WO2014097272A2

WO2014097272A2 - Method for production of (s,s)-6-benzyloctahydro-1h-pyrrolo[3,4-b]pyridine, an intermediate of azabicyclo pyridine derivatives

Info

Publication number: WO2014097272A2
Application number: PCT/IB2013/061274
Authority: WO
Inventors: Jigar BHAVSAR; Akhilendra SINGH; Bhuwan Bhaskar; Anil Kumar
Original assignee: Mankind Research Centre
Priority date: 2012-12-21
Filing date: 2013-12-23
Publication date: 2014-06-26
Also published as: WO2014097272A3; CN105143219A

Abstract

The present invention relates to a cost effective process for the production of (S,S)-6- benzyloctahydro-1H-pyrrolo[3,4-b]pyridine of Formula (I), an important intermediate for the manufacture of azabicyclo pyridine derivatives.

Description

METHOD FOR PRODUCTION OF (S,S)-6-BENZYLOCTAHYDRO-lH- PYRROLO[3,4-B]PYRIDINE, AN INTERMEDIATE OF AZABICYCLO PYRIDINE

DERIVATIVES Field of Invention:

The present invention, in general, relates to the method for the production of (S,S)-6- benzyloctahydro-lH-pyrrolo[3,4-b]pyridine of Formula-I in high yields and purity.

More particularly, the present invention provides an industrially applicable and economical process by means of providing de-aromatization of 6-benzyl-5H-pyrrolo[3,4-b]pyridine- 5,7(6H)-dione and in situ resolution in a solvent system to get (4aR,7aS)-6-benzyltetrahydro- lH-pyrrolo[3,4-b]pyridine-5,7(6H,7aH)-dione monotartarate salt which upon hydrolysis and in situ reduction using metal borohydride-ether or boron triflouride complex in solvent system comprising of at least one non-ethereal solvent gives (S,S)-6-benzyloctahydro-lH- pyrrolo[3,4-b]pyridine of Formula-I with purity > 98.0%

Formula-I

Background of the Invention:

(S,S)-6-benzyloctahydro-lH-pyrrolo[3,4-b]pyridine, represented by Formula-I is an important intermediate for the synthesis of azabicyclo pyridine derivatives which are required for the manufacture of many valuable pharmaceutically active ingredients like quinolone and naphthyridine derivatives having antibacterial effectiveness.

Formula-I

EP350733 and CA1340553 disclose a process for the preparation of racemic 6- benzyloctahydro-lH-pyrrolo[3,4-b]pyridine via coupling of pyridine-2,3-dicarboxylic acid of Formula-1 with benzylamine to form 6-benzyl-pyrrolo[3,4-b]pyridine-5,7-dione of Formula- 2, followed by de-aromatization via catalytic hydrogenation to generate compound of Formula-3 and Lithium Aluminium Hydride (LAH) in tetrahydrofuran to give racemic compound represented by Formula-4.

Scheme-I

Formula-1 Formula-2 Formula-3 Formula-4 (Racemic)

The major drawback of above said process is that there is no resolution of the racemic mixture to form the specific isomer. Also, reduction of compound of Formula-3 involves use of reagents like Lithium Aluminium Hydride, which is an expensive reagent and hazardous to life forms, hence making reaction conditions unsuitable for large scale production.

Indian patent application number 329/CHE/2008 discloses a process for the preparation of (S,S)-6-benzyloctahydro-lH-pyrrolo[3,4-b]pyridine of Formula-I, comprising reaction of compound of Formula-3 with Vitride in the presence of toluene as a solvent and heated at temperature of 27°C to 30°C for lh followed by tartarate salt preparation in solvent like Dimethyl formamide (DMF) to give compound of Formula-6 which upon hydrolysis gives compound of Formula-I.

Scheme-II

Formula-I The major drawback of above said process is that the reduction is being performed by using an expensive reducing agent like Vitride on a racemic mixture. Also, as the compound is a racemic mixture, reduction of keto groups is done for both isomers, desired (4aR,7aS) and undesired (4aS,7aR) hence requiring more amount of reducing agent and making process uneconomical for large scale production.

WO2012131629, discloses preparation of racemic as well as chiral 6-benzyloctahydro-lH- pyrrolo[3,4-b]pyridine by reducing racemic or chiral 6-benzyl-5,7-dioxo octahydropyrrolo[3,4-b] pyridine with aluminium trichloride or dimethyl sulphate and hydride like sodium borohydride in either tetrahydrofuran or dimethoxy ethane at 20-30°C for 18h.

The above said process is a time consuming reduction step as it requires more than 18h for the completion of reaction. Also, solvents like tetrahydrofuran are required to be distilled out before extracting the compound in non-ethereal organic solvents like toluene resulting into time engulfing work up procedure and wastage of an expensive organic solvent tetrahydrofuran. This not only leads to increase in cost of production but also, make process lengthy and tiresome. US2002001642 discloses a process for the preparation of racemic 6-benzyloctahydro-lH- pyrrolo[3,4-b]pyridine comprising steps of: (i) reaction of molten tetrahydro-6- (phenylmethyl)-lH-pyrrolo[3,4-b]pyridine-5,7(6H)-dione of Formula-3 at a temperature of 110°C with lithium aluminium hydride as a reducing agent in the presence of mixture of tetrahydrofuran and toluene as a solvent, (ii) the reaction mixture was stirred at a reflux temperature for 5h and then cooled the reaction mixture to a temperature of 20°C, (ii) a separately prepared solution of citric acid and sulphuric acid was then charged to the reaction suspension followed by extraction in tetrahydrofuran and toluene mixture.

Here, the process requires firstly, use of hazardous reagents like lithium aluminium hydride and secondly, tedious work up process involving use of citric acid and sulphuric acid, thereby rendering the process tedious, lengthy and industrially not applicable. JP2001039979, discloses the reduction of racemic 6-benzyl-5,7-dioxo octahydropyrrolo[3,4- b] pyridine of Formula-3 in aluminium trichloride and sodium borohydride in THF wherein compound of Formula-3 in THF is added to aluminium trichloride and THF solution followed by addition of sodium borohydride to give racemic 6-benzyloctahydro-lH- pyrrolo[3,4-b]pyridine of Formula-4.

