FIELD OF THE INVENTION:
The present invention provides commercially and industrial applicable process for the
preparation sodium (s)-4-oxo-4,6,7,8-tetrahydropyrrolo[l,2-a]pyrimidine-6-
carboxylate of formula (II), which is a key intermediate for the preparation of Vibegron.
Vibegron is a selective P3-adrenoreceptor agonist for the treatment of patients with j overactive bladder (OAB). Vibegron is chemically known as (6S)-Pyrrolo(l,2-a)pyrimidine-6-carboxamide,4,6,7,8-tetrahydro-N-(4-(((2S,5R)-5-((R)-hydroxyphenyl methyl)-2-pyrrolidinyl)methyl)phenyl)-4-oxo of formula (I).
U.S.Pat.No.8,247,415 discloses a process for the preparation of (6S)-4-oxo-4,6,7,8-tetrahydropyrrolo[l,2-a]pyrimidine-6-carboxylic acid formula (VIII), which is comprising by reacting methyl (2S)-5-methoxy-3,4-dihydro-2H-pyrrole-2-carboxylate of formula (III) with beta lactam of formula (IV) to get methyl (6S)-4-oxo-4,6,7,8-tetrahydropyrrolo[l,2-a]pyrimidine-6-carboxylate of formula (V) and which is further treating with hydrochloric acid in presence of tetrahydrofuran, methanol in water to produce formula (VIII).

U.S.Pat.No.9,822,121 discloses a process for the preparation sodium (s)-4-oxo-4,6,7,8-tetrahydropyrrolo[l,2-a]pyrimidine-6-carboxylate of formula (II), which is comprising by reacting methyl (2S)-5-methoxy-3,4-dihydro-2H-pyrrole-2-carboxylate of formula (III) with beta lactam formula (IV) in presence of ethyl benzene to get (6S)-4-oxo-4,6,7,8-tetrahydropyrrolo[l,2-a]pyrimidine-6-carboxylate of formula (V) and which is further reacting with sodium hydroxide in presence of methanol, water and hydrochloric acid to get formula (II). The above synthetic process is illustrated as per the following Scheme-II:
The above said process several disadvantages in making process for the preparation sodium (s)-4-oxo-4,6,7,8-tetrahydropyrrolo[l,2-a]pyrimidine-6-carboxylate of formula (II). Wherein this reaction process 10% chiral isomer and impurities was generated, these concerned impurities will not be eliminated during isolation of ester intermediate of formula (v) and sodium salt of formula (II).
Aforesaid reasons above there is a need to produce sodium (s)-4-oxo-4,6,7,8-tetrahydropyrrolo[l,2-a]pyrimidine-6-carboxylate of formula (II), synthetically by industrially applicable method to ensure the availability with high purity.
Hence, there is consequently a need development for new methods to sort out prior art existing methods. So, our inventors have developed a method for the preparation of sodium (s)-4-oxo-4,6,7,8-tetrahydropyrrolo[l,2-a]pyrimidine-6-carboxylate of formula

(II). The present invention is providing a simple, high purity and good yield on industrial applicable process.
SUMMARY OF THE INVENTION
The present invention provides a process for the preparation sodium (s)-4-oxo-4,6,7,8-
tetrahydropyrrolo[l,2-a]pyrimidine-6-carboxylate of formula (II), comprising the steps
of:
a) reacting methyl (2S)-5-methoxy-3,4-dihydro-2H-pyrrole-2-carboxylate of formula (III) with 3-aza-tricyclo[4.2.1.02'5]non-7-en-4-one (beta lactam) of formula (IV) in presence of methyl or ethyl benzene to produce (6S)-methyl-4-oxooctahydro pyrrolo[l,2-a]pyrimidine-6-carboxylate of formula (V),
b) hydrolyzing of formula (V) with sodium hydroxide in presence of polar protic solvent and followed by treating with chiral amine to produce chiral amine salt of (S)-4-oxo-4,6,7,8-tetrahydropyrrolo[l,2-a]pyrimidine-6-carboxylic acid of formula (VI),
c) treating of formula (VI) with strong acid in presence of polar protic solvent to produce (6S)-methyl-4-oxooctahydropyrrolo[l,2-a]pyrimidine-6-carboxylate of formula (V), and

