Claims:
1. A process for preparation of (4aS,7aS)-2,3,4,4a,5,6,7,7a-octahydro-lH-pyrrolo[3,4-b]pyridine of formula (A)

From (4aR,7aS)-6-benzyl-1,2,3,4,4a,7a-hexahydropyrrolo[3,4-b]pyridine-5,7-dione of Formula (II)

comprising the steps of:
i) reducing (4aR,7aS)-6-benzyl-l,2,3,4,4a,7a-hexahydropyrroIo[3,4-b]pyridine-5,7-dione using a suitable reducing agent; and
ii) carrying out debenzylation of product in step i) in presence of a suitable catalyst to obtain (4aS,7aS)-2,3,4,4a,5,6,7,7a-octahydro-lH-pyrrolo[3,4-b]pyridine of formula (A),
wherein a process for preparing (4aR,7aS)-6-benzyl-l,2,3,4,4a,7a-hexahydropyrrolo[3,4-b]pyridine-5,7-dione of formula (II), comprising the steps of:
a) reacting D-(-)-tartaric acid in water with Cis 6-benzyl-l,2,3,4,4a,7a-hexahydropyrrolo[3,4-b]pyridine-5,7-dione of formula (I)

thereby forming tartrate salt of (4aR,7aS)-6-benzyl-l,2,3,4,4a,7a-hexahydropyrrolo[3.4-b]pyridine-5,7-dione therein; and
b) reacting tartrate salt in step a) with a base thereby obtaining (4aR,7aS)-6- benzyl--l,2,3,4,4a,7a-hexahydropyrrolo[3,4-b]pyridine-5,7-dione of formula (II).

2. The process as claimed in claim 1, wherein the base is selected from one or more of the following sodium bicarbonate, potassium bicarbonate, liquid ammonia, ammonium hydroxide and ammonia gas.

3. The process as claimed in claim 1, wherein the reducing agent used in step i) is selected from one or more of the following Lithium Aluminium hydride (LAH), Sodium bis-(2-methoxyethoxy)aluminium hydride commonly known as Vitride®, sodium borohydride along with activating agents selected from boron trifluoride etherate (BF3(C2O5)2O], dimethyl sulfate, aluminium chloride, calcium chloride and/or mixtures therof.

4. The process as claimed in claim 1, wherein said reaction is carried out in presence of a solvent selected from a group of dimethylformamide, tetrahydrofiiran, dichloromethane, dimethoxyethane, acetonitrile, dimethyl sulfoxide, 1,4-dioxane, toluene, ethereal solvents and/or mixtures thereof.

5. The process as claimed in claim 1, wherein said reaction is carried out in presence of complex formed by aluminium chloride, sodium borohydride and dimethoxy ethane.

6. The process as claimed in claim 1, wherein the catalyst is pd/C.

7. A process for preparation of (4aS,7aS)-2,3,4,4a,5,6,7,7a-octahydro-lH-pyrrolo[3,4-bjpyridine of formula (A)

from (4aR,7aS)-6-benzyl-1,2,3,4,4a,7a-hexahydropyrrolo[3,4-b]pyridine-5,7-dione of Formula (II)

comprising the steps of:
i) reducing (4aR,7aS)-6-benzyl-l,2,3,4,4a,7a-hexahydropyrrolo[3,4-b]pyridine-5,7-dione formed by a process using a suitable reducing agent; and
ii) carrying out debenzylation of product in step i) in presence of a suitable catalyst thereby obtaining (4aS,7aS)-2,3,4,4a,5,6,7,7a-octahydro-lH-pyrrolo[3,4-b]pyridine of formula (A),
wherein a process for preparing (4aR,7aS)-6-benzyl-1,2,3,4,4a,7a-hexahydropyrrolo[3,4-b]pyridine-5,7-dione of formula (II), comprising the steps of:
a) reacting D-(-)-tartaric acid in a solvent mixture of IPA and acetonitrile with Cis 6-benzyl--l,2,3,4,4a,7a-hexahydropyrrolo[3,4-b]pyridine-5,7-dione of formula (I)

thereby forming (4aR,7aS)-6-benzyl-l,2,3,4,4a,7a-hexahydropyrrolo[3,4-b]pyridine-5,7-dione tartrate salt therein; and
b) reacting tartrate salt in step a) with a base thereby obtaining (4aR,7aS)-6-benzyl-l,2,3,4,4a,7a-hexahydropyrrolo[3,4-b]pyridine-5,7-dione of formula (II).

8. The process as claimed in claim 7, wherein the solvent mixture is taken in the ratio of 2:1 to 4:3.

9. The process as claimed in claim 7, wherein the solvent mixture is taken in the ratio of 3:2.
10. The process as claimed in claim 7, wherein, the base is selected from one or more of the following sodium bicarbonate, potassium bicarbonate, liquid ammonia, ammonium hydroxide and ammonia gas.

11. The process as claimed in claim 7, wherein the reducing agent used in step i) is selected from one or more of the following Lithium Aluminium hydride (LAH), Sodium bis-(2-methoxyethoxy)aluminium hydride commonly known as Vitride®, sodium borohydride along with activating agents selected from boron trifluoride etherate (BF3(C2O5)2O], dimethyl sulfate, aluminium chloride, calcium chloride and/or mixtures thereof.

12. The process as claimed in claim 7, wherein said reaction is carried out in presence of a solvent selected from a group of dimethylformamide, tetrahydrofuran, dichloromethane, dimethoxyethane, acetonitrile, dimethyl sulfoxide, 1,4-dioxane, toluene, ethereal solvents and/or mixtures thereof.

13. The process as claimed in claim 7, wherein said reaction is carried out in presence of complex formed by aluminium chloride, sodium borohydride and dimethoxy ethane.

