Claims:We Claim:
1. A process for the preparation of compound of formula (IA),

the process comprising,
(a) reacting 3a,4,7,7a-tetrahydro-1H-isoindole-1,3(2H)-dione of formula (2),

with suitable reducing agents in dry solvent to obtain the corresponding amine of formula (3);

(b) reacting 2,3,3a,4,7,7a-hexahydro-1H-isoindole of formula (3) with suitable protecting agent to obtain compound of formula (4);

(c) oxidation of tert-butyl 1,3,3a,4,7,7a-hexahydro-2H-isoindole-2-carboxylate of formula (4) by suitable oxidizing agents in presence of TBAB to get its corresponding pyrrolo diacetic acid of formula (5); and

(d) treating 2,2'-(1-(tert-butoxycarbonyl)pyrrolidine-3,4-diyl)diacetic acid of formula (5) with acetic anhydride and weak base to obtain compound of formula (1A).

2. The process as claimed in claim 1 wherein in step (a), the suitable reducing agent is selected from Lithium aluminum hydride or Borane dimethyl sulfide complex.
3. The process as claimed in claim 1 wherein in step (a), the suitable solvent is selected from THF or diethyl ether or suitable mixture thereof.
4. The process as claimed in claim 1 wherein in step (b), the suitable protecting agent is selected from Boc anhydride, Cbz chloride, benzyl bromide, acetyl chloride, mesyl chloride or tosyl chloride.
5. The process as claimed in claim 1 wherein in step (c), the oxidizing agent is selected from catalytic ruthenium oxide with sodium metaperiodate, catalytic ruthenium dichloride with sodium metaperiodate, potassium permanganate and hydrogen peroxide.
6. The process as claimed in claim 1 wherein in step (d), wherein the weak base is selected from sodium acetate, potassium acetate, sodium bicarbonate, potassium bicarbonate and sodium carbonate.
7. A process for the preparation of compound of formula (IA),

the process comprising:
(a) reacting Benzyl amine of formula (6),

with alkylating agents in dry solvent to obtain the activated dienes (Dimethyl 4,4'-(benzylazanediyl)(2E,2'E)-bis(but-2-enoate) (7),

(b) intramolecular reductive cyclization of dimethyl 4,4'-(benzylazanediyl)(2E,2'E)-bis(but-2-enoate) (7) with Mg/methanol to get dimethyl 2,2'-((3R,4S)-1-benzylpyrrolidine-3,4-diyl)diacetate (8);

(c) debenzylation of dimethyl 2,2'-((3R,4S)-1-benzylpyrrolidine-3,4-diyl)diacetate (8) using Pd/C mediated hydrogenation with a suitable protecting agent to get dimethyl 2,2'-((3R,4S)-1-(tert-butoxycarbonyl)pyrrolidine-3,4-diyl)diacetate (9);

(d) hydrolysis of dimethyl 2,2'-((3R,4S)-1-(tert-butoxycarbonyl)pyrrolidine-3,4-diyldiacetate of formula (9) by using NaOH in methanol and water to get its corresponding pyrrolo diacetic acid of formula (5); and

(e) treating 2,2'-(1-(tert-butoxycarbonyl)pyrrolidine-3,4-diyl)diacetic acid of formula (5) with acetic anhydride and a weak base to obtain compound of formula (1A).

8. The process as claimed in claim 7 wherein in step (a), the suitable base is selected from triethyl amine, diisopropylethyl amine, pyridine, sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, sodium hydride and DBU.
9. The process as claimed in claim 7 wherein in step (a), the suitable solvent is selected from dichloromethane, chloroform, tetrahydrofuran, 1,4-dioxane, dimethyl formamide, methanol, ethanol or suitable mixture thereof.
10. The process as claimed in claim 7 wherein in step (b), the suitable protecting agent is selected from Boc anhydride, Cbz chloride, benzyl bromide or acetyl chloride.
11. The process as claimed in claim 7 wherein in step (e), the suitable base is selected from sodium acetate, potassium acetate, sodium carbonate sodium bicarbonate or potassium bicarbonate.

