DESC:Field of the Invention:
The present application relates to an improved process for the preparation of Vonoprazan fumarate, and intermediates thereof, which is represented by the following structural formula-I.

Formula-I

Background of the Invention:
Vonoprazan approved as fumarate salt (TAK-438, Formula I), is chemically known as 1-[5-(2-fluorophenyl)-1-(pyridin-3- ylsulfonyl)-1H-pyrrol-3-yl]-N-methyl methanamine fumarate, one of the primary members of potassium-competitive acid blocker for the treatment of drug induced peptic ulcers. Vonoprazan fumaric acid salt was approved as oral tablet in 2014 Japan and approved as a combination drug in 2022 USA.

The US patent US7977488B2 first reported Vonoprazan or salt thereof and process for the preparation thereof. The said process involves one of the key intermediate, 5-(2-fluorophenyl)-1- (pyridin-3-ylsulfonyl)-1H-pyrrole-3-carbaldehyde very critical and involved in the formation of Vonoprazan fumarate.
The US patent US8822694B2 reported an alternative process for the preparation of vonoprazan and intermediates thereof such as 5-(2-fluorophenyl)-1H-pyrrole-3-carbaldehyde using different reagents and processes.
The US patent US9487485B2 reported an alternative process for the preparation of first vonoprazan and intermediate thereof such as 5-(2-fluorophenyl)-1H-pyrrole-3-carbaldehyde using different process and raw materials.
Based on the drawbacks in prior art processes, there is a need for providing an improved process for the preparation of vonoprazan, its intermediates which involves simple experimental procedures, well suited to industrial production, which avoids the use of column chromatography purification, and which affords high pure vonoprazan fumarate salt.
The present invention provides various processes for preparation of vonoprazan fumarate, intermediates thereof, which is efficient, industrially viable and cost effective.
Brief Description:
The first aspect of the present invention is to provide an improved process for the preparation of compound of formula-I.
Brief description of the drawings:
Figure 1: Illustrates the PXRD pattern of crystalline form of compound of formula-I
Figure 2: Illustrates the IR spectrum of crystalline form of compound of formula-I
Detailed Description:
As used herein the term “suitable solvent” used in the present invention refers to “hydrocarbon solvents” such as n-hexane, n-heptane, cyclohexane, petether, toluene, pentane, cycloheptane, methyl cyclohexane, m-, o-, or p-xylene and the like; “ether solvents” such as dimethoxymethane, tetrahydrofuran, 1,3-dioxane, 1,4-dioxane, furan, diethyl ether, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, diethylene glycol dimethyl ether, diethylene glycol diethyl ether, triethylene glycol dimethyl ether, anisole, t-butyl methyl ether, 1,2-dimethoxy ethane and the like; “ester solvents” such as methyl acetate, ethyl acetate, isopropyl acetate, n-butyl acetate and the like; “polar-aprotic solvents such as dimethylacetamide (DMA), dimethylformamide (DMF), dimethylsulfoxide (DMSO), N-methylpyrrolidone (NMP) and the like; “chloro solvents” such as dichloromethane, dichloroethane, chloroform, carbontetra chloride and the like; “ketone solvents” such as acetone, methyl ethyl ketone, methyl isobutyl ketone and the like; “nitrile solvents” such as acetonitrile, propionitrile, isobutyronitrile and the like; “alcoholic solvents” such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol, 2-nitroethanol, 2-fluoroethanol, 2,2,2-trifluoroethanol, ethylene glycol, 2-methoxyethanol, l,2-ethoxyethanol, diethylene glycol, 1, 2, or 3-pentanol, neo-pentyl alcohol, t-pentyl alcohol, diethylene glycol monoethyl ether, cyclohexanol, benzyl alcohol, phenol, or glycerol and the like; “polar solvents” such as water or mixtures thereof.
As used herein the present invention the term “suitable base” refers to inorganic or organic base. Inorganic base refers to “alkali metal carbonates” such as sodium carbonate, potassium carbonate, lithium carbonate and the like; “alkali metal bicarbonates” such as sodium bicarbonate, potassium bicarbonate and the like; “alkali metal hydroxides” such as sodium hydroxide, potassium hydroxide, lithium hydroxide and the like; “alkali metal alkoxides” such as sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, sodium tert.butoxide, potassium tert-butoxide, lithium tert-butoxide and the like; alkali metal hydrides such as sodium hydride, potassium hydride, lithium hydride and the like; alkali metal amides such as sodium amide, potassium amide, lithium amide and the like; and organic bases such as like dimethylamine, diethylamine, diisopropyl amine, diisopropyl ethylamine, diisobutylamine, triethylamine, pyridine, piperidine, 4-dimethyl amino pyridine (DMAP), N-methyl morpholine (NMM), or mixtures thereof.
The term “reducing” agent used in the present invention refers suitable reducing reagents are selected from Lithium aluminium hydride, sodium borohydride, BF3 etherate solution, Pd/C, Ray-nickel;
The first aspect of the present invention provides an improved process for the preparation of compound of formula-I.