Here, it is observed that there is an uncertainty of the success of the reaction. As hydride reagent is added after addition of the compound, metal halide like aluminium trichloride sometimes is not able to make complex with hydride resulting into less or no reaction.

Also, as reduction is performed on racemic compound, it requires double amount of reducing agent as will be required when performed on desired chiral compound.

The processes disclosed in the prior art involves not only time engulfing steps but also multiple isolations, tedious work-ups, time consuming purification processes and expensive reagents, thereby making process lengthy, low yielding and uneconomical at commercial scale production.

It is therefore, the object of present invention to improve upon the limitations and to provide simple, efficient and cost-effective process by producing (S,S)-6-benzyloctahydro-lH- pyrrolo[3,4-b]pyridine of Formula-I, with high purity and yield by utilizing commercially viable raw materials and solvents.

Objects and Summary of Invention:

It is a principal object of present invention to provide a commercially viable, economical, simple and safe process for producing (S,S)-6-benzyloctahydro-lH-pyrrolo[3,4-b]pyridine, an important intermediate for synthesis of azabicyclo pyridine derivatives. It is yet another object of the present invention to provide a method for production of (S,S)-6- benzyloctahydro-lH-pyrrolo[3,4-b]pyridine represented by Formula-I, from chiral 6-benzyl- 5,7-dioxo octahydropyrrolo[3,4-b] pyridine, at industrial scale employing user-friendly and cost-efficient reagents and solvents.

Formula-I

It is further object of the present invention to provide a high yielding and environment friendly process for preparing (S,S)-6-benzyloctahydro-lH-pyrrolo[3,4-b]pyridine represented by Formula-I, wherein the process employs minimal purification steps and wastage of material.

Accordingly, the present invention provides a process for production of (S,S)-6- benzyloctahydro-lH-pyrrolo[3,4-b]pyridine represented by Formula-I;

Formula-I

comprising the steps of:

i) de-aromatization of compound of Formula-2

Formula-2

in presence of metal catalyst;

ii) in situ resolution of the resultant with D(-)-tartaric acid in a solvent system to get compound of Formula-7 tartarate

Formula-7

said solvent system comprising of aprotic and protic solvent in the ratio of 1 :0.2-1.0;

iii) tartarate hydrolysis in presence of base in organic solvent (s) to get free base of compound of Formula-7; and

iv) in situ reduction of free base of compound of Formula-7 with metal borohydride- ether or boron trifluoride complex in solvent system to get compound of Formula-I, said solvent system comprises of at least one non-ethereal solvent,

v) racemisation of undesired isomer of Formula-8,

Formula-8

with chlorinating agent in a solvent system to get chlorine-amine intermediate, said solvent system comprising of organic solvent or mixture of organic solvent with water;

vi) in situ dehydrochlorination of said chlorine-amine intermediate with base to get compound of Formula-9;

Formula-9

vii) high pressure hydrogenation in presence of metal catalyst;

viii) resolution with D(-) tartaric acid, to get compound of Formula-7;

ix) obtaining compound of Formula-I from said compound of Formula-7. In accordance to one aspect of the present invention, the method for the production of (S,S)- 6-benzyloctahydro-lH-pyrrolo[3,4-b]pyridine represented by Formula-I;

Formula-I

comprising the steps of:

i) de-aromatization of compound of Formula-2,

Formula-2

in presence of metal catalyst;

ii) in situ resolution with D(-)-tartaric acid in a solvent system to get compound of Formula-7,

Formula-7

iii) tartarate hydrolysis in presence of base in organic solvent to get free base of compound of Formula-7;

iv) in situ reduction of said free base with reducing agent like metal borohydride-ether or boron triflouride complex in solvent system to get compound of Formula-I, said solvent system comprises of at least one non-ethereal solvent.

In accordance to other aspect of the present invention, the method of preparation of (S,S)-6- benzyloctahydro-lH-pyrrolo[3,4-b]pyridine represented by Formula-I;

Formula-I

comprises the steps of:

i) tartarate hydrolysis of compound of Formula-7,

tartarate

Formula-7

in presence of base in organic solvent to get free base of compound of Formula-7;

ii) in situ reduction of free base with metal borohydride-ether or boron triflouride complex in solvent system to get compound of Formula-I, said solvent system comprises of at least one non-ethereal solvent.

In said phase, the compound of Formula-7 can be prepared according to the process of the present invention, or according to the conventionally known processes.

In accordance to another aspect of the present invention, the metal borohydride-ether complex used in the process comprises of metal borohydride and ether solvent in the form of complex.

In accordance to one other aspect of the present invention, the metal borohydride-boron trifluoride complex used in the process comprises of mixture of metal borohydride and boron trifluoride complex system.

In accordance to yet another aspect of the present invention, method for the production of (S,S)-6-benzyloctahydro-lH-pyrrolo[3,4-b]pyridine represented by Formula-I;

Formula-I

comprises the steps of:

i) de-aromatization of compound of Formula-2,

Formula-2

in presence of metal catalyst;

Formula-7

(4aR,7aS)-6-benzyltetrahydro-lH-pyrrolo[3,4-b]pyridine-5,7(6H,7aH)-dione mono tartarate salt, wherein, said solvent system comprises a mixture of aprotic and protic solvent in the ratio of 1 :0.2-1.0, and

iii) obtaining compound of Formula-I from said compound of Formula-7.

In this phase, the compound of Formula-I can be obtained from compound of Formula-7 according to the process of the present invention, or according to the conventionally known processes.

In accordance to further aspect of the present invention, method for the production of (S,S)-6- benzyloctahydro-lH-pyrrolo[3,4-b]pyridine represented by Formula-I;

Formula-I

comprises the steps of:

i) racemisation of isomer of Formula-8,

Formula-8

ii) in situ dehydrochlorination of said chlorine-amine intermediate with base to get compound of Formula-9,

Formula-9

iii) and obtaining compound of Formula-I from said compound of Formula-9.