d) saltifying of formula (V) with sodium hydroxide in presence of polar protic solvent to produce sodium (s)-4-oxo-4,6,7,8-tetrahydropyrrolo[l,2-a]pyrimidine-6-carboxylate of formula (II).
The present invention provides a process for the preparation of sodium (s)-4-oxo-4,6,7,8-tetrahydropyrrolo[l,2-a]pyrimidine-6-carboxylate of formula (II). The present invention is also provides commercially viable and industrial applicable process for the preparation of formula (II).
In one embodiment of the present invention provides a process for the preparation
sodium (s)-4-oxo-4,6,7,8-tetrahydropyrrolo[l,2-a]pyrimidine-6-carboxylate of formula
(II), comprising the steps of:
a) reacting methyl (2S)-5-methoxy-3,4-dihydro-2H-pyrrole-2-carboxylate of formula (III) with 3-aza-tricyclo[4.2.1.02'5]non-7-en-4-one (beta lactam) of formula (IV) in presence of methyl or ethyl benzene to produce (6S)-methyl-4-oxooctahydropyrrolo[ 1,2-a]pyrimidine-6-carboxylate of formula (V),
b) hydrolyzing of formula (V) with sodium hydroxide in presence of polar protic solvent and followed by treating with chiral amine to produce chiral amine salt of (S)-4-oxo-4,6,7,8-tetrahydropyrrolo[l,2-a]pyrimidine-6-carboxylic acid of formula (VI),

c) treating of formula (VI) with strong acid in presence of polar protic solvent to produce (6S)-methyl-4-oxooctahydropyrrolo[l,2-a]pyrimidine-6-carboxylate of formula (V), and
d) saltifying of formula (V) with sodium hydroxide in presence of polar protic solvent to produce sodium (s)-4-oxo-4,6,7,8-tetrahydropyrrolo[l,2-a]pyrimidine-6-carboxylate of formula (II).
According to an embodiment of the present invention, wherein methyl (2S)-5-methoxy-3,4-dihydro-2H-pyrrole-2-carboxylate of formula (III) was reacting with 3-aza-tricyclo [4.2.1.02'5]non-7-en-4-one (beta lactam) of formula (IV) in presence of methyl or ethyl benzene at 20-3 0°C, the resulted reaction mixture was gradually heated to 110-130°C and stirred for 48 hours at same temperature to get (6S)-methyl-4-oxooctahydropyrrolo[l, 2-a]pyrimidine-6-carboxylate of formula (V).
According to an embodiment of the present invention, wherein (6S)-methyl-4-oxooctahydropyrrolo[l,2-a]pyrimidine-6-carboxylate of formula (V) was hydrolyzed in presence of aqueous sodium hydroxide and polar protic solvent at 0-15°C. The reaction mixture pH was adjusted to 1.0 to 3.0 with hydrochloric acid at 0-15°C and stirred for 10-30 minutes at same temperature, followed by treating with chiral amine.