14. The process as claimed in claim 7, wherein the catalyst is Pd/C.
, Description:

FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
COMPLETE SPECIFICATION
(See Section 10, Rule 13)

IMPROVED PROCESS FOR SYNTHESIS OF MOXIFLOXACIN INTERMEDIATE (S,S)-2,8-DIAZABICYCLO[4.3.0]NONANE

AARTI INDUSTRIES LIMITED, A COMPANY INCORPORATED UNDER THE COMPANIES ACT, 1956, HAVING ADDRESS, 71, UDYOG KSHETRA, 2ND FLOOR, MULUND GOREGAON LINK ROAD, MULUND (W) MUMBAI, 400080, MAHARASHTRA, INDIA

THE FOLLOWING SPECIFICATION PARTICULARLY DESCRIBES THE INVENTION AND THE MANNER IN WHICH IT IS TO BE PERFORMED


Field of the Invention
The present invention relates to Moxifloxacin intermediates and more particularly to an improved process for the preparation of Moxifloxacin intermediates (S,S)-2,8-diazabicyclo[4.3.0]nonane.

Background and prior art
(4aS,7aS)-2,3,4,4a,5,6,7,7a-octahydro-lH-pyrrolo[3,4-b]pyridine of formula (A), also referred to as (4aS, 7aS)-Octahydro-lH-pyrrole[3,4-b]pyridine and also named as (S,S)-2.8-Diazabycyclo[4.3.0] nonane is well-known in the art as an important intermediate in the manufacturing of Moxifloxacin and many other pharmaceutically active ingredients. The (4aS,7aS)-2,3,4,4a,5,6,7,7a-octahydro-lH-pyrrolo[3,4-b]pyridine of formula (A) is illustrated below-

This intermediate is a most critical to prepare as it has two chiral centres and both having S-configuration. Various processes are known in art for the preparation of this intermediate.

Prior art patents EP0550903, EP1077979 and US5468742 describe resolution of cis-8-benzyl-2,8-diazabicyclo[4.3.0]nonane using D(-)-tartaric acid or L(+)-tartaric acid in dimethyl formamide. It is generally found advantageous to resolve a compound into single enantiomer during the initial stages of the process, as the reduction of dione is performed on chiral compound thereby requiring less amount of reducing agent as will be required when performed on racemic compound to obtain high throughput in the synthesis.

For example, US6235908 reports resolution of cis benzylpyrrolopiperidine using L-(+)-tartaric acid to form (S,S)-benzyl pyrrolopiperidine tartrate wherein the resolution is carried out in mixture of alcohol and water. The alcohol used in said process is selected from sec-butanol, iso-butanol, iso-amyl alcohol, iso-octanol, butanol and ethanol. The process disclosed seeding of (S,S)-benzyl pyrrolopiperidine tartrate along with re-crystallization from alcohol and water mixture in the ratio of 85:15. As mentioned in the description of said patent document, for re-crystallization process, about 4-6 litres of Ethanol/water or 8-9 litres of butanol/water mixture is used for 1 Kg of (S,S)-8-benzyl— 2,8-diazabicycIo[4.3.0]nonane-L(+) tartrate. Thus, the process was found to consume high amount of alcoholic solvents for re-crystallization which would make industrial processes commercially infeasible.

Another example, US5468742 and US5480879 disclose resolution of cis-8-benzyl-7,9-dioxo-2,8-diazabicycIo[4.3.0]-nonane with D(-) tartaric acid or L(+)-tartaric acid wherein the resolution was carried out in solvent dimethyl formamide. However, said process also needs further purification by crystallization from methoxyethanol. The resolution was carried out in solvent mixture of ethanol and acetonitrile, preferably using 410 ml of ethanol and 25 ml of acetonitrile for resolution of 24.1 g of racemic compound. Thus, said process was found to consume high amount of alcoholic solvent. Also said method needed further purifications by re-crystallization from mixture of ethanol and ethylene glycol monomethyl ether. Thus said process involves lengthy operations for getting desired enantiomer in adequate purity. Thus said process is found unsuitable for preparation on industrial scale.

Accordingly, there exists a need to develop a process for preparing (4aR,7aS)-6-benzyl-1,2,3,4,4a,7a-hexahydropyrrolo[3,4-b]pyridine-5,7-dione and ultimately (4aS,7aS)-2,3,4,4a,5,6,7,7a-octahydro-lH-pyrrolo[3,4-b]pyridine which avoids excess usage of alcoholic solvents. Also, there exists a need of a process that provides better yield with higher chiral purity thereby facilitating easy racemization of undesired isomer.

Objects of the invention
An object of present invention is to provide an improved resolution process for synthesis of Moxifloxacin intermediate, (S,S)-2,8-diazabicyclo[4.3.0]nonane.

Another object of the present invention is to provide a resolution process of cis-8-benzyl-7,9-dioxo-2,8-diazabicyclo[4.3.0]-nonane that avoids excess usage of alcoholic solvents.

Yet another object of the present invention is to provide a resolution process that avoids lengthy work-ups and additional purification for getting desired product.

Another object of the present invention is to provide a resolution process that racemizes and recycles the undesired isomer for increasing overall yield of said process.

Yet another object of present invention is to provide a process for the preparation of (S,S)-2,8-diazabicyclo[4.3.0]nonane having higher chiral purity, higher yield, industrially feasible and applicable.

Summary of the invention
In a preferred embodiment, the present invention provides a stereo-specific synthesis of Moxifloxacin intermediate (4aS,7aS)-2,3,4,4a,5,6,7,7a-octahydro-lH-pyrrolo[3,4-bjpyridine of formula (A), which comprises resolution of cis compound 6-benzyl-l,2,3,4,4a,7a-hexahydropyrrolo[3,4-b]pyridine-5,7-dione of formula (I) using D(-)-tartaric acid. The reaction mechanism of said process is schematically represented as follows-

In this preferred embodiment, the resolution reaction is carried out in presence of solvents selected from Toluene, Acetone, water and/or mixtures thereof. In this one preferred embodiment, the reaction is carried out with water as a solvent.

