so many other reducing agents such as boranes to convert the compound of formula II into compound of formula I. However, there is no embodiment relating to use of any other reducing agent such as borane and it neither mentions source of borane nor the difference between results when reaction is carried out with any other reducing agent such as borane compared to when the same reaction is carried out with L1AIH₄ which is the main feature of the invention disclosed in '531. As per '531 best possible mode of enablement is to use L1AIH₄ as a reducing agent to convert compound of formula II into compound of formula I. Moreover '531 neither motivates nor teaches the superiority of use of any other reducing agent such as borane alone or in combination with any catalyst over the use of L1AIH₄ or vice versa.

The shortcomings of the processes disclosed in the prior art for the preparation of racemic 6,6-dimethyl-3-azabicyclo-[3.1.0]-hexane of formula I and its corresponding salts are: 1. Restricted use of lithium aluminum hydride on the large scale which is very expensive and because of its pyrophoric and dusting nature hence difficult to handle, and unsafe.

2. Pyrophoric nature of palladium / charcoal in its dry state making its use difficult and unsafe on large industrial scale.

Taking into consideration all these shortcomings there is a need for an industrially safe and economical process which can bridge the gaps in the processes disclosed in the prior art for the preparation of intermediate compound of formula III which is a key intermediate for the preparation of compound of formula PI.The excellence of the invention lies in the superiority in the use of alkali metal borohydride in combination with an acid over the hydrides which is not disclosed in the prior art. Accordingly, there remains a need for an improved economical process of providing intermediate useful for commercial scale preparation of the key intermediate useful in the treatment or prevention of one or more symptoms of hepatitis C.

In the present invention, inventors have tried various reducing agents to replace unsafe and expensive lithium aluminium hydride. Inventors observed that while conducting the reaction for the preparation of racemic 6,6-dimethyl-3-azabicyclo-[3.1.0]-hexane of formula I, no reaction proceeds when alkali metal borohydride such as sodium borohydride is used alone. Similarly when the same reaction is conducted using vitride chemically known as sodium bis(2-methoxyethoxy) aluminium hydride results in the formation of 18-20% impurity. However, inventors could develop a smooth, efficient and economical process for the preparation of racemic 6,6-dimethyl-3-azabicyclo-[3.1.0]- hexane of formula I. As described hereinabove that alkali metal borohydride alone was found to be inefficient for the reduction of the compound of formula II to give compound of formula I. However, use of alkali metal borohydride in combination with an acid for the reduction of compound of formula II to give a compound of formula I worked very efficiently. Therefore, inventive feature of the present invention for the preparation of racemic 6,6-dimethyl-3-azabicyclo-[3.1.0]-hexane of formula I lies in the reaction of compound of formula II with alkali metal borohydride in combination with an Acid. The same inventive feature can also be applied for the preparation of compound of formula I from compound of formula IV via compound of formula V. Another key feature of the invention is the debenzylation of compound of formula V either by hydrogenation in presence of palladium hydroxide or by heating with 1-chloro-ethylchloroformate.

Disclosure of the compound to be followed in entire specification is as follows:

Formula I is 6,6-dimethyl-3-azabicyclo-[3.1.0]-hexane.

Formula II (Rl is H) is 6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4- dione.

Formula III is esters of 6,6-dimethyl-3-azabicyclo-[3.1.0]-hexane carboxylic acid.

Formula IV is 3-benzyl-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4- dione.

Formula V is 3-benzyl-6,6-dimethyl-3-azabicyclo[3.1.0]hexane.

Formula VI is salt of 6,6-dimethyl-3-azabicyclo-[3.1.0]-hexane. presented by IA is 6,6-dimethyl-3-azabicyclo-[3.1.0]-hexane.

represented by IB is 6,6-dimethyl-3-azabicyclo-[3.1.0]-hexane (1R, 2S, 5S) nitrile H °°^0H represented by IC is 6,6-dimethyl-3-azabicyclo-[3.1.0]-hexane (1R, 2S, 5S) carboxylic acid

C^OOMerepresented by III is Methyl 6,6-dimethyl-3-azabicyclo- [3.1.0]- hexane (1R, 2S, 5S) carboxylate

OBJECT OF THE INVENTION:

First aspect of the invention is to provide an efficient and economical process for the preparation of racemic 6,6-dimethyl-3-azabicyclo-[3.1.0]- hexane of formula I from compound of formula II using alkali metal borohydride in combination with acid.