The reaction mixture solvent was distilled out at 60°C under reduced pressure, further added solvent and allow to stir for 30-40 minutes at same temperature. The resultant mixture was cooled to room temperature,the obtain solid was filtered and washed with polar protic solvent to produce chiral amine salt of (S)-4-oxo-4,6,7,8-tetrahydropyrrolo[l,2-a]pyrimidine-6-carboxylic acid of formula (VI).
According to an embodiment of the present invention, wherein chiral amine salt of (S)-4-oxo-4,6,7,8-tetrahydropyrrolo[l,2-a]pyrimidine-6-carboxylic acid of formula (VI) is treated with strong acid in present of polar protic solvent at 20-40°C and then heated to 60-80°C and stirred for 3.5-6.5 hours at same temperature, after completion of the reaction (checked by TLC). The reaction mass was cooled to 20-30°C and filtered the sulphate salt of chiral amine and washed with polar protic solvent. The obtain filtrate was distilled out completely under reduced pressure and it was cooled to 25-30°C , further added dichloromethane at 25-30°C.
The resultant mixture was added to purified water and then pH was adjusted to 5.0-7.0 with 10% sodium carbonate solution to separate the layers. The separated dichloromethane layer was distilled out completely at below 60°C and it was isolated /recrystallized from ethyl acetate and methyl tertiary butyl ether mixture to produce (6S)-methyl-4-oxooctahydropyrrolo[ 1,2-a]pyrimidine-6-carboxylate formula (V),
According to an embodiment of the present invention, wherein (6S)-methyl-4-oxooctahydropyrrolo[l,2-a]pyrimidine-6-carboxylate formula (V) was added with polar protic solvent were added into flask at 20-30°, the resulted homogenous solution was cooled to 0-10°C and its was slowly added with 3N sodium hydroxide solution into flask at same temperature and maintained reaction mixture stirred for 1 -2 hour at 0-5°C, check the sample for reaction completion (Checked by TLC). After completion of reaction and the reaction mixture was adjusted pH to 6.0-7.0 with 5N hydrochloric acid solution at 0-10°C.
Toluene was added to reaction mixture and stirred for 10-20 minutes to separate the layers. The obtain aqueous layer was washed with toluene, followed by addition of isopropyl alcohol at 20-40°C and stirred for 1-2 hour. The resultant material was filtered, washed with isopropyl alcohol and dry the material at 40-60°C for 40-50 hours under vacuum to produce sodium (s)-4-oxo-4,6,7,8-tetrahydropyrrolo[l,2-a]pyrimidine-6-carboxylate formula (II).

According to the embodiment of present invention, the polar protic solvent is selected from methanol, ethanol, n-propanol, isopropanol, n-butanol, purified water and mixture thereof; strong acid is selected from the group consisting of sulfuric acid (H2SO4), hydrochloric acid (HO), nitric acid (HNO3), hydrobromic acid (HBr), hydroiodic acid (HI), perchloric acid (HC104) and chloric acid (HCIO3).
According to the embodiment of present invention, the chiral amine is selected from (R)-(+)-l-phenylethylamine or (R)-(+)-l-(2-naphthyl) ethylamine.
Advantages of the present invention:
1. The present invention main advantage of chiral amine salt of formula (VI) preparation to remove the 10% of (6R)-methyl-4-oxooctahydropyrrolo[l,2-a]pyrimidine-6-carboxylate, which is formed during diels alder reaction.
2. The present invention provides the compound of formula (II) purity was increased up to 99.9%, and all possible impurities will be eliminated during chiral amine salt of formula (VI) preparation.
3. The present invention improved with respect to quality and yield by doing chiral amine salts of formula (VI) preparation.
4. The present invention provides the compound of formula (II) with high purity and good yield.
The process details of the invention are provided in the examples given below, which are provided by way of illustration only and therefore should not be construed to limit the scope of the invention.