In an alternative embodiment, the present invention provides a stereo-specific synthesis of Moxifloxacin intermediate (4aS,7aS)-2,3,4,4a,5,6,7,7a-octahydro-lH-pyrrolo[3,4-b]pyridine of formula (A), which comprises resolution of cis compound 6-benzyl-l,2,3,4,4a,7a-hexahydropyrrolo[3,4-b]pyridine-5,7-dione of formula (I) using D(-)-tartaric acid. The reaction can be schematically represented as follows.

The resolution reaction is carried out in a solvent mixture of iso-propyl alcohol and acetonitrile.

The processes of present invention avoid use of excess Alcoholic solvents/ hazardous solvents in said processes thereby making these processes industrially feasible. The desired isomer obtained after resolution reaction shows chiral purity in a range of about 97-99%. The processes of the present invention avoid purification by re-crystallizations or by any other techniques known in the art. These processes avoid lengthy workups and also avoid use of large amounts of solvents required for re-crystallization. The undesired isomer is isolated and racemized and recycled back for resolution in said processes thereby avoiding yield loss thereof and making them substantially cost-effective.

Detailed description of the invention
While this document contains many specifics, these should not be construed as limitations on the scope of an invention that is claimed or of what may be claimed, but rather as descriptions of features specific to particular embodiments. Certain features that are described in this document in the context of separate embodiments can also be implemented in combination in a single embodiment. Conversely, various features that are described in the context of a single embodiment can also be implemented in multiple embodiments separately or in any suitable sub-combination. Moreover, although features may be described above as acting in certain combinations and even initially claimed as such, one or more features from a claimed combination can in some cases be excised from the combination, and the claimed combination may be directed to a sub-combination or a variation of a sub-combination. Similarly, while operations are depicted in the drawings in a particular order, this should not be understood as requiring that such operations be performed in the particular order shown or in sequential order, or that all illustrated operations be performed, to achieve desirable results.

Only a few examples and implementations are disclosed. Variations, modifications, and enhancements to the described examples and implementations and other implementations can be made based on what is disclosed.

Examples are set forth herein below and are illustrative of different amounts and types of reactants and reaction conditions that can be utilized in practicing the disclosure. It will be apparent, however, that the disclosure can be practiced with other amounts and types of reactants and reaction conditions than those used in the examples, and the resulting devices various different properties and uses in accordance with the disclosure above and as pointed out hereinafter.
As used in the specification the singular forms "a" "an" and "the" include plural references unless the context clearly dictates otherwise. Thus, for example, reference to "a solvent" includes mixtures of solvents, reference to "an agent" includes mixtures of two or more such agents, and the like.

In one preferred embodiment, the present invention provides stereo-specific synthesis of intermediate (4aS,7aS)-2,3,4,4a,5,6,7,7a-octahydro-lH-pyrroIo[3,4-b]pyridine of formula (A).

wherein said process comprises preparation of (4aR,7aS)-6-benzyl-l,2,3,4,4a,7a-hexahydropyrrolo[3,4-b]pyridine-5,7-dione of formula (II) such that Cis compound 6-benzyl-l,2,3,4,4a,7a-hexahydropyrrolo[3,4-b]pyridine-5,7-dione of formula (I) is resolved using D(-)-tartaric acid. The process of the present invention in this one preferred embodiment is as shown in scheme-1 below-

Accordingly. in an initial step, Cis compound 6-benzyl-1,2,3,4,4a,7a-hexahydropyrrolo[3,4-b]pyridine-5,7-dione of formula (I) is added to resolving agent D(-)-tartaric acid in water to form a mixture. In next step, said mixture is stirred at a room temperature. In next step, reaction may be carried out in solvent mixture of toluene and water or acetone and water. In this step, the solid tartrate salt of (4aR,7aS)-6-benzyl-l,2,3,4,4a,7a-hexahydropyrrolo[3,4-b]pyridine-5,7-dione is formed. The solid is filtered and suck dried. In next step, the salt is washed with a solvent selected from acetone and toluene followed by drying thereof. The isolated product shows a chiral purity in a range of about 97-99%. It is understood here that said process avoids need of further purification by crystallization or any other technique in this embodiment.

In next step, the solid tartrate salt of (4aR,7aS)-6-benzyl-l,2,3,4,4a,7a-hexahydropyrrolo[3,4-b]pyridine-5,7-dione is converted into (4aR,7aS)-6-benzyl-l,2,3,4,4a,7a-hexahydropyrrolo[3,4-b]pyridine-5,7-dione of formula (II) by reacting the salt with a suitable base. In this embodiment, the base is selected from sodium bicarbonate, potassium bicarbonate, ammonium hydroxide and ammonia gas. The process is carried out in a solvent selected from toluene and chloroform.
The Tartrate salt is added to the solvent and the solution is cooled to a temperature of 15-25 °C. In this step, Water is added followed by addition of a base wherein the solution becomes clear after addition of the base. The reaction mixture is stirred. The solvent layer is separated and dried over sodium sulfate and solvent is distilled off to get (4aR,7aS)-6-benzyl-l,2,3,4,4a,7a-hexahydropyirolo[3,4-b]pyridine-5,7-dione of formula (II). It is understood here that the chiral purity is preferably greater than 98% and HPLC purity is preferably greater than 99%.

In next step, a filtrate layer containing unwanted isomer is isolated by a racemization reaction. After racemization of unwanted isomer the same is again re-cycled for the preparation of desired isomer. It is understood here however that if the resolution is carried out in water then after filtration the aqueous layer is directly taken for isolation of undesired isomer. Alternatively, if the mixture of toluene and water or acetone and water is used as solvent in the resolution then after filtration of desired isomer pH is adjusted to 8.2 to 8.5 using a suitable base. In this preferred embodiment, the toluene layer is taken for solvent recovery and the aqueous layer containing undesired isomer is taken for further work up.