In this phase, the compound of Formula-I can be obtained from compound of Formula-9 according to the process of the present invention, or according to the conventionally known processes.

In accordance to furthermore aspect of the present invention, method for the production of (S,S)-6- benzyloctahydro-lH-pyrrolo[3,4-b]pyridine represented by Formula-I;

Formula-I

comprises the steps of:

i) racemisation of undesired isomer of Formula-8,

Formula-8

Formula-9

iii) high pressure hydrogenation in presence of metal catalyst;

iv) in situ resolution with D(-) tartaric acid to get compound of Formula-7,

. tartarate

Formula-7 (4aR,7aS)-6-benzyltetrahydro-lH-pyrrolo[3,4-b]pyridine-5,7(6H,7aH)-dione mono tartarate salt, and

v) obtaining compound of Formula-I from said compound of Formula-7.

In accordance with still another aspect of the present invention, the process of reduction of (4aR, 7aS)-6-benzyltetrahydro-lH-pyrrolo[3,4-b]pyridine-5,7(6H, 7aH)-dione, employs metal borohydride-ether complex prepared with the use of relatively less amount of ethereal solvent, thereby making the process cost-effective and industrially applicable. Also, the process of reduction of (4aR, 7aS)-6-benzyltetrahydro-lH-pyrrolo[3,4-b]pyridine-5,7(6H, 7aH)-dione, employs use of reducing agents like boron trifluoride/borohydride complex system in presence of solvent system comprising of at least one non-ethereal solvent.

Yet another aspect of the present invention provides preparation of the chiral (S,S)-6- benzyloctahydro-lH-pyrrolo[3,4-b]pyridine represented by Formula-I, in high yield having purity of > 98%. In accordance with further aspect of the present invention, it may be noted that it is possible to obtain the compound of Formula-I by following:

a) the process for preparing the compound of Formula-7 in accordance with the present invention, followed by performing the remaining steps as per the conventional procedures;

or

b) the process for preparing the compound of Formula-7 in accordance with the conventional methods and following the procedure of reduction to form compound of Formula-I, in accordance with the teachings of the present invention;

or

c) the process of racemisation of compound of Formula-8 in accordance with the teachings of the present invention, followed by performing the remaining steps as per the conventional procedures; d) the process of racemisation of compound of Formula-8 in accordance with the conventional methods and following the procedure of hydrogenation and resolution to form compound of Formula-7, in accordance with the teachings of the present invention. The above and other aspects of the present invention are further attained and supported by the following embodiments described herein. However, the described embodiments are in accordance with the best mode of practice and the scope of the invention is not restricted to the described embodiments herein after. Detailed Description of the Invention:

While the invention is susceptible to various modifications and alternative forms, specific embodiment thereof will be described in detail below. It should be understood, however that it is not intended to limit the invention to the particular forms disclosed, but on the contrary, the invention is to cover all modifications, equivalents, and alternative falling within the scope of the invention as defined by the appended claims.

The steps of a method may be providing more details that are pertinent to understanding the embodiments of the present invention and so as not to obscure the disclosure with details that will be readily apparent to those of ordinary skill in the art having benefit of the description herein.

Further characteristics and advantages of the process according to the invention will result from the description herein below of preferred exemplary embodiments, which are given as indicative and non-limiting examples.

The present invention provides an improved and industrially advantageous process for the production of (S,S)-6-benzyloctahydro-lH-pyrrolo[3,4-b]pyridine represented by Formula-I.

According to the present invention there is provided an improved method for production of (S,S)-6-benzyloctahydro-lH-pyrrolo[3,4-b]pyridine represented by Formula-I, with high purity and yield, which is amenable at large scale production. In accordance to one embodiment, the present invention provides a method for the production of (S,S)-6-benzyloctahydro-lH-pyrrolo[3,4-b]pyridine represented by Formula-I;

Formula-I

comprising the steps of:

i) tartarate hydrolysis of (4aR,7aS)-6-benzyltetrahydro-lH-pyrrolo[3,4-b]pyridine- 5,7(6H,7aH)-dione mono tartarate salt represented by Formula-7,

Formula-7

in presence of base in organic solvent (s) to get free base;

ii) in situ reduction of said free base with metal borohydride-ether or boron trifluoride complex in a solvent system to get (S,S)-6-benzyloctahydro-lH-pyrrolo[3,4-b]pyridine represented by Formula-I, said solvent system comprises of at least one non-ethereal solvent.

In other embodiment of the present invention, the metal borohydride-ether complex used in the process comprises of metal borohydride and ether solvent in the form of complex. In accordance to another embodiment of the present invention, metal borohydride-ether complex once prepared can be used immediately after the complex preparation or stored for longer time period as an effective reducing agent.

In accordance with another aspect of the present invention, the process of reduction of (4aR, 7aS)-6-benzyltetrahydro-lH-pyrrolo[3,4-b]pyridine-5,7(6H, 7aH)-dione, employs use of reducing agents like boron trifluoride /borohydride complex system in solvent system comprising mixture of at least one non-ethereal solvent like halogenated solvent and one aprotic solvent. In yet another embodiment of the present invention, metal borohydride of metal borohydride- ether complex used in the process is aluminium borohydride.

In further embodiment of the present invention, the ether solvent used to form metal borohydride-ether complex is selected from the group consisting of ethylene glycol dimethyl ether, tetrahydrofuran (THF), methyl-tetrahydrofuran, dimethoxyethane (DME) and more preferably tetrahydrofuran (THF) and ethylene glycol dimethyl ether.

In still another embodiment of the present invention, the solvent system used in combination with metal borohydride-ether complex is selected from hydrocarbons and halogenated solvents such as toluene, benzene, xylene (o,m,p), dichloroethane (DCE) or mixture thereof. The most preferred solvent used in the process is toluene and dichloroethane (DCE).