Dated this the 08th day of August 2016

[GAYATRI BHASIN]
Of SUBRAMANIAM & ASSOCIATES
Attorneys for the applicants
, Description:FORM 2

THE PATENTS ACT, 1970
(39 of 1970)
&
The Patent Rules, 2003

COMPLETE SPECIFICATION
(See section 10 and rule 13)

TITLE OF THE INVENTION

“PROCESS FOR THE PREPARATION OF HEXAHYDROCYCLOPENTA[C]PYRROL-5(1H)-ONE AND INTERMEDIATES THEREOF”

We, CADILA HEALTHCARE LIMITED, an Indian company incorporated under the Companies Act, 1956, of Zydus Tower, Satellite Cross Roads, Ahmedabad – 380015, Gujarat, 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 an improved process for the preparation of hexahydrocyclopenta[c]pyrrol-5(1H)-one compounds of the general formula (I) and intermediates thereof.
BACKGROUND OF THE INVENTION
Patent applications WO2014151936 and WO2014152018 describes the utility of hexahydrocyclopenta[c]pyrrol-5(1H)-one formula (I), which are intermediates useful for the synthesis of certain cyclopentapyrroles derivatives, useful for the treatment of macular degeneration. JMC, 57(18), 7731, 2014 and JMC, 58(15), 5863, 2015, discloses few such bicyclic [3.3.0]-octahydrocyclopenta[c]pyrrole derivatives as antagonists of retinol binding protein 4, for the treatment of atrophic age-related macular degeneration and Stargardt disease. octahydro-cyclopenta[c]pyrroles were reported as inhibitors of the type1 glycine transporter (GlyT1), for the treatment of schizophrenia, BMCL, 20, 907, 2010.
Patent application WO2009045992 describes the utility of hexahydrocyclopenta[c]pyrrol-5(1H)-one formula (I) as intermediates of 5-(Pyridin-2-yl)tetrazole derivatives which are c-MET protein kinase inhibitors, used in the treatment of proliferative diseases. In these references, the synthetic procedures were reported for the synthesis of hexahydrocyclopenta[c]pyrrol-5(1H)-one of formula (I) as per Scheme 1:
Scheme 1

The patent application WO 2013021054 describes the use of compound of formula (I) as an intermediate to cyclopenta[c]pyrrole substituted 3,4-dihydro-1H-[1,8]naphthyridinones, useful as antibacterial agents. Compound of formula (I) was prepared, using alternate synthetic strategy that employs Pauson-Khand cyclocarbonylation in Scheme 2.

Scheme 2

This route (Scheme 2) was also reported in Tetrahedron, 49(23), 5047, 1993 and an improved procedures have been reported in Organic Letters, 4(22), 3983, 2002.
Thus, hexahydrocyclopentapyrrolone derivatives represent an essential pharmacophore for diversified pharmacological activities. However, there is still need for an improved process for the preparation of hexahydrocyclopenta[c]pyrrol-5(1H)-one compound of formula (I) and intermediates thereof.
In view of the preparation methods available for compound of formula (I), there is a need for simple and cost effective processes for the preparation of hexahydrocyclopenta[c]pyrrol-5(1H)-one, compounds of formula (I) that provides improved efficiency per reaction volume in terms of yield, and purity.
SUMMARY OF THE INVENTION
In one general aspect, there is provided a process for the preparation of compound of formula (I),

Formula (I)

Wherein R is selected from H, C1-C4 alkyl, O=COC1-C4 alkyl, benzyl, SO2C1-C4 alkyl
In another general aspects the present invention in particular provides an improved process for the preparation of hexahydrocyclopenta[c]pyrrol-5(1H)-one, compounds of the formula (IA) and intermediates thereof.

DETAILED DESCRIPTION OF THE INVENTION
As used herein, the term “reflux temperature” refers to the boiling point of the solvent.
As used herein, the term ‘THF’ refers to tetrahydrofuran, the term ’DIPEA’ refers to N,N-diisopropylethylamine, the term’MeOH’ refers to methanol, the term ‘NaOH’ refers to sodium hydroxide, the term ‘Boc’ refers to tert-Butyloxycarbonyl group, the term Cbz refers to carbobenzyloxy group, ‘TBAB’ refers to tetrabutylammonium bromide, ‘HCl’ refers to hydrochloric acid, ‘Pd/C’ refers to palladium-charcoal, “HPLC” refers to High Performance Liquid Chromatography, ‘IR’ refers to infrared, ‘KBr’ refers to potassium bromide, ‘g’ refers to gram, ‘mL’ refers to milliliter,
The above and other objects of the present invention are attained by the improved process for the preparation of hexahydrocyclopenta[c]pyrrol-5(1H)-one compounds of the formula (IA) and intermediates thereof.
In one general aspect, there is provided a process for the preparation of compound of formula (I),