In next step, the undesired isomer is isolated from filtrate by adjusting pH to alkaline using suitable base. In this particular embodiment, the base is selected from sodium bicarbonate, potassium bicarbonate, ammonium hydroxide and ammonia gas. In this step, the undesired isomer (4aS,7aR)-6-benzyI-l,2,3,4,4a,7a-hexahydropyrrolo[3,4-b]pyridine-5,7-dione thus formed is extracted with a solvent selected from toluene and chloroform. In next step, organic layers are washed with water followed by distillation thereof under reduced pressure to give undesired isomer (4aS,7aR)-6-benzyl-l,2,3,4,4a,7a-hexahydropyrrolo[3,4-b]pyridine-5,7-dione. In this step, the undesired isomer thus obtained is actually a mixture of -70% (4aS,7aR)-isomer and -30% (4aR,7aS)-isomer which is racemized and recycled back in the process of the present invention.

In next step, the undesired isomer so obtained is added to a solvent selected from MDC or Toluene. In this step, suitably alkali alkoxide is added and the reaction mixture is stirred till the completion of the reaction. The alkali alkoxide used therein is selected from Sodium methoxide, potassium tert-butoxide and sodium iso-propoxide, preferably sodium methoxide. The reaction is preferably carried out at room temperature.

In next step, a predefined amount of Acetic acid is gradually added to the reaction mixture with stirring followed by addition of water with stirring for 10 minutes. In this step, an aqueous layer is extracted with MDC. In next step, all the organic layers so obtained are combined and dried over sodium sulfate. Preferably, the MDC is distilled under vacuum to get thick oil of cis 6-benzyl-l,2,3,4,4a,7a-hexahydropyrrolo[3,4-b]pyridine-5,7-dione. The chiral HPLC showed the ratio of (4aS,7aR)-isomer to (4aR,7aS)-isomer is 50:50. In next step, Cis 6-benzyl-1,2,3,4,4a,7a-hexahydropyrrolo[3,4-b]pyridine-5,7-dione is again recycled for resolution using D(-)-Tartaric acid by the above-mentioned process of the present invention.

In next step, the desired isomer (4aR,7aS)-6-benzyl-l,2,3,4,4a,7a-hexahydropyrrolo[3,4-b]pyridine-5,7-dione compound of formula (II) is reduced to remove oxo groups therefrom to preferably form (4aS,7aS)-6-benzyl-l,2,3,4,4a,5,7,7a-octahydropyrrolo[3,4-b]pyridine compound of formula (III) that has a chiral purity at least 98% and HPLC purity at least 97%. It is understood here that the reduction reaction is carried out in presence of suitable reducing agents wherein the reducing agents are selected from Lithium Aluminium hydride (LAH), Sodium bis-(2-methoxyethoxy)aluminium hydride commonly known as Vitride®, sodium borohydride along with activating agents selected from boron trifluoride etherate (BF3(C205)2O], dimethyl sulfate, aluminium chloride, calcium chloride and/or mixtures thereof. The reduction reaction is preferably carried out in presence of solvent selected from dimethylformamide, tetrahydrofuran, dichloromethane, dimethoxyethane, acetonitrile, dimethyl sulfoxide, 1,4-dioxane, toluene, ethereal solvents and/or mixtures thereof. The reduction reaction of the present invention is carried out at temperature in a range of about 10-50°C.

However, the reduction reaction may also be carried out in presence of a complex formed by aluminium chloride, sodium borohydride and dimethoxy ethane in presence of catalytic amount of calcium chloride and preferably at room temperature. The process is schematically represented as shown in scheme 2 below.

As illustrated in scheme 2, (4aS,7aS)-6-benzyl-l,2,3,4,4a,5,7,7a-octahydropyrrolo[3,4-b]pyridine of formula (III) is de-benzylated to form (4aS,7aS)-2,3,4,4a,5,6,7,7a-octahydro-lH-pyrrolo[3,4-b]pyridine compound of formula (A). The de-benzylation reaction is preferably carried out in presence of catalyst Pd/C and in presence of a solvent selected from aromatic solvent and alcoholic solvent. The reaction is preferably carried out at a temperature in a range of about 25-100°C. In this particular embodiment, the debenzylation reaction is preferably carried out in presence of 5% pd/C wet catalyst, using methanol as a solvent and at a temperature of about 60-70°C. In this one embodiment, the observed chiral purity is greater than 98% and GC purity is greater than 99%.

In an embodiment of the present invention, the cis compound 6-benzyl-l,2,3,4,4a,7a-hexahydropyrrolo[3,4-b]pyridine-5,7-dione of formula (I) may be prepared by reduction of 6-benzylpyrrolo[3,4-b]pyridine-5,7-dione of formula (Y) wherein said reduction reaction is preferably carried out in presence of suitable catalyst selected from palladium, nickel, platinum in a suitable solvent. In this one embodiment, the solvent is selected from toluene, acetic acid, water and the alcoholic solvent selected from methanol, ethanol, propanol and butanol. Preferably, said reduction reaction is carried out at a temperature in a range of about 25-110°C.

In this particular embodiment, the reduction reaction is carried out in presence of 5% pre-washed pd/C in toluene as a solvent and at a temperature of about 90 to 100°C. Catalyst is washed with methanol followed by washing with toluene.
As illustrated above, in an embodiment, 6-benzylpyrrolo[3,4-b]pyridine-5,7-dione of formula (Y) may prepared by reacting pyridine-2,3-dicarboxyIic acid (X) with acetic anhydride and benzylamine such that said reaction is carried out without solvent or in a solvent selected from toluene, xylenes, MDC, chloroform and/or mixture thereof and at a temperature in a range of about 25-110°C. Alternatively, said reaction may be carried out in a mixture of xylenes at a temperature in a range of about 60-70°C.

In alternative embodiment, the present invention provides a process for stereo-specific synthesis of intermediate (4aS,7aS)-2,3,4,4a,5,6,7,7a-octahydro-lH-pyrrolo[3,4-b]pyridine of formula (A).

