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

Formula-I

Background of the Invention:
Tegoprazan, chemical name is (S)-7-((5,7-difluorochroman-4-yl)oxy)-N,N,2-trimethyl-1H-benzo [d] imidazole-5-carboxamide and is a potent and high-selective potassium-competitive acid blocker (P-CAB) with a fast onset of action and the ability to control gastric pH for a prolonged period of time, indicated for the treatment of acid-related gastrointestinal diseases. Tegoprazan’s strong and sustained effect is due to its ability to be slowly cleared from the gastric glands and exertion of effects independent of acid levels is approved in China and Korea, developed by Raqualia pharma in the form of tablet.

The US patent US7723321B2 is first reported Tegoprazan and pharmaceutically acceptable salts. The US’321 disclosed various processes for intermediates of tegoprazan. The said patent reported purification of tegoprazan by column chromatography on silica gel eluting with a mixture of dichloromethane, ethyl acetate and methanol.
The US patent US9493425B2 reported alternative process for preparation of intermediates of tegoprazan.
The US patent US11535610B2 reported various salts and process for preparation of tegoprazan and the said patent also reported amorphous form of tegoprazan.
The patent US9908870B2 reported crystalline form-A of tegoprazan.
Based on drawbacks in the prior art process and certain limitations, there is a need for providing an improved process for the preparation of tegoprazan, which involves simple experimental procedures, well suited to industrial production, which avoids the use of column chromatography purification, and which affords highly pure tegoprazan.
The present invention provides a novel process for preparation of tegoprazan and intermediates thereof and free from other impurities or isomers and nitroso amine impurities. The present invention involves cost effective key starting material, reagents and solvents, and suitable industrial production.
Brief Description:
The first aspect of the present invention is to provide an improved process for (S)-7-((5,7-difluorochroman-4-yl)oxy)-N,N,2-trimethyl-1H-benzo[d]imidazole-5-carboxamide compound of formula-I.
The second aspect of the present invention is to provide a process for the preparation of N-(2-(benzyloxy)-4-cyano-6-nitrophenyl) acetamide a compound of formula-5.
The third aspect of the present invention is to provide 4-amino-3-(benzyloxy)-5-nitrobenzonitrile with a compound of formula-4.

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, pet ether, 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), dimethyl sulfoxide (DMSO), N-methyl pyrrolidone (NMP) and the like; “chloro solvents” such as dichloromethane, dichloroethane, chloroform, carbon tetrachloride 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 aluminum hydride, sodium borohydride, BF3 etherate solution, Pd/C, Raney-nickel;
The first aspect of the present invention is to provide an improved process for (S)-7-((5,7-difluorochroman-4-yl)oxy)-N,N,2-trimethyl-1H-benzo[d]imidazole-5-carboxamide compound of formula-I,
comprising of:
a) reacting compound of formula-1 with suitable reagent, solvent to provide compound of formula-2.

b) brominating the compound of formula-2 with suitable reagent, solvent to provide compound of formula-3,

c) reacting the compound of formula-3 with suitable reagent, solvent to provide compound of formula-4,


d) reacting the compound of formula-4 with suitable reagent, solvent to provide compound of formula-5,


e) cyclizing the compound of formula-5 with suitable reagent, solvent to provide the compound of formula-6,

f) hydrolyzing of the compound of formula-6 with suitable reagent, solvent to provide the compound of formula-7 or salts thereof,


g) reacting the compound of formula-7 with suitable reagent, solvent to provide the compound of formula-8,


h) reacting the compound of formula-8 with compound of formula-A using suitable reagent, solvent to provide the compound of formula-9,


i) deprotecting the compound of formula-9 using suitable reagent and solvent to provide compound of formula-10,

j) coupling the compound of formula-10 with compound of formula-B using suitable reagent, solvents to provide compound of formula-11,

k) deprotecting the compound of formula-11 using suitable reagent, solvents to provide compound of formula-I