In yet another embodiment of the present invention, the reducing agent used for reduction of ketone groups is selected from metal borohydride-boron trifluoride complex like BF₃.THF/metal borohydride, BF₃.Et₂0/ metal borohydride, BF₃.ACN/ metal borohydride. Most preferably BF₃.THF/ metal borohydride complex system is used as reducing agent.

In further embodiment of the present invention, the metal borohydride of BF₃.THF / metal borohydride complex system is selected from sodium borohydride or potassium borohydride. More preferably, metal borohydride used is sodium borohydride.

Furthermore, the solvent system used in combination with BF₃.THF/ metal borohydride complex system comprises of the mixture of one non-ethereal solvent like halogenated solvent and one aprotic solvent. The halogenated solvent is selected from dichloromethane, dichloroethane, o-dichlorobenzene, chloroform and carbon tetrachloride. The most preferred halogenated solvent is dichloromethane. The aprotic solvent is selected from ether and nitriles such as tetrahydrofuran, dimethoxyethane, cyclohexane, methyl-tetrahydrofuran, diglyme and acetonitrile. The most preferred aprotic solvent is tetrahydrofuran.

In further embodiment of the present invention, the ratio of halogenated solvent to aprotic solvent is in the range of 0.5-3.0:3.0-6.0 and more preferably, 1.5-2.0: 5.0-6.0. In a specific embodiment of the present invention, the duration for the reaction is 0.5 to 6h.

The reaction is carried out at temperature range of -5 to 80°C, preferably between 10-40°C.

In furthermore embodiment of the present invention, the base used for hydrolysis of compound of Formula-7 is selected from inorganic base like hydroxides, carbonates, alkoxides, bicarbonates or mixture thereof. The preferred base is selected from sodium carbonate, sodium hydroxide, sodium bicarbonate, potassium hydroxide, potassium carbonate, potassium bicarbonate or mixture thereof. The most preferred base is sodium hydroxide and sodium carbonate.

In accordance with the second embodiment, the present invention further provides a method for the production of (S,S)-6-benzyloctahydro-lH-pyrrolo[3,4-b]pyridine represented by Formula-I,

Formula-I

comprising in situ reduction of 6-benzyl-5H-pyrrolo[3,4-b]pyridine-5,7(6H)-dione represented by Formula-2,

Formula-2

in presence of metal catalyst followed by D(-)-tartaric acid in a solvent system to give (4aR,7aS)-6-benzyltetrahydro-lH-pyrrolo[3,4-b]pyridine-5,7(6H,7aH)-dione mono tartarate salt represented by Formula-7, without isolation of the intermediate; . tartarate

Formula-7

wherein, said solvent system comprises of mixture of aprotic and protic solvent in the ratio of

1 : 0.2-1.0. In other embodiment of the present invention, the solvent system comprises a mixture of at least one protic with aprotic solvent wherein said protic solvent is selected from the group of C1-C4 alcohols, preferably, methanol and ethanol and aprotic solvent is selected from ketone and ester such as acetone, methyl ethyl ketone, n-butyl acetate and ethyl acetate, more preferably acetone.

In another embodiment of the present invention, the ratio of aprotic to protic solvent is 1 :0.2- 1.0. The most preferred range is between 1 :0.2-0.5.

In yet another embodiment of the present invention, the reaction is carried out at 20-90°C, preferably 30-70°C.

In further embodiment of the present invention, the acid used for resolution is D(-)-tartaric acid and the metal catalyst used for de-aromatization is selected from palladium on carbon and platinum oxide.

In accordance with the third embodiment, the present invention provides a method for the production of (S,S)-6- benzyloctahydro-lH-pyrrolo[3,4-b]pyridine represented by Formula-I;

Formula-I comprising the steps of:

i) racemisation of undesired isomer; (4aS,7aR)-6-benzyltetrahydro-lH-pyrrolo[3,4- b]pyridine-5,7(6H,7aH)-dione represented by Formula-8,

Formula-8

ii) dehydrochlorination with base to get 6-benzyl-3,4-dihydro-lH-pyrrolo[3,4-b]pyridine- 5,7(2H,6H)-dione represented by Formula-9,

Formula-9

without isolation of chlorine-amine intermediate;

iii) high pressure hydrogenation in presence of metal catalyst;

iv) in situ resolution with D(-) tartaric acid, to get (4aR,7aS)-6-benzyltetrahydro-lH- pyrrolo[3,4-b]pyridine-5,7(6H,7aH)-dione mono tartarate salt represented by Formula-7,

. tartarate

Formula-7

without isolation of intermediate.

v) conversion of said compound of Formula-7 to compound of Formula-I In other embodiment of the present invention, the chlorinating agent used in the process is trichloroisocyanuric acid.

The mole ratio of (4aS,7aR)-undesired isomer to trichloroisocyanuric acid is in the range of 1 :0.25-1.0.

In another embodiment of the present invention, the solvent system used in racemisation process comprises of organic solvent or mixture of organic solvent with water. In another embodiment, the organic solvent used in the process of racemisation is selected from the group of aprotic solvent such as toluene, benzene, cyclohexane, xylene, dichloromethane, chloroform, dichloroethane, and the like or, combination of two or more solvents from the list above thereof.

In yet another embodiment of the present invention, the base used for dehydrochlorination is selected from amines especially tertiary amines such as triethyl amine, diisopropyl ethyl amine, dimethyl aniline or mixture thereof.

In further embodiment, the metal catalyst is selected from palladium on carbon and platinum oxide.

The racemisation of undesired isomer is carried out at temperature range of 0-60°C. Most preferably, the temperature range is between 15-45°C.

In accordance to another aspect of the present invention, the intermediates; racemic 6- benzyltetrahydro-lH-pyrrolo[3,4-b]pyridine-5,7(6H,7aH)-dione, (4aR,7aS)-6- benzyltetrahydro- 1 H-pyrrolo [3 ,4-b]pyridine-5 , 7(6H, 7aH)-dione and chlorine-amine intermediate are not isolated and are in situ proceeded to next steps.