In this alternative embodiment, said process comprises an initial step of preparation of (4aR,7aS)-6-benzyl-l,2,3,4,4a,7a-hexahydropyrrolo[3,4-b]pyridine-5,7-dione of formula (II) wherein Cis compound 6-benzyl-l,2,3,4,4a,7a-hexahydropyrrolo[3,4-b]pyridine-5,7-dione of formula (I) is resolved using D(-)-tartaric acid, said process is as shown in scheme 1.1 below-

In this step, Cis compound 6-benzyl-l,2,3,4,4a,7a-hexahydropyirolo[3,4-b]pyridine-5,7-dione of formula (I) is added to a mixture of isopropyl alcohol and acetonitrile and stirred well to get a clear solution. In next step, a resolving agent D (-)-tartaric acid is added to the reaction mixture. In this step, the reaction mixture is stirred at room temperature followed by heating said mixture to reflux and gradually cooling to a room temperature. The solvent mixture of IP A and acetonitrile is added in the ratio form 2:1 to 4:3, preferably 3:2 in this particular embodiment.

The solid tartrate salt of (4aR,7aS)-6-benzyl-l,2,3,4,4a,7a-hexahydropyrrolo[3,4-b]pyridine-5,7-dione is formed which is filtered and suck dried. In next step, said salt is washed with a solvent mixture of isopropyl alcohol and acetonitrile followed by drying thereof. It is understood here that the isolated product shows a chiral purity in a range of about 98-99% and no further purification by crystallization or any other technique is needed.

In next step, the solid tartrate salt of (4aR,7aS)-6-benzyl-l, 2,3,4,4a,7a-hexahydropyrrolo[3,4-b]pyridine-5,7-dione is converted into (4aR,7aS)-6-benzyl-l,2,3,4,4a,7a-hexahydropyrrolo[3,4-b]pyridine-5,7-dione of formula (II) by reacting the salt with a suitable base. In this alternative embodiment, the base is selected from sodium bicarbonate, potassium bicarbonate, ammonium hydroxide and ammonia gas. The process is carried out in a solvent selected from toluene and chloroform. The Tartrate salt is added to the solvent and the solution is cooled to 15-25°C. In further step, water is added followed by addition of a base. It is observed that the solution becomes clear after addition of the base.

The reaction mixture is stirred. In this step, the solvent layer is separated and dried over sodium sulfate and solvent is distilled off to obtain (4aR,7aS)-6-benzyl-l,2,3,4,4a,7a-hexahydropyrrolo[3,4-b]pyridine-5,7-dione of formula (II) that has a chiral purity at least 98% and HPLC purity is at least 99%.

In next step, racemization of unwanted isomer isolated from filtrate, which is again recycled for the preparation of desired isomer. It is understood here that if the resolution is carried out in water, after filtration the aqueous layer is directly taken for isolation of undesired isomer. Alternatively, if the mixture of toluene and water or acetone and water is used as solvent in the resolution, then pH is adjusted to 8.2 to 8.5 using a suitable base after filtration of desired isomer. In this step, the toluene layer is taken for solvent recovery and an aqueous layer containing undesired isomer is taken for further work up.

The undesired isomer is isolated from filtrate by adjusting pH to alkaline using a suitable base. It is understood here that the base is selected from sodium bicarbonate, potassium bicarbonate, ammonium hydroxide and ammonia gas. The undesired isomer (4aS,7aR)-6-benzyl-l52,3,4,4a,7a-hexahydropyrrolo[3,4-b]pyridine-5s7-dione thus formed is extracted with a solvent selected from toluene and chloroform.

In further step, organic layers are washed with water followed by distillation thereof under reduced pressure to give undesired isomer (4aS,7aR)-6-benzyl-l,2,3,4,4a,7a-hexahydropyrrolo[3,4-b]pyridine-5,7-dione. In this embodiment, the undesired isomer is actually a mixture of -70% (4aS,7aR)-isomer and -30% (4aR,7aS)-isomer which is racemized and recycled back in the process of the present invention.

In next step, the undesired isomer so obtained is added to a solvent selected from MDC or Toluene. Preferably, a suitable amount of alkali alkoxide is added and the reaction mixture is stirred till the completion of the reaction. The alkali alkoxide used therein is preferably selected from sodium methoxide, potassium tert-butoxide and sodium iso-propoxide, and most preferably sodium methoxide. The reaction is carried out at room temperature.

In next step, a predefined amount of Acetic acid is added gradually with stirring. Preferably, water is added and stirred for at least 10 minutes to obtain an aqueous layer that is extracted with MDC. All the organic layers so obtained are combined and dried over sodium sulfate followed by vaccum distillation to remove MDC to obtain thick oil of cis 6-benzyl-l,2,3,4,4a,7a-hexahydropyrroIo[3,4-b]pyridine-5,7-dione. It is understood here that, the chiral HPLC showed the ratio of (4aS,7aR)-isomer to (4aR,7aS)-isomer to be 50:50. This Cis 6-benzyl-l,2,3,4,4a,7a-hexahydropyn'oIo[3,4-b]pyridine-5,7-dione is further recycled for resolution using D(-)-Tartaric acid by following said process of the present invention.