[I ]
l) optionally purifying the compound obtained in step-k) using suitable reagent’s , solvents to provide the pure compound of formula-I.
Wherein in step-a), b), c), d), e), f), g), h), i), j), k) and l) 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, water or any mixture thereof; the suitable temperature is 0-100°C.
Wherein in step-a) suitable reagent is selected from benzyl chloride, benzyl bromide, benzyl iodide, NaI, KI, CuI, inorganic base, organic base and mixture thereof.
Wherein in step-b) suitable reagents are selected from N-bromo succinimide, bromine, bromine in acetic acid, 5,5-Dibromo-2,2-dimethyl-4,6-dioxy-1,3-dioxane;
Wherein in step-c) suitable reagent is selected from CuCN, KCN, NaCN, ZN(CN)2, NaI, KI, CuI, Palladium catalyst and mixture thereof.
Wherein in step-d) suitable reagents are selected from acetic acid, acetic anhydride, sulfuric acid, trifluoro acetic acid, HCl and mixture thereof.
Wherein in step-e) suitable reagents is selected from iron power, zinc powder, acetic acid, Con.HCl, dil.HCl, ammonium chloride, sodium dithionate, Pd/C, Raney-Nickel, PtO2 and mixture thereof. Wherein in step-f) suitable reagents is selected from inorganic base such as KOH, NaOH, LiOH , Ba(OH)2, Ca(OH)2, sulfuric acid, Con. HCl and dil. HCl;
Wherein in step-g) suitable reagents are selected from methane sulfonyl chloride, methyl chloro formate, ethyl chloroformate, thionyl chloride, EDC-HCl, HATU, DCC, CDI, organic base and dimethyl amine solution, dimethylamine (g) and mixture thereof.
Wherein in step-h) suitable reagents are selected from para toluene sulfonyl chloride, Sodium hydride, organic base and mixture thereof.
Wherein in step-i) suitable reagents is selected from Pd/C, Pd(OH)2, PtO2, Ray-Ni, ammonium chloride, ammonium formate, under hydrogen gas, acetic acid, HCl and mixture thereof;
Wherein in step-j) suitable reagents is selected from diethyl azodicarboxylate (DEAD) or diisopropyl azodicarboxylate (DIAD) and triphenylphosphine. tributylphosphine, 1,1'-(azo dicarbonyl) dipiperidine (ADDP) and mixture thereof;
Wherein in step-k) suitable reagents are selected from inorganic base such as KOH, NaOH, LiOH , Ba(OH)2, Ca(OH)2 and mixture thereof.
Wherein in step-l) suitable reagents is selected from HCl, HBr, Acetic acid, trifluoro acetic acid, citric acid, malic acid, para toluene sulfuric acid, tartaric acid, formic acid, fumaric acid, organic base, inorganic base and mixture thereof.
The preferred embodiment of the present invention is to provide an novel process for (S)-7-((5,7-difluorochroman-4-yl)oxy)-N,N,2-trimethyl-1H-benzo[d]imidazole-5-carboxamide compound of formula-I,
comprising of:
a) reacting compound of formula-1 with benzyl chloride in presence of potassium carbonate in DMF to provide compound of formula-2,

b) brominating the compound of formula-2 with N-bromosuccinamide to provide compound of formula-3,

c) reacting the compound of formula-3 with CuCN in presence of copper iodide in NMP, ammonia solution to provide compound of formula-4,


d) reacting the compound of formula-4 with acetic anhydride in presence of acetic acid, sulfuric acid to provide compound of formula-5,


e) cyclizing the compound of formula-5 with iron powder in acetic acid to provide the compound of formula-6,

f) hydrolyzing the compound of formula-6 with potassium hydroxide in ethylene glycol followed by acidification to provide the compound of formula-7a,


g) reacting the compound of formula-7a with dimethylamine in presence of EDC-HCl, HOBt, triethylamine in DMF to provide the compound of formula-8,


h) reacting the compound of formula-8 with compound of formula-A in presence of triethyl amine in dichloromethane to provide the compound of formula-9,


i) deprotecting the compound of formula-9 using raney nickel in isopropanol to provide compound of formula-10,

j) coupling the compound of formula-10 with compound of formula-B in presence of triphenylphosphine in DIAD in MDC to provide compound of formula-11,

k) deprotecting the compound of formula-11 using trifluoroacetic acid in THF to provide compound of formula-I.