Wherein R is selected from H, C1-C4 alkyl, O=COC1-C4 alkyl, benzyl, SO2C1-C4 alkyl.
In one embodiment the present invention provides an improved process for the preparation of hexahydrocyclopenta[c]pyrrol-5(1H)-one of the formula (IA) and intermediates thereof as described in Scheme-3;

The process comprises,
(a) Reacting 3a,4,7,7a-tetrahydro-1H-isoindole-1,3(2H)-dione of formula (2),

with suitable reducing agents, in dry solvent to obtain the corresponding amine (3);

(b) Reacting 2,3,3a,4,7,7a-hexahydro-1H-isoindole of formula (3), with suitable protecting agent to obtain compound of formula (4);

(c) Oxidation of tert-butyl 1,3,3a,4,7,7a-hexahydro-2H-isoindole-2-carboxylate, of formula (4), by suitable oxidizing agents, in presence of TBAB to get its corresponding pyrrolo diacetic acid of formula (5); and

(d) Treating 2,2'-(1-(tert-butoxycarbonyl)pyrrolidine-3,4-diyl)diacetic acid of formula (5), with acetic anhydride and weak base, to obtain compound of formula (1A).

In general, the reducing agent in step (a) may be selected from Lithium aluminum hydride or Borane dimethyl sulfide complex, and the dry solvents used such as THF or diethyl ether. In particular, Preferably, Lithium aluminum hydride in dry THF may be used.
In general, the protecting agent in step (b) may be selected from Boc anhydride, Cbz chloride, benzyl bromide, acetyl chloride, mesyl chloride, tosyl chloride. Optionally base if required may be selected from triethyl amine diisopropylethyl amine, pyridine, Sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, sodium hydride and DBU. Preferably Boc anhydride without base in THF is used.
In general, the oxidizing agent in step (c) may be selected from catalytic ruthenium oxide along with sodium metaperiodate, catalytic ruthenium dichloride with sodium metaperiodate, potassium permanganate and hydrogen peroxide. Preferably potassium permanganate is used.
In general, the weak base in step (d) may be selected from sodium acetate, potassium acetate, sodium bicarbonate, potassium bicarbonate and sodium carbonate. Preferably sodium acetate is used.
In general reactions are performed in one or more solvents may include methanol, ethanol, acetone, methyl acetate, ethyl acetate, isopropyl acetate, acetonitrile, dimethyl formamide, toluene, dichloromethane, N-methylpyrrolidone, tetrahydrofuran, 2-methyl tetrahydrofuran, dimethyl acetamide and dimethyl sulfoxide.

In another general aspect there is provided an alternate process for the preparation of compound of formula (1A) as described in Scheme 4:

The process comprises,
(a) Reacting Benzyl amine of formula (6),

with alkylating agents in dry solvent to obtain the activated dienes (Dimethyl 4,4'-(benzylazanediyl)(2E,2'E)-bis(but-2-enoate) (7),

(b) Intramolecular reductive cyclization of dimethyl 4,4'-(benzylazanediyl)(2E,2'E)-bis(but-2-enoate) (7) with Mg/methanol to get dimethyl 2,2'-((3R,4S)-1-benzylpyrrolidine-3,4-diyl)diacetate (8);

(c) Debenzylation of dimethyl 2,2'-((3R,4S)-1-benzylpyrrolidine-3,4-diyl)diacetate (8) using Pd/C mediated with a suitable protecting agent to get dimethyl 2,2'-((3R,4S)-1-(tert-butoxycarbonyl)pyrrolidine-3,4-diyl)diacetate (9);

(d) Hydrolysis of dimethyl 2,2'-((3R,4S)-1-(tert-butoxycarbonyl)pyrrolidine-3,4-diyldiacetate of formula (9) by using NaOH in methanol and water to get its corresponding pyrrolo diacetic acid of formula (5); and

(e) Ttreating 2,2'-(1-(tert-butoxycarbonyl)pyrrolidine-3,4-diyl)diacetic acid of formula (5) with acetic anhydride and a weak base to obtain compound of formula (1A).