Example-1:
Process for the preparation of (6»V)-methyl-4-oxooctahydropyrrolo[l,2-
a] pyrimidine-6-carboxylate
A mixture of ethyl benzene (260 ml), methyl (2S)-5-methoxy-3,4-dihydro-2H-pyrrole-2-carboxylate (130 gm) and 3-aza-tricyclo[4.2.1.02'5]non-7-en-4-one (beta lactam) (84.5 gm) were added to round bottom flask at 25-30°C. The resulted reaction mixture was gradually heated to 120-125°C and it was stirred for 48 hours at same temperature, check the sample for reaction complies by HPLC.
The reaction mixture was cooled to 25-30°C, added toluene (390 ml), purified water (650 ml) and it was stirred for 30 minutes at 25-30°C. The reaction mixture was filter through hyflow bed and wash with purified water (130 ml), further it was stir for 10 minutes to separate the two layers. The separated aqueous layer was washed with toluene (130 ml), followed by addition of methylene chloride (910 ml) and it stir to separate the two layers. The separated methylene chloride layer was washed with brine solution (250 ml), further it was charged with activated carbon (13.0gm) and stir for 10 min. The reaction mass was filter through hyflow bed and wash with methylene chloride (260ml), the obtain filtrate was distilled out completely at below 50°C under reduced pressure to get (6S)-methyl-4-oxooctahydropyrrolo[l,2-a]pyrimidine-6-carboxylate (130 gm).
^-NMR (400 MHz, CDC13) 5 7.2 (s, ID), 2.283-2.356 (m, 2H), 2.512-2.618 (m, 2H), 3.064-3.140 (m, 2H), 3.193-3.285 (m, 2H), 3.816 (s, 3H), 5.093-5.124 (d of d, 1H), 6.308-6.325 (d, 1H), 7.879-7.896 (d, 1H).
Yield - 80.9% Enantiomeric purity - 92% Purity by HPLC - -85%
Example-2:
Process for the preparation of (6»V)-methyl-4-oxooctahydropyrrolo[l,2-
a] pyrimidine-6-carboxylate

A mixture of methyl benzene (130 ml), methyl (2S)-5-methoxy-3,4-dihydro-2H-pyrrole-2-carboxylate (65 gm) and 3-azatricyclo[4.2.1.02'5]non-7-en-4-one (beta lactam) (42.25 gm) were added to round bottom flask at 25-30°C. The resulted reaction mixture was gradually heated to 120-125°C with distillation to remove the some low boiling by-products in order to reach the mass temperature to 120-125°C and it was stirred for 72 hours at same temperature, check the sample for reaction complies by HPLC. If reaction complies (Checked by TLC).
The reaction mixture solvent (methyl benzene) was distilled out under vacuum at 120 °C and allow to cool at 25-30°C, further added toluene (200 ml), purified water (325 ml) and it was stir for 30 min at 25-30°C. The reaction mass was filter through hyflow bed and wash with purified water (130 ml), the obtain filtrate was stir for 10 min at room temperature to separate the two layers. The separated aqueous layer was washed with toluene (130 ml), followed by addition of methylene chloride (450ml) and stir for 10 min. to separate the two layers. The separated methylene chloride layer was washed with brine solution (125 ml), further it was charged with activated carbon (5.0gm) and stir for 10 min. The reaction mass was filter through hyflow bed and wash with methylene chloride (130ml), the obtain filtrate was distilled out completely at below 50°C under reduced pressure to get (6S)-methyl-4-oxooctahydropyrrolo[l,2-a]pyrimidine-6-carboxylate (66 gm).
^-NMR (400 MHz, CDC13) 5 7.2 (s, ID), 2.283-2.356 (m, 2H), 2.512-2.618 (m, 2H), 3.064-3.140 (m, 2H), 3.193-3.285 (m, 2H), 3.816 (s, 3H), 5.093-5.124 (d of d, 1H), 6.308-6.325 (d, 1H), 7.879-7.896 (d, 1H).
Yield-82.1% Enantiomeric purity - 90% Purity by HPLC - -85%
Example-3:
Process for the preparation of (/?)-l-phenylethanamine salt of (»V)-4-oxo-4,6,7,8-
tetrahydropyrrolo[l,2-a]pyrimidine-6-carboxylic acid
(6S)-methyl-4-oxooctahydropyrrolo[l,2-a]pyrimidine-6-carboxylate (88 gm) was added to solution of methanol (264 ml) and purified water (176 ml) at room temperature and allow to cool at 0-10°C, slowly added 3N sodium hydroxide solution (158 ml) at 0-

