Description:FIELD OF THE INVENTION:
The present invention relates to process for the preparation of (2S, 3aS ,7aS)-Octahydro-1H-indole-2-carboxylic acid, and more particularly to an improved process for the preparation of (2S, 3aS ,7aS)-Octahydro-1H-indole-2-carboxylic acid of formula (A) with high chiral purity, high yield, and high industrial applicability.

BACKGROUND OF THE INVENTION:
(2S,3aS,7aS)-Octahydro-1H-indole-2-carboxylic acid of compound of formula (A) is an important key intermediate compound that forms the core structure of the anti-hypertensive drugs such as Perindopril and salts thereof and antiviral drugs such as Odalasvir and salts thereof.

Perindopril Odalasvir
Compound (A) exists in eight stereoisomers and (2S,3aS,7aS)-isomer is of prime importance in the activity of these drugs. Various attempts for the synthesis of this isomer using chemical resolution and enzymatic resolution are reported.
The United States Patent Application US 4,935,525 to Michel Vincent, Bagneux and others discloses a preparation of compound of formula (A) as shown in scheme 1 below.

Scheme 1
The process involves preparation of ethyl ester of indol-2-carboxylic acid. The ethyl ester of indol-2-carboxylic acid is subjected to hydrogenation using tin-hydrochloric acid to form (R,S)-ethoxycarbonyl indoline, the S-isomer is separated using a-methylbenzylamine. (S)-Ethyoxycarbonyl is then subjected to hydrogenation using platinum, nickel, palladium, or rhodium particularly 5% rhodium to form compound (A). The desired (2S, 3aS, 7aS)-isomer is separated from the (2S, 3aR, 7aR)-isomer by a crystallization from lower aliphatic alcohol, acetonitrile, dioxane and ethyl acetate, by itself or mixed with each other or mixed with water. However, the process mentioned above does not provide any detailing about purity of (S,S,S)-stereoisomer.
The cited literature reference "Efficient access to N-protected derivatives of (R,R,R)-and (S,S,S)-octahydroindole-2-carboxylic acid by HPLC resolution" to Carlos Cativiela and others in Tetrahedron: Asymmetry, Volume 18, Issue 19, 27 September 2007, Pages 2358-2364" discloses a hydrogenation of indoline-2-carboxylic acid in acetic acid in the presence of PtO2 as shown in scheme 2 below.

Scheme 2

In the hydrogenation reaction, the solvent is evaporated to dryness and the resulting residue is first crystallized from ethanol and then from a mixture of dioxane–water to afford racemic white solid. The reported time for completion of the reaction is 24 hours. N-Boc protected benzyl ester of this chiral compound is further subjected to HPLC resolution on chiral column.
PCT Application WO2007062865 to Chen Weiren and others discloses a catalytic hydrogenation of ethyl (S)-indoline-2-carboxylate hydrochloride in ethanol and using Pd/C. The reaction mixture is hydrogenated at 60°C and 50 bar under stirring until the hydrogen has been consumed. The catalyst is filtered, and then the filtrate is hydrolyzed using sodium hydroxide. After work up (2S, 3aS, 7aS)-octahydro-lH-indole-2- carboxylic acid is isolated and obtained as white powder of 40% yield.
The United State Patent US 7,666,896 to Rajendra Narayanrao Kankan and others discloses a process for preparation of (2S, 3aS, 7aS)-octahydroindale-2-carboxylic acid by hydrogenation of (S)-indoline-2-carboxylic acid in an alkaline medium under 5-20 bar pressure in presence of Rh/Alumina at 50°C.
The processes known in the art for preparing compound of formula (A) are not satisfactory in respect of the cost, recyclability, and re-use of the hydrogenation catalyst.
Thus, there is a need for an improved process for the preparation of compound of formula (A), so that a high purity grade of the final product is obtained without substantial amounts of undesired by-products. There is also a need for the process for the preparation of compound of formula (A) that has higher yield, industrial scalability, and cost efficiency.

SUMMARY OF THE INVENTION:
The present invention describes a process for the preparation of compound of formula (A). More particularly one aspect of present invention relates to the stereo-specific synthesis of (2S,3aS,7aS)-Octahydro-1H-indole-2-carboxylic acid of formula (A) and another aspect of present invention relates to synthesis of compound of formula (I) by resolving indoline-2-carboxylic acid of formula (II).