In general, benzyl amine (6), dialkylated with (E)-methyl 4-bromobut-2-enoate in step (a) in the presence of suitable base, which can be selected from triethyl amine, diisopropylethyl amine, pyridine, sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, sodium hydride and DBU. Solvent which can be protic or aprotic such as dichloromethane, chloroform, tetrahydrofuran, 1,4-dioxane, dimethyl formamide, methanol and ethanol. Where diisopropylethylamine and methanol at 45?C to 50 is preferable to get activated dienes (Dimethyl 4,4'-(benzylazanediyl)(2E,2'E)-bis(but-2-enoate) (7);
In general, debenzylation of dimethyl 2,2'-((3R,4S)-1-benzylpyrrolidine-3,4-diyl)diacetate (8) step c) may be carried out using Palladium catalyst mediated hydrogenation in protic solvent such as methanol or ethanol followed by protection of amine using Boc anhydride, Cbz chloride, benzyl bromide, acetyl chloride. In particular Boc anhydride without base in methanol and Pd/C is preferable to get dimethyl 2,2'-((3R,4S)-1-(tert-butoxycarbonyl)pyrrolidine-3,4-diyl)diacetate (9);
In general, the weak base in step (e) may include one or more of sodium acetate, potassium acetate, sodium bicarbonate, potassium bicarbonate and sodium carbonate. Preferably sodium acetate is used.
Analytical instruments/techniques used:
HPLC
The chemical purity of all the intermediates and final compounds were analyzed by analytical HPLC, at ?max 210nm, using column YMC J’ SPHERE C18 (150 X 4.6) x 4µ on SHIMADZU series under the following conditions: Detector: UV absorption photometer, Wavelength: 210 nm, Column temperature, 30 oC, Flow rate: 1.0 mL/min., Injection Vol.: 5 mL, Mobile Phase: 0.05% TFA in water: ACN (Gradient), Diluent: Water: Acetonitrile (50:50).
GC: GC analysis carried out on Agilent Technologies (Model 7890A), column HD-5, Mobile Phase: Helium gas, injection volume 1 mL.
Melting points were taken on Mettler Toledo’s FP90 Thermosystem.
1H NMR was taken on Bruker TOPSIN 2.0 400 MHz.
13C NMR was taken on Bruker TOPSIN 2.0 100 MHz.
Infrared (IR) spectrum has been recorded on a Shimadzu FTIR-8400 model spectrophotometer, between 400 cm-1 and 4000 cm-1, with a resolution of 4 cm-1 in a KBr pellet.
The Mass spectrum has been recorded on a Shimadzu LCMS 8040 model, between 50 – 2000 m/z. The C, H, N analysis was carried out on Thermo Electron Corporation (EA1112).
The examples and preparations provided below further illustrate and exemplify the compounds of the present invention and methods of preparing such compounds. It is to be understood that the scope of the present invention is not limited in any way by the scope of the following examples and preparations.

Example-1
Synthesis of (cis) 2,3,3a,4,7,7a-hexahydro-1H-isoindole(3)

