DESC:FIELD OF THE INVENTION
The present invention relates to an improved process for the preparation of Vibegron, which 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).

However, the process described in the above patents for the preparation of Vibegron is 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 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 which are reproducible and provides Vibegron having pharmaceutical grade purity.

None of the prior art process involve use of compound of formula (IV) 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 (VI) with compound of formula (V) in the presence of base and coupling agent 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 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).

Another object of the present invention is to provide an improved process for the preparation of Vibegron crystalline form which comprises;
(a) Dissolving Vibegron in suitable solvent and
(b) Isolating Vibegron crystalline form.

In yet another object of the present invention is to provide compound of formula (IV).

Yet another object of the present invention is to provide use of compound of formula (IV) 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 (VI) with compound of formula (V) in the presence of base and coupling agent 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 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).

Another aspect of the present invention is to provide an improved process for the preparation of Vibegron crystalline form which comprises;
(a) Dissolving Vibegron in suitable solvent and
(b) Isolating Vibegron crystalline form.

In yet another aspect of the present invention is to provide compound of formula (IV).

Yet another aspect of the present invention is to provide use of compound of formula (IV) 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 (VI) with compound of formula (V) in the presence of base and coupling agent 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 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).

Step (a) is carried out in the presence of base and phase transfer catalyst in suitable solvent at 0-10°C.

Step (b) is carried out in the presence of base in suitable solvent at 35-45°C.

In step (c) deprotection is carried out in the presence of acid in suitable solvent at 25-35°C.

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.

Another embodiment of the present invention is to provide an improved process for the preparation of Vibegron crystalline form which comprises;
(a) Dissolving Vibegron in suitable solvent and
(b) Isolating Vibegron crystalline form.

Isolation of Vibegron crystalline form is carried out by employing any of the
techniques, but not limited to cooling, decantation, filtration by gravity or
suction, centrifugation, adding solvent to make slurry followed by filtration,
solvent evaporation, solvent-anti solvent system, rotational distillation using a
device such as buchi rotavapor, distillation under vacuum and the like.

In yet another embodiment of the present invention is to provide compound of formula (IV).

Yet another embodiment of the present invention is to provide use of compound of formula (IV) for the preparation of Vibegron of formula (I).

In above embodiments, 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.

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

EXAMPLES
Example 1: Preparation of 4-nitrophenyl (S)-4-oxo-4,6,7,8-tetrahydro pyrrolo[1,2-a]pyrimidine-6-carboxylate (Formula IV)
To as solution of Methylene chloride (900 ml) add (S)-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxylic acid (Formula VI) (100 gm), 4-Nitrophenol (Formula V) (81.08 gm), 4-Dimethylaminopyridine (6.78 gm) at 25-35°C. Cool the reaction mass at 0-10°C. Add N,N’-Dicyclohexylcarbodiimide (DCC) solution (DCC(137.41 gm) in Methylene chloride (250 ml)) in reaction mass by maintaining reaction temperature at 0-10°C. Stir the reaction mass at 0-10°C till completion of reaction. Filter the reaction mass at 0-10°C and wash wet cake with Methylene chloride (250 ml) at 20-30°C. Collect the Methylene chloride (MDC) filtrate and distilled out under vacuum at below 60°C. Add Cyclohexane (100 ml) to residue and heat the reaction mass at 60°C. Distill out reaction mass under vacuum at below 60°C. Add Cyclohexane (100 ml) to residue and heat the reaction mass at 60°C. Distill out reaction mass under vacuum at below 60°C. Degas the reaction mass under vacuum at below 60°C for 30-45 min. Add Cyclohexane (1000 ml) and Isopropyl alcohol (1000 ml) in reaction mass. Heat the reaction mass at 65-75°C and slowly cool the reaction mass at 25-35°C within 3-4 hrs. Cool the reaction mass at 0-10°C and stir for 2-3 hrs at 0-10°C. Filter the reaction mass at 0-10°C and wash wet cake with Cyclohexane (400 ml) at 25-35°C. Dry the wet product in in hot air oven at 25-35°C for 2-3 hrs and at 65-75°C till LOD NMT 1.0% w/w.
Dry Weight: 125 to 150 gm.

