Claims:

1. 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:
a. reacting cis 6-benzyl-l,2,3,4,4a,7a-hexahydropyrrolo[3,4-b]pyridine-5,7-dione of Formula (I)

with D-(-)-tartaric acid in acetonitrile and water forming a tartarate salt of (4aR,7aS)-6-benzyl-l,2,3,4,4a,7a-hexahydropyrrolo[3.4-b]pyridine-5,7-dione and a mixture of (4aS,7aR)-6-benzyl-l,2,3,4,4a,7a-hexahydropyrrolo[3.4-b]pyridine-5,7-dione and (4aR,7aS)-6-benzyl-l,2,3,4,4a,7a-hexahydropyrrolo[3.4-b]pyridine-5,7-dione;
b. separating tartarate salt of (4aR,7aS)-6-benzyl-l,2,3,4,4a,7a-hexahydropyrrolo[3.4-b]pyridine-5,7-dione formed in step (a) from the mixture of (4aS,7aR)-6-benzyl-l,2,3,4,4a,7a-hexahydropyrrolo[3.4-b]pyridine-5,7-dione and (4aR,7aS)-6-benzyl-l,2,3,4,4a,7a-hexahydropyrrolo[3.4-b]pyridine-5,7-dione; and
c. reacting the tartrate salt of (4aR,7aS)-6-benzyl-l,2,3,4,4a,7a-hexahydropyrrolo[3.4-b]pyridine-5,7-dione with a base forming (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 separating said tartrate salt comprises filtering (4aR,7aS)-6-benzyl-l,2,3,4,4a,7a-hexahydropyrrolo[3.4-b]pyridine-5,7-dione tartrate from said mixture of (4aS,7aR)-6-benzyl-l,2,3,4,4a,7a-hexahydropyrrolo[3.4-b]pyridine-5,7-dione and (4aR,7aS)-6-benzyl-l,2,3,4,4a,7a-hexahydropyrrolo[3.4-b]pyridine-5,7-dione.

3. The process as claimed in claim 1, wherein the mixture of (4aS,7aR)-6-benzyl-l,2,3,4,4a,7a-hexahydropyrrolo[3.4-b]pyridine-5,7-dione and (4aR,7aS)-6-benzyl-l,2,3,4,4a,7a-hexahydropyrrolo[3.4-b]pyridine-5,7-dione is in a ratio of 80:20 to 90:10.

4. The process as claimed in claim 1, wherein D-(-)-tartaric acid used is in 0.38 - 0.42 mole equivalents of compound of Formula (I).

5. The process as claimed in claim 1, wherein the acetonitrile and water solvent mixture is taken in the ratio of 99.8:0.2 - 99:1.

6. The process as claimed in claim 3, wherein the acetonitrile and water solvent mixture is taken in the ratio of 99.6:0.4 - 99:1.

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

8. The process as claimed in claim 1, wherein said process further comprises the step of:
(i) adding L-Tartaric acid to the said filtrate and forming a tartrate salt of (4aS,7aR)-6-benzyl-l,2,3,4,4a,7a-hexahydropyrrolo[3.4-b]pyridine-5,7-dione and a tartrate salt of (4aR,7aS)-6-benzyl-l,2,3,4,4a,7a-hexahydropyrrolo[3.4-b]pyridine-5,7-dione;
(ii) isolating the mixture of tartrate salt of (4aS,7aR)-6-benzyl-l,2,3,4,4a,7a-hexahydropyrrolo[3.4-b]pyridine-5,7-dione and a tartrate salt of (4aR,7aS)-6-benzyl-l,2,3,4,4a,7a-hexahydropyrrolo[3.4-b]pyridine-5,7-dione by filtration;
(iii) dissolving the isolated mixture of tartrate salt in a chlorinated solvent and adding a base forming a mixture of (4aS,7aR)-6-benzyl-l,2,3,4,4a,7a-hexahydropyrrolo[3.4-b]pyridine-5,7-dione and (4aR,7aS)-6-benzyl-l,2,3,4,4a,7a-hexahydropyrrolo[3.4-b]pyridine-5,7-dione; and
(iv) racemizing the mixture of (4aS,7aR)-6-benzyl-l,2,3,4,4a,7a-hexahydropyrrolo[3.4-b]pyridine-5,7-dione and (4aR,7aS)-6-benzyl-l,2,3,4,4a,7a-hexahydropyrrolo[3.4-b]pyridine-5,7-dione forming cis 6-benzyl-l,2,3,4,4a,7a-hexahydropyrrolo[3,4-b]pyridine-5,7-dione of Formula (I).

9. The process as claimed in claim 8, wherein the chlorinated solvent is selected from methylene dichloride, and/or chloroform.

10. The process as claimed in claim 8, wherein the base is selected from sodium bicarbonate, potassium bicarbonate, liquid ammonia, ammonium hydroxide and/or ammonia gas.
11. The process as claimed in claim 8, wherein racemizing comprises treating the mixture of (4aS,7aR)-6-benzyl-l,2,3,4,4a,7a-hexahydropyrrolo[3.4-b]pyridine-5,7-dione and (4aR,7aS)-6-benzyl-l,2,3,4,4a,7a-hexahydropyrrolo[3.4-b]pyridine-5,7-dione with alkali alkoxide.

12. The process as claimed in claim 11, wherein the alkali alkoxide is selected from a group of sodium methoxide, potassium t-butoxide and sodium iso-propoxide.