In a 100L fixed glass assembly, THF (23 L) was charged and cooled externally with dry ice to -5 to 0 °C. Lithium aluminum hydride powder (2; 1.0 kg, 26.3 mol) was added portion wise, over a period of 1.5 hour, while maintaining internal temperature below 5 °C. Tetrahydrophthalimide (1.53 kg, 10.12 mol) was added portion wise, over a period of 1hour, with an internal temperature less than 5 °C. Reaction mixture was warmed to room temperature and stirred at room temperature for 1 hour. The reaction mixture was refluxed at 66 - 67 °C for 16 hours.
Reaction mixture was cooled to room temperature and subsequently up to -10 °C with dry ice. The reaction mixture was quenched with dropwise addition of ice water (750 mL), while maintaining internal temperature below 5 °C. Upon completion of water addition, the reaction mixtures turn out to be thick slurry. Additional THF (6 L) and solid sodium sulfate (~1.5 KG) was added followed by dropwise addition of KOH solution (15 %; 180 g KOH dissolved in 1200 mL of water), over a period of 1hour, while maintaining an internal temperature below 5 °C. Additional water (1 L) and solid sodium sulfate (2 KG) was added and the reaction mixture was slowly warmed to room temperature. At room temperature it was stirred for another 30 minutes and the solid inorganic material was filtered off through hyflo supercel bed.
Inorganic solid impurity was washed twice with THF (2 x 15 L), combined THF layer was dried over sodium sulfate, filtered and concentrated in vacuo to yield 2,3,3a,4,7,7a-hexahydro-1H-isoindole (3), as an oil, which was used in next the reaction, without any further purification. MS (ESI-MS):m/z 124 (M+H)+; 1H NMR (400 MHz, CDCl3) ? 5.70 (s, 2H), 3.06 (m, 2H), 2.71 (m, 2H), 2.28-2.18 (m, 4H), 1.90 (m, 2H).

Example-2
Synthesis of (cis) tert-butyl 3a,4,7,7a-tetrahydro-1H-isoindole-2(3H)-carboxylate (4)

50L SS reactor was charged with 2,3,3a,4,7,7a-hexahydro-1H-isoindole (3; 1.247 kg, 10.12 mol), dissolved in THF (23 L) and cooled up to 0 to -5 °C. Boc-anhydride (2.94 L, 12.65 mol) was added drop wise, while maintaining an internal temperature between 0-5 °C, over a period of 30 minutes. The reaction mixture was warmed to room temperature and stirred at room temperature for 16 hour. To the reaction mixture, solution of glycine (0.600 kg, 7.99 mol) and sodium carbonate (1.80 kg, 16.98 mol), dissolved in water (12 L) was added, at room temperature and stirred for additional 20 hours. The reaction mixture was concentrated in vaccuo to remove THF and dried in vaccuo. The n-Hexane (25 L) and additional water (8 L) was added and stirred at room temperature for 15 minutes. The reaction mixture was filtered in vaccuo through hyflo supercel and the layers were separated. Organic layer (hexane) was kept aside and the aqueous layer was extracted with n-hexane (2 x 20 L). Combined organic layer was washed with water (2 x 20 L) and brine (20 L). Hexane layer was stirred with activated charcoal (~500 g), for 1 hour at room temperature, filtered through hyflo supercel. Combined hexane was dried over sodium sulfate, filtered, concentrated and dried in vacco to afford tert-butyl 3a,4,7,7a-tetrahydro-1H-isoindole-2(3H)-carboxylate (4; 1.914kg, 85 % yield) as a brown oil. MS (ESI-MS):m/z 224 (M+H)+; 1H NMR (400 MHz, CDCl3) ? 5.65 (s, 2H), 3.40 (m, 2H), 3.17 (m, 1H), 3.08 (m, 1H), 2.33-2.20 (m, 4H), 1.91 (m, 2H), 1.46 (s, 9H).

Example-3
Synthesis of (cis) 2,2'-(1-(tert-butoxycarbonyl)pyrrolidine-3,4-diyl)diacetic acid (5)

A 50 L glass assembly (equipped with a condenser and a thermometer pocket) was charged with a solution of tert-butyl 3a,4,7,7a-tetrahydro-1H-isoindole-2(3H)-carboxylate (4; 0.50 kg, 2.239 mol), dissolved in n-pentane (2.5 L) and cooled externally with a dry ice up to 0 °C. Freshly prepared solution of potassium permanganate (1.06 kg, 6.717 mol) and tetrabutylammonium bromide (0.108 kg, 0.335 mol) dissolved in water (20 L) was added to reaction mixture, at 0-5 °C, in 2.5 hours. Additionally, the reaction mixture was stirred at 0-5 °C, for 1 hour.
The reaction mixture was filtered through hiflow supercel, residual solid was slurry washed with water (2 x 2L). The combined filtrate was washed with ethyl acetate (3 L) and the organic layer was separated. The aqueous layer was acidified with 1N HCl solution (pH ~ 3) and extracted with ethyl acetate (3 x 10 L). The combined ethyl acetate layer was washed with brine (10 L), treated with activated charcoal (500 g) and filtered through hiflow supercel. The organic solvent was distilled in vaccuo to afford title compound (0.53 KG) as off white solid, which was purified by solvent treatment. Ethyl acetate (0.75 L) was added and the solid was stirred for 30 minutes, at room temperature, slowly n-hexane (1.5 L) was added and stirred for 90 minutes. White solid product was filtered in vacuo and washed with 30 % ethyl acetate in n-hexane (0.5 L). White solid product was dried for 2 hours to yield 2,2'-(1-(tert-butoxycarbonyl)pyrrolidine-3,4-diyl)diacetic acid (5; 0.47 kg, 73 % yield). MS (ESI-MS):m/z 288 (M+H)+; 1H NMR (400 MHz, DMSO-d6) ? 12.24 (s, 2H), 3.37 (m, 2H), 3.00 (m, 2H), 2.49 (m, 2H), 2.32 (m, 2H), 2.19 (m, 2H), 1.40 (s, 9H).