In next step, the desired isomer (4aR,7aS)-6-benzyl-l,2,3.4,4a,7a-hexahydropyrrolo[3,4-b]pyridine-5,7-dione compound of formula (II) is reduced to remove oxo groups thereby forming (4aS,7aS)-6-benzyI-l,2,3,4,4a,5,7,7a-octahydropyrrolo[3,4-b]pyridine compound of formula (III) having a chiral purity greater than 98% and HPLC purity greater than 97%. The reduction reaction is carried out in presence of suitable reducing agents. It is understood here that the reducing agent is selected from Lithium Aluminium hydride (LAH), Sodium bis-(2-methoxyethoxy)aluminium hydride commonly known as Vitride®, sodium borohydride along with activating agents selected from boron trifluoride etherate (BF3(C2O5)2O], dimethyl sulfate, aluminium chloride, calcium chloride and/or mixtures thereof. In this step, the reduction reaction is carried out in presence of solvent selected from dimethylformarnide, tetrahydrofuran, dichloromethane, dimethoxyethane, acetonitrile, dimethyl sulfoxide, 1,4-dioxane, toluene, ethereal solvents and/or mixtures thereof. Preferably, the reduction reaction is carried out at a temperature in a range of about 10-50°C. However, it is understood here that said reduction reaction may be carried out in presence of a complex formed by aluminium chloride, sodium borohydride and dimethoxy ethane in presence of catalytic amount of calcium chloride and preferably at a room temperature. The process is schematically represented as shown in scheme 2.1 below-

As illustrated, (4aS,7aS)-6-benzyl-l,2,3,4,4a,5,7,7a-octahydropynx)lo[3,4-b]pyridine of formula (III) is de-benzylated to form (4aS,7aS)-2,3,4,4a,5,6,7,7a-octahydro-lH-pyrrolo[3,4-b]pyridine compound of formula (A) wherein said reaction is carried out in presence of Pd/C catalyst and in presence of a solvent selected from aromatic solvent and alcoholic solvent and at a temperature in a range of about 25-100°C. In this one particular embodiment, the debenzylation reaction is preferably carried out in presence of 5% pd/C wet catalyst, using methanol as a solvent and at a temperature in a range of about 60-70°C. Accordingly, the chiral purity is observed to be greater than 98% and GC purity is observed to be greater than 99%.

In an embodiment, the cis compound 6-benzyI-l,2,3,4,4a,7a-hexahydropyrrolo[3,4-b]pyridine-5,7-dione of formula (I) may be prepared by reduction of 6-benzylpyrrolo[3,4-b]pyridine-5,7-dione of formula (Y) wherein said reduction is preferably carried out at a temperature in a range of about 25-110°C and in presence of a suitable catalyst, a suitable solvent and a suitable alcoholic solvent. In this one particular embodiment, the catalyst is selected from palladium, nickel, platinum. The suitable solvent is selected from toluene, acetic acid, and water. The alcoholic solvent is selected from methanol, ethanol, propanol and butanol. In this one particular embodiment, the reduction is carried out in presence of 5% pre-washed pd/C in toluene solvent and at a temperature in a range of about 90 to 100°C. However, said catalyst is washed with methanol followed by washing with toluene.

As illustrated, the 6-benzylpyrrolo[3,4-b]pyridine-5,7-dione of formula (Y) is prepared by reacting pyridine-2,3-dicarboxylic acid (X) with acetic anhydride and benzylamine wherein said reaction is carried out without use of solvent or in a solvent selected from toluene, xylenes, MDC, chloroform and/or mixture thereof. The reaction is carried out at temperature in a range of about 25-110°C. Alternatively, said reaction is carried at a temperature in a range of about 60-70°C in mixture of xylenes.

EXAMPLES
Only a few examples and implementations are disclosed. Variations, modifications, and enhancements to the described examples and implementations and other implementations can be made based on what is disclosed.
Examples are set forth herein below and are illustrative of different amounts and types of reactants and reaction conditions that can be utilized in practicing the disclosure. It will be apparent, however, that the disclosure can be practiced with other amounts and types of reactants and reaction conditions than those used in the examples, and the resulting devices various different properties and uses in accordance with the disclosure above and as pointed out hereinafter.

Example 1
Preparation of 6-benzylpyrrolo[3,4-b]pyridine-5,7-dione
Pyridine 2,3-dicarboxylic acid (100 g) was added to acetic anhydride (100 ml) at 25-30°C. The mixture was heated to 70-80°C for 3-4 hours. Xylene (300 ml) was added to the reaction mixture and solvent was distilled under vacuum. The reaction mixture was cooled to 25-30° C and xylene (200 ml) was added. Benzylamine (76 g) was added to the reaction mixture. After completion of the reaction acetic anhydride (100 ml) was added slowly to the reaction mixture and heated to 60-70°C for 3 hours. The solvent was distilled below 60°C maintaining the reaction slurry. The solid thus obtained was filtered and purified by water (123 g). It was observed that 6-benzylpyrrolo[3,4-b]pyridine-5,7-dione thus obtained was having a yield of about 85%.

Example 2
Preparation of Cis 6-benzyl-l,23,4,4a,7a-hexahydropyrrolo[3,4-b]pyridine-5,7-dione
5% Pd/C (2 g) was charged in methanol (15 ml) and stirred for 5 minutes. The catalyst was filtered under nitrogen and washed with methanol (15 ml). This 5% pd/C was again slurried with toluene (15 ml). The slurry was filtered and catalyst was washed with Toluene (15 ml). The 6-benzylpyrrolo[3,4-b]pyridine-5,7-dione (100 g) was added to toluene (400 ml) in 1 Lit autoclave. Subsequently, 5% of above pre-washed Pd/C catalyst (2 g) was added to the reaction mixture. The reaction mixture was heated to 95-100°C under nitrogen (2x1 kg/cm3) and hydrogen (2xlkg/cm3) under 10kg/cm3 pressure. After completion of the reaction the reaction mass was cooled to 30°C and hydrogen pressure was removed. The catalyst was filtered under nitrogen atmosphere. Toluene was distilled under vacuum to obtain Cis 6-benzyI-l,2,3,4,4a,7a-hexahydropyrroIo[3,4-b]pyridine-5,7-dione(102g).

Example 3
Preparation of (4aR,7aS)-6-benzyl-l,2,3,4,4a,7a-hexahydropyrrolo[3,4-b]pyridine-5,7-dione Tartrate
(D)-(-)-tartraric acid (110 g) was dissolved in water (1500 ml) to form a solution. Cis 6-benzyl-1,2,3,4,4a,7a-hexahydropyrrolo[3,4-b]pyridine-5,7-dione (300 g) obtained in example 2 was gradually added in 10-30 minutes to the solution of Tartaric acid. At 20-25°C, solid of (4aR,7aS)-6-benzyl-l,2,3,4,4a,7a-hexahydropyrrolo[3,4-b]pyridine-5,7-dione Tartrate was observed to be formed in the mixture. The reaction mass was stirred for 30-60 minutes at 20-25°C. The solid was filtered and suck dried (wt. 150 gm) which was having a chiral purity of 99.0 % and an HPLC purity of 99.0 %.