13. The process as claimed in claim 8, wherein said process comprises recycling cis 6-benzyl-l,2,3,4,4a,7a-hexahydropyrrolo[3,4-b]pyridine-5,7-dione of Formula (I).

14. 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)

comprising the steps of:
i) reducing (4aR,7aS)-6-benzyl-l,2,3,4,4a,7a-hexahydropyrroIo[3,4-b]pyridine-5,7-dione of Formula (II) as claimed in claim 1 to a compound of Formula (III); and
ii) debenzylating the compound of Formula (III) to form (4aS,7aS)-2,3,4,4a,5,6,7,7a-octahydro-lH-pyrrolo[3,4-b]pyridine of Formula (A).

15. The process as claimed in claim 14, reducing (4aR,7aS)-6-benzyl-l,2,3,4,4a,7a-hexahydropyrroIo[3,4-b]pyridine-5,7-dione of Formula (II) comprises a reducing agent, an activating agent and a solvent.

16. The process as claimed in claim 15, wherein the reducing agent is selected from one or more of lithium aluminium hydride (LAH), sodium bis-(2-methoxyethoxy)aluminium hydride, sodium borohydride.

17. The process as claimed in claim 15, wherein the activating agent is selected from boron trifluoride etherate (BF3(C2O5)2O], dimethyl sulfate, aluminium chloride, calcium chloride and/or mixtures thereof.

18. The process as claimed in claim 15, wherein the solvent is selected from a group of dimethylformamide, tetrahydrofiiran, dichloromethane, dimethoxyethane, acetonitrile, dimethyl sulfoxide, 1,4-dioxane, toluene, ethereal solvents and/or mixtures thereof.

19. The process as claimed in claim 14, wherein debenzylating compound of Formula (III) comprises a catalyst.

20. The process as claimed in claim 19, wherein the catalyst is Palladium/Carbon (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


The application for Patent of Addition is referred to the Applicant’s patent 321410 for Improved process for synthesis of Moxifloxacin Intermediate (S,S)-2,8-diazabicyclo[4.3.0]nonane.

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

Background of the Invention
(4aS,7aS)-2,3,4,4a,5,6,7,7a-octahydro-1H-pyrrolo[3,4-b]pyridine of Formula (A), also referred to as (4aS, 7aS)-Octahydro-1H-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-1H-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-diazabicyclo[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-diazabicyclo[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.

The Applicant’s Patent 321410 discloses 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) from cis 6-benzyl-l,2,3,4,4a,7a-hexahydropyrrolo[3,4-b]pyridine-5,7-dione of Formula (I). The said patent discloses resolution of cis 6-benzyl-l,2,3,4,4a,7a-hexahydropyrrolo[3,4-b]pyridine-5,7-dione of Formula (I) using D(-)-tartaric acid in presence of water or in presence of a solvent mixture of iso-propyl alcohol (IPA) and acetonitrile. However, the solvent recovery was very poor as the solvent mixture IPA and acetonitrile forms an azeotrope mixture and it was very difficult to separate the solvent from such a mixture and therefore. Further, there was formation of IPA ester impurity and chiral purity was achieved on near lower limit.
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-1H-pyrrolo[3,4-b]pyridine which avoids complete usage of alcoholic solvent. Also, there exists a need of a process that provides better yield with substantially higher chiral purity thereby.
Summary of the invention
In a general aspect, the present invention provides a stereo-specific synthesis of Moxifloxacin intermediate (4aS,7aS)-2,3,4,4a,5,6,7,7a-octahydro-1H-pyrrolo[3,4-b]pyridine of Formula (A):

In an embodiment, the present invention provides 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).

The process of the present invention includes reacting cis 6-benzyl-l,2,3,4,4a,7a-hexahydropyrrolo[3,4-b]pyridine-5,7-dione of Formula (I)