The process of stereo-specific synthesis of intermediate (2S,3aS,7aS)-octahydro-1H-indole-2-carboxylic acid of formula (A) includes hydrogenation of compound of formula (I) in the aqueous medium in presence of a metal catalyst and an alkali to form compound of formula (A).
The process of synthesis of compound of formula (I) by resolving indoline-2-carboxylic acid of formula (II) includes a plurality of steps. The process includes the steps of adding compound of formula (II) to the solution (R)-(+)-a-methylbenzylamine in a solvent, heating the reaction mixture, gradually cooling the reaction mass, isolating (R)-a-methylbenzylamine salt of (S)-isomer of formula (I-SA) by filtration, reacting compound of formula (I-SA) with predefined acid or alkali to form compound of formula (I) in aqueous medium followed by isolation and racemization of (R)-isomer to form compound of formula (II), and recovery of resolving agent (R)-a-methylbenzylamine.

DESCRIPTION OF THE INVENTION:
References in the specification to "one embodiment" or "an embodiment" means that a particular feature, structure, characteristic, or function described in connection with the embodiment is included in at least one embodiment of the invention. The appearances of the phrase “in one embodiment” in various places in the specification are not necessarily all referring to the same embodiment.
References in the specification to “preferred embodiment” means that a particular feature, structure, characteristic, or function described in detail thereby omitting known constructions and functions for clear description of the present invention.
The foregoing description of specific embodiments of the present invention has been presented for purposes of illustration and description. They are not intended to be exhaustive or to limit the present invention to the precise forms disclosed and obviously many modifications and variations are possible in light of the above teaching.
The inventors of the present invention have developed a process for the preparation of compound of formula (A) that provides higher yield of compound (A) and is efficient in recovery and re-use of the catalyst in the process. The process is cost effective with higher chiral purity even at higher scale production.
In one aspect the present invention relates to stereo-specific synthesis of intermediate (2S,3aS,7aS)-octahydro-1H-indole-2-carboxylic acid of formula (A).

The stereo-specific synthesis of intermediate (2S,3aS,7aS)-octahydro-1H-indole-2-carboxylic acid of formula (A) includes:
hydrogenation of (2S)-indoline-2-carboxylic acid of formula (I) at a predefined temperature and predefined pressure in the aqueous medium in presence of a metal catalyst and an alkali to form compound of formula (A).

Scheme 3

In this embodiment of the present invention, the alkali used for hydrogenation in step (a) is selected from hydroxides, carbonates and bicarbonates of alkali metal or alkaline earth metal. The metal catalyst used for hydrogenation in step (a) is Ruthenium on carbon. The hydrogenation is carried out at predefined temperature of 60-140°C, preferably at 70-110°C under predefined hydrogen pressure of 15 - 30 kg, preferably of 20-25 kg pressure.
In a preferred embodiment, the hydrogenation is carried out wherein the catalyst loading is 1-10% wet, preferably 5% Ruthenium on carbon is used in the process. The alkali used for hydrogenation is preferably selected from sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate and potassium bicarbonate. More preferably the alkali used is selected from sodium hydroxide and sodium bicarbonate.
Further, in a preferred embodiment, recovering and recycling of the Ruthenium catalyst employed in the process of preparation of Compound of Formula (A) is described. After completion of the reaction, the reaction mass is filtered, and the catalyst is recovered under nitrogen. The catalyst recovered is washed with water and the recycled catalyst is used as a fresh catalyst in the next batch.
The process is carried out with optimum efficiency leading to efficient recovery and recycling of >90% of catalyst used.

In another aspect, the present invention relates to synthesis of compound of formula (I) by resolving indoline-2-carboxylic acid of formula (II).

In an embodiment, synthesis of compound of formula (I) by resolving indoline-2-carboxylic acid of formula (II) includes steps of:
a. adding compound of formula (II) to the solution (R)-(+)-a-methylbenzylamine in a predefined solvent having predefined moisture content;

b. heating the reaction mixture at predefined temperature;
c. gradually cooling the reaction mass to predefined temperature;
d. isolating (R)-a-methylbenzylamine salt of (S)-isomer of formula (I-SA) by filtration;

e. reacting compound of formula (I-SA) with predefined acid or alkali to form compound of formula (I) in aqueous medium;

f. isolation and racemization of (R)-isomer to form compound of formula (II); and

g. recovery of resolving agent (R)-a-methylbenzylamine.
The schematic representation of synthesis of compound of formula (I) by resolving indoline-2-carboxylic acid of formula (II) of the present invention is shown below.