Example 4
Preparation of (4aR,7aS)-6-benzyl-l,2,3,4,4a,7a-hexahydropyrroIo[3,4-b]pyridine-5,7-dione
(4aR,7aS)-6-benzyl-l,2,3,4,4a,7a-hexahydropyrrolo[3,4-b]pyridine-5,7-dione Tartrate (100 g) was charged in toluene (300 ml) and water (100 ml). pH of the reaction mixture was observed to be 3-3.5. Subsequently, Liq ammonia (52 g) was added to the reaction mixture. The reaction mixture became clear and reaction mass was stirred for 20-30 minutes. Toluene and water layers were separated. Aqueous layer was again extracted with toluene (100 mlx2). Subsequently, all the Toluene layers were mixed and washed with water (100mlx2) and dried over sodium sulfate. The Toluene layer was distilled under vacuum distillation to get oil of (4aR,7aS)-6-benzyl-l,2,3,4,4a,7a-hexahydropyrrolo[3,4-b]pyridine-5,7-dione (60 g) having both the chiral purity and HPLC purity of about 99.0 %.

Example 5
Preparation of (4aS,7aR)-6-benzyl-l,2,3,4,4a,7a-hexahydropyrrolo[3,4-b]pyridine-5,7-dione
The filtrate obtained in Example-3 was added with Sodium bicarbonate (27.4 g) gradually to form (4aS,7aR)-6-benzyl-l,2,3,4,4a,7a-hexahydropyrrolo[3,4-b]pyridine-5,7-dione free base which was then extracted with toluene (300 ml x2). All the organic layers were mixed and washed with water (300 mlx2). The Toluene layer was distilled under vacuum distillation to get oil of (4aS,7aR)-6-benzyl-l,2,3,4,4a,7a-hexahydropyrrolo[3,4-b]pyridine-5,7-dione (185 g). The chiral HPLC showed the ratio of (4aS,7aR)-isomer to (4aR,7aS)-isomer was 70:30.

Example 6
Preparation of (4aR,7aS)-6-benzyl-l,2,3,4,4a,7a-hexahydropyrrolo[3,4-b]pyridine-5,7-dione Tartrate
To the mixture of IPA (300 ml) and acetonitrile (200 ml), Cis 6-benzyI-l,2,3,4,4a,7a-hexahydropyrrolo[3,4-b]pyridine-5,7-dione (100 g) obtained in example 2 was gradually added. The mixture was stirred well to get a clear solution. D(-)-Tartaric acid (31 g) was added to the reaction mixture and mixture was stirred well for 30 minutes. The reaction mixture was stirred to reflux for 30 minutes. The reaction mass was cooled gradually to room temperature and the solid obtained was filtered and suck dried. The solid was washed with 100 ml of solvent mixture IPA (60 ml) and acetonitrile (40 ml). The solid was again suck dried. The solid of (4aR,7aS)-6-benzyl-l,2,3,4,4a,7a-hexahydropyrrolo[3,4-b]pyridine-5,7-dione Tartrate formed is dried under vacuum at 50°C to get (54 gms) having Chiral Purity 99.0% and HPLC Purity: 99.0%.

Example 7
Preparation of (4aR,7aS)-6-benzyl-l,2,3,4,4a,7a-hexahydropyrroIo[3,4-b]pyridine-5,7-dione Tartrate

To the mixture of IPA (600 L) and acetonitrile (400 L), Cis 6-benzyl-1,2,3,4,4a,7a-hexahydropyrrolo[3,4-b]pyridine-5,7-dione (200 kg) was gradually added. The mixture was stirred well to get a clear solution. D(-)-Tartaric acid (62 kg) was added to the reaction mixture and mixture was stirred well for 30 minutes. The reaction mixture was stirred to reflux for 30 minutes. The reaction mass was cooled gradually to room temperature and the solid obtained was filtered and suck dried. The solid was washed with 200 L of solvent mixture IPA (120 L) and acetonitrile (80 L). The solid was again suck dried. The solid of (4aR,7aS)-6-benzyl-l,2,3,4,4a,7a-hexahydropyrrolo[3,4-b]pyridine-5,7-dione Tartrate formed is dried under vacuum at 50°C to get (54 gms) with Chiral Purity 99.0% and HPLC Purity: 99.0%.

Example 8
Racemization of (4aS,7aR)-6-benzyl-l,2,3,4,4a,7a-hexahydropyrrolo[3,4-b]pyridine-5,7-dione to form Cis 6-benzyl-l,2,3,4,4a,7a-hexahydropyrrolo[3,4-b]pyridine-5,7-dione
The undesired (4aS,7aR)-isomer obtained in Example- 5 (100 g) was added with MDC (250 ml). The reaction mixture was stirred at 25°C to get clear brown solution. Subsequently, Sodium methoxide (3.5gm x 2) was added in the reaction mixture in two lots with the intervals of 5 minutes. The reaction mixture was stirred for 15 minutes at 25°C and the temperature was raised to 30°C. The reaction mixture was stirred under nitrogen atmosphere for 2 hours. Subsequently, the reaction mass was cooled and acetic acid (7.9 g) was added gradually in 10-15 minutes. The reaction mixture was stirred for 20 minutes. Water (100 ml) was added to said reaction mass and stirred for 10 minutes to form an aqueous layer therein. The aqueous layer was then extracted with MDC (100 ml x2). MDC layers were mixed and washed with water (100 ml). MDC layers were dried over sodium sulfate (10 g). MDC was distilled under vacuum at 40-42°C to get thick oil of Cis 6-benzyl-l,2,3,4,4a,7a-hexahydropyrrolo[3,4-b]pyridine-5,7-dione (85 gms) (50:50 by Chiral HPLC). This Cis 6-benzyl-l,2,3,4,4a,7a-hexahydropyrrolo[3,4-b]pyridine-5,7-dione was again resolved using D(-)-Tartaric acid as described in Examples 3 and 4.