with D-(-)-tartaric acid in acetonitrile and water forming tartarate salt of (4aR,7aS)-6-benzyl-l,2,3,4,4a,7a-hexahydropyrrolo[3.4-b]pyridine-5,7-dione and a mixture of (4aS,7aR)-6-benzyl-l,2,3,4,4a,7a-hexahydropyrrolo[3.4-b]pyridine-5,7-dione and (4aR,7aS)-6-benzyl-l,2,3,4,4a,7a-hexahydropyrrolo[3.4-b]pyridine-5,7-dione. The tartarate salt of (4aR,7aS)-6-benzyl-l,2,3,4,4a,7a-hexahydropyrrolo[3.4-b]pyridine-5,7-dione formed is separated from the mixture of (4aS,7aR)-6-benzyl-l,2,3,4,4a,7a-hexahydropyrrolo[3.4-b]pyridine-5,7-dione and (4aR,7aS)-6-benzyl-l,2,3,4,4a,7a-hexahydropyrrolo[3.4-b]pyridine-5,7-dione and then reacted with a base forming (4aR,7aS)-6- benzyl--l,2,3,4,4a,7a-hexahydropyrrolo[3,4-b]pyridine-5,7-dione of Formula (II).
The tartrate salt of (4aR,7aS)-6-benzyl-l,2,3,4,4a,7a-hexahydropyrrolo[3.4-b]pyridine-5,7-dione can be separated from said mixture of (4aS,7aR)-6-benzyl-l,2,3,4,4a,7a-hexahydropyrrolo[3.4-b]pyridine-5,7-dione and (4aR,7aS)-6-benzyl-l,2,3,4,4a,7a-hexahydropyrrolo[3.4-b]pyridine-5,7-dione by filtration.
The mixture of (4aS,7aR)-6-benzyl-l,2,3,4,4a,7a-hexahydropyrrolo[3.4-b]pyridine-5,7-dione and (4aR,7aS)-6-benzyl-l,2,3,4,4a,7a-hexahydropyrrolo[3.4-b]pyridine-5,7-dione in the filtrate is in a ratio of 80:20 to 90:10. D-(-)-tartaric acid used is in 0.38 - 0.42 mole equivalents of compound of Formula (I). The acetonitrile and water solvent mixture can be in the ratio of 99.8:0.2 - 99:1. Preferably, the acetonitrile and water solvent mixture can be in the ratio of 99.6:0.4 - 99:1.
The tartrate salt of (4aR,7aS)-6-benzyl-l,2,3,4,4a,7a-hexahydropyrrolo[3.4-b]pyridine-5,7-dione can be reacted with a base selected from one or more of the sodium bicarbonate, potassium bicarbonate, liquid ammonia, ammonium hydroxide and/or ammonia gas.
In an embodiment, the process of the present invention further comprises the step of recovering and recycling cis 6-benzyl-l,2,3,4,4a,7a-hexahydropyrrolo[3,4-b]pyridine-5,7-dione of Formula (I). The step comprises adding L-Tartaric acid to the said filtrate forming a tartrate salt of (4aS,7aR)-6-benzyl-l,2,3,4,4a,7a-hexahydropyrrolo[3.4-b]pyridine-5,7-dione and a tartrate salt of (4aR,7aS)-6-benzyl-l,2,3,4,4a,7a-hexahydropyrrolo[3.4-b]pyridine-5,7-dione and isolating the said salts by filtration. The isolated mixture of tartrate salt obtained is dissolved in a chlorinated solvent and base can be added to form mixture of (4aS,7aR)-6-benzyl-l,2,3,4,4a,7a-hexahydropyrrolo[3.4-b]pyridine-5,7-dione and (4aR,7aS)-6-benzyl-l,2,3,4,4a,7a-hexahydropyrrolo[3.4-b]pyridine-5,7-dione. Racemizing the mixture of (4aS,7aR)-6-benzyl-l,2,3,4,4a,7a-hexahydropyrrolo[3.4-b]pyridine-5,7-dione and (4aR,7aS)-6-benzyl-l,2,3,4,4a,7a-hexahydropyrrolo[3.4-b]pyridine-5,7-dione forming cis 6-benzyl-l,2,3,4,4a,7a-hexahydropyrrolo[3,4-b]pyridine-5,7-dione of Formula (I).
The chlorinated solvent can be selected from methylene dichloride, and/or chloroform. The base for isolating the mixture of (4aS,7aR)-6-benzyl-l,2,3,4,4a,7a-hexahydropyrrolo[3.4-b]pyridine-5,7-dione and (4aR,7aS)-6-benzyl-l,2,3,4,4a,7a-hexahydropyrrolo[3.4-b]pyridine-5,7-dione can be selected from sodium bicarbonate, potassium bicarbonate, liquid ammonia, ammonium hydroxide and/or ammonia gas.
The step of racemization comprises treating the mixture of (4aS,7aR)-6-benzyl-l,2,3,4,4a,7a-hexahydropyrrolo[3.4-b]pyridine-5,7-dione and (4aR,7aS)-6-benzyl-l,2,3,4,4a,7a-hexahydropyrrolo[3.4-b]pyridine-5,7-dione with alkali alkoxide. The alkali alkoxide can be selected from a group of sodium methoxide, potassium t-butoxide and sodium iso-propoxide. The process comprises recycling cis 6-benzyl-l,2,3,4,4a,7a-hexahydropyrrolo[3,4-b]pyridine-5,7-dione of Formula (I).

In another embodiment, 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) is provided. The process comprises reducing (4aR,7aS)-6-benzyl-l,2,3,4,4a,7a-hexahydropyrroIo[3,4-b]pyridine-5,7-dione of Formula (II) to compound of Formula (III); and debenzylating the compound of Formula (III) forming (4aS,7aS)-2,3,4,4a,5,6,7,7a-octahydro-lH-pyrrolo[3,4-b]pyridine of Formula (A).
The step of reducing compound of Formula (II) to compound of Formula (III) is in the presence of a reducing agent, activating agent and a solvent. The reducing agent can be selected from one or more of the following lithium aluminium hydride (LAH), sodium bis-(2-methoxyethoxy)aluminium hydride, sodium borohydride along with activating agents selected from boron trifluoride etherate (BF3(C2O5)2O], dimethyl sulfate, aluminium chloride, calcium chloride and/or mixtures thereof. The solvent for reducing step can be selected from a group of dimethylformamide, tetrahydrofiiran, dichloromethane, dimethoxyethane, acetonitrile, dimethyl sulfoxide, 1,4-dioxane, toluene, ethereal solvents and/or mixtures thereof.
In another embodiment, debenzylating compound of Formula (III) to compound of Formula (A) is carried out in presence of a catalyst. The catalyst can be selected from Palladium on Carbon (Pd/C).