The second aspect of the present invention is to provide a process for N-(2-(benzyloxy)-4-cyano-6-nitrophenyl) acetamide compound of formula-5.
a) reacting the compound of formula-3 with CuCN in presence of copper iodide in NMP, ammonia solution to provide compound of formula-4,


d) reacting the compound of formula-4 with acetic anhydride in presence of acetic acid, sulfuric acid to provide compound of formula-5,


The third aspect of the present invention is 4-amino-3-(benzyloxy)-5-nitrobenzonitrile a compound of formula-4,


The other aspect of the present invention is compound of formula having the structure,

Where R is mono or multi substitution with alkyl, alkoxy, halo, cyano, nitro or H.
The other aspect of the present invention compound of formula-I is having particle size distribution of D90 <300 µm, D50 <150 µm. D10 <75 µm.
The compound of formula-I produced by the process of the present invention has purity of at least about 95%; preferably of at least about 97%; more preferably of at least 20 about 98%; most preferably of at least 99% as measured by HPLC.
The other isomer of compound of formula-I is having preferably < 0.5 %, more preferably < 0.15 %; and other related impurities are preferably < 0.5 %, more preferably < 0.15 % in compound of formula-I of the present invention.
The process of the present invention can be represented schematically as follows:
Scheme-1:

The second aspect of the present invention is to provide a process for (S)-7-((5,7-difluorochroman-4-yl)oxy)-N,N,2-trimethyl-1H-benzo[d]imidazole-5-carboxamide compound of formula-I
Scheme-2:




The other aspect of the present invention is to provide a process for compound of formula-8,

The other aspect of the present invention is to provide a process for compound of formula-8;