Scheme 4
In an embodiment of the present invention, the predefined solvent used in step (a) is selected from ethanol and isopropyl alcohol, preferably the solvent used is isopropyl alcohol having predefined moisture content of 4-6%.
In an embodiment of the present invention, heating of the reaction mixture in step (b) is carried out at predefined temperature of 50-90 °C, preferably at 55-80 °C and more preferably at 65-70 °C.
In an embodiment of the present invention, gradual cooling the reaction mass in step (c) is carried out from 50-55 °C to predefined temperature of 30-35°C and stirred.
In an embodiment of the present invention, reacting compound of formula (I-SA) in step (e) with predefined acid is selected from HCl, H2SO4 and acetic acid, or predefined alkali is selected from metal hydroxide, carbonates, and ammonia to form compound of formula (I) in aqueous medium.
The isolation and racemization of (R)-isomer to form compound of formula (II) in step (f) is carried out by two routes.
In an embodiment, in route 1 the isolation and racemization of (R)-isomer to form compound of formula (II) is carried out by following steps:
i. distilling the filtrate obtained in step (d);
ii. adding water to the filtrate obtained in step (i);
iii. adjusting the pH of the reaction mixture to 3.5 - 4.5 using predefined acid selected from HCl, H2SO4 and acetic acid;
iv. isolating (R)-isomer by filtration;
v. adding (R)-isomer to water and predefined alkali selected from metal hydroxide, carbonates, and ammonia;
vi. heating to predefined temperature of 135-175 °C for predefined time of 3-10 hours with stirring;
vii. gradually cooling the reaction mass to predefined temperature of 30-35 °C and pH is adjusted to 3.5 - 4.5 using predefined acid selected from HCl, H2SO4 and acetic acid; and
viii. isolating compound of formula (II) by filtration.

In another embodiment, in route 2 the isolation and racemization of (R)-isomer to form compound of formula (II) is carried out by following steps:
i. distilling the filtrate obtained in step (d);
ii. adding water to the filtrate obtained in step (i);
iii. adjusting the pH of the reaction mixture to 10-12 using predefined alkali selected from metal hydroxide, carbonates, and ammonia;
iv. isolating (R)-a-methylbenzylamine by extraction with suitable solvent;
v. adjusting the pH of the reaction mixture to 3.5 - 4.5 using predefined acid selected from HCl, H2SO4 and acetic acid;
vi. isolating (R)-isomer by filtration;
vii. adding (R)-isomer to water and predefined alkali selected from metal hydroxide, carbonates, and ammonia;
viii. heating to predefined temperature of 135-175 °C for predefined time of 3-10 hours with stirring;
ix. gradually cooling the reaction mass to predefined temperature of 30-35 °C and pH is adjusted to 3.5 - 4.5 using predefined acid selected from HCl, H2SO4 and acetic acid; and
x. isolating compound of formula (II) by filtration.

The process includes the recovery of resolving agent (R)-amethylbenzylamine in step (g) by two paths.
In path1, the recovery of resolving agent (R)-a-methylbenzylamine is carried out by following steps:
i. adjusting the predefined pH of the filtrate obtained in step (e) and step (iv) of route 1 of isolation and racemization of (R)-isomer to form compound of formula (II) to 10-12 using predefined alkali selected from metal hydroxide, carbonates, and ammonia;
ii. adding a suitable organic solvent to the reaction mixture obtained in above mentioned step and stirring;
iii. separating the layers and distilling the organic layer under vacuum; and
iv. isolating the pure (R)-a-methylbenzylamine by distillation of the mass obtained.
In path 2 the recovery of resolving agent (R)-a-methylbenzylamine is carried out by following steps:
i. distilling the organic layer under vacuum; and
ii. isolating the pure (R)-a-methylbenzylamine by distillation of the mass obtained.
These and other embodiments will be apparent to those of skill in the art and others in view of the following detailed description of some embodiments. It should be understood, however, that this summary and the detailed description illustrate only some examples of various embodiments and are not intended to be limiting to the invention as claimed. The following examples illustrate the invention but are not limiting thereof.