Description of the Invention
The present invention provides a stereo-specific synthesis of Moxifloxacin intermediate (4aS,7aS)-2,3,4,4a,5,6,7,7a-octahydro-1H-pyrrolo[3,4-b]pyridine of Formula (A). The initial step of the process is the preparation of (4aR,7aS)-6-benzyl-1,2,3,4,4a,7a-hexahydropyrrolo[3,4-b]pyridine-5,7-dione of Formula (II). A cis compound 6-benzyl-1,2,3,4,4a,7a-hexahydropyrrolo[3,4-b]pyridine-5,7-dione of Formula (I) is resolved using D(-)-tartaric acid in presence of a solvent acetonitrile or a mixture of acetonitrile and water.

A brief flow of the process of preparing the compound of Formula (A) according to an embodiment of the present invention is shown below:

In an embodiment, the present invention provides 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).

Cis 6-benzyl-l,2,3,4,4a,7a-hexahydropyrrolo[3,4-b]pyridine-5,7-dione of Formula (I)

is reacted with D-(-)-tartaric acid in acetonitrile and water forming a tartarate salt of (4aR,7aS)-6-benzyl-l,2,3,4,4a,7a-hexahydropyrrolo[3.4-b]pyridine-5,7-dione and a mixture of isomers (4aS,7aR)-6-benzyl-l,2,3,4,4a,7a-hexahydropyrrolo[3.4-b]pyridine-5,7-dione and (4aR,7aS)-6-benzyl-l,2,3,4,4a,7a-hexahydropyrrolo[3.4-b]pyridine-5,7-dione.

The cis compound of Formula (I) can be added to acetonitrile or mixture of acetonitrile and water. The acetonitrile and water solvent mixture can be taken in the ratio of about 99.8:0.2 - 99:1. Preferably the said mixture can be taken in the ratio of 99.6:0.4 - 99:1. The reaction mixture i.e. the cis compound of Formula (I) along with the solvent mixture is then heated to 80-85°C with or without steam. Preferably, steam is applied to the reaction mixture. The cis compound of Formula (I) is resolved using a resolving agent D-(-)-tartaric acid. D-(-)-tartaric acid is added to the reaction mixture, preferably in lot at an interval of 5 minutes to 10 minutes at 80-85°C. The addition of D-(-)-tartaric acid is preferably done in lots, as sufficient time is available for formation of the desired isomer tartarate salt in a crystalline form. The amount of D-(-)-tartaric acid added can be about 0.38 - 0.42 mole equivalents of compound of Formula (I). The reaction product containing precipitated solid of (4aR,7aS)-6-benzyl-1,2,3,4,4a,7a-hexahydropyrrolo[3,4-b] pyridine-5,7-dione Tartrate, and the mixture of isomers (4aS,7aR)-6-benzyl-1,2,3,4,4a,7a-hexahydropyrrolo[3,4-b]pyridine-5,7-dione and (4aR,7aS)-6-benzyl-1,2,3,4,4a,7a-hexahydropyrrolo[3,4-b]pyridine-5,7-dione in acetonitrile is cooled to 35°C-40°C.