Comprising of:
a) reacting compound of formula-1 in presence of suitable reagents, solvent to provide compound of formula-3,

Formula-1 Formula-3
b) cyclizing of the compound obtained in step-a) with suitable reagent, solvent to provide compound of formula-4,

Formula-4

c) reacting of compound of formula-4 in presence of suitable reagent, solvent to provide compound of formula-5,

Formula-5
d) reducing the compound of formula-5 using the suitable reagents, solvents to provide compound of formula-6,

Formula-6
e) oxidizing the compound of formula-6 with suitable reagent, solvent to provide compound of formula-7, and optionally purifying the compound-7,

Formula-7
f) coupling the compound of formula-7 with compound of formula-8 in presence of suitable reagent, solvent to provide pure compound of formula-9,

Formula-8 Formula-9
g) reacting the pure compound of formula-9 with suitable reagents, solvents to provide salt compound of formula-10,

Formula-10

h) purifying the compound of formula-10 using suitable reagents, solvents to provide the pure compound of formula-I.
Wherein in step-a) suitable reagents are selected from bromine, DBDMH –dibromo dimethyl hydantoin, copper bromide, N-bromosuccinimide, p-Toluenesulfonic acid, AIBN and mixture thereof, solvents are selected from acetic acid, ethyl acetate, chlorinated solvents
suitable reagents are selected from ethyl cyanoacetate, organic base or inorganic base and mixture thereof;
Wherein in step-b) suitable reagents are selected from HCl in organic solvent; solvents are selected from ester solvents, alcoholic solvents, acetone solvents, ether solvents, hydrocarbon solvents and mixture thereof.
Wherein in step-c) suitable reagents are selected from palladium carbon, aluminum carbon under hydrogen gas atmosphere.
Wherein in step-d) suitable reagents are selected from sodium ethoxide, vetride, lithium aluminum hydride, diisobutyl aluminum hydride, sodium borohydride, calcium borohydride; boron trifluoride;
Wherein in step-e) suitable reagents are selected from manganese dioxide, potassium permanganate, pyridinium chlorochromate (PCC), dimethyl sulfoxide-acetic anhydride, tetrapropylammonium Perruthenate-NMMO and mixture thereof;
wherein in step-f) the suitable reagents are selected from organic base or inorganic base, wherein in step-g) the suitable reagents are selected from sodiumborohydride, sodium cyano borohydride, triacetoxy sodiumborohydride, aqueous solution monomethylamine, alcoholic solution of monomethylamine, fumaric acid.
Wherein in step-a to h) the suitable solvent is selected from hydrocarbon solvents, chloro solvents, ether solvents, polar aprotic solvents, polar protic solvents, ester solvent, nitrile solvent, ketone solvents, alcohol solvent, acetic acid and water or any mixture thereof.

The embodiment of the present invention provides an improved process for the preparation of compound of formula-I.