EXAMPLES:
Example 1
Preparation of 1-acetylindoline-2-carboxylic acid
Triethylamine (74 ml) and 4-dimethylamino pyridine (1g) was charged to acetone (400 ml) and the mixture was stirred at 30-35 °C for 10 minutes. The temperature was raised to 40-45 °C and indol-2-acetic acid was charged lot-wise in about 60 minutes. The mixture was stirred for 45 minutes at 45 °C. The reaction mass was then cooled to 15-20°C and acetic anhydride (95.01 gm) was charged slowly and stirred for 1-2 hours at 15-20 °C. Aqueous HCl was prepared separately by mixing concentrated HCl (100 ml) in water (700 ml) at 5-10 °C and the reaction mass was quenched in this aqueous HCl acid solution. The mass was stirred for 30 minutes and filtered. The solid was washed with water (100 ml). The precipitate was dried under vacuum at 50-55 °C for 7-8 hours to get 1-acetylindoline-2-carboxylic acid (112 gm, 88% yield).

Example 2
Preparation of 1-acetylindoline-2-carboxylic acid
1 gm of the 5% wet Pd/C was charged to the mixture of 1-acetylindoline-2-carboxylic acid (100 gm) isolated in Example 1 and acetic acid (750 ml). The reaction mixture was stirred for 10 -15 minutes at 30-35 °C. Hydrogen gas pressure (8 kg) was applied, and the mixture was heated to 70-72 °C and stirred for 2-3 hours. The mass was filtered through hyflow bed and washed with acetic acid (100 ml). Solvent was distilled out under vacuum from the filtrate at 75-80 °C. The mass was cooled to 55-60 °C and water (100 ml) was charged. The mass was stirred for 30 minutes at 55-60 °C and cooled to 30-35 °C. The mass was filtered and suck dried. The wet solid obtained was suspended in ethyl acetate (200 ml) and the temperature was raised to 55-60 °C. The reaction mass was stirred for 30 minutes and cooled to 30-35 °C. The reaction mass was further cooled to 5-10 °C and stirred for 60 minutes. The reaction mass was filtered and washed with ethyl acetate (50 ml) and suck dried. The solid was further dried under vacuum at 50-55 °C for 8 hrs. to get 1-acetylindoline-2-carboxylic acid (88 gm, 88%).

Example 3
Preparation of indoline-2-carboxylic acid
1-acetylindoline-2-carboxylic acid (100 gm) obtained in Example 2 was charged to concentrated HCl (250 ml) at 30-35 °C and the mixture was stirred for 15-16 hours. The pH was adjusted to 3.8 - 4.1 using aqueous sodium hydroxide and the mass was stirred for 60 minutes at 10-15 °C. The slurry was filtered and washed with water (50 ml x 2) and suck dried. The solid was further dried under vacuum at 50-55 °C for 8 hrs. to get indoline-2-carboxylic acid (75.7 gm, 95.2%).