The tartrate salt of (4aR,7aS)-6-benzyl-l,2,3,4,4a,7a-hexahydropyrrolo[3.4-b]pyridine-5,7-dione thus formed is separated from the mixture of isomers (4aS,7aR)-6-benzyl-l,2,3,4,4a,7a-hexahydropyrrolo[3.4-b]pyridine-5,7-dione and (4aR,7aS)-6-benzyl-l,2,3,4,4a,7a-hexahydropyrrolo[3.4-b]pyridine-5,7-dione by filtration. The separated tartrate salt can be further washed with acetonitrile, suck dried and isolated having a chiral purity of 99.0% and an HPLC purity of 99.0%.
The isolated tartrate salt is then converted to (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 base. The conversion of the tartrate salt to the desired isomer can preferably be carried out in a solvent selected from toluene or chloroform. The tartrate salt is added to the solvent and the solution is cooled to 0° to 10°C. The base is added to the mixture at 0°C to 10°C and stirred for 5 minutes. The base can be selected from sodium bicarbonate, potassium bicarbonate, ammonium hydroxide and ammonia gas. The aqueous and the organic layers formed are separated and the organic layer can be collected and dried over sodium sulfate. A stabilizer is optionally added to prevent double bond formation at the bridge carbon which may further contribute to isomeric impurities. Stabilizer can be selected from an antioxidant. Preferably, an antioxidant such as butyrated hydroxy toluene (BHT) is optionally added to the organic layer comprising the said solvent. The organic layer is then distilled under vacuum below 50°C to 80°C obtaining (4aR,7aS)-6-benzyl-1,2,3,4,4a,7a-hexahydropyrrolo[3,4-b]pyridine-5,7-dione of Formula (II) having a chiral purity of 99.0% to 99.7% and HPLC purity of 99.0 % to 99.8%.
The filtrate thus obtained after separation of the tartrate salt of (4aR,7aS)-6-benzyl-l,2,3,4,4a,7a-hexahydropyrrolo[3.4-b]pyridine-5,7-dione has a mixture of isomers (4aS,7aR)-6-benzyl-1,2,3,4,4a,7a-hexahydropyrrolo[3,4-b]pyridine-5,7-dione and (4aR,7aS)-6-benzyl-1,2,3,4,4a,7a-hexahydropyrrolo[3,4-b]pyridine-5,7-dione in the ratio of 80:20 to 90:10. The filtrate is kept aside for further recovery and recycle of said isomers.
In an embodiment, the process for recovery of tartrate salt of (4aS,7aR)-6-benzyl-1,2,3,4,4a,7a-hexahydropyrrolo [3,4-b]pyridine-5,7-dione and tartrate salt of (4aR,7aS)-6-benzyl-1,2,3,4,4a,7a-hexahydropyrrolo[3,4-b]pyridine-5,7-dione and recycle of cis 6-benzyl-1,2,3,4,4a,7a-hexahydropyrrolo[3,4-b]pyridine-5,7-dione of Formula I from the mixture of isomers of (4aS,7aR)-6-benzyl-1,2,3,4,4a,7a-hexahydropyrrolo[3,4-b] pyridine-5,7-dione and (4aR,7aS)-6-benzyl-1,2,3,4,4a,7a-hexahydropyrrolo[3,4-b]pyridine-5,7-dione is provided.
The filtrate is heated to 80°C to 85°C and then distilled to about 45% to 55 % of the filtrate. L-Tartaric acid is added to the said filtrate, preferably in lots, at an interval of 8 minutes to 10 minutes at 80°C to 85°C forming a reaction mixture. The addition of L-tartaric acid is done in lots, as sufficient time is available for formation of the tartarate salt in a crystalline form. D-Tartaric acid can also be used to form a tartrate salt. However, D-tartaric acid forms tartrate salt only with the desired isomer i.e. (4aR,7aS)-6-benzyl-l,2,3,4,4a,7a-hexahydropyrrolo[3.4-b]pyridine-5,7-dione. L-tartaric acid forms a salt with both the isomers i.e. (4aS,7aR)-6-benzyl-l,2,3,4,4a,7a-hexahydropyrrolo[3.4-b]pyridine-5,7-dione and (4aR,7aS)-6-benzyl-l,2,3,4,4a,7a-hexahydropyrrolo[3.4-b]pyridine-5,7-dione. Further, L-Tartaric acid is cheaper and cost effective as compared to D-Tartaric acid. The reaction mixture is maintained at 80°C to 85°C for 4 hours to 5 hours after complete addition of L-Tartaric acid. Further, the mixture of tartarate salt is cooled and filtered to isolate the tartrate salt of (4aS,7aR)-6-benzyl-l,2,3,4,4a,7a-hexahydropyrrolo[3.4-b]pyridine-5,7-dione and the tartrate salt of (4aR,7aS)-6-benzyl-l,2,3,4,4a,7a-hexahydropyrrolo[3.4-b]pyridine-5,7-dione. The ratio of (4aS,7aR)-6-benzyl-1,2,3,4,4a,7a-hexahydropyrrolo[3,4-b]pyridine-5,7-dione tartrate salt and (4aR,7aS)-6-benzyl-1,2,3,4,4a,7a-hexahydropyrrolo[3,4-b]pyridine-5,7-dione tartarate salt obtained is 80:20 to 90:10.

In another embodiment, recycling cis 6-benzyl-l,2,3,4,4a,7a-hexahydropyrrolo[3,4-b]pyridine-5,7-dione of Formula (I) from the isolated mixture of (4aS,7aR)-6-benzyl-1,2,3,4,4a,7a-hexahydropyrrolo[3,4-b]pyridine-5,7-dione tartarate salt and (4aR,7aS)-6-benzyl-1,2,3,4,4a,7a-hexahydropyrrolo[3,4-b]pyridine-5,7-dione tartarate salt is provided. The isolated mixture of tartrate salt is dissolved in a chlorinated solvent selected from methylene dichloride (MDC), and/or chloroform and a base is added forming a mixture of (4aS,7aR)-6-benzyl-l,2,3,4,4a,7a-hexahydropyrrolo[3.4-b]pyridine-5,7-dione and (4aR,7aS)-6-benzyl-l,2,3,4,4a,7a-hexahydropyrrolo[3.4-b]pyridine-5,7-dione. The pH of the solution is adjusted to 8-8.5 using a suitable base selected from sodium bicarbonate, potassium bicarbonate, ammonium hydroxide and/or ammonia gas. The reaction mixture is further stirred for 2 hours by maintaining the pH to 8-8.5. The reaction mixture is then centrifuged and further filtered wherein the L-(+)-ammonium tartrate is separated from the said mixture. The filtrate comprising mixture of (4aS,7aR)-6-benzyl-1,2,3,4,4a,7a-hexahydropyrrolo [3,4-b]pyridine-5,7-dione and (4aR,7aS)-6-benzyl-1,2,3,4,4a,7a-hexahydropyrrolo[3,4-b] pyridine-5,7-dione is treated with an antioxidant such as butyrated hydroxy toluene (BHT) and heated to 40°C to 50°C and is gradually cooled up to 25 to 35°C. The said mixture is racemized forming cis 6-benzyl-l,2,3,4,4a,7a-hexahydropyrrolo[3,4-b]pyridine-5,7-dione of Formula (I). Racemization is done by treating the mixture with an alkali alkoxide. The alkali alkoxide can be selected from a group of sodium methoxide, potassium t-butoxide and sodium iso-propoxide and most preferably sodium methoxide. The alkali alkoxide can be charged gradually at 25°C to 35°C to the reaction mixture and further the reaction mixture obtained is maintained for 3 hours to 5 hours at 25°C to 35°C. Acetic acid is then added slowly and cooled to -10°C to 0°C. 20% NaCl solution is then charged to the mixture under constant stirring for 15 minutes. The organic layer containing cis 6-benzyl-1,2,3,4,4a,7a-hexahydropyrrolo[3,4-b]pyridine-5,7-dione is dried over sodium sulfate. The layer is then distilled under atmospheric pressure to collect Cis 6-benzyl-1,2,3,4,4a,7a-hexahydropyrrolo[3,4-b]pyridine-5,7-dione of Formula (I) having HPLC purity of 75% to 85.0%. The cis 6-benzyl-l,2,3,4,4a,7a-hexahydropyrrolo[3,4-b]pyridine-5,7-dione of Formula (I) can be recycled for resolution with D(-)-Tartaric acid.
The process is schematically represented as shown in scheme 1.1 below-