Example-4
Synthesis of (cis) tert-butyl 5-oxohexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (1A)

A 20L four neck round bottom flask (equipped with a double surface condenser and a thermometer pocket) was charged with acetic anhydride (5.34 L, 56.6 mol), followed by slow addition of 2,2'-(1-(tert-butoxycarbonyl)pyrrolidine-3,4-diyl)diacetic acid (5; 1.11 kg, 3.86 mol). The reaction mixture was heated at 135 °C, for 45 minutes. Sodium acetate (0.269 kg, 3.28 mol) was added to the reaction mixture portion wise, over a period of 30 minutes and additionally, the reaction mixture was heated at 135 °C for 30 minutes.
The reaction mixture was cooled up to 5-10 °C, MeOH (5L) was added dropwise, while maintaining an internal temperature between 10 -15 °C, addition of methanol was completed within 2 hours and the reaction mixture was cooled up to -5°C. The reaction mixture was poured in to 10 L ice water and slowly solid sodium carbonate (~6 Kg, pH ~10) was added, followed by cyclohexane addition (~25 L). The reaction mixture was stirred for 15 minutes and filtered through hiflow supercel to remove solid inorganic waste and the organic layer was separated from the aqueous layer. The aqueous layer was extracted with cyclohexane (2 x 20L). The combined organic solvent was dried over sodium sulfate and concentrated in vaccuo to afford crude product (~ 800 g).
The crude product was purified by recrystallization from cyclohexane. The crude product was dissolved in cyclohexane (3 L) at 60 °C. Allowed it to cool gradually to room temperature and then cooled up to 5-10 °C in an ice bath, for 1 hour. The light yellow colored solid product was filtered and dried in vaccuo to afford pure tert-butyl 5-oxohexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (1A; 0.58 Kg, 66.6 % yield). MS (ESI-MS):m/z 226 (M+H)+; 1H NMR (400 MHz, CDCl3) ? 3.66 (m, 2H), 3.22 (m, 2H), 2.92 (m, 2H), 2.48 (m, 2H), 2.16 (m, 2H), 1.46 (s, 9H).
Example-5
Synthesis of Dimethyl 4,4'-(benzylazanediyl)(2E,2'E)-bis(but-2-enoate) 7

To a stirred solution of benzyl amine (6; 1.0 Kg, 9.33 mol) and DIPEA (3.86 Kg, 29.9 mol), in dry MeOH (20 L), at room temperature under inert atmosphere, in a 50 L SS reactor (equipped with a condenser and a thermometer pocket) was added (E)-methyl 4-bromobut-2-enoate (4.18 Kg, 38.0 mol) in a portion. Reaction mixture was heated to 45 °C for 16 h and evaporated to give crude product.
Crude product was purified by column chromatography, pure fractions were concentrated and dried in vaccuo to afford pure (2E,2'E)-dimethyl 4,4' (benzylazan-ediyl)bis(but-2-enoate), 7, 1.55 Kg, 50 % yield, as yellow oil. MS (ESI-MS):m/z 304 (M+H)+; 1H NMR (400 MHz, CDCl3) ? 7.34-7.32 (m, 5H), 7.00-6.94 (m, 2H), 6.08-6.03 (m, 2H), 3.75 (s, 6H), 3.62 (s, 2H), 3.55-3.22 (m, 4H).