Example 4
Preparation of (2S)-indoline-2-carboxylic acid (I)
a. Preparation of (R)-(+)-a-Methylbenzylamine salt of (2S)-indoline-2-carboxylic acid (I-SA):
(R)-(+)-a-Methylbenzylamine (RAMBA) (371.1gm) was charged to the mixture of IPA (5000 ml) and water (200ml) at 30-35 °C. The reaction mixture was stirred for 15 min. The temperature of the mixture was raised to 65-70 ? and stirred for 15 minutes. Indoline-2-carboxylic acid (500 gm) prepared in Example 3 was charged to the above reaction mass in lot-wise in about 60-75 minutes at 65-70 ?. The reaction mixture was stirred for 60 minutes at 65-70 ?. The mixture was gradually cooled to 50-55 ? and stirred for four hours. The mixture was further cooled to 30-32 ? and stirred for 3 hours. The slurry obtained was filtered and washed with IPA (250 ml). The filtrate 1 obtained is kept aside for recovery of other isomer. (R)-(+)-a-Methylbenzylamine salt of (2S)-indoline-2-carboxylic acid was suck dried and further dried under vacuum for 5-6 hours. (Dry wt. 250 gm).
b. 1. Preparation of (2S)-indoline-2-carboxylic acid (I):
(R)-(+)-a-Methylbenzylamine salt of (2S)-indoline-2-carboxylic acid (250 gm) was charged to water (750 ml) at 30-35 °C. The pH was adjusted to 3.8 - 4.0 using concentrated HCl. The reaction mass was stirred for 60 min at 30-35 °C and the slurry was filtered. The filtrate 2 obtained is kept aside for recovery of resolving agent (R)-(+)-a-Methylbenzylamine. (2S)-indoline-2-carboxylic acid (I) obtained was washed with water (125 ml) and sucked dried. The solid was further dried under vacuum at 50-55 °C for 8 hrs. to get indoline-2-carboxylic acid (135 gm, 27%).
2. Preparation of (2S)-indoline-2-carboxylic acid (I):
(R)-(+)-a-Methylbenzylamine salt of (2S)-indoline-2-carboxylic acid (250 gm) was charged to water (750 ml) at 30-35 °C. The pH was adjusted to 10-12 using 30% Aq. NaOH solution. To this added MDC (500 ml) and stirred for 15 min. Aqueous layer was separated and cooled to 10-15 °C and pH is adjusted to 3.8 to 4.0. The reaction mass was stirred for 60 min at 30-35 °C and the slurry was filtered. (2S)-indoline-2-carboxylic acid (I) obtained was washed with water (125 ml) and sucked dried. The solid was further dried under vacuum at 50-55 °C for 8 hrs. to get (2S)-indoline-2-carboxylic acid (130 gm, 26%).
c. 1. Recovery of the R-(+)-a-Methylbenzylamine:
Filtrate from Example 4.b.1 was taken, and pH is adjusted to 10 to 12 using 30% Aq. Sodium hydroxide solution. Added MDC (250 ml) and stirred for 15 min. Layer gets separated. To aqueous layer one more extraction of MDC (250 ml) given. Combined MDC layers were washed with water (200 ml). Organic layer was distilled to remove solvent below 50 °C followed by distillation of the R-(+)-a-Methylbenzylamine under vacuum NLT 650 mm Hg below 120 °C.
2. Recovery of the R-(+)-a-Methylbenzylamine:
Organic layers from example 4.b.2 were distilled to remove solvent below 50 °C followed by distillation of the R-(+)-a-Methylbenzylamine under vacuum NLT 650 mm Hg below 120 °C.

Example 5
Preparation of (2S, 3aS ,7aS)-octahydro-1H-indole-2-carboxylic acid (A)
Sodium bicarbonate solution was prepared by adding and stirring sodium bicarbonate (51.5 gm) in water (700 ml) to get a clear solution. (2S)-indoline-2-carboxylic acid (I) obtained in Example 4.b.1 (100 gm) was charged to the above prepared sodium bicarbonate solution lot-wise at 30-35 °C. The reaction mixture was stirred for 30 minutes. 5% Ru/C (10 g,) was charged to the reaction mass. 20-22 kg of hydrogen pressure was applied at 30-35 °C. The temperature was raised to 80-85 °C and the mass was stirred for 4-6 hours. The reaction mass was cooled to 30-35 °C and hydrogen pressure was released and the mass was filtered. The catalyst separated by filtration was washed with water (100 ml) and stored under nitrogen. This catalyst was reused in the next batch.
Wash the filtrate with MDC (200 ml) and pH of the aqueous layer was adjusted to 4.5 with dilute sulfuric acid. The resulting aqueous layer was washed with MDC (200 ml). The layers were separated, and the aqueous layer was concentrated under vacuum. Methanol (1000 ml) was charged, and the hot mixture was stirred for 1-1.5 hours. The reaction mixture was filtered to remove inorganics and washed with methanol. Filtrate was distilled under vacuum at 50-55°C to get the residue. Acetone (700 ML) was charged to the residue at 30-35°C and refluxed for 1-1.5 hours. Cooled the reaction mixture to 30-35 °C and further gradually cooled to 15-20 °C. The mixture was stirred for 2 hours and filtered. Dried the resulting solid under vacuum at 55-60 °C for 7-8 hours to get (2S, 3aS ,7aS)-octahydro-1H-indole-2-carboxylic acid (84.5 gms, 82%).
HPLC purity - 99.2%
Chiral Purity: 98.5%