(S)-7-((5,7-difluorochroman-4-yl)oxy)-N,N,2-trimethyl-1H-benzo[d]imidazole-5-carboxamide compound of formula-I produced by the present invention can be further micronized or milled to get the desired particle size to achieve desired solubility profile based on different forms of pharmaceutical composition requirements. Techniques that may be used for particle size reduction include, but not limited to ball, roller and hammer mills, and jet mills, milling or marinization may be performed before drying, or after the completion of drying of the product.
PXRD analysis of (S)-7-((5,7-difluorochroman-4-yl)oxy)-N,N,2-trimethyl-1H-benzo[d]imidazole-5-carboxamide compound of formula-I was carried out using BRUKER D8 ADVANCED/AXS X-Ray diffractometer using Cu Ka radiation of wavelength 1.5406 A° and continuous scan speed of 0.03°/min. IR spectra were recorded on a Perkin-Elmer FTIR spectrometer.
(S)-7-((5,7-difluorochroman-4-yl)oxy)-N,N,2-trimethyl-1H-benzo[d]imidazole-5-carboxamide compound of formula-I used in the present invention is synthesized by the prior known processes.
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 [2-(benzyloxy)-4-bromo-6-nitroaniline]
A round bottom flask was charged with dimethylformamide (300 ml), 2-amino-3-nitrophenol (100 g), benzyl chloride (98.51 g) and potassium carbonate (116.5 g) at 25-35°C and raised the reaction mass temperature to 45-55°C, and stirred for 2h. Cooled the reaction mixture to 25-35°C and charged ethyl acetate (500 ml) and water (1000 ml). The reaction mixture is stirred for 10 min and separated into two layers, the aqueous layer was extracted with ethyl acetate (500 ml) and the organic layer was charged into another RBF and charged N-Bromo succinimide (149.85 g) at 25-35°C, the reaction mass temperature was raised to 60-70°C and stirred for 3h at same temperature. The reaction mass was distilled-off and charged the reaction mass with IPA and stirred for 3h at 60-70°C. Cooled the reaction mixture to 25-35°C, filtered the reaction mass and washed with isopropanol and dried to get the title compound.
Yield: 200.0 g
Example-2: Preparation of compound of formula-5 [N-(2-(benzyloxy)-4-cyano-6-nitrophenyl) acetamide]
A round bottom flask was charged with N-Methyl-2-pyrrolidone (500 ml), compound-3 (100 g), CuCN (31 g) and CuI (2.9 g) at 25-35°C stirred for 10 min and heated the reaction mass to 155-165°C and stirred for 10 h. Cooled the reaction mass to 25-35°C, gradually charged with aqueous ammonia solution (1000 ml) at 25-35°C and the reaction mass was heated to 55-65°C and stirred for 30 min. The reaction mass was filtered and washed with aqueous ammonia (10 vol) to obtain the compound. The wet compound was charged with ethyl acetate (1000 ml) and heated to 55-65°C and stirred for 30 min. Filtered the reaction mass and washed with ethyl acetate, distilled the organic layer to obtain solid. The obtained solid is charged with premixed solution of water and IPA (1:1) at 25-35°C, stirred at 60-70°C for 40 min and gradually cooled the solution and filtered the reaction mass and washed with water to obtain the wet compound.
The obtained wet compound was charged into another RB flask and charged with acetic acid (700 ml), acetic anhydride (150 ml) at 25-35°C and stirred for 10 min. Charged sulphuric acid (3.02 g), water at 25-35°C and stirred for 40 min. Filtered the reaction mass and washed with water and dried to obtain the title compound.
Yield: 80 g.
Example-3: Preparation of compound of formula-7 [7-(benzyloxy)-2-methyl-1H-benzo[d]imidazole-5-carboxylic acid.
A round bottom flask was charged with acetic acid (500 ml), compound-5 (100 g) and iron powder (53.87 g) and raised the temperature to 75-85°C and stirred for 4h. Cooled the reaction mass to 55-65°C, charged with ethyl acetate (500 ml) and stirred for 30 min. Filtered the reaction mass and washed with ethyl acetate (5 vol) and distilled-off the organic layer to obtain a solid. The obtained solid compound was charged with water (1000 ml), stirred for 40 min and filtered the reaction mass and washed with water. The obtained solid was charged into another RB flask at 25-35°C, charged with ethylene glycol (500 ml), potassium hydroxide (1087.8 g) and stirred for 15 min. The temperature of the reaction mass is raised to 155-165°C, the reaction mass temperature is maintained the same for 2h. Cooled to 5-15°C, adjusted the pH of the reaction mass to 6 by using HCl solution (500 ml). The reaction mass is stirred for 20 min at 5-15°C, filtered the reaction mass and washed with water (10 vol) and dried to obtain the title compound.
Yield: 85g.