In another embodiment, 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) is provided. Reducing (4aR,7aS)-6-benzyl-l,2,3,4,4a,7a-hexahydropyrroIo[3,4-b]pyridine-5,7-dione of Formula (II) forming a compound of Formula (III); and

debenzylating the compound of Formula (III) forming (4aS,7aS)-2,3,4,4a,5,6,7,7a-octahydro-lH-pyrrolo[3,4-b]pyridine of Formula (A).
The process is schematically represented as shown in scheme 1.2 below-

The desired isomer (4aR,7aS)-6-benzyl-1,2,3,4,4a,7a-hexahydropyrrolo[3,4-b]pyridine-5,7-dione compound of Formula (II) is reduced to remove oxo groups thereby forming (4aS,7aS)-6-benzyl-1,2,3,4,4a,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 of compound of Formula (II) to a compound of Formula (III) can be carried out in the presence of suitable reducing agent, activating agent and a solvent. The reducing agent can be selected from lithium aluminium hydride (LAH), sodium bis-(2-methoxyethoxy)aluminium hydride commonly known as Vitride®, sodium borohydride. The activating agents can be selected from boron trifluoride etherate (BF3(C2O5)2O], dimethyl sulfate, aluminium chloride, calcium chloride and/or mixtures thereof. The solvent can be selected from dimethylformamide, 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.
(4aS,7aS)-6-benzyl-1,2,3,4,4a,5,7,7a-octahydropyrrolo[3,4-b]pyridine of Formula (III) is then debenzylated to form (4aS,7aS)-2,3,4,4a,5,6,7,7a-octahydro-1H-pyrrolo[3,4-b]pyridine 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°C to 100°C. Debenzylation reaction can preferably be 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°C to 70°C. The chiral purity of (4aS,7aS)-2,3,4,4a,5,6,7,7a-octahydro-1H-pyrrolo[3,4-b]pyridine of Formula (A) is 99.0% to 99.9% and GC purity is observed to be of 99.0% to 99.9%.

In another embodiment, a process of preparing cis 6-benzyl-1,2,3,4,4a,7a-hexahydropyrrolo[3,4-b] pyridine-5,7-dione of Formula (I) is provided. Reducing 6-benzylpyrrolo[3,4-b] pyridine-5,7-dione of Formula (Y) wherein said reduction can preferably be 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 embodiment, the catalyst is selected from palladium, nickel, platinum. The suitable solvent can be selected from toluene, acetic acid, and water. The alcoholic solvent can be 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. The process is schematically represented as shown in scheme 1.3 below-

The 6-benzylpyrrolo[3,4-b]pyridine-5,7-dione of Formula (Y) is prepared by reacting pyridine-2,3-dicarboxylic acid of Formula (X) with acetic anhydride and benzylamine wherein said reaction is carried out without use of solvent or in presence of a solvent selected from toluene, xylenes, methylene dichloride (MDC), chloroform and/or mixture thereof. The reaction is carried out at temperature in a range of about 25–110°C. The said reaction is carried at a temperature in a range of about 60-70°C in mixture of xylenes.
The process of present invention avoids and/or reduces the use of excess alcoholic solvents or 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 99%. The processes of the present invention avoid purification by re-crystallizations or by any other techniques known in the art. The formation of impurity of the present invention at plant level is minimized apparently improving the quality of the product and ultimately avoiding the yield loss. 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.

EXAMPLES
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 (Formula Y)
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-1,2,3,4,4a,7a-hexahydropyrrolo[3,4-b]pyridine-5,7-dione (Formula I)

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 (2x1kg/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-benzyl-1,2,3,4,4a,7a-hexahydropyrrolo[3,4-b]pyridine-5,7-dione (102 g) of Formula (I).

Example 3
Preparation of (4aR,7aS)-6-benzyl-1,2,3,4,4a,7a-hexahydropyrrolo[3,4-b]pyridine-5,7- dione Tartrate

