DESC:FIELD OF THE INVENTION
The present invention relates to an improved process for the preparation of Vibegron and intermediates thereof. Vibegron is represented by the following structural formula (I).

BACKGROUND OF THE INVENTION
Vibegron is a selective ß3-adrenoreceptor agonist for the treatment of patients with overactive bladder (OAB). Vibegron is chemically known as (6S)-N-[4-[[(2S,5R)-5-[(R)hydroxy(phenyl)methyl]pyrrolidin-2-yl]methyl]phenyl]-4-oxo-7, 8-dihydro-6H-pyrrolo[1,2-a]pyrimidine-6-carboxamide of formula (I).

WO2009124167A1 discloses a process for preparing Vibegron which is shown schematically by below Scheme.

In this reaction scheme, coupling of compounds of formula (IX) and (X) to obtain compound of formula (XI) which is deprotected by using acid to obtain Vibegron.

WO2013062881A1 discloses a process for preparing Vibegron which is shown schematically by below Scheme.

In this reaction scheme, a process for preparing Vibegron by coupling of compounds of formula (i-11) and (i-12).

WO2014150639A1 discloses a process for preparing Vibegron which is shown schematically by below Scheme.

In this reaction scheme, a process for preparing Vibegron by coupling of compounds of formula (I-6) and (A-2).

WO2013062878A1 discloses a process for preparing Vibegron intermediate which is shown schematically by below Scheme.

However, the process described in the above patents for the preparation of Vibegron and its intermediates are tedious and suffers from many disadvantages like poor yield, low purity and not feasible to economical large-scale production. To overcome this problem, it is necessary to develop a new and cost-effective process for the preparation of large-scale production of Vibegron and its intermediates with high purity.

Thus, the present invention fulfills the need of the art and provides an improved and industrially applicable process for preparation of Vibegron and its intermediates which are reproducible and provides Vibegron having pharmaceutical grade purity.

None of the prior art process involve use of compound of formula (IX) and (XI) for the preparation of Vibegron. The present invention provides a process for the preparation of Vibegron via coupling of compounds of formula (IV) and (III) to obtain compound of formula (II) which is deprotected by using acid to obtain Vibegron. Further this process is reproducible and provide Vibegron having Pharmaceutical grade purity.

OBJECTS OF THE INVENTION
The main object of the present invention is to provide an improved process for the preparation of Vibegron of formula (I) which comprises:

(a) Reacting compound of formula (V) with Boc anhydride in the presence of base in suitable solvent to obtain compound of formula (IV).

(b) Reacting compound of formula (IV) with compound of formula (III) in the presence of base and coupling agent in suitable solvent to obtain compound of formula (II).

(c) Deprotecting compound of formula (II) in the presence of acid in suitable solvent to obtain Vibegron of formula (I).

In yet another object of the present invention is to provide an improved process for the preparation of compound of formula (V) which comprises:
(a) Condensing compound of formula (X) with compound of formula (XI) or (XII) in the presence of acid or base in suitable solvent to obtain compound of formula (IX).

(b) Dehydrating compound of formula (IX) in the presence of base in suitable solvent to obtain compound of formula (VIII).

(c) Reducing compound of formula (VIII) in the presence of suitable reducing agent in suitable solvent to obtain compound of formula (VII)

(d) Cyclizing compound of formula (VII) in the presence of acid in suitable solvent to obtain compound of formula (VI)

(e) Reducing compound of formula (VI) in the presence of suitable reducing agent in suitable solvent to obtain compound of formula (V)

Yet another object of the present invention is to provide an improved process for the preparation of compound of formula (XI) which comprises:

(a) Reacting compound of formula (XIV) with methyl magnesium bromide in suitable solvent to obtain compound of formula (XIII)

(b) Reducing compound of formula (XIII) with suitable reducing agent followed by treating with di-tert-butyl dicarbonate in suitable solvent to obtain compound of formula (XII)

(c) Reacting compound of formula (XII) with lithium hexamethyldisilazide and trimethylsilyl chloride in suitable solvent to obtain compound of formula (XI)

Yet another object of the present invention is to provide an improved process for the preparation of compound of formula (XII) which comprises:

(a) Reacting compound of formula (XVII) with N,O-dimethyl hydroxylamine hydrochloride in suitable solvent to obtain compound of formula (XVI)

(b) Reducing compound of formula (XVI) with suitable reducing agent followed by treating with di-tert-butyl dicarbonate in suitable solvent to obtain compound of formula (XV)

(c) Reacting compound of formula (XV) with methyl magnesium bromide in suitable solvent to obtain compound of formula (XII)

Yet another object of the present invention is to provide compound of formula (IX).