Example-4: Preparation of compound of formula-8 [7-(benzyloxy)-N, N, 2-trimethyl-1H-benzo[d]imidazole-5-carboxamide]
A round bottom flask was charged with dichloromethane (1000 ml), compound-7 (100 g), EDC-HCl (66.6 g), hydroxy benzotriazole (53.2 g), dimethylamine hydrochloride (114.4 g) and triethylamine (287 g) and stirred for 6h at 25-35°C. The reaction mass was quenched with water and stirred for 15 min at 25-35°C. The both layers were separated and distilled-off the organic layer to obtain the title compound.
Yield: 85 g
Example-5: Preparation of formula-9 [4-(benzyloxy)-N, N, 2-trimethyl-1-tosyl-1H-benzo[d]imidazole-5-carboxamide
A round bottom flask was charged with dichloromethane (1000 ml), compound-8 (100 g), p-toluene sulfonic acid (110 g), triethylamine (130 g) at 25-35°C and stirred the reaction mass for 3h at 35-45°C. The reaction mass is slowly quenched with water, stirred for 15 min and separated the layers. The organic layer was washed with sodium carbonate solution and distilled-off the organic layer to obtain the title compound.
Yield: 120 g
Example-6: Preparation of compound of formula-10 (4-hydroxy-N, N, 2-trimethyl-1-tosyl-1H-benzo[d]imidazole-6-carboxamide)
A round bottom flask was charged with tetrahydrofuran (1000 ml), compound-9 (100 g) and palladium carbon (100 g) at 25-35°C and stirred under hydrogen gas atmosphere for 4h at 35-45°C. Filtered the reaction mass, distilled-off the organic layer to obtain the title compound.
Yield: 60 g
Example-7: Preparation of compound of formula-10 (4-hydroxy-N, N, 2-trimethyl-1-tosyl-1H-benzo[d]imidazole-6-carboxamide)
A round bottom flask was charged with tetrahydrofuran (100 ml), compound-9 (10 g) and Ray-Nickel (10 g) at 25-35°C and stirred under hydrogen gas pressure for 4 h at 35-45°C. Filtered the reaction mass, distilled-off the organic layer to obtain the title compound.
Yield: 60 g
Example-8: Preparation of compound of formula-I ((S)-4-((5, 7-difluorochroman-4-yl) oxy)-N, N, 2-trimethyl-1H-benzo[d]imidazole-6-carboxamide)
A round bottom flask was charged with toluene (1000 ml), compound-10 (100 g), compound-B (R)-5, 7-difluorochroman-4-ol) and triphenyl phosphine (126.47 g) at 25-35°C. The reaction mass was cooled to 10-20°C, added diisopropyl azo dicarboxylate (97.46 g) gradually for 15 min and stirred for 3 h at 25-35°C. Cooled the reaction mixture to 0-10°C and filtered at 0-10°C, distilled-off the filtrate solution to obtain the residue.
The above obtained residue was charged with tetrahydro furan (500 ml) at 25-35°C, stirred the reaction mass for 10 min and charged with 2, 2, 2-trifluoroacetic acid (61.06 g) and heated the reaction mass to 50-60°C and stirred for 4 h at the same temperature. Cooled the reaction mass to 25-35°C, followed by addition of toluene (1000 ml), sodium carbonate (20 g) gradually at same temperature and stirred the reaction mass for 15 min and separated layers. The organic layer was charged with sodium chloride and stirred the reaction mass for 10 min and separated into two layers. The organic layer was charged into another RB flask and charged with L-tartaric acid (120 g) at 25-35°C and stirred for 10 min at 25-35°C and separated into two layers. The aqueous layer was charged with toluene at 25-35°C, stirred for 10 min and separated into two layers. The aqueous layer was charged with sodium carbonate solution slowly into the reaction mass, followed by addition of di chloromethane (1000 ml) at 25-35°C, stirred the reaction mass for 10 min at 25-35°C and separated into two layers. Distilled-off the organic layer completely under vacuum below 50°C, added acetone to the above solid and stirred for 2h. Filtered the solid and washed with acetone and charged above solid and acetone and stirred for 2h at 25-35°C. Filtered the solid compound and dissolved in methanol and distilled-off the organic layer completely. Further, the obtained compound was charged with chilled water stirred for 40 min and filtered the solid and washed with water and dried to obtain the title compound.
Yield: 60 g.
Example-9: Preparation of crystalline form-A of Tegoprazan
A round bottom flask was charged with compound of formula-I (5 g), acetone (25 ml) and stirred for 2h at 25-35°C. Filtered the solid and washed with acetone and charged the solid with acetone (15 ml) and stirred for 2 h at 25-35°C. Filtered the solid and washed with acetone and dried to obtain the title compound.
Yield: 2.6 g
Example-10: Preparation of amorphous form of Tegoprazan