Acetonitrile (800 ml) with moisture content (0.5%) is charged to Cis 6-benzyl-1,2,3,4,4a,7a-hexahydropyrrolo[3,4-b]pyridine-5,7-dione (200 g) of Formula (I) obtained in example 2 (200 g) and the mixture was stirred. The steam was applied and the mass was heated to 80-85°C. (D)-(-)-tartaric acid (49 g) was charged to the reaction mixture in 9 lots of (5g) and 1 lot of (4g) at an interval of 10 minutes at 80-85°C. The reaction mass obtained containing precipitated solid of (4aR,7aS)-6-benzyl-1,2,3,4,4a,7a-hexahydropyrrolo[3,4-b] pyridine-5,7-dione Tartrate and the mixture of isomers (4aS,7aR)-6-benzyl-1,2,3,4,4a,7a-hexahydropyrrolo[3,4-b]pyridine-5,7-dione and (4aR,7aS)-6-benzyl-1,2,3,4,4a,7a-hexahydropyrrolo[3,4-b]pyridine-5,7-dione in acetonitrile was cooled to 35-40°C. The tartarate salt of (4aR,7aS)-6-benzyl-1,2,3,4,4a,7a-hexahydropyrrolo[3,4-b] pyridine-5,7-dione was isolated by filtration and further washed with acetonitrile (400 ml). The solid was suck dried and (4aR,7aS)-6-benzyl-1,2,3,4,4a,7a-hexahydropyrrolo[3,4-b] pyridine-5,7-dione Tartrate salt was isolated. The salt was slurried in acetonitrile (4V) and heated to 80-85°C and maintained for 10 hours. The mass was cooled to 35-40°C. The solid comprising (4aR,7aS)-6-benzyl-1,2,3,4,4a,7a-hexahydropyrrolo[3,4-b] pyridine-5,7-dione Tartrate salt was filtered and suck dried (wt. 125 gm) which was having a chiral purity of 99.0% and an HPLC purity of 99.0 %. The filtrate containing mixture of isomers (4aS,7aR)-6-benzyl-1,2,3,4,4a,7a-hexahydropyrrolo[3,4-b] pyridine-5,7-dione and (4aR,7aS)-6-benzyl-1,2,3,4,4a,7a-hexahydropyrrolo[3,4-b]pyridine -5,7-dione in the ratio of (86.78:13.22) was kept aside for further recovery of isomers.

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

(4aR,7aS)-6-benzyl-1,2,3,4,4a,7a-hexahydropyrrolo[3,4-b]pyridine-5,7-dione Tartrate (70 g) as obtained in example 3 was charged in chloroform (420 ml). The reaction mixture was stirred for 15 minutes at room temperature. Chilling was applied to the reaction mass to 0-5°C and chilled aqueous ammonia (40 ml) was charged gradually over period of 5 minutes. The mixture was stirred at 0-5°C for 5 minutes. The layers were separated and aqueous layer was extracted with chloroform (35 ml). The organic layer containing (4aR,7aS)-6-benzyl-1,2,3,4,4a,7a-hexahydropyrrolo[3,4-b] pyridine-5,7-dione was dried over sodium sulfate. BHT (1 g) was charged to the organic layer of chloroform was distilled below 80°C. The oil of (4aR,7aS)-6-benzyl-1,2,3,4,4a,7a- hexahydropyrrolo[3,4-b]pyridine-5,7-dione (Wt. 42g) of Formula (II) having both the chiral purity and HPLC purity of about 99.0 % was isolated.

Example 5
Recovery of tartarate salt of (4aS,7aR)-6-benzyl-1,2,3,4,4a,7a-hexahydropyrrolo [3,4-b]pyridine-5,7-dione tartarate and 4aR,7aS)-6-benzyl-1,2,3,4,4a,7a- hexahydropyrrolo[3,4-b]pyridine- 5,7-dione
The filtrate containing mixture of isomers (4aS,7aR)-6-benzyl-1,2,3,4,4a,7a-hexahydropyrrolo[3,4-b] pyridine-5,7-dione and (4aR,7aS)-6-benzyl-1,2,3,4,4a,7a-hexahydropyrrolo[3,4-b]pyridine -5,7-dione obtained in example 3 was raised to 80-85°C and 50% of the filtrate was distilled out. L(+)-tartaric acid (80 g) was charged to the filtrate in 10 lots of 8 gm each at an interval of 10 minutes at 80-85°C. The reaction mixture was maintained for 5 hours at 80-85°C after complete addition. The mixture was gradually cooled to 35-40°C and filtered. The precipitate of (4aS,7aR)-6-benzyl-1,2,3,4,4a,7a-hexahydropyrrolo[3,4-b]pyridine-5,7-dione tartarate salt and (4aR,7aS)-6-benzyl-1,2,3,4,4a,7a-hexahydropyrrolo[3,4-b]pyridine-5,7-dione tartarate salt was washed with acetonitrile (140 ml). The precipitate containing mixture of (4aS,7aR)-6-benzyl-1,2,3,4,4a,7a-hexahydropyrrolo[3,4-b]pyridine-5,7-dione tartarate salt and (4aR,7aS)-6-benzyl-1,2,3,4,4a,7a-hexahydropyrrolo[3,4-b]pyridine-5,7-dione tartarate salt was suck dried and further dried under vacuum at 50°C. The ratio of (4aS,7aR)-6-benzyl-1,2,3,4,4a,7a-hexahydropyrrolo[3,4-b]pyridine-5,7-dione tartarate salt and (4aR,7aS)-6-benzyl-1,2,3,4,4a,7a-hexahydropyrrolo[3,4-b]pyridine-5,7-dione tartarate salt obtained was 86.78:13.22.