Yet another object of the present invention is to provide compound of formula (XI).

Yet another object of the present invention is to provide use of compounds of formula (IX) and (XI) for the preparation of Vibegron of formula (I).

SUMMARY OF THE INVENTION
The main aspect of the present invention is to provide an improved process for the preparation of Vibegron of formula (I) which comprises:

(a) Reacting compound of formula (V) with Boc anhydride in the presence of base in suitable solvent to obtain compound of formula (IV).

(b) Reacting compound of formula (IV) with compound of formula (III) in the presence of base and coupling agent in suitable solvent to obtain compound of formula (II).

(c) Deprotecting compound of formula (II) in the presence of acid in suitable solvent to obtain Vibegron of formula (I).

In yet another aspect of the present invention is to provide an improved process for the preparation of compound of formula (V) which comprises:
(a) Condensing compound of formula (X) with compound of formula (XI) or (XII) in the presence of acid or base in suitable solvent to obtain compound of formula (IX).

(b) Dehydrating compound of formula (IX) in the presence of base in suitable solvent to obtain compound of formula (VIII).

(c) Reducing compound of formula (VIII) in the presence of suitable reducing agent in suitable solvent to obtain compound of formula (VII)

(d) Cyclizing compound of formula (VII) in the presence of acid in suitable solvent to obtain compound of formula (VI)

(e) Reducing compound of formula (VI) in the presence of suitable reducing agent in suitable solvent to obtain compound of formula (V)

Yet another aspect of the present invention is to provide an improved process for the preparation of compound of formula (XI) which comprises:

(a) Reacting compound of formula (XIV) with methyl magnesium bromide in suitable solvent to obtain compound of formula (XIII)

(b) Reducing compound of formula (XIII) with suitable reducing agent followed by treating with di-tert-butyl dicarbonate in suitable solvent to obtain compound of formula (XII)

(c) Reacting compound of formula (XII) with lithium hexamethyldisilazide and trimethylsilyl chloride in suitable solvent to obtain compound of formula (XI)

Yet another aspect of the present invention is to provide an improved process for the preparation of compound of formula (XII) which comprises:

(a) Reacting compound of formula (XVII) with N,O-dimethyl hydroxylamine hydrochloride in suitable solvent to obtain compound of formula (XVI)

(b) Reducing compound of formula (XVI) with suitable reducing agent followed by treating with di-tert-butyl dicarbonate in suitable solvent to obtain compound of formula (XV)

(c) Reacting compound of formula (XV) with methyl magnesium bromide in suitable solvent to obtain compound of formula (XII)

Yet another aspect of the present invention is to provide compound of formula (IX).

Yet another aspect of the present invention is to provide compound of formula (XI).

Yet another aspect of the present invention is to provide use of compounds of formula (IX) and (XI) for the preparation of Vibegron of formula (I).

DETAILED DESCRIPTION OF THE INVENTION
The main embodiment of the present invention is to provide an improved process for the preparation of Vibegron of formula (I) which comprises:

(a) Reacting compound of formula (V) with Boc anhydride in the presence of base in suitable solvent to obtain compound of formula (IV).

(b) Reacting compound of formula (IV) with compound of formula (III) in the presence of base and coupling agent in suitable solvent to obtain compound of formula (II).

(c) Deprotecting compound of formula (II) in the presence of acid in suitable solvent to obtain Vibegron of formula (I).

Wherein the suitable base which could be employed in step (a) & (b) may be selected from group comprising of inorganic bases such as lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, lithium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, lithium bicarbonate, cesium bicarbonate and organic bases such as triethyl amine, methyl amine, ethyl amine, 1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU), isopropyl amine, diisopropylamine, diisopropylethylamine, N-methylmorpholine, N-ethylmorpholine, piperidine, 4-dimethylaminopyridine, morpholine, pyridine or mixtures thereof.