Example 9
Preparation of (4aS,7aS)-6-benzyl-l,2,3,4,4a,5,7,7a-octahydropyrrolo[3,4-b]pyridine
Sodium borohydride (9.3g) was dissolved in tetrahydrofuran (80ml) and the suspension formed was cooled to a temperature of 5°C to 10°C. Dimethyl sulphate (15.2g) was added drop wise to the reaction mixture and said reaction mixture was heated to a 30°C and stirred for 2 hours. The reaction mixture was then cooled to 5°C to 10°C. A solution of (4aR,7aS)-6-benzyl-l,2,3,4,4a,7a-hexahydropyrrolo[3,4-b]pyridine-5,7-dione (lOg) in tetrahydrofuran was added to said reaction mixture dropwise and warmed to a temperature of 30°C. The reaction mixture was then stirred at 20°C to 30°C till completion of the reaction. Tetrahydrofuran was distilled out and toluene (50ml) was added to the reaction mixture. Concentrated hydrochloric acid (20ml) dissolved in water (40ml) was added dropwise to the reaction mixture that was heated to 80°C to 85°C with constant stirring. Subsequently, the reaction mixture was cooled to 25°C to 30°C to precipitate the solid followed by filtration thereof. The filtrate obtained during filtration formed two layers and aqueous layer was separated from the reaction mixture. The separated aqueous layer was then cooled to a temperature of 5°C to 10°C and the pH of the reaction mixture was adjusted to 12 using sodium hydroxide solution. Subsequently, the toluene (50ml) was charged to the reaction mixture and the reaction mixture was stirred for 15 min thereby forming two layers such that an aqueous layer was extracted with toluene. All the organic layers were combined and washed with brine solution. The organic layer was dried over sodium sulphate and evaporated to dryness to obtain the product (4aS,7aS)-6-benzyl-l,2,3,4,4a,5,7,,a-octahydropyrrolo[3,4-b]pyridine of the present invention having yield of about 84.6 %, a chiral purity of about 99.0 % and HPLC purity of about 97.1%.

Example 10
Preparation of (4aS,7aS)-6-benzyl-l,2,3,4,4a,5,7,7a-octahydropyrroIo[3,4-b]pyridine
Dimethoxy ethane (DME) (400 ml) was cooled to 5-10°C. A1C13 (110 g) was charged lot wise (lot size NMT 5% of total A1C13) below 10°C to the reaction mixture and stirred for 15 minutes at 10-15°C. Sodium borohydride (95gms) was charged (lot size NMT 5% of total NaBH4) below l5°C to form a complex. Calcium chloride (1 g) was added to the complex. Dimethoxy ethane (100 ml) was added to said reaction mixture followed by warming thereof to 45°C and maintaining the same for 2 hours. The reaction mixture was gradually cooled to 25°C to 30°C. The milky suspension was obtained which was further slowly added to solution of (4aR,7aS)-6-benzyl-l,2,3,4,4a,7a-hexahydropyrrolo[3,4-b]pyridine-5,7-dione (100 g) in toluene (100 ml) at 25°C to 30°C. The reaction mixture was maintained at 25°C to 30°C till the completion of the reaction. The milky suspension was slowly quenched in ice-cold water (1 lit). Subsequently, solvent dimethoxy ethane was distilled at 85-95°C. The reaction mixture then was cooled up to 25°C to 30°C and Cone. HC1 (200 ml) was added slowly in said reaction mixture The reaction mixture was then heated up to 90-95°C for 2 hours. The reaction mixture was then chilled to 10-15°C and 50% NaOH solution (400 ml) was added slowly at a temperature below 10°C followed by slow warming thereof to room temperature. Subsequently, Toluene (300 ml) was charged in solution and stirred for 30 mins. Organic layer was isolated and aqueous layer was transferred to next step. Subsequently, Toluene (200ml) was charged and the mixture was stirred for 30 mins and aquous layer was transferred to next step. Both organic layers were combined and washed with water (100ml X 2) and dried over sodium sulfate (50gms) and concentrated to get oil (4aS,7aS)-6-benzyl-1,2,3,4,4a,5,7,7a-octahydropyrrolo[3,4-bjpyridine (80 gms) having a chiral purity of 99.0 % and HPLC purity of 97.6%.

Example 11
Preparation of (4aS,7aS)-2,3,4,4a,5,6,7,7a-octahydro-lH-pyrrolo[3,4-b]pyridine
(4aS,7aS)-6-benzyl-l,2,3,4,4a,5,7,7a-octahydropyrrolo[3,4-b]pyridine (100 gm) was charged to methanol (400 ml) and Charcoal (3 gm) was added therein followed by stirring thereof for 30 mins. The solution was then filtered through Hyflo bed (25gm) and washed with methanol (100 ml). The filtrate was then charged in 1 or 2 Lit Autoclave in which 5% wet Pd/C (3 g) was charged. Autoclave was flushed three times with nitrogen and hydrogen. The reaction mixture was then heated up to 70-75°C. Hydrogen pressure was adjusted to 6 kg/cm2. The reaction was maintained at 70-75°C for 10-12 hrs. After completion of the reaction, the reaction mass was cooled to 25-30°C,. The reaction mixture was filtered through hyflo bed (25gm). The filtrate was concentrated under vacuum distillation at 60°C to get Oil of (4aSJaS)-2,3,4,4a,5,6,7,7a-octahydro-lH-pyrrolo[3,4-b] (50 - 58 gm). The oil was further purified by Vacuum distillation to get final pure product (48 gms) having chiral purity of about 99.0 % and a GC purity of about 99.12%.