Path I:

when Rl is H

Second aspect of the invention is to provide a process for the preparation of corresponding salts of racemic 6,6-dimethyl-3-azabicyclo-[3.1.0]- hexane of formula VI from compound of formula II using sodium borohydride in combination with an acid.

Π vr

when Rl is H X is anion like CI, Br, I, N03, HS04 Third aspect of the invention is the utility of the compound of formula I for the preparation of key intermediate of formula III and compound of formula PI thereof.

IA !B

Fourth aspect of the invention is to provide a process for the preparation of racemic 6,6-dimethyl-3-azabicyclo-[3.1.0]-hexane of formula I from caronic anhydride of formula ΙΓ via compounds of formulae IV and V using alkali metal borohydride in combination with acid .

Path II:

Fifth aspect of the invention is to provide a process for the preparation of racemic 6,6-dimethyl-3-azabicyclo-[3.1.0]-hexane of formula I from caronic anhydride of formula IF via compounds of formulae IV and V using alkali metal borohydride in combination with acid and its utility of the compound of formula I for the preparation of key intermediate of formula III via Enzymatic desymmetrization followed by cyanation, hydrolysis and esterification as shown in the scheme below.

Sixth aspect of the invention is to provide a novel process for the preparation of the compound of formula V from compound of formula IV.

IV

Seventh aspect of the invention is to provide a novel process for the conversion of compound of formula V into compound of formula I by hydrogenation using palladium hydroxide or by heating in 1-chloro- ethylchloro formate.

SUMMARY OF THE INVENTION:

The present invention discloses an efficient and economical process for the preparation of racemic 6, 6-dimethyl-3-azabicyclo-[3.1.0]-hexane of formula I and its salts from compound of formula II comprising alkali metal borohydride in combination with acid.

The present invention also discloses an improved process for the preparation of racemic 6, 6-dimethyl-3-azabicyclo-[3.1.0]-hexane of formula I and its salts from compound of formula IV using alkali metal borohydride in combination with acid followed by debenzylation of the compound of formula V comprising palladium hydroxide or by heating in 1-chlro-ethylchloroformate yielding the compound of formula I.

DETAILED DESCREPTION OF THE INVENTION:

Reference will now be made in detail to the preferred embodiments of the invention.- This invention may, however, be embodied in many different forms and should not be construed as limited to the embodiments set forth herein. In addition, and as will be appreciated by one of the skill in the art, the invention may be embodied as a method, system or process.

An efficient and economical processes for the preparation of racemic 6,6- dimethyl-3-azabicyclo-[3.1.0]-hexane of formula I and its corresponding salts of formula VI are illustrated in the following reaction schemes. The following schemes illustrate the preparation of the compound of formula I and its salts from compound of formula II comprising alkali metal borohydride in combination with acid.

Compound of formula I is commercially available or known in the art. Present invention relates to an improvement over the processes known in the art to overcome the shortcomings therein in the prior art. In an embodiment compound of formula I is prepared by reacting compound of formula II with alkali metal borohydride in combination with acid in a single step with higher yield and high purity.

Scheme I

when R l is H

Scheme II of the present invention relates to an improved process for the preparation of compound of formula VI comprising reduction of compound of formula II using alkali metal borohydride in combination with acid and insitu converting into corresponding salts of formula VI with higher yield and good purity.

Scheme II

I ^V[

Π X is anion like CI, Br, I, N03, HS04

Scheme III discloses an improved process which overcomes the shortcomings of processes reported in the prior art that comprises reduction followed by debenzylation. In the said process reduction of the compound of formula IV is carried out using alkali metal borohydride in combination with acid yielding compound of formula V. Compound of formula V is debenzylated by hydrogenation using palladium hydroxide or by heating in 1-chloro- ethylchloro formate resulting into compound of formula I. Scheme III

Reduction of the compound of formulae II or IV yields compound of formula I. Reducing agent is selected from the group of alkali metal borohydride consisting of lithium borohydride, sodium borohydride, potassium borohydride and the like. Preferable reducing agent is sodium borohydride.

Acid is selected from mineral acid, lewis acid. Mineral acid is selected from HC1, H₂S0₄ and the like. Preferably mineral acid is H₂S0₄. Lewis acid is selected from magnesium bromide.BF3 etherate, BF₃ etherate, Ferric chloride, aluminium chloride and the like. Preferably lewis acid is BF₃ etherate.