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 as solution of N, N’-Dimethylformamide (400 ml) add tert-butyl (2S,5R)-2-(4-aminobenzyl)-5-((R)-hydroxy(phenyl)methyl)pyrrolidine-1-carboxylate (Formula III) (100 gm), 4-nitrophenyl (S)-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxylate (Formula IV) (90.64 gm) at 25-35°C. Cool the reaction mass at 20-30°C. Add N, N-Diisopropylethylamine (43.93 gm) in reaction mass by maintaining reaction temperature at 20-30°C. Heat the reaction mass at 35-45°C and stir the reaction mass at 35-45°C till completion of reaction. Add Isopropyl alcohol (1500 ml) in reaction mass. Cool the reaction mass at 20-30°C and stir for 2-3 hrs. Further cool the reaction mass at 0-10°C and stir the reaction mass for 2-3 hrs at 0-10°C. Filter the reaction mass at 0-10°C and wash wet cake with mixture of N, N’-Dimethylformamide (50 ml) + Isopropyl alcohol (450 ml) at 25-35°C. Dry the wet product in in hot air oven at 25-35°C for 2-3 hrs and at 65-75°C till LOD NMT 1.0% w/w.
Dry Weight: 100 to 130 gm.

Example 3: Preparation of Vibegron (Formula I)
To as solution of Methylene chloride (400 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) (100 gm) at 30±5°C. Add 2,2,2-Trifluoroacetic acid (209.76 gm) at 25-45°C into reaction mass. Cool and stir the reaction mass at 25-35°C till completion of reaction. Distilling MDC / Trifluoro acetic acid under vacuum (NLT 650 mm Hg) at below 45°C. Add MTBE (400 ml) below 45°C and stir the reaction mass 5-10 minutes below 45°C. Distill out reaction mass under vacuum (NLT 650 mm Hg) below 45°C. Add MTBE (1200 ml) into residue at 30±5°C and stir for 100-120 minutes. Filter the reaction mass and wash wet cake under nitrogen with MTBE (3 x 200 ml). Add Methanol (100 ml) and Acetonitrile (250 ml) to wet cake at 30±5 °C and stir for 100-120 minutes. Cool the reaction mass at 20-30°C and stir for 2-3 hrs. Further cool the reaction mass at 0-10°C and stir the reaction mass for 2-3 hrs at 0-10°C. Filter the reaction mass at 0-10°C and wash the wet cake under nitrogen with Acetonitrile (100 ml). Dry the wet cake in Vacuum tray dryer under vacuum (NLT 650 mm Hg) at 30±5 °C for 2-3 hrs and at 40±5 °C till LOD NMT 2.0% w/w.
Dry Weight: 65 to 70 gm.

Example 4: Preparation of Vibegron Crystalline Form (Formula I)
To as solution of Isopropyl alcohol (400 ml) and Process water (300 ml) add Vibegron (Formula I) (100 gm). Stir reaction mass for 60-90 min to obtain a solution at 25-35°C. Cool the reaction mass at 20-30°C and stir for 2-3 hrs. Further cool the reaction mass at 0-10°C and stir the reaction mass for 2-3 hrs at 0-10°C. Filter the reaction mass at 0-10°C and wash wet cake with mixture of Process water (50 ml) and Isopropyl alcohol (50 ml)) at 25-35°C. Dry the wet cake in hot air oven at 25-35°C for 2-3 hrs and at 65-75°C till LOD NMT 1.0% w/w.
Dry Weight: 80 to 90 gm.

The process of present invention is depicted in following scheme.

,CLAIMS:We claim:
1. An improved process for the preparation of Vibegron of formula (I) which comprises;

(a) Reacting compound of formula (VI) with compound of formula (V) in the presence of base and coupling agent 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 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 triethyl amine, methyl amine, ethyl amine, isopropyl amine, diisopropylamine, diisopropylethylamine, N-methylmorpholine, N-ethylmorpholine, piperidine, 4-dimethylaminopyridine, morpholine and pyridine.

3. The process as claimed in claim 1, wherein suitable coupling agent for step (a) 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.

6. An improved process for the preparation of Vibegron crystalline form which comprises;
(a) Dissolving Vibegron in suitable solvent and
(b) Isolating Vibegron crystalline form.

7. The process as claimed in claim 6, wherein suitable solvent for step (a) 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.

8. A compound of formula (IV).

9. Use of compound of formula (IV) for the preparation of Vibegron of formula (I).