Compound of Formula-2 is prepared according to the teachings of the prior art, such as those described in IN329/CHE/2008; Jingxi Yu Zhuanyong Huaxuepin, 19(1), 43-44, 2011 and Zhongguo Yiyao Gongye Zazhi, 35(3), 129-131, 2004. Also, according to the teachings of prior art, Bulletin de la Societe Chimique de France (1966), (9), 3014-16; it is observed that metal borohydride like aluminium borohydride is prepared by reaction of aluminium trichloride with lithium borohydride in a proper solvent and resulting aluminium borohydride form complex with the solvent used in the reaction.

JP2012067033, discloses the use of aluminium borohydride as a reducing agent wherein aluminium borohydride is prepared by reacting sodium borohydride and aluminium trichloride in solvents like tetrahydrofuran at <30°C. CN101857199, also teaches the preparation of the ammonia adduct of aluminium borohydrides by reacting aluminium salt with metal (Na, Li, Ca) borohydride under heating conditions followed by bubbling inert gas and reaction with ammonia at low temperatures for a longer duration. Learnings from the above mentioned prior art form the basis for preparation of aluminium borohydride-ether complex as a reducing agent in the present invention.

Further, according to fourth embodiment, the present invention provides an advantage in sequential addition of borohydride, the boron triflouride complex and the dione. This sequence is preferred, as it initially leads to the activation of reducing agent (BF₃.TFIF/NaBH₄) resulting into active reduction of diones. Such schematic addition not only shrinks the overall time required for the reduction of the keto groups but also ascertains the completion of reaction and results into increase in the yields of the reaction. Furthermore, the present invention is illustrated in detail by way of following examples. The examples are given herein for illustration of the invention and are not intended to be limited thereof.

Example 1 : Preparation of aluminium borohydride-tetrahydrofuran complex* as a reducing agent

To 400ml of tetrahydrofuran was added 91.5g (0.68mol) of aluminium chloride and stirred the solution for 30 min at room temperature. Reaction mass was then cooled to 20-30°C followed by addition of 54g (1.43mol) of sodium borohydride. Stirred the reaction mass at 30°C for 3h and the resulting suspension was then filtered under nitrogen to get a clear solution of aluminium borohydride-tetrahydrofuran complex (AlfBH^ HF complex). Example 2: Preparation of aluminium borohydride-ethylene glycol dimethyl ether complex* as a reducing agent

Replaced tetrahydrofuran in example 1 with ethylene glycol dimethyl ether to get aluminium borohydride-diglyme complex (AlfBH^ diglyme complex). Example 3 : Preparation of aluminium borohydride-Dimethoxy ethane complex* as a reducing agent

To 250ml of Dimethoxyethane was added 45.75g (0.34mol) of aluminium chloride and stirred the solution for 30 min at room temperature. Further reaction was proceeded as per example 1 to get a clear solution of aluminium borohydride-Dimethoxy ethane complex (ΑΚΒΗ .ΡΜΕ complex).

* Aluminium borohydride-ether complex are stored under nitrogen and are observed to be stable at room temperature. Example 4: Preparation of (4aR,7aS)-6-benzyltetrahydro-lH-pyrrolo[3,4-blpyridine-

5,7(6FL7aH)-dione mono tartarate salt represented by Formula-7 To an autoclave was added lOOg (0.42mol) of 6-benzyl-5H-pyrrolo[3,4-b]pyridine-5,7(6H)- dione and 300ml of methanol followed by addition of catalyst, Pd/C. The reaction mass was then stirred under hydrogen pressure of 20-25 Kg/cm² at 60°C till completion of reaction. Filtered the reaction mass and added 1000ml of acetone to the methanol layer so obtained followed by addition of 52.25g (0.35mol) of D(-)-tartaric acid to get the clear solution. The reaction mass was then allowed to cool at room temperature and stirred for 5h. Filtration was carried to get solid compound. Dissolved the solid so obtained in 85% aq. isopropyl alcohol and heated to reflux to get clear solution. Cooled the reaction mass to room temperature followed by filtration to get 45g of (4aR,7aS)-6-benzyltetrahydro-lH-pyrrolo[3,4-b]pyridine- 5,7(6H,7aH)-dione mono tartarate salt. It can be observed that in accordance with the teachings of present invention, the process of preparation of compound of Formula- 7 is done without isolation of intermediate, (4aR,7aS)- 6-benzyltetrahydro-lH-pyrrolo[3,4-b]pyridine-5,7(6H,7aH)-dione, by effectively using the leftover solvent of catalytic de-aromatization process like methanol, to get (4aR,7aS)-6- benzyltetrahydro-lH-pyrrolo[3,4-b]pyridine-5,7(6H,7aH)-dione mono tartarate salt which is contrary to the understanding from prior art wherein, (4aR,7aS)-6-benzyltetrahydro-lH- pyrrolo[3,4-b]pyridine-5,7(6H,7aH)-dione firstly, is isolated by distillation of methanol, which is discarded, and then resolution is performed using an acid in a solvent system. This aspect of present invention provides advantages such as (a) evading not merely number of additional process steps but also wastage of solvents like methanol; (b) enabling the reaction to be conducted in an in situ manner; (c) making the process easier for commercial adoption.

Example 5: Preparation of (S,S)-6-benzyloctahydro-lH-pyrrolo|^"3,4-b^"|pyridine represented by Formula-I using AlfBH^ HF complex as reducing agent.