Comprising of:

a)reacting compound of formula-1 with 1,3,-dibromo-5,5-dimethylhydantoin in presence of para toluene sulfonic acid in dichloromethane, further treating ethyl cyanoacetate in presence trimethylamine to provide compound of formula-3,

Formula-1 Formula-3

b)cyclizing of the compound obtained in step-a) with ethyl acetate HCl solvent to provide compound of formula-4,

Formula-4

c)reacting of compound of formula-4 in presence of Pd/C under hydrogen gas atmosphere, triethyl amine in methanol, to provide compound of formula-5,

Formula-5

d) reducing the compound of formula-5 with DIBAL-H in tetrahydrofuran to provide compound of formula-6,

Formula-6

e) oxidizing the compound of formula-6 with potassium permanganate in acetone to provide compound of formula-7,

Formula-7

f) coupling the compound of formula-7 with compound of formula-8 in presence of triethyl amine, DMAP in acetonitrile to provide pure compound of formula-9,

Formula-8 Formula-9

g) reacting the pure compound of formula-9 with monomethyl amine, sodium borohydride, fumaric acid in dichloromethane to provide compound of formula-10,

Formula-10

h) purifying the compound of formula-10 using fumaric acid, acetone, methanol, dimethyl formamide, water and ammonia to provide the pure compound of formula-I.

The present invention related to a process for the preparation of Vonoprazan fumarate described in schematic representation in scheme-I