Example 6
Preparation of (2S, 3aS ,7aS)-octahydro-1H-indole-2-carboxylic acid (A)
Sodium Hydroxide solution was prepared by adding and stirring sodium hydroxide (24.53 gm) in water (700 ml) to get a clear solution. (2S)-indoline-2-carboxylic acid (I) obtained in example 4b) (100 gm) was charged to the above prepared sodium hydroxide solution lot-wise at 30-35 °C. The reaction mixture was stirred for 30 minutes. 5% Ru/C (10 g,) was charged to the reaction mass. 20-22 kg of hydrogen pressure was applied at 30-35 °C. The temperature was raised to 80-85 °C and the mass was stirred for 4 hours. The reaction mass was cooled to 30-35 °C and hydrogen pressure was released and the mass was filtered. The catalyst separated by filtration was washed with water (100 ml) and stored under nitrogen. This catalyst is reused in the next batch.
Wash the filtrate with MDC (200 ml) and pH of the aqueous layer was adjusted to 4.5 with dilute sulfuric acid. The resulting aqueous layer was washed with MDC (200 ml). The layers were separated, and the aqueous layer was concentrated under vacuum. Methanol (1000 ml) was charged, and the hot mixture was stirred for 1-1.5 hours. Filtered the reaction mixture to remove inorganics and washed with methanol. Filtrate was distilled under vacuum at 50-55°C to get the residue. Acetone (700 ML) was charged to the residue at 30-35°C and refluxed for 1-1.5 hours. Cooled the reaction mixture to 30-35 °C and further gradually cooled to 15-20 °C. The mixture was stirred for 2 hours and filtered. Dried the resulting solid under vacuum at 55-60 °C for 7-8 hours to get (2S, 3aS ,7aS)-octahydro-1H-indole-2-carboxylic acid (82.5 gms, 80%).
HPLC purity - 99.3%
Chiral Purity: 98.4%
Example 7
Preparation of (2S, 3aS ,7aS)-octahydro-1H-indole-2-carboxylic acid (A)
Sodium Hydroxide solution was prepared by adding and stirring sodium hydroxide (24.53 gm) in water (700 ml) to get a clear solution. (2S)-indoline-2-carboxylic acid (I) obtained in example 4b) (100 gm) was charged to the above prepared sodium hydroxide solution lot-wise at 30-35 °C. The reaction mixture was stirred for 30 minutes. 5% Ru/C (10 g,) was charged to the reaction mass. 20-22 kg of hydrogen pressure was applied at 30-35 °C. The temperature was raised to 80-85 °C and the mass was stirred for 4-6 hours. The reaction mass was cooled to 30-35 °C and hydrogen pressure was released and the mass was filtered. The catalyst separated by filtration was washed with water (100 ml) and stored under nitrogen. This catalyst is reused in the next batch. Recovered catalyst weight was 9 gm.
Filtrate was taken in clean and dry RBF and pH was adjusted to 4.5 with dilute sulfuric acid. The resulting reaction mass was concentrated under a vacuum. Methanol (1000 ml) was charged, and the hot mixture was stirred for 1-1.5 hours. Filtered the reaction mixture to remove inorganics and washed with methanol. Filtrate was distilled under vacuum at 50-55 °C to get the residue. 1,4-dioxane (1000 ml) and water (200 ml) was charged to the residue at 30-35°C and refluxed for 1-1.5 hours. Cooled the reaction mixture to 30-35 °C, stirred for 2 hours and filtered. Dried the resulting solid under vacuum at 55-60 °C for 7-8 hours to get (2S, 3aS ,7aS)-octahydro-1H-indole-2-carboxylic acid (84.5 gms, 82%).
HPLC purity - 99.9%
Chiral Purity: 98.8%
Example 8
Preparation of (2S, 3aS ,7aS)-octahydro-1H-indole-2-carboxylic acid (A) using recovered catalyst
The catalyst was recovered and recycled in next batch containing (2S)-indoline-2-carboxylic acid (100 gm). Recovered 5% Ru/C catalyst and fresh 5% Ru/C catalyst (1 gm) was charged, and the process as explained in example 5 was followed.
Similarly, series of experiments were carried out using recovered catalyst and results are summarized in the Table below.
Table-1: Catalyst Recycle study with Top up of fresh catalyst
Sr. No. Catalyst 5% Ru/C cycle Catalyst Loading (w/w) (2S, 3aS ,7aS)-octahydro-1H-indole-2-carboxylic acid (% purity in reaction mass) during reaction monitoring Reaction time
1 Fresh 10% 91.77 4 h
2 R1 10 R + 1%Fresh 96.45 4 h
3 R2 10 R1 + 1%Fresh 90.85 4 h
4 R3 10 R2 + 1%Fresh 90.91 6 h
5 R4 10 R3 + 1%Fresh 89.39 4 h
6 R5 10 R4 + 1%Fresh 86.42 4 h
7 R6 10 R5 + 1%Fresh 89.38 4 h
8 R7 10 R6 + 1%Fresh 92.93 4 h
9 R8 10 R7 + 1%Fresh 90.06 4 h
10 R9 (after 30-day storage) 10 R8 + 1%Fresh 96.72 4 h