Solvent used for the reduction of the compound of formula II or IV is selected from tetrahydrofuran, 2-methyl tetrahydrofuran, tert-butyl methyl ether, 1,2-dimethoxyethane, toluene or mixtures of two or more thereof. Preferably solvent is tetrahydrofuran. Optionally the product is isolated by distillation of solvent. Reduction reaction to convert compound of formula II and IV to compound of formula I is carried out at a temperature from about -20°C to about 80°C.

Solvent for the hydrogenation for debenzylation of the compound of formula V is selected from aliphatic alcohols or substituted chloroformates. Preferably aliphatic alcohol is selected from ethanol, methanol or the like. More preferably aliphatic alcohol is methanol. Substituted chloroformates is selected from 2,2,2-trichloro ethyl formate , 1-chloro-ethylchloroformate and the like. Preferably substituted chloroformates is 1-chloro-ethylchloroformate.

In an embodiment compound of formula I is converted into the corresponding salt (compound of formula VI) by reacting it with a suitable acid. Suitable acids comprise but not limited to mineral acids selected from HC1, HBr, HI, HN03, or H2S04 and the like. In a preferred embodiment it is preferred to use suitable organic solvents to provide a mineral acid solution for this treatment.

Compound of formula I may also be converted into esters of 6,6- dimethyl-3-azabicyclo-[3.1.0]-hexane carboxylic acid of formula ΠΙ by the known procedures as given in US2010/0145069 or US7723531.

Optionally the compound of formula I made by the efficient and economical process disclosed herein can be further converted into the compound of formula III and thereby into compound of formula PI.

In the present invention inventors have used the concept of Enzymatic desymmetrization yielding 6,6-dimethyl-3-azabicyclo-[3.1.0]-hex-2-ene of formula IA which is then taken for the cyanation through the sulphonate adduct formation using sodium bisulphite yielding 6,6- dimethyl-3-azabicyclo-[3.1.0]-hexane (1R, 2S, 5S) nitrile of formula IB. The compound of formula IB is then hydrolysed using methanolic HCL yielding 6,6-dimethyl-3-azabicyclo-[3.1.0]-hexane (1R, 2S, 5S) carboxylic acid followed by its ester formation using methanol and thionyl chloride resulting into methyl 6,6-dimethyl-3-azabicyclo-[3.1.0]- hexane (1R, 2S, 5S) carboxylate.

In an embodiment compound of formula I is prepared by reacting compound of formula II with sodium borohydride in combination with BF₃ etherate as an acid in THF as a solvent in a single step with higher yield 88-90 % and high purity of 98-99%. In another embodiment compound of the formula I is prepared by reacting the caronic anhydride of the formula ΙΓ with benzyl amine to obtain compound of formula IV followed by its reaction with sodium borohydride in combination with BF₃ etherate as an acid in THF as a solvent affording compound of formula V and further debenzylation using either the process of hydrogenation using palladium hydroxide or heating in chloroformates to obtain compound of formula I.

In another embodiment the compound of the formula I which itself is prepared by the reduction of the compounds of formula II or IV using sodium borohydride in combination with BF₃ etherate as an acid is converted into compound of the formula III via Enzymatic desymmetrization followed by cyanation as shown and described hereinabove in third aspect of the present invention).

The present invention can be shown by the following schematic representations:

1.

when R 1 is H

2.

II VI

X is anion like CI, Br, I, N03,

when R I is H

HS04 3.

Both the paths of the present invention and its further conversion into III can be summarized by the following schematic representation in PART I. Conversion of the compound of formula I into III comprises i) Enzymatic desymmetrization producing 6,6-dimethyl-3-azabicyclo-[3.1.0]-hex-2- ene of formula IA ii) Cyanation producing 6,6-dimethyl-3-azabicyclo- [3.1.0]-hexane(lR, 2S, 5S) nitrile of formula IB and iii) Hydrolysis producing alkyl ester of 6,6-dimethyl-3-azabicyclo-[3.1.0]-hexane(lR, 2S, 5S) carboxylic acid of formula III as represented in PART II.

PART I:

R is alkyl group Given below are the compound of formula PI wherein esters of 6,6- dimethyl-3-azabicyclo-[3.1.0]-hexane carboxylic acid of formula III is used as a key intermediate and are HCV inhibitors.

are same as defined above

30

31

Taking into consideration the utility of the esters of 6,6-dimethyl-3- azabicyclo-[3.1.0]-hexane carboxylic acid of formula III and hence 6,6- dimethyl-3-azabicyclo-[3.1.0]-hexane thereof, even a small improvement in the process for the preparation of 6,6-dimethyl-3-azabicyclo-[3.1.0]- hexane of formual I contributes a lot towards the preparation of esters of 428

6,6-dimethyl-3-azabicyclo-[3.1.0]-hexane carboxylic acid which is a key intermediate for the preparation of a large quantity of pharmaceuticals used as HCV inhibitors.