Example 6
Preparation of Cis 6-benzyl-1,2,3,4,4a,7a-hexahydropyrrolo[3,4-b]pyridine-5,7-dione (50:50)
The precipitate of (4aS,7aR)-6-benzyl-1,2,3,4,4a,7a-hexahydropyrrolo[3,4-b]pyridine-5,7-dione tartarate salt and (4aR,7aS)-6-benzyl-1,2,3,4,4a,7a-hexahydropyrrolo[3,4-b]pyridine-5,7-dione tartarate salt (177 gm) obtained in example 5, was charged to MDC (1060 ml) with constant stirring at room temperature. The pH of the reaction mixture was adjusted to 8-8.5 by purging ammonia gas. The reaction mixture was stirred for 2 hours by maintaining pH to 8-8.5. The reaction mass containing L-(+)-ammonium tartarate solid and mixture of (4aS,7aR)-6-benzyl-1,2,3,4,4a,7a-hexahydropyrrolo[3,4-b]pyridine-5,7-dione and (4aR,7aS)-6-benzyl-1,2,3,4,4a,7a-hexahydropyrrolo[3,4-b]pyridine-5,7-dione isomers in the MDC layer was centrifuged. The mass was filtered and L-(+)-ammonium tartarate was separated. To the filtrate containing (4aS,7aR)-6-benzyl-1,2,3,4,4a,7a-hexahydropyrrolo [3,4-b]pyridine-5,7-dione and (4aR,7aS)-6-benzyl-1,2,3,4,4a,7a-hexahydropyrrolo[3,4-b] pyridine-5,7-dione, BHT (250 mg) was added and heating was applied. 50% of the reaction mass was distilled out at 45°C under pressure. The filtrate was gradually cooled up to 30°C. Sodium methoxide solution (5.5 g in 6 ml methanol) was charged gradually at 30°C. The mixture obtained was maintained for 4 hours at 30°C. Acetic acid (5.9 gm) was added slowly to the reaction mass and cooled to -5°C. 20% NaCl solution (50ml) was charged to the mixture under constant stirring and stirred further for 15 minutes. The organic layer containing Cis 6-benzyl-1,2,3,4,4a,7a-hexahydropyrrolo[3,4-b]pyridine-5,7-dione was dried over sodium sulfate. The layer was distilled under atmospheric pressure to collect Cis 6-benzyl-1,2,3,4,4a,7a-hexahydropyrrolo[3,4-b]pyridine-5,7-dione of Formula (I) (Wt. 80gm) having HPLC purity of about 80.0%. This obtained compound is recycled in the process.

Example 7
Preparation of (4aS,7aS)-6-benzyl-1,2,3,4,4a,5,7,7a-octahydropyrrolo[3,4-b]pyridine (Formula III)

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-1,2,3,4,4a,7a-hexahydropyrrolo[3,4-b]pyridine-5,7-dione (10g) of Formula (II) as obtained from example 4 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 (4aS,7aS)-6-benzyl-1,2,3,4,4a,5,7,7a-octahydropyrrolo[3,4-b]pyridine of Formula (III) having yield of about 84.6 %, a chiral purity of about 99.0 % and HPLC purity of about 97.1%.

Example 8
Preparation of (4aS,7aS)-6-benzyl-1,2,3,4,4a,5,7,7a-octahydropyrrolo[3,4-b]pyridine (Formula III)

Dimethoxy ethane (DME) (400 ml) was cooled to 5-10°C. AlCl3 (110 g) was charged lot wise (lot size NMT 5% of total AlCl3) 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) below15°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-1,2,3,4,4a,7a-hexahydropyrrolo[3,4-b]pyridine-5,7-dione (100 g) of Formula (II) as obtained from example 4 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 Conc. HCl (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 (200 ml) was charged and the mixture was stirred for 30 mins and aqueous 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-b]pyridine of Formula (III) (80 gms) having a chiral purity of 99.0 % and HPLC purity of 97.6%.

Example 9
Preparation of (4aS,7aS)-2,3,4,4a,5,6,7,7a-octahydro-1H-pyrrolo[3,4-b]pyridine (Formula A)

(4aS,7aS)-6-benzyl-1,2,3,4,4a,5,7,7a-octahydropyrrolo[3,4-b]pyridine (100 gm) of Formula (III) as obtained from examples 7 / 8 was charged to methanol (400 ml) and Charcoal (3 gm) was added therein followed by stirring thereof for 30 minutes. 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 mixture 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 (4aS,7aS)-2,3,4,4a,5,6,7,7a-octahydro-1H-pyrrolo[3,4-b] pyridine of Formula (A) (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%.

Example 10
The (4aS,7aS)-2,3,4,4a,5,6,7,7a-octahydro-1H-pyrrolo[3,4-b] pyridine of Formula (A) prepared as per Example 9 was compared with compound of Formula (A) as prepared by main granted patent invention 321410 wherein the cis compound 6-benzyl-1,2,3,4,4a,7a-hexahydropyrrolo[3,4-b]pyridine-5,7-dione of Formula (I) is resolved using D(-)-tartaric acid in presence of mixture of iso-propyl alcohol (IPA) and acetonitrile. The HPLC purity and the chiral purity prepared by the said granted patent and the present invention is presented in Table 1.
Table 1: Comparative data
Batch number Old process
IPA + Acetonitrile Old process
IPA + Acetonitrile Batch number Present Invention
Acetonitrile Present Invention
Acetonitrile
HPLC purity Chiral Purity HPLC purity Chiral Purity
PR-178-III Oil/I/022/17-18 96.94 98.80 PR-178-III Oil/V/040/18-19 99.8 99.6
PR-178-III Oil/I/087/17-18 97.08 98.76 PR-178-III Oil/V/046/18-19 99.8 99.3
PR-178-III Oil/I/088/17-18 96.68 99.0 PR-178-III Oil/V/049/18-19 99.8 99.2
PR-178-III Oil/I/095/17-18 98.61 94.02 PR-178-III Oil/V/051/18-19 99.8 99.5