The catalyst is recycled 10 times with 1% Top-up of fresh catalyst. The reaction proceeds smoothly without deterioration of the catalyst efficiency, the recovered catalyst was stored for month and used in reaction. The product formation was > 85% as shown in the above table. Also, the catalyst recycle study without top up of the fresh catalyst is performed. The reaction proceeds smoothly using recovered catalyst without top up of fresh catalyst.
Table-2: Catalyst recycle study without top up of fresh catalyst
Sr. No. Catalyst 5% Ru/C cycle Catalyst Loading (w/w) (2S, 3aS ,7aS)-octahydro-1H-indole-2-carboxylic acid (% purity in reaction mass) during reaction monitoring Reaction time
1 Fresh 10% 97.65 4 h
2 R1 10 R 96.07 4 h
3 R2 10 R1 97.62 4 h
4 R3 10 R2 93.97 4 h

Based on the above observations it is concluded that catalyst is recyclable with or without top up of fresh catalyst. Many more cycles were possible with or without top up of fresh catalyst. The recycling reduces the catalyst cost tremendously and catalyst consumption for each batch is 10% fresh top up loading that is required.
Example: 9
Impact of moisture content on yield and chiral purity
Below table shows the impact of moisture content on yield and chiral purity:
Solvent Moisture (%) % yield Chiral purity
IPA 3.18 43.62 85.56
IPA 5.08 30.42 97.92
IPA 5.30 30.05 96.98
IPA 6.36 30.05 98.35

In the context of the present invention, the process of the present invention provides higher chiral purity and higher yield of compound of formula (A) without substantial amounts of undesired by-products. Further, the process of the present invention for the preparation of compound of formula (A) is industrially and economically feasible due to recyclability and reuse of catalyst and resolving agent (R)-(+)-a-methylbenzylamine with higher efficiency.
Moreover, in the process of the present invention >90% of the catalyst is recovered and recycled as a fresh catalyst efficiently. This makes the process economically feasible, as recovering and recycling of the catalyst reduces the cost of the catalyst drastically.
The embodiments were chosen and described in order to best explain the principles of the present invention and its practical application, to thereby enable others, skilled in the art to best utilize the present invention and various embodiments with various modifications as are suited to the particular use contemplated.
It is understood that various omission and substitutions of equivalents are contemplated as circumstance may suggest or render expedient, but such are intended to cover the application or implementation without departing from the scope of the present invention.
, Claims:We claim:
1. A process for preparation of (2S,3aS,7aS)-Octahydro-1H-indole-2-carboxylic acid of formula (A),

comprising step of:
hydrogenation of compound of formula (I) at a predefined temperature and predefined pressure in the aqueous medium in presence of a metal catalyst and an alkali to form compound of formula (A).

2. The process as claimed in claim 1, wherein the alkali used for hydrogenation in step (a) is selected from hydroxides, carbonates and bicarbonates of alkali metal or alkaline earth metal.
3. The process as claimed in claim 1 and claim 2, wherein the alkali used for hydrogenation in step (a) is selected from sodium hydroxides, potassium hydroxide, lithium hydroxide and sodium bicarbonate, sodium carbonate, potassium carbonate.

4. The process as claimed in claim 1, wherein the process of hydrogenation in step (a) is carried out under predefined hydrogen pressure of 15-30 kg.

5. The process as claimed in claim 1, wherein in the process of hydrogenation in step (a) the catalyst used is 1-15% Ruthenium on carbon.

6. The process as claimed in claim 1, wherein in the process of hydrogenation in step (a) the catalyst loading is 1-10%.

7. The process as claimed in claim 1, wherein the process of hydrogenation in step (a) is carried out at predefined temperature of 60-140°C.

8. The process as claimed in any of the preceding claims, wherein the process further includes recovering and reusing the metal catalyst in the process.