The following non limiting examples are provided to illustrate further the present invention, It will be apparent to those skilled in the art that many modifications, variations and alterations to the present disclosure, both to materials, methods and reaction conditions, may be practiced. All such modifications, variations and alterations are intended to be within the spirit and scope of the present inventions. Specific examples of the preferable compounds represented by the general formula PI related to the present invention are provided, although the present invention is not limited thereto.

Example 1: 6, 6-dimethyl-3-azabicyclo [3.1.0] hexane: To a well- stirred suspension of 6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4- dione of formula II, Rl is Hydrogen, (2.0 g, 14.38 mmol) in dry THF (20.0 mL) sodium borohydride (1.64 g, 43.16 mmol) was added at - 30 to -20 °C. BF₃. Et₂0 (43.16 mmol) was then added slowly at the same temperature. Reaction mixture was then stirred for 7-8 hrs at 40 to 50 °C temperature. THF was then distilled off followed by stripping of toluene to remove the THF. Reaction mass was cooled and unreacted NaBH₄ was quenched with methanol (5.0 mL), diluted with water (100 mL), and extracted with toluene (3 x 25 mL). The combined toluene layers were washed with water and dried over anhydrous sodium sulfate. The solvent was removed under the reduced pressure keeping the temperature below 55°C to get 6, 6-dimethyl-3-azabicyclo [3.1.0] hexane as a colorless liquid (1.3g) with GC purity of 96%.

Example 2: 6, 6-dimethyl-3-azabicycIo [3.1.0] hexane hydrochloride:

To a well-stirred suspension of 6,6-dimethyl-3-azabicyclo[3.1.0]hexane- 2,4- dione of formula II Rl is Hydrogen (2.0 g, 14.38 mmol) in dry THF (20.0 mL) sodium borohydride (1.64 g, 43.16 mmol) was added at - 30 to -20 °C. BF₃. Et₂0 (43.16 mmol) was then added slowly at the same temperature. Reaction mixture was then stirred for 7-8 hrs at 40 to 50 °C temperature. THF was then distilled off followed by stripping of toluene to remove the THF. Reaction mass was cooled and unreacted NaBH4 was quenched with methanol (5.0 mL), diluted with water (100 mL), and extracted with toluene (3 x 25 mL). The combined toluene layers were washed with water and dried over anhydrous sodium sulfate. HC1 gas was then purged at 5 - 10 °C to make 6, 6-dimethyl-3-azabicyclo [3.1.0] hexane hydrochloride. Maintain the reaction mass at 10 °C for 30 min. Product was filtered off under inert condition then Dry compound under vacuum at 40 - 45 °C to get 1.7 g dry compound with GC purity of 95%.

Example 3: Preparation of 6,6-Dimethyl-3-aza-bicyclo[3.1.0]hexane- 2,4-dione (II): 560 (4moles) gm of Caronic anhydride and 280 gm urea (4.6 moles) was charged. Contents were heated at 160 - 170°C till the completion of the reaction. Reaction mass was brought at 55°C and 1125 ml MDC was added and stirring was continued for 15-20 minutes followed by the addition of 560 mL water and stirring continued. MDC layer was separated and dried over sodium sulphate. MDC was distilled off and residual MDC was removed by the stripping of toluene. Toluene was distilled off under reduced pressure. The reaction mixture was cooled to 0 to 10°C over a 5 hour period till the product was crystallized. The crystals were collected by filtration, washed, and dried to yield compound II as a white crystalline powder.

Example 4: 3-benzyl-6,6-dimethyl-3-azabicyclo [3.1.0] hexane-2,4- dione To a flask were charged 51.32 g of 6,6-Dimethyl-3-aza- bicyclo[3.1.0]hexane-2,4-dione II (0.37 mol, 1 eq.) and 50 mL TBME. While stirring, the mixture was cooled to between 0 and 10° C, and 40 mL benzylamine (39.24 g, 0.37mol, leq) was added drop wise over approximately 30 minutes. After the addition was complete, the TBME was removed by distillation at between 60 and 70° C and the mixture was gradually heated to an internal temperature between 170 and 180° C. The solution was maintained between 170 and 180° C for approximately 3 to 5 hours to complete the cyclization. The resulting solution was cooled to between 60 and 70° C, and 100 mL of a solution of 5% water in isopropanol was added and the mixture was cooled to room temperature. After cooling further to between 0 and 10° C, the product was isolated by filtration, rinsed with clean, cold isopropanol, and dried in a vacuum oven to afford 70.99 g of the benzyl imide of formula IV.