The process described in the present invention was demonstrated in examples illustrated below. These examples are provided as illustration only and therefore should not be construed as limitation of the scope of the invention.
Examples:
Example-1: Preparation of compound of formula-3 (ethyl 2-cyano-4-(2-fluorophenyl)-4-oxobutanoate)
A round bottom flask was charged with compound-1 (100 g), dichloromethane (700 mL), p-toluene sulfonic acid (6.88 g) and 1, 3-dibromo-5,5-dimethylhydantoin (124.2 g) at 20-30°C and stirred at 30-40°C for 28 hr. The reaction mixture was charged with water (300 mL) and stirred for 10 min and separated the two layers. The aqueous layer was charged with dichloromethane and separated, the combined organic layers ware washed with sodium carbonate solution and dried over sodium sulfate. The organic layer was charged with ethyl cyanoacetate (81.88 g) and triethylamine (112.07 g) at 0-10°C and stirred for 2 hr at same temperature. The reaction mixture was stirred at 25-35°C for 30 min and distilled off the solution completely and dried to get the title compound.
Yield: 67.0 g
Example-2: Preparation of compound of formula-4 (ethyl 2-chloro-5-(2-fluorophenyl)-1H-pyrrole-3-carboxylate).
A round bottom flask was charged with compound-3 (100 g), ethyl acetate HCl (300 mL) at 20-30°C and stirred for 3 days at same temperature. Filtered the unwanted solid and washed with methyl tert-butyl ether. The reaction mixture was distilled off completely at 20-30°C, co-distilled with ethyl acetate. The obtained compound was charged in ethyl acetate and stirred for 2 hr, the resulting solid was filtered and dried to get the title compound.
Yield: 30.0 g
Example-3: Preparation of compound of formula-5.
A round bottom flask was charged with compound-4 (100 g), methanol (100 mL), triethyamine (100 mL), Pd/C (20 g) under hydrogen gas and stirred the solution at 20-30°C for 20 hr. The reaction mixture was washed with methanol and distilled off completely and gradually cooled to 20-30°C, charged with water, dichloromethane and stirred for 10 min. The both layers were separated, again the aqueous layer was extracted with dichloromethane and the combined organic layer was distilled off completely to get the residue compound. The obtained compound was charged with n-heptane at 20-30°C and stirred for 16 hr at same temperature. The precipitated solid was filtered and washed with n-heptane and dried to get the title compound.
Yield: 78.66 g
Example-4: Preparation of compound of formula-6.
A round bottom flask was charged with compound-5 (100 g), tetrahydrofuran (500 mL) and stirred for 15 min. The reaction mixture was cooled to -60 to -70°C, charged with DIBAL-H (100 mL) in drop wise manner and stirred for 6 hr at same temperature. The reaction mixture was quenched with water at -45 to -50°C and gradually raised the temperature to 20-30°C and stirred for 4 hr at same temperature. The unwanted solid was filtered and washed with ethyl acetate and separated the two layers. The organic layer was washed with ammonium chloride and dried over sodium sulfate and evaporated the organic layer to get the title compound.
Yield: 50.0 g
Example-5: Preparation of compound of formula-7.
A round bottom flask was charged with compound-6 (100 g), acetone (1L), and potassium permanganate (103.3 g) and stirred for 3 hr at 20-30°C. The unwanted solid was filtered and washed with acetone (200 mL). The organic layer was distilled off completely and charged with dichloromethane and water at 20-30°C and stirred for 15 min. The organic layer was separated, further charged with activated carbon and stirred for 15 min and filtered. The organic layer was distilled off completely to get the title compound.
Yield: 80.0 g
Example-6: Preparation of compound of formula-8.
A round bottom flask was charged with pyridine-3-sulfonic acid (100 g), phosphoryl chloride (100 ml), and phosphorous pentachloride (196.3 g) at 20-30°C and heated the temperature to 105-115°C and stirred for 6 hr at same temperature. The reaction mixture was cooled and distilled off, the obtained compound was charged with dichloromethane and water. The reaction mass pH was adjusted to 6.0 by using sodium carbonate solution and stirred for 15 min and separated two layers. The aqueous layer was extracted with dichloromethane and the combined organic layers were washed with sodium chloride solution and dried over sodium sulfate and distilled off the solvent completely to get the title compound.
Yield: 90.3 g
Example-7: Preparation of compound of formula-9.
A round bottom flask was charged with compound-7 (100 g), acetonitrile (500 mL) under nitrogen atmosphere stirred at 35-40°C for 20 min. The reaction mixture was charged with 4-dimethylaminopyridine (12.91 g), triethylamine (192.54 g) and stirred for 15 min at same temperature. A solution of compound-8 (130.8 g) in acetonitrile was charged slowly to the above reaction mixture in drop wise and stirred for 15 min at 35-40°C. The reaction mixture was gradually cooled to 0-10°C, charged with ethyl acetate, water and ammonium chloride and stirred for 10 min. The precipitated solid was filtered and washed with mixture of water and ethyl acetate and dried to obtain title compound.
Yield: 136.95 g
Example-8: Preparation of compound of formula-10
A round bottom flask was charged with compound-9 (100 g), methanol (500 mL) at 25-35°C and gradually cooled the reaction mass to 10-20°C and stirred for 10 min. The reaction mixture was charged with monomethyl amine solution in methanol (100 mL) and stirred for 1 hr at 10-20°C and charged with sodium borohydride (7.2 g) slowly in portion wise about 40 min and stirred for 1 hr. The reaction mixture temperature was gradually raised to 20-30°C, charged with dichloromethane and water stirred for 15 min at same temperature. The both layers were separated and the aqueous layer was extracted with dichloromethane and washed organic layer with sodium chloride and distilled off the organic layer completely to get the residue compound.
The obtained compound was charged with dimethyl formamide (200 mL) and fumaric acid (35.13 g) at 25-35°C and maintained the reaction mixture for 90 min at same temperature. The precipitated compound was filtered and washed with water. The obtained compound was charged with acetone, dimethyl formamide and water stirred for 2 hr. The precipitated solid compound was filtered and washed with water.