10°C, check the completion of the reaction progress by TLC and then pH of the reaction mixture was adjusted to 1.0-2.0 with hydrochloric acid at 0-10°C and stirred for 10-15 minutes at same temperature and added (R)-(+)-l-phenylethylamine (31 gm). The reaction mixture solvent (methanol) was distilled out at below 60°C under reduced pressure, further added toluene (176 ml) and distilled out to remove traces. The obtain residue was added to isopropanol (265 ml) and heated to 40-50°C, further it was cooled to 25-30°C and stirred for 30 minutes at same temperature. The resultant solid was filtered, washed with isopropanol (50 ml) and dried at 50-60°C to get (R)-l-phenylethanamine salt of (S)-4-oxo-4,6,7,8-tetrahydropyrrolo[l,2-a]pyrimidine-6-carboxylic acid (98 gm).
Yield-71.7%
Enantiomeric purity - >99.5%
Purity by HPLC- > 99.0%.
Example-4:
Process for the preparation of (/?)-l-naphthylethylamine salt of (»S)-4-oxo-4,6,7,8-
tetrahydropyrrolo[l,2-a]pyrimidine-6-carboxylic acid
(6S)-methyl-4-oxooctahydropyrrolo[l,2-a]pyrimidine-6-carboxylate (88 gm) was added to solution of methanol (264 ml) and purified water (176 ml) at room temperature and allow to cool at 0-10°C, slowly added 3N sodium hydroxide solution (158 ml) at 0-10°C, check the completion of the reaction progress by TLC and then pH of the reaction mixture was adjusted to 1.0-2.0 with hydrochloric acid at 0-10°C and stirred for 10-15 minutes at same temperature and added (R)-(+) naphthyl benzyl amine (31 gm). The reaction mixture solvent (methanol) was distilled out at below 60°C under reduced pressure, further added toluene (176 ml) and distilled out to remove traces. The obtain residue was added to isopropanol (265 ml) and heated to 40-50°C, further it was cooled to 25-30°C and stirred for 30 minutes at same temperature. The resultant solid was filtered, washed with isopropanol (50 ml) and dried at 50-60°C to get (R)-l-naphthylethylamine salt of (S)-4-oxo-4,6,7,8-tetrahydropyrrolo[l,2-a]pyrimidine-6-carboxylic acid.

Yield - 70.3 % Enantiomeric purity - >99.5% Purity by HPLC - > 99.0%
Example-5:
Process for the preparation of (6»V)-methyl-4-oxooctahydropyrrolo[l,2-
a] pyrimidine-6-carboxylate
(R)-l-phenylethanamine salt of (S)-4-oxo-4,6,7,8-tetrahydropyrrolo[l,2-a]pyrimidine-6-carboxylic acid was dissolved in a methanol (500ml), followed by addition of sulphuric acid (38 ml) at 25-30°C. The resulted reaction mixture was gradually raised temperature to 65-70°C and stirred for 4-6 hours at same temperature, after completion of the reaction (checked by TLC), then the reaction mas was cooled to 25-30°C. The obtain solid was filtered and washed with methanol, the resulted filtrate was distilled out completely under reduced pressure at 25-30°C to get a residue.
Further added dichloromethane and purified water to a residue and pH was adjusted to 6.0-7.0 with 10% sodium carbonate solution, stir for 10 minutes to separate the layers. The separated dichloromethane layer was distilled out completely at below 50°C, further it was recrystallized with ethylacetae and methyl tertiary butyl ether. The resultant solid was filtered and dried at 40-50°C to get (6S)-methyl-4-oxooctahydropyrrolo[l,2-a]pyrimidine-6-carboxylate (40 gm).
^-NMR (400 MHz, CDC13) 5 7.2 (s, ID), 2.283-2.356 (m, 2H), 2.512-2.618 (m, 2H), 3.064-3.140 (m, 2H), 3.193-3.285 (m, 2H), 3.816 (s, 3H), 5.093-5.124 (d of d, 1H), 6.308-6.325 (d, 1H), 7.879-7.896 (d, 1H).
Yield - 88.6%
Enantiomeric purity - >99.9%
Purity by HPLC - > 99.8%.
Example-6:
Process for the preparation of Sodium (»V)-4-oxo-4,6,7,8-tetrahydropyrrolo[l,2-
a] pyrimidine-6-carboxylate