Wherein the suitable coupling agent which could be employed in step (a) may be selected from group comprising of N, N’-dicyclohexylcarbodiimide (DCC), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), 1,1’-carbonyldiimidazole (CDI), 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyl uranium hexafluoro
Phosphate (HBTU), O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium-tetrafluoroborate (TBTU), (1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU), (1-Cyano-2-ethoxy-2-oxoethylidenaminooxy)dimethylamino-morpholino-carbenium hexa fluorophosphate (COMU) and the like.
Wherein the suitable acid which could be employed in step (c) may be selected from group comprising of inorganic acid selected from hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, sulfamic acid and organic acid such as formic acid, acetic acid, trifluoro acetic acid, methanesulfonic acid, ethane sulfonic acid, benzene sulfonic acid, trifluoromethane sulfonic acid, p-toluenesulfonic acid, tartaric acid, mandelic acid, malic acid, maleic acid, succinic acid, malonic acid, oxalic acid, dibenzoyl tararic acid, lactic acid, cinnamic acid and the like

wherein the suitable solvents which could be employed in step (a), (b) and (c) may be selected from group comprising of alcohols such as methanol, ethanol, 1-propanol, 2-propanol, butanol, ketones such as acetone, ethyl methyl ketone, methyl isobutyl ketone, esters such as ethyl acetate, methyl acetate, propyl acetate, isopropyl acetate, ethers such as diethyl ether, tetrahydrofuran, dioxane, diisopropyl ether, dimethyl ether, methyl tertiary butyl ether, 1,2-dimethoxyethane, aromatic hydrocarbon such as benzene, toluene, xylene, chlorobenzene, nitrobenzene, aliphatic hydrocarbons such as hexane, cyclohexane, heptane, halogenated hydrocarbons such as dichloromethane, dichloroethane, chloroform, carbon tetrachloride, dialkylformamides such as dimethyl formamide, dialkylsulfoxides such as dimethyl sulfoxide, dialkylacetamides such as N, N-dimethyl acetamide, alkylpyrrolidone such as N-methyl pyrrolidone, nitriles such as acetonitrile, propionitrile; water or mixtures thereof.

In yet another embodiment of the present invention is to provide an improved process for the preparation of compound of formula (V) which comprises:
(a) Condensing compound of formula (X) with compound of formula (XI) or (XII) in the presence of acid or base in suitable solvent to obtain compound of formula (IX).

(b) Dehydrating compound of formula (IX) in the presence of base in suitable solvent to obtain compound of formula (VIII).

(c) Reducing compound of formula (VIII) in the presence of suitable reducing agent in suitable solvent to obtain compound of formula (VII)

(d) Cyclizing compound of formula (VII) in the presence of acid in suitable solvent to obtain compound of formula (VI)

(e) Reducing compound of formula (VI) in the presence of suitable reducing agent in suitable solvent to obtain compound of formula (V)

Yet another embodiment of the present invention is to provide an improved process for the preparation of compound of formula (XI) which comprises:

(a) Reacting compound of formula (XIV) with methyl magnesium bromide in suitable solvent to obtain compound of formula (XIII)

(b) Reducing compound of formula (XIII) with suitable reducing agent followed by treating with di-tert-butyl dicarbonate in suitable solvent to obtain compound of formula (XII)

(c) Reacting compound of formula (XII) with lithium hexamethyldisilazide and trimethylsilyl chloride in suitable solvent to obtain compound of formula (XI)

Yet another embodiment of the present invention is to provide an improved process for the preparation of compound of formula (XII) which comprises:

(a) Reacting compound of formula (XVII) with N,O-dimethyl hydroxylamine hydrochloride in suitable solvent to obtain compound of formula (XVI)

(b) Reducing compound of formula (XVI) with suitable reducing agent followed by treating with di-tert-butyl dicarbonate in suitable solvent to obtain compound of formula (XV)

(c) Reacting compound of formula (XV) with methyl magnesium bromide in suitable solvent to obtain compound of formula (XII)

Yet another embodiment of the present invention is to provide compound of formula (IX).

Yet another embodiment of the present invention is to provide compound of formula (XI).

Yet another embodiment of the present invention is to provide use of compounds of formula (IX) and (XI) for the preparation of Vibegron of formula (I).

The following examples illustrate the present invention but should not be construed as limiting the scope of the invention.