The obtained solid was charged with dichloromethane and adjusted the pH to 9.5 with aq. ammonia at 25-35°C and stirred for 10 min. Separated the organic layer and extracted the aqueous layer with dichloromethane. The combined organic layers were washed with ammonium chloride, and distilled off the solvent completely to get residue compound.
The obtained compound was charged with dimethyl formamide (60 ml) and fumaric acid (24.94 g) and stirred the reaction mass for 90 min at 25-35°C. Filtered the resulting solid and washed with water and stirred for 40 min at 25-35°C and dried to obtain the title compound.
Yield: 77.0 g
Example-9: Preparation of compound of formula-I
A round bottom flask was charged with compound-10 (100 g), acetone (700 mL) at 20-30°C and raised the temperature to 60-70°C and stirred for 30 min at same temperature. The reaction mixture was charged with water slowly and charged activated carbon at 60-70°C and stirred for 15 min. Filtered the solid compound and washed with water in acetone. The resulting solution was cooled to 10-20°C and stirred for 2 hr, The precipitated solid was filtered and dried to get the title compound.
Yield: 84.48 g; The PXRD is depicted in figure -1
Example-10: Preparation of compound of formula-I
A round bottom flask was charged with compound-10 (50 g), methanol (300 mL) at 20-30°C and raised the temperature to 50-60°C and stirred for 30 min at same temperature. The reaction mixture was charged with water slowly and charged activated carbon at 50-60°C and stirred for 15 min. Filtered the solid compound and washed with water in methanol. The resulting solution was cooled to 10-20°C and stirred for 2 hr, The precipitated solid was filtered and dried to get the title compound. The obtained compound PXRD is similar to the figure-1
Yield: 44 g
Example-11: Preparation of compound of formula-8.
A round bottom flask was charged with pyridine-3-sulfonic acid (100 g), phosphoryl chloride (100 ml), and phosphorous pentachloride (196.3 g) at 20-30°C and heated the temperature to 105-115°C and stirred for 6 hr at same temperature. Distilled-off the solvent completely and cooled to -5 to 5°C, the obtained compound was charged with dichloromethane and water and stirred for 10 min. The reaction mass pH was adjusted to about 6.0 by using solution of sodium carbonate and stirred for 15 min at -5 to 5°C and separated the two layers. The aqueous layer was extracted with dichloromethane and the combined organic layers were washed with sodium chloride and dried over sodium sulfate and distilled-off the solvent completely to get the title compound.
Yield: 90.3 g
Example-12: Preparation of compound of formula-9.
A round bottom flask was charged with compound-7 (100 g), acetonitrile (500 mL) under nitrogen atmosphere stirred at 35-40°C for 20 min. The reaction mixture was charged with 4-dimethylaminopyridine (12.91 g), triethylamine (192.54 g) and stirred for 15 min at same temperature. Compound-8 (117.34 g) was charged slowly to the above reaction mixture in drop wise and stirred for 15 min at 50-60°C and further and stirred for 15 min. The reaction mixture was gradually cooled to 0-10°C, charged with ethyl acetate (100 ml), water (1200 ml) and ammonium chloride (100 g) at 0-10°C and stirred for 10 min at same temperature. The precipitated solid was filtered and washed with mixture of water (80 ml) and acetonitrile (20 ml) and dried to obtain the title compound.
Yield: 136.95 g
Example-13: Preparation of compound of formula-10
A round bottom flask was charged with compound-9 (100 g), methanol (500 mL) at 25-35°C and gradually cooled the reaction mass to 10-20°C was charged with monomethyl amine solution in methanol (100 mL) and stirred for 1 hr at 10-20°C. Further, charged with sodium borohydride (5.72 g) slowly in portion wise about 40 min and stirred for 1 hr at 10-20°C. The reaction mixture temperature was gradually raised to 20-30°C, again charged with sodium borohydride (1.14 g) for 30 min at 20-30°C and stirred for 40 min.
The reaction mixture was quenched with dichloromethane (500 ml) and water (500 ml) stirred for 15 min at 20-30°C. The both layers were separated and the aqueous layer was extracted with dichloromethane and the combined organic layer was washed with sodium chloride and distilled- off the organic layer completely to get the residue compound.
The obtained residue compound was charged with dimethyl formamide (200 mL) and fumaric acid (35.13 g) at 25-35°C and maintained the reaction mixture for 90 min at same temperature. The precipitated compound was filtered and washed with water (200 ml). The obtained wet compound was charged with acetone (7.0 vol), dimethyl formamide (60 ml), raised the temperature to 60-70°C and charged with water (350 ml) about 1 hr and stirred for 30 min. Distilled-off the solvent completely, maintained resulting solution for 30 min at 75-85°C, cooled to 20-30°C and maintained for 90 min at same temperature. The precipitated solid compound was filtered and washed with water (100 ml) to get the wet compound.
The obtained wet compound was charged with water (300 ml) at 20-30°C, charged with dichloromethane (300 ml) and adjusted the pH to 9.5 with aq. ammonia (100 ml) at 25-35°C and stirred for 10 min. Separated the organic layer and extracted the aqueous layer with dichloromethane. The combined organic layers were washed with ammonium chloride solution, and distilled-off the solvent completely to get residue compound.
The obtained compound was charged with dimethyl formamide (150 ml) and fumaric acid (24.94 g), maintained for 90 min at 20-30°C. Filtered the resulting solid and washed with water (100 ml). An another RB flask was charged wet compound, water (400 ml) at 20-30°C, and stirred for 40 min. Filtered the obtain solid, washed with water and dried to obtain the title compound. The obtained compound PXRD is similar to the figure-1.
Yield: 77.0 g
Purity by HPLC: 99.63 %
Example-14: Preparation of compound of formula-I
A round bottom flask was charged with compound-10 (100 g), acetone (700 mL) at 20-30°C and raised the temperature to 60-70°C and stirred for 30 min at same temperature. The reaction mixture was charged with water (390 ml) slowly and charged activated carbon (5 g) at 60-70°C and stirred for 15 min. Filtered the solid compound through hyflow and washed with water and acetone. The filtrate solution was cooled to 10-20°C, the precipitated solid was stirred for 3 hr and filtered the solid and washed with acetone, water and dried to get the title compound.
Yield: 75.0 g; The obtained compound PXRD is similar to the figure-1.
Purity by HPLC: 99.97 %.