Example 5: Synthesis of 3-benzyl-6, 6-dimethyl-3-azabicyclo [3.1.0] hexane:

To a well-stirred suspension of 3-benzyl-6,6-dimethyl-3-azabicyclo [3.1.0] hexane-2,4-dione (2.0 g, 8.17 mmol) in dry THF (20.0 ml) sodium borohydride (0.99 g, 26.17 mmol) was added at -20 - 30°C. BF₃. Et₂0 (26.17 mmol) was then added slowly at the same temperature. Reaction mixture was then stirred for 7-8 hrs at 40 -50°, THF was distilled out followed by stripping of toluene to remove the residual THF. The reaction mass was cooled and unreacted NaBH₄ was quenched with methanol (5.0 ml), diluted with water (100 mL), and extracted with toluene (3 x 25 mL). The combined toluene layers were washed with water and dried over anhydrous sodium sulfate. Toluene layer was cooled and the HC1 gas was purged at 5 - 10°C to make 6, 6-dimethyl-3- azabicyclo [3.1.0] hexane hydrochloride. Maintain the reaction mass at 10°C for 30 min. Product was filtered off under inert atmosphere. The compound was dried under vacuum at 40 - 45°C to get 1.5 g dry compound.

Example 6: Synthesis of 6, 6-dimethyl-3-azabicyclo [3.1.0] hexane (Debenzylation):

Process A: To a solution of 3-benzyl-6,6-dimethyl-3- azabicyclo[3.1.0]hexane (5.0 g ,24.83mmol)(V) in 1 ,2- dichloroethane (10 ml) was added chloroethylchloroformate (5.32 gm, 37.2 mmol) at 0°C. The reaction mixture was heated to 55°C for 4 h. Further chloroethylchloroformate (0.5ml) was added and heating continued for 2 h. The reaction mixture was evaporated to dryness. MeOH (15ml) was added and the reaction mixture was heated at 65 °C for 3 h. A grey precipitate had formed; this was isolated by filtration and washed with Et2O. 6,6-dimethyl-3-azabicyclo-[3.1.0]-hexane hydrochloride was obtained as a grey powder (3.0 gm).

Process B:

To a well-stirred suspension of -3-benzyl-6, 6-dimethyl-3-azabicyclo [3.1.0] hexane (10.0 g, 49.6 mmol) and (2.0 gm of Pd/ (OH) or pd/c in Methanol in Autoclave. The Autoclave was flushed with Nitrogen and Hydrogen gas was supplied at 5 -7 kg/cm2 for 4 - 5 hrs at room temperature. After completion of reaction, Palladium hydroxide was removed by filtration and methanolic hydrochloric acid was added at 10 - 15°C Methanol was distilled out up to slurry which was cooled at 5 - 10°C and product was filtered off as hydrochloride salt. The product was dried under vacuum at 40 - 45°C to get 5.8 g dry (1R, 5S)-6, 6-dimethyl- 3-azabicyclo [3.1.0] hexane hydrochloride.

Example 7: 6, 6-dimethyl-3-azabicyclo [3.1.0] hexane hydrochloride:

To a well-stirred suspension of 6,6-dimethyl-3-azabicyclo[3.1.0]hexane- 2,4- dione (2.0 g, 14.3 mmol) in dry THF (20.0 mL) sodium borohydride (1.63 g, 43.11 mmol) was added at -20 - 30°C. H₂SO₄ (7.18 mmol) was then added slowly at the same temperature. Reaction mixture was stirred for 7-8 hrs at 40 -50 °C. THF was distilled off followed by stripping of toluene to remove the residual THF. Cool the reaction mass and extracted with toluene (3 x 25 mL). The combined organic layers were washed with water and dried over anhydrous sodium sulfate, tolune containing product was chilled and HCL was purged at 5 - 10 °C to make 6, 6- dimethyl-3-azabicyclo [3.1.0] hexane hydrochloride. Maintain the reaction mass at 10°C for 30 min. Product was filtered off under inert condition. The titled product was dried under vacuum at 40 - 45 °C to get 1.25 g dry compound.