Example-6
Synthesis of dimethyl 2,2'-((3R,4S)-1-benzylpyrrolidine-3,4-diyl)diacetate (8)

To a stirred solution of (2E,2'E)-dimethyl 4,4' (benzylazan-ediyl)bis(but-2-enoate) (7; 1.20 Kg, 3.96 mol), in dry MeOH (36 L), at room temperature, under inert atmosphere in a 100 L glass assembly (equipped with a condenser and a thermometer pocket) was added freshly activated magnesium turnings (0.96 Kg, 39.6 mol). Reaction mixture was heated at 70 °C for 6 h.
The reaction mixture was cooled upto 5-10 °C, ice cold 2N HCl (20 L) was added slowly, followed by addition of ethyl acetate (50 L). Reaction was stirred for 15 minutes, filtered through hiflow supercel, to remove solid inorganic waste and the ethyl acetate layer was separated from the aqueous layer. The aqueous layer was extracted with ethyl acetate (2 x 30 L). Combined ethyl acetate layer was dried over sodium sulfate and concentrated in vaccuo to afford crude dimethyl 2,2'-((3R,4S)-1-benzylpyrrolidine-3,4-diyl)diacetate (8; 0.90 Kg, 74.5% yield), MS (ESI-MS):m/z 306 (M+H)+. Crude product was used as such for next step reaction.

Example-7
Synthesis of dimethyl 2,2'-((3R,4S)-1-(tert-butoxycarbonyl)pyrrolidine-3,4-diyl)diacetate (9)

To a stirred solution of dimethyl 2,2'-((3R,4S)-1-benzylpyrrolidine-3,4-diyl)diacetate (8; 0.85 kg, 2.78 mmol) in dry MeOH (8 L), at room temperature, in a hydrogenation vessel was added Pd/C (0.060 Kg, 0.55 mol) and Boc anhydride (0.72 Kg, 3.34 mol). Above reaction was subjected for hydrogenation, under 50 psi, for 12 h at 25oC.Reaction mixture was filtered through celite and concentrated to get dimethyl 2,2'-((3R,4S)-1-(tert-butoxycarbonyl)pyrrolidine-3,4-diyl)diacetate (9; 0.53 Kg, 60.4 % yield) as yellow oil. MS (ESI-MS):m/z 316 (M+H)+; 1H NMR (400 MHz, CDCl3) ? 3.70(s, 6H), 3.54 (m, 2H), 3.07 (m, 2H), 2.72 (m, 1H), 2.51 (m, 1H), 2.40-2.29 (m, 4H), 1.46 (s, 9H).

Example – 8
Synthesis of 2,2'-((3R,4S)-1-(tert-butoxycarbonyl)pyrrolidine-3,4-diyl)diacetic acid (5)

To a stirred solution of dimethyl 2,2'-(1-(tert-butoxycarbonyl)-pyrrolidine-3,4-diyl)diacetate (9; 0.520 Kg, 1.64 mol), in MeOH (5 L) and water (2.5 L), in a 20L four neck round bottom flask, at room temperature was added NaOH (0.26 Kg, 6.60 mol). Reaction was stirred for 18 h at 25oC. The reaction mixture was cooled upto 0 to 5oC and acidified using 10 % citric acid solution (pH 6). Further, ethyl acetate was added (10 L), stirred for 15 minutes and organic layer was separated from the water layer. The water layer was extracted with ethyl acetate (2 x 3 L). Combined ethyl acetate layer was dried over sodium sulfate and concentrated in vaccuo to afford 2,2'-((3R,4S)-1-(tert-butoxycarbonyl)pyrrolidine-3,4-diyl)diacetic acid (5; 0.37 Kg, 80% yield), as white solid. MS (ESI-MS):m/z 288 (M+H)+; 1H NMR (400 MHz, DMSO-d6) ? 12.24 (s, 2H), 3.37 (m, 2H), 3.00 (m, 2H), 2.49 (m, 2H), 2.32 (m, 2H), 2.19 (m, 2H), 1.40 (s, 9H).
Finally, compound 5 converted to (cis) tert-butyl 5-oxohexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (1A), following the procedure described in Scheme-3, Example-4.