,CLAIMS:We claim:
1. An improved process for the preparation of compound of formula-I.

Comprising of:
a)reacting compound of formula-1 with 1,3,-dibromo-5,5-dimethylhydantoin in presence of para-toluenesulfonic acid in dichloromethane, further treating ethyl cyanoacetate in presence trimethylamine to provide compound of formula-3,

Formula-1 Formula-3

b)cyclizing of the compound obtained in step-a) with ethyl acetate HCl solvent to provide compound of formula-4,

Formula-4

c)reacting of compound of formula-4 in presence of Pd/C under hydrogen gas atmosphere, triethyl amine in methanol, to provide compound of formula-5,

Formula-5

d) reducing the compound of formula-5 with diisobutylaluminum hydride (DIBAL-H) in tetrahydrofuran to provide compound of formula-6,

Formula-6

e) oxidizing the compound of formula-6 with potassium permanganate in acetone to provide compound of formula-7,

Formula-7

f) coupling the compound of formula-7 with compound of formula-8 in presence of triethyl amine, DMAP in acetonitrile to provide pure compound of formula-9,

Formula-8 Formula-9

g) reacting the pure compound of formula-9 with monomethyl amine, sodium borohydride, fumaric acid in dichloromethane to provide compound of formula-10,

Formula-10

h) purifying the compound of formula-10 using fumaric acid, acetone, methanol, dimethyl formamide, water and ammonia to provide the pure compound of formula-I.
2. An improved process for preparation of compound of formula-7
Comprising of:
a)reacting compound of formula-1 with 1,3,-dibromo-5,5-dimethylhydantoin in presence of para-toluenesulfonic acid in dichloromethane, further treating ethyl cyanoacetate in presence trimethylamine to provide compound of formula-3,

Formula-1 Formula-3

b)cyclizing of the compound obtained in step-a) with ethyl acetate HCl solvent to provide compound of formula-4,

Formula-4

c)reacting of compound of formula-4 in presence of Pd/C under hydrogen gas atmosphere, triethyl amine in methanol, to provide compound of formula-5,

Formula-5

d) reducing the compound of formula-5 with diisobutylaluminum hydride (DIBAL-H) in tetrahydrofuran to provide compound of formula-6,

Formula-6

e) oxidizing the compound of formula-6 with potassium permanganate in acetone to provide compound of formula-7,

Formula-7

3. Vonoprazan fumaric acid according to the preceding claims is having particle size distribution of D90 <300 pm.
4. Vonoprazan fumaric acid according to the preceding claims is having purity of at least about 95%; preferably of at least about 97%; more preferably of at least about 98%; most preferably of at least about 99.9% as measured by HPLC;