Example 8. Preparation of 6, 6-dimethyl-3-(lR,2S,5S)-azabicyclo

[3.1.0] hexane nitrile via corresponding hex-2-ene: 100 gm of 6, 6- dimethyl-3-azabicyclo [3.1.0] hexane base was added into 452 mL DM water containing 126 gm of sodium bisulphite to get the BS solution. In the mean while enzymatic solution was prepared by adding 2gm enzyme CDX - 616, 2.1 gm of catalase and 0.3 gm of antifoam in 50 ml of freshly boiled DM water. This enzymatic solution was then added into the base solution mentioning the pH at 7.4 using 3M sodium hydroxide in about 30 hours. After the completion of the reaction the mass was give a washing with 100 mL and the aqueous later so obtained was used for the cyanation using 54 gm sodium cyanide dissolved in 162 mL DM water at 5°C. Stirring was continued till the completion of the reaction. The reaction mass was filtered and added with 500 mL MDC under the stirring. MDC layer was separated and dried over sodium sulphate .MDC was distilled out under reduced pressure at temperature not exceeding 40°C to get an oil around 90 gm of 6, 6-dimethyl-3-(lR,2S, 5S)- azabicyclo [3.1.0] hexane nitrile.

Example 9: Preparation of 6, 6-dimethyl-3-(lR,2S,5S)-azabicyclo

[3.1.0] hexane carboxylic acid: Methanolic solution containing 81 gm (0.367 mol) 6, 6-dimethyl-3-(lR,2S,5S)-azabicyclo [3.1.0] hexane nitrile was charged into methanol saturated with hydrogen chloride at -5 to 5°C in a period of an hour. Temperature was gradually brought to 30-35°C and was maintained for 8-10 hours. Solid ammonium chloride was removed by filtration. Filtrate so collected was added with 400 mL water and contents were heated for another 10-15 hours at 45-50°C till the hydrolysis was complete. Methanol was distilled off under the reduced pressure and titled product was isolated as its hydrochloride. Example 10: Preparation of Methyl 6, 6-dimethyl-3-(lR, 2S, 5S)- azabicyclo [3.1.0] hexane carboxylate: 100 gm (0.522mol) of 6, 6- dimethyl-3-(lR,2S,5S)-azabicyclo [3.1.0] hexane carboxylic acid was charged into 500mL methanol. The contents were cooled to 0°C and thionyl chloride was added dropwise maintain the temperature between 0-10°C. Temperature was gradually brought to 30-35°C and stirring was continued for 4 hours till the completion of the reaction. Thionyl chloride and methanol is distilled off under the reduced pressure. Apply the vacuum to the contents free from thionyl chloride and methanol. The titled product was precipitated from isopropanol and ethyl acetate. The product was filtered off and dried under vacuum. Yield obtained is 95gm.

Claims

CLAIMS: We claim:

1. A process for the preparation of compound of formula I and its salts thereof comprising reacting compound of the formula II with alkali metal borohydride in the presence of an acid

Formula I

Formula II

wherein Rl is hydrogen

2. Process of claim 1 wherein metal borohydride is selected from lithium borohydride, sodium borohydride, potassium borohydride and the like.

3. Process of claim 2 wherein metal borohydride is sodium borohydride.

4. Process of claim 1 wherein acid is selected from HCl, H₂SO₄ and the like. Preferably mineral acid is H₂SO₄. , magnesium bromide. BF3 etherate, BF₃ etherate, Ferric chloride, aluminium chloride and the like.

5. Process of claims 4 wherein acid is BF3 etherate.

6. A process for the preparation of compound of formula I and its salts thereof comprising

i) reaction of the compound of the formula II with alkali metal borohydride in the presence of an acid

Formula Π

wherein R 1 benzyl

debzylation comprising palladium/charcoal palladium hydroxide

7. Process of claim 6 wherein metal borohydride is selected from lithium borohydride, sodium borohydride, potassium borohydride and the like. Preferable reducing agent is sodium borohydride.

8. Process of claim 6 wherein metal borohydride is sodium borohydride.

9. Process of claim 7 wherein acid is selected from HCl, H₂S0₄ and the like. Preferably mineral acid is H₂S0₄. , magnesium bromide.BF3 etherate, BF₃ etherate, Ferric chloride, aluminium chloride and the like.

10. Process of claim 9 wherein Lewis acid is BF3 etherate.