To the solution of 49.5g (0.125mol) of (4aR,7aS)-6-benzyltetrahydro-lH-pyrrolo[3,4- b]pyridine-5,7(6H,7aH)-dione mono tartarate salt in 90ml of toluene was added 100ml of water at 25°C. Adjusted the pH of the reaction mass to 9.0-9.5 by addition of aq. sodium hydroxide solution and separated the two layers. The toluene layer containing the free base, (4aR,7aS)-6-benzyltetrahydro-lH-pyrrolo[3,4-b]pyridine-5,7(6H,7aH)-dione, was then added to 150g of aluminium borohydride in tetrahydrofuran (A1(BH₄)₃.THF complex) as prepared in example in 1, and stirred the reaction mass at 30-35°C for 4h. After completion of reaction, 150ml of aq. sodium hydroxide was added to the reaction mass followed by separation of organic layer. Added hydrochloric acid to the organic layer and heated the resulting reaction mixture under reflux for one hour. Separated the layers and adjusted the pH of aqueous layer to 14.0 using saturated solution of sodium hydroxide followed by extracted of compound in toluene. Collected the toluene layers and concentrated under reduced pressure to get 21.5g of (S,S)-6-benzyloctahydro-lH-pyrrolo[3,4-b]pyridine.

Example 6: Preparation of (S,S)-6-benzyloctahydro-lH-pyrrolo|^"3,4-b^"|pyridine represented by Formula-I using AKBH_j DME complex as reducing agent

To the solution of 16.4g (0.041mol) of (4aR,7aS)-6-benzyltetrahydro-lH-pyrrolo[3,4- b]pyridine-5,7(6H,7aH)-dione mono tartarate salt in 30ml of toluene was added 35ml of water at 25°C. Adjusted the pH of the reaction mass to 9.0-9.5 by addition of aq. sodium hydroxide and separated the two layers. The toluene layer containing the free base, (4aR,7aS)-6-benzyltetrahydro-lH-pyrrolo[3,4-b]pyridine-5,7(6H,7aH)-dione, was then added drop to 60g of aluminium borohydride in dimethoxy ethane (A1(BH₄)₃.DME complex) as prepared in example 3, and stirred the reaction mass at 30-35°C for 4h. After completion of reaction, 50ml of aq. sodium hydroxide was added to the reaction mass followed by separation of organic layer. Added hydrochloric acid to the organic layer and heated the resulting reaction mixture under reflux for one hour. Separated the layers and adjusted the pH of aqueous layer to 14.0 using saturated solution of sodium hydroxide followed by extracted of compound in toluene. Collected the toluene layers and concentrated under reduced pressure to get 7.16g of (S,S)-6-benzyloctahydro-lH-pyrrolo[3,4-b]pyridine.

Example 7: Preparation of (S,S)-6-benzyloctahydro-lH-pyrrolo|^"3,4-b^"|pyridine represented by Formula-I using Al(BH₄)₃.diglyme complex as reducing agent.

Replaced aluminium borohydride in dimethoxy ethane (A1(BH₄)₃.DME complex) in Example 6 with aluminium borohydride ethylene glycol dimethyl ether complex (Al(BH4)3.diglyme complex) to get 7.0g of (S,S)-6-benzyloctahydro-lH-pyrrolo[3,4-b]pyridine.

Example 8: Preparation of (S,S)-6-benzyloctahydro-lH-pyrrolo|^"3,4-b^"|pyridine represented by Formula-I using freshly prepared A1(BH₄)₃.THF complex as reducing agent.

To 200ml of tetrahydrofuran was slowly added 45.78g (0.344mol) of aluminium chloride and stirred the solution for 30 min at room temperature. Reaction mass was then cooled to 30°C followed by addition of 27. Og (0.710mol) of sodium borohydride and stirred the reaction mass at 30°C for 3h to get aluminium borohydride. THF complex. Meanwhile, to another Round Bottom Flask was added 82g (0.208mol) of (4aR,7aS)-6-benzyltetrahydro-lH- pyrrolo[3,4-b]pyridine-5,7(6H,7aH)-dione mono tartarate salt in 150ml of toluene and 160ml of water at 25°C. Adjusted the pH of the above reaction mass to 9.0-9.5 by addition of aq. sodium carbonate solution and separated the two layers. The toluene layer containing free base, (4aR,7aS)-6-benzyltetrahydro-lH-pyrrolo[3,4-b]pyridine-5,7(6H,7aH)-dione, was then added to the aluminium borohydride in tetrahydrofuran complex prepared above and stirred the reaction mass at 30-35°C for 3-4h. After completion of reaction, 250ml of aq. sodium hydroxide was added to the reaction mass followed by separation of organic layer. Added hydrochloric acid to the organic layer and heated the resulting reaction mixture under reflux for one hour. Separated the layers and adjusted the pH of aqueous layer to 14.0 using saturated solution of sodium hydroxide followed by extracted of compound in toluene. Collected the toluene layers and concentrated under reduced pressure at 55-60°C to get 37.5g of (S,S)-6-benzyloctahydro-lH-pyrrolo[3,4-b]pyridine. Example 9: Preparation of (S,S)-6-benzyloctahydro-lH-pyrrolo|^"3,4-b^"|pyridine represented by Formula-I using BF3.etherate and sodium borohydride as a reducing agent

Charged 46.5g (1.22 mol) of sodium borohydride to 550ml of tetrahydrofuran and cooled the reaction mass to 0-5°C followed by addition of 174.56g (1.23mol) of BF3.etherate and stirred the reaction mass at room temperature for 45min to activate the above said reducing agent. Added solution of lOOg (0.41 mol) of (4aR,7aS)-6-benzyltetrahydro-lH-pyrrolo[3,4- b]pyridine-5,7(6H,7aH)-dione dissolved in 100ml of dichloromethane at 5°C and stirred at room temperature for 5-6h. Distilled off the reaction solvent under reduced pressure and added 500ml of 2N sodium hydroxide at room temperature. Added 300ml of toluene and stirred the reaction mass at ambient temperature for 30min. Separated the layers and acidified the organic layer thence collected by hydrochloric acid. Heated the reaction mass to 70-80°C for 2h. Separated the aqueous layer followed by basification with concentrated sodium hydroxide solution below 20°C. Extracted the compound in toluene and concentrated under vacuum to get 84g (95%) of (S,S)-6-benzyloctahydro-lH-pyrrolo[3,4-b]pyridine Example 10: Preparation of (S,S)-6-benzyloctahydro-lH-pyrrolo|^"3,4-b^"|pyridine represented by Formula-I using BF3.etherate and sodium borohydride as a reducing agent