EXAMPLES
Example 1: Preparation of tert-butyl(2S,5R)-2-(4-aminobenzyl)-5-((R)-hydroxy(phenyl)methyl)pyrrolidine-1-carboxylate (Formula IV)
To a solution of MDC (50 mL) add (R)-((2R,5S)-5-(4-aminobenzyl)pyrrolidin-2-yl)(phenyl)methanol (Formula V)(12 gm) and Boc anhydride (9.3 gm) followed by K2CO3 (18 mL) and the resulting solution stirred at room temperature under nitrogen atmosphere for 2 to 4 hr. Distilling MDC at below 45°C. Add oxalic acid solution (20 mL) and mixture was then extracted with dichloromethane (50 mL). The combined organic layers were dried over Na2SO4. Distill out reaction mass under vacuum below 45°C. Add MTBE (50 ml) and Methanol (50 ml) into residue at 30±5°C and stir for 2 to 4 hr. Filter the reaction mass and wash the wet cake under nitrogen with MTBE (50 ml) and Methanol (50 ml). Dry the wet product in hot air oven at 25-35°C for 2-3 hrs.
Example 2: Preparation of tert-butyl (2R, 5S)-2-((R)-hydroxy (phenyl) methyl)-5-(4-((S)-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamido)benzyl)pyrrolidine-1-carboxylate (Formula II)
To a solution of N,N-dimethylformamide (100 ml) add tert-butyl (2S,5R)-2-(4-aminobenzyl)-5-((R)-hydroxy(phenyl)methyl)pyrrolidine-1-carboxylate (Formula IV) (20 gm) and sodium (S)-4-oxo-4,6,7,8,-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxylate (Formula III) (10 gm) at 20-30°C. Add HATU (15 gm) and TEA (30 ml) at 0°C. The reaction mixture was stirred from 0°C. to ambient temperature for 2 to 4 hr. Add water (500 ml) in reaction mass. Cool the reaction mass at 20-30°C and stir for 2-3 hrs. Filter the reaction mass and wash wet cake with water (500 ml). Dry the wet product in hot air oven at 25-35°C for 2-3 hrs.

Example 2: Preparation of Vibegron (Formula I)
To as solution of Methylene chloride (50 ml) add tert-butyl (2R,5S)-2-((R)-
hydroxy(phenyl)methyl)-5-(4-((S)-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]
pyrimidine-6-carboxamido)benzyl)pyrrolidine-1-carboxylate (Formula II) (5 gm) at 30±5°C. Add HCl (20 ml) at 25-45°C into reaction mass. The reaction mixture was stirred at 25-35°C for 2-4 hr. Distilling MDC/HCl under vacuum at below 45°C. Add saturated solution of Na2CO3 to make the PH value to 8-9. The mixture was then extracted with dichloromethane(50 ml). The combined organic layers were dried over Na2SO4. Distill out reaction mass under vacuum below 45°C. Add DMF (50 ml) and Methanol (50 ml) into residue at 30±5°C and stir for 2 to 4 hr. Filter the reaction mass and wash the wet cake under nitrogen with DMF (50 ml) and Methanol (50 ml). Dry the wet product in hot air oven at 25-35°C for 2-3 hrs.

The process of present invention is depicted in following schemes.
SCHEME-IA

SCHEME-IB

SCHEME-II

SCHEME-III
,CLAIMS:We Claim:
1. An improved process for the preparation of Vibegron of formula (I) which comprises:
(a) Reacting compound of formula (V) with Boc anhydride in the presence of base in suitable solvent to obtain compound of formula (IV).

(b) Reacting compound of formula (IV) with compound of formula (III) in the presence of base and coupling agent in suitable solvent to obtain compound of formula (II).

(c) Deprotecting compound of formula (II) in the presence of acid in suitable solvent to obtain Vibegron of formula (I).

2. The process as claimed in claim 1, wherein suitable base for step (a) and (b) is selected from sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, triethyl amine, isopropyl amine, diisopropylamine, diisopropylethylamine, N-methylmorpholine, piperidine, 4-dimethylaminopyridine, morpholine and pyridine.

3. The process as claimed in claim 1, wherein suitable coupling agent for step (b) is selected from N, N’-dicyclohexylcarbodiimide (DCC), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), 1,1’-carbonyldiimidazole (CDI) and (1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU).

4. The process as claimed in claim 1, wherein suitable acid for step (c) is selected from hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, sulfamic acid, formic acid, acetic acid and trifluoro acetic acid.

5. The process as claimed in claim 1, wherein suitable solvent for step (a), (b) and (c) is selected from methanol, ethanol, 1-propanol, 2-propanol, butanol, ethyl methyl ketone, methyl isobutyl ketone, ethyl acetate, methyl acetate, propyl acetate, dichloromethane, dichloroethane, chloroform, carbon tetrachloride, diethyl ether, tetrahydrofuran, dioxane, diisopropyl ether, methyl tertiary butyl ether, dimethyl formamide, dimethyl sulfoxide, N, N-dimethyl acetamide, hexane, cyclohexane, heptane, acetonitrile, water or mixtures thereof.