(6S)-methyl-4-oxooctahydropyrrolo[l,2-a]pyrimidine-6-carboxylate (40gm), methanol (120 ml) and purified water (80 ml) were added into flask, stir at 25-30°C and allow to cool at 0-5°C, further slowly added 3N sodium hydroxide solution (75 ml) at 0-5°C and stirred for 1 hour (check the sample for reaction completion by TLC). The reaction mixture pH was adjusted to 6.5-7.0 with 5N Hydrochloric acid solution (40ml) at 0-10°C, followed by addition of toluene (200 ml) and stirred for 10 min. to separate the layers. The separated aqueous layer was washed with toluene (200 ml) and added isopropyl alcohol, the resulted mass was cooled to 25-30°C and it was stirred for 1 hour. The obtained material was filtered, washed with isopropyl alcohol and dry the material at 50-60°C for 48-50 hours under vacuum to get sodium (S)-4-oxo-4,6,7,8-tetrahydropyrrolo[l,2-a]pyrimidine-6-carboxylate (40 gm).
^-NMR (400 MHz, DMSO-d6) 5 2.490 & 3.391 (s, D6), 1.999-2.093 (m, 2H), 2.210-2.316 (m, 2H), 2.793-2.858 (q, 2H), 2.917-3.011 (m, 2H), 4.584-4.606 (d, 1H), 6.101-6.117 (d, 2H), 7.774-7.790 (d, 2H).
Yield-96.15%
Related substances by HPC - >99.8%
Enantiomeric purity - > 99.9%

We Claim:
1. A process for the preparation sodium (s)-4-oxo-4,6,7,8-tetrahydropyrrolo[l,2-a] pyrimidine-6-carboxylate of formula (II), comprising the steps of:
a) reacting methyl (2S)-5-methoxy-3,4-dihydro-2H-pyrrole-2-carboxylate of formula (III) with 3-aza-tricyclo[4.2.1.02'5]non-7-en-4-one (beta lactam) of formula (IV) in presence of methyl or ethyl benzene to produce (6S)-methyl-4-oxooctahydropyrrolo[ 1,2-a]pyrimidine-6-carboxylate of formula (V),
b) hydrolyzing of formula (V) with sodium hydroxide in presence of polar protic solvent and followed by treating with chiral amine to produce chiral amine salt of (S)-4-oxo-4,6,7,8-tetrahydropyrrolo[l,2-a]pyrimidine-6-carboxylic acid of formula (VI),
c) treating of formula (VI) with strong acid in presence of polar protic solvent to produce (6S)-methyl-4-oxooctahydropyrrolo[l,2-a]pyrimidine-6-carboxylate of formula (V), and
d) saltifying of formula (V) with sodium hydroxide in presence of polar protic solvent to produce sodium (s)-4-oxo-4,6,7,8-tetrahydropyrrolo[l,2-a]pyrimidine-6-carboxylate of formula (II).

2. The process as claimed in claim 1, wherein the polar protic solvent is selected from methanol, ethanol, n-propanol, isopropanol, n-butanol, purified water and mixture thereof.
3. The process as claimed in claim 1, wherein the chiral amine is selected from (R)-(+)-l-phenylethylamine or (R)-(+)-l-(2-naphthyl)ethylamine.
4. The process as claimed in claim 1, wherein the strong acid selected from sulfuric acid (H2SO4), hydrochloric acid (HC1), nitric acid (HNO3), hydrobromic acid (HBr), hydroiodic acid (HI), perchloric acid (HCIO4) and chloric acid (HCIO3).