To the solution of 83g (0.21mol) of (4aR,7aS)-6-benzyltetrahydro-lH-pyrrolo[3,4- b]pyridine-5,7(6H,7aH)-dione mono tartarate salt in 100ml of dichloromethane was added 25% aqueous sodium carbonate solution to adjust the pH of the reaction mass to 9.0-9.5. Stirred the reaction mass at room temperature for 30min and separated the two layers. Meanwhile to another round bottom flask, charged 21.7g (0.57 mol) of sodium borohydride to 275ml of tetrahydrofuran and cooled the reaction mass to 0-5°C followed by addition of 93g (0.65mol) of BF3.etherate and stirred the reagent at room temperature for 45min to activate the above said reducing agent. Added the former dichloromethane containing the free base of (4aR,7aS)-6-benzyltetrahydro-lH-pyrrolo[3,4-b]pyridine-5,7(6H,7aH)-dione to the activated reducing agent at 5°C and stirred at room temperature for 5-6h. Distilled the reaction solvent under reduced pressure and added 100ml of toluene and 500ml of 2N sodium hydroxide solution followed by stirring at ambient temperature for 30min. separated the layers and acidified the organic layer thence collected by hydrochloric acid. Heated the reaction mass to 70-80°C for 2h. Separated the aqueous layer followed by basification with concentrated sodium hydroxide solution below 20°C. Extracted the compound in toluene and concentrated under vacuum to get 41. lg (93.0%) of (S,S)-6-benzyloctahydro-lH-pyrrolo[3,4- b]pyridine.

In accordance with the learning from the present invention, the use of metal borohydride - ether or boron trifluoride complex as reducing agent in sequential manner completes the reaction in short period of time which is contrary to prior art (18-24h) and as the reduction of diones is performed in solvent system comprising of one or more organic solvent wherein one solvent is other than ethereal solvent, eases the time engulfing work up and purification process thereby making process easier to be performed at commercial scale. In addition to the above, the process follows in situ path wherein the free base, (4aR,7aS)-6-benzyltetrahydro- lH-pyrrolo[3,4-b]pyridine-5,7(6H,7aH)-dione, is not isolated thereby reducing number of isolation, purification and drying processes. This provides an additional advantage of (a) plummeting the overall time required for preparation of (S,S)-6-benzyloctahydro-lH- pyrrolo[3,4-b]pyridine; (b) making process cheap to be ran commercially. Furthermore, in accordance to the teachings of present invention, reduction is being performed on chiral compound thereby requiring less amount of reducing agent as will be required when performed on racemic compound.

Example 11 : Preparation of 6-benzyl-3,4-dihydro-lH-pyrrolo[3,4-blpyridine-5,7(2H,6H)- dione represented by Formula-9, in single organic solvent.

To the solution of 25g (0.102mol) of (4aS,7aR)-6-benzyltetrahydro-lH-pyrrolo[3,4- b]pyridine-5,7(6H,7aH)-dione in 125 ml of toluene was added 12. Og (0.0512mol) of trichloroisocyanuric acid and stirred the reaction at 25-30°C for lh. After completion of reaction, de-mineralised water was added to the reaction mass and separated the toluene layer followed by addition of 10.3 g (0.102mol) of triethyl amine while maintaining the temperature between 30-35°C. Stirred the reaction mass at 30-35°C till completion of reaction and separated the organic layer followed by distillation under reduced pressure to get 23.5g of 6- benzyl-3,4-dihydro-lH-pyrrolo[3,4-b]pyridine-5,7(2H,6H)-dione. Example 12: Preparation of 6-benzyl-3,4-dihydro-lH-pyrrolo[3,4-blpyridine-5,7(2H,6H)- dione represented by Formula-9, in mixture of organic solvents To the mixture of 4.77g (0.0204mol) of trichloroisocyanuric acid in 50 ml of water was added a solution of lOg (0.0409mol) of (4aS,7aR)-6-benzyltetrahydro-lH-pyrrolo[3,4- b]pyridine-5,7(6H,7aH)-dione dissolved in 50 ml of toluene was and stirred the reaction at room temperature for lh. After completion of reaction, separated the two layers and added 4.2g (0.0409mol) of triethyl amine to the toluene layer so obtained, while maintaining the temperature between 30-35°C. Stirred the reaction mass at 30-35°C till completion of reaction and separated the organic layer followed by distillation under reduced pressure to get 9.4g of 6-benzyl-3,4-dihydro-lH-pyrrolo[3,4-b]pyridine-5,7(2H,6H)-dione.

In accordance with the teachings from the present invention, the use of trichloroisocyanuric acid followed by base follows different route for racemisation wherein trichloroisocyanuric acid, firstly chlorinate the chiral compound to give chlorine-amine intermediate, which is followed by addition of base that results into dehydrochlorination to give racemised compound. There are no major side products observed during the progress of the reaction which is contrary to the prior art, CN101429199, which claims the use of manganese dioxide (Mn0₂) for racemisation of undesired isomer. It is observed that the use of Mn0₂ results into formation of equivalent amount of manganese oxide as a side product which makes reaction mass thick and hence need to be removed periodically from the reaction mass. Such kind of side products are not observed with trichloroisocyanuric acid. This aspect of present invention provides advantages such as (a) evading formation of side products; (b) ease of work up and purification processes; (c) making the process environmental affable; and (d) making process easier for commercial adoption.

Claims

What Claimed Is:

1. A process for the production of (S,S)-6-benzyloctahydro-lH-pyrrolo[3,4- b]pyridine represented by Formula-I;

Formula-I

comprising the steps of:

i) de-aromatization of compound of Formula-2

Formula-2

in presence of metal catalyst;

ii) in situ resolution of the resultant with D(-)-tartaric acid in a solvent system to get compound of Formula-7

Formula-7

v) racemisation of undesired isomer of Formula-8,

Formula-8

Formula-9

vii) high pressure hydrogenation in presence of metal catalyst;

viii) resolution with D(-) tartaric acid, to get compound of Formula-7;

ix) obtaining compound of Formula-I from said compound of Formula-7.