9. A process as claimed in claim 1, wherein preparation of compound of formula (I) by resolving indoline-2-carboxylic acid of formula (II) includes the steps of:
a. adding compound of formula (II) to the solution (R)-(+)-a-methylbenzylamine in a predefined solvent having predefined moisture content;

b. heating the reaction mixture at predefined temperature;
c. gradually cooling the reaction mass to predefined temperature;
d. isolating (R)-a-methylbenzylamine salt of (S)-isomer of formula (I-SA) by filtration;

e. reacting compound of formula (I-SA) with predefined acid or alkali to form compound of formula (I) in aqueous medium;

f. isolation and racemization of (R)-isomer to form compound of formula (II); and

g. recovery of resolving agent (R)-a-methylbenzylamine.

10. The process as claimed in claim 9, wherein the process of step (a) of adding compound of formula (II) to the solution (R)-(+)-a-methylbenzylamine is carried out using predefined solvent selected from ethanol and iso-propyl alcohol

11. The process as claimed in claim 10, wherein the predefined solvent is iso-propyl alcohol having moisture content of 4-6%.

12. The process as claimed in claim 9, wherein heating of the reaction mixture in step (b) is carried out at predefined temperature of 50-90 °C.
13. The process as claimed in claim 9, wherein gradual cooling of the reaction mass in step (c) is carried out at predefined temperature of 30-35°C and stirred.

14. The process as claimed in claim 9, wherein the predefined acid in step (e) is selected from HCl, H2SO4 and acetic acid; predefined alkali is selected from metal hydroxide, carbonates, and ammonia to form compound of formula (I) in aqueous medium.

15. The process as claimed in claim 9, wherein the isolation and racemization of (R)-isomer to form compound of formula (II) includes the steps of:
i. distilling the filtrate obtained in step (d);
ii. adding water to the filtrate obtained in step (i);
iii. adjusting the predefined pH of the reaction mixture to 3.5 - 4.5 using acid selected from HCl, H2SO4 and acetic acid;
iv. isolating (R)-isomer by filtration;
v. adding (R)-isomer to water and alkali selected from metal hydroxide, carbonates, and ammonia;
vi. heating to temperature of 135-175 °C for predefined time of 3-10 hours with stirring;
vii. gradually cooling the reaction mass to temperature of 30-35 °C and pH is adjusted to 3.5 - 4.5 using acid selected from HCl, H2SO4 and acetic acid; and
viii. isolating compound of formula (II) by filtration.

16. The process as claimed in claim 9, wherein the isolation and racemization of (R)-isomer to form compound of formula (II) includes the steps of:
i. distilling the filtrate obtained in step (d);
ii. adding water to the filtrate obtained in step (i);
iii. adjusting the predefined pH of the reaction mixture to 10 - 12 using alkali selected from metal hydroxide, carbonates, and ammonia;
iv. isolating (R)-a-methylbenzylamine by extraction with suitable solvent;
v. adjusting the pH of the reaction mixture to 3.5 - 4.5 using acid selected from HCl, H2SO4 and acetic acid;
vi. isolating (R)-isomer by filtration;
vii. adding (R)-isomer to water and alkali selected from metal hydroxide, carbonates, and ammonia;
viii. heating to temperature of 135-175 °C for time of 3-10 hours with stirring;
ix. gradually cooling the reaction mass to temperature of 30-35 °C and pH is adjusted to 3.5 - 4.5 using acid selected from HCl, H2SO4 and acetic acid; and
x. isolating compound of formula (II) by filtration.

17. The process as claimed in claims 1 and 9, wherein the recovery of resolving agent (R)-a-methylbenzylamine includes the steps of:
i. adjusting the predefined pH of the filtrate obtained in step (e) and step (iv) of isolation and racemization of (R)-isomer to form compound of formula (II) to 10 – 12 using alkali selected from metal hydroxide, carbonates, and ammonia;
ii. adding a suitable organic solvent to the reaction mixture obtained in above mentioned step and stirring;
iii. separating the layers and distilling the organic layer under vacuum; and
iv. isolating the pure (R)-a-methylbenzylamine by distillation of the mass obtained.

18. The process as claimed in claims 1 and 9, wherein, the recovery of resolving agent (R)-a-methylbenzylamine includes the steps of:
i. distilling the organic layer under vacuum; and
ii. isolating the pure (R)-a-methylbenzylamine by distillation of the mass obtained.

Dated this 25th day of April 2023.

For AARTI PHARMALABS LIMITED

Mahurkar Anand Gopalkrishna
IN/PA-1862
(Agent for Applicant)