2. A process for the production of (S,S)-6-benzyloctahydro-lH-pyrrolo[3,4- b]pyridine represented by Formula-I;

Formula-I

comprising the steps of:

i) de-aromatization of compound of Formula-2

Formula-2 in presence of metal catalyst;

Formula-7

iv) in situ reduction of free base of compound of Formula-7 with metal borohydride- ether or boron trifluoride complex in solvent system to get compound of Formula-I, said solvent system comprises of at least one non-ethereal solvent.

3. The process according to claim 2, wherein said metal borohydride-ether complex comprises of metal borohydride and ether solvent in the form of complex.

4. The process according to claim 2, wherein the said metal borohydride-boron trifluoride complex is selected from the group of BF₃.THF/ metal borohydride, BF₃.Et₂0/ metal borohydride, or BF₃.ACN/ metal borohydride.

5. The process according to claim 3, wherein said metal borohydride is aluminium borohydride.

6. The process according to claim 3, wherein said ether solvent is selected from the group of ethylene glycol dimethyl ether, tetrahydrofuran (TFIF), methyl- tetrahydrofuran and dimethoxy ethane.

7. The process according to claim 4, wherein the said metal borohydride is selected from sodium borohydride or potassium borohydride.

8. A process for the production of (S,S)-6-benzyloctahydro-lH-pyrrolo[3,4-b]pyridine represented by Formula-I;

Formula-I

comprising the steps of:

i) tartarate hydrolysis of compound of Formula-7,

. tartarate

Formula-7

in presence of base in organic solvent (s) to get free base of compound of Formula-7;

ii) in situ reduction of said free base with metal borohydride-ether or boron triflouride complex in solvent system to get compound of Formula-I, said solvent system comprises of atleast one non-ethereal solvent.

9. The process according to claim 8, wherein said solvent system used in step (ii), in combination with metal borohydride-ether complex is a mixture of one or more non-ethereal solvent selected from hydrocarbons and halogenated solvents such as toluene, benzene, xylene (o,m,p) and dichloroethane (DCE).

10. The process according to claim 8, wherein said solvent system used in step (ii), in combination with metal borohydride-boron triflouride complex system is a mixture of at least one non-ethereal solvent like halogenated solvent and one aprotic solvent.

11. The process according to claim 10, wherein said halogenated solvent is selected from the group of dichloro methane, dichloroethane, o-dichlorobenzene, chloroform, carbon tetrachloride and mixture thereof.

12. The process according to claim 10, wherein said aprotic solvent is selected from the group of tetrahydrofuran, dimethoxyethane, cyclohexane, methyl-tetrahydrofuran, diglyme, acetonitrile and mixture thereof.

13. The process according to claim 10, wherein the ratio of halogenated solvent to aprotic solvent in the solvent system is 0.5-3.0:3.0-6.0

14. The process according to claim 8, wherein said free base, (4aR,7aS)-6- benzyltetrahydro-lH-pyrrolo[3,4-b]pyridine-5,7(6H,7aH)-dione, is not isolated.

15. A process for the production of (S,S)-6-benzyloctahydro-lH-pyrrolo[3,4- b]pyridine represented by Formula-I;

Formula-I

comprising the steps of:

i) de-aromatization of compound of Formula-2,

Formula-2

in presence of metal catalyst;

ii) in situ resolution with D(-)-tartaric acid in a solvent system to get compound of

Formula-7,

Formula-7

wherein, said solvent system comprises a mixture of aprotic and protic solvent in the ratio of 1 :0.2-1.0; and

iii) obtaining compound of Formula-I from said compound of Formula-7.

16. The process according to claim 15, wherein said metal catalyst is selected from palladium on carbon and platinum oxide.

17. The process according to claim 15, wherein said protic solvent is selected from the group of C1-C4 alcohols.

18. The process according to claim 15, wherein said aprotic solvent is selected from ketones and esters.

19. A process for the production of (S,S)-6-benzyloctahydro-lH-pyrrolo[3,4- b]pyridine represented by Formula-I;

Formula-I

comprising the steps of:

i) racemisation of isomer of Formula-8,

Formula-8

ii) in situ dehydrochlorination of said chlorine-amine intermediate with base to get compound of Formula-9;

Formula-9

iii) high pressure hydrogenation in presence of metal catalyst;

iv) resolution with D(-) tartaric acid, to get compound of Formula-7; and

. tartarate

Formula-7

v) obtaining compound of Formula-I from said compound of Formula-7.

20. The process according to claim 19, wherein said chlorinating agent is trichloroisocyanuric acid.

21. The process according to claim 19, wherein said organic solvent is selected from an aprotic solvent such as toluene, benzene, cyclohexane, xylene, dichloromethane, chloroform, dichloroethane or a combination thereof.

22. The process according to claim 19, wherein said base is selected from the tertiary amines like triethyl amine, diisopropyl ethyl amine, dimethyl aniline or mixture thereof.

23. The process according to claim 19, wherein said chlorine-amine intermediate, is not isolated.

24. The process for the preparation of (S,S)-6-benzyloctahydro-lH-pyrrolo[3,4- b]pyridine comprising the steps of:

(i) hydrolysing (4aR, 7aS)-6-benzyltetrahydro-lH-pyrrolo[3,4-b]pyridine-5,7(6H, 7aH)-dione tartarate salt in a halogenated solvent to obtain a free base,

(ii) optionally isolating the said free base,

(iii) activating a reducing agent by addition of a boron trifluoride complex to metal borohydride and aprotic solvent mixture,

(iv) adding the free base dissolved in halogenated solvent to the activated reducing agent of step (iii),

(v) distilling the reaction solvent, and

(vi) isolating and drying the (S,S)-6-benzyloctahydro-lH-pyrrolo[3,4-b]pyridine.