A round bottom flask was charged with compound of formula-I (5 g), acetone (25 ml) and stirred for 2 h at 25-35°C. Filtered the solid and washed with acetone and the solid compound was charged with acetone (15 ml) at 25-35°C, stirred for 2h. Filtered the solid compound and washed with acetone, further the solid was charged with methanol (25 ml) and stirred for 1 h. Distilled out the organic layer completely under vacuum at below 50°C, after distillation charged the residue with chilled water (25 ml) and stirred for 40 min. Filtered the solid, washed with water (5V) and dried at 55-65°C for 6h to obtain the title compound.
Yield: 2.3 g.
Example-11: Preparation of crystalline form-B of Tegoprazan
A round bottom flask was charged with compound of formula-I (1 g), acetonitrile (8 ml) at 25-35°C, raised the temperature of reaction mass to 55-65°C and maintained for 2 h at same temperature. The reaction mass was cooled to 25-35°C and maintained for 3 h and filtered the solid and washed with acetonitrile and dried at 40-50°C to obtain the title compound.
Yield: 0.7 g.
Example-12: Preparation of crystalline form-B of Tegoprazan
A round bottom flask was charged with compound of formula-I (1 g), n-heptane (10 ml) at 25-35°C, raised the temperature of reaction mass to 80-90°C and maintained for 72 h at same temperature. Filtered the solid and washed with n-heptane and dried at 55-65°C for 4h to obtain the title compound.
Yield: 0.7 g.
Example-13: Preparation of crystalline form-B of Tegoprazan
A round bottom flask under nitrogen condition was charged with compound of formula-I (1 g), MTBE (10 ml) at 25-35°C and maintained the reaction mass for 48h at same temperature. Filtered the solid and washed with MTBE (1 ml) and dried at 50-60°C for 4h to obtain the title compound.
Yield: 0.6 g.
Example-14: Preparation of crystalline form-B of Tegoprazan
A round bottom flask at room temperature was charged with compound of formula-I (1 g), n-heptane (1 ml), isopropyl acetate (10 ml) at 25-35°C and the reaction mass was maintained for 48h at 75-85°C. Filtered the solid and dried under vacuum at 50-60°C for 4h to obtain the title compound.
Yield: 0.55 g.
Example-15: Preparation of crystalline form-B of Tegoprazan
A round bottom flask at room temperature was charged with compound of formula-I (1 g), MTBE (10 ml), ethyl acetate (1 ml) at 25-35°C and maintained for 48h at same temperature. Filtered the solid and dried under vacuum at 50-60°C for 4h to obtain the title compound.
Yield: 0.5 g.
Example-16: Preparation of compound of formula-3 [2-(benzyloxy)-4-bromo-6-nitroaniline]
A round bottom flask was charged with dimethyl formamide (200 ml), 2-amino-3-nitrophenol (100 g), benzyl chloride (98.3 g) and potassium carbonate (116.5 g) at 25-35°C and raised the reaction mass temperature to 45-55°C and stirred for 2h. Cooled the reaction mixture to 25-35°C and charged ethyl acetate and water. The reaction mixture was stirred for 10 min and separated into two layers. The aqueous layer was extracted with ethyl acetate. Further the combined organic layer was charged with N-Bromo succinimide (140 g) at 25-35°C, the reaction mass temperature was raised to 60-70°C and stirred for 3 h at same temperature. The reaction mass was distilled off and further charged with IPA and stirred for 3h at 60-70°C. Filtered the solid obtained and further the compound was charged with water and stirred for 1h. Filtered the obtained solid and dried to get the title compound.
Yield: 180.5 g
Example-17: Preparation of compound of formula-5 [N-(2-(benzyloxy)-4-cyano-6-nitrophenyl) acetamide]
A round bottom flask was charged with N-methyl-2-pyrrolidone (500 ml), compound-3 (100 g), Copper(I) cyanide (36 g) and Copper (I) iodide (2.9 g) at 25-35°C stirred for 10 min and heated the reaction mass to 155-165°C and stirred for 10 h. Cooled the reaction mass to 50-60°C, gradually charged with aqueous ammonia solution and stirred for 40 min. The reaction mass was filtered and washed with aqueous ammonia to obtain the solid compound. The wet compound was charged with ethyl acetate and heated to 55-65°C and stirred for 30 min. Filtered the reaction mass and washed with ethyl acetate, distilled off the organic layer to obtain the solid compound. The obtained compound was charged with a mixture of water and isopropanol and stirred at 60-70°C for 40 min. Cooled, filtered the reaction mass and washed with water and dried to obtain the compound of formula-4.
The obtained compound of formula-4 was charged with acetic acid (700 ml), acetic anhydride (150 ml) at 25-35°C and sulphuric acid (3.02 g) and stirred for 3 h. The reaction mixture was quenched with water and filtered the resulting solid and washed with water and dried to obtain the title compound.
Yield: 53.6 g.
Example-18: Preparation of compound of formula-7a [7-(benzyloxy)-2-methyl-1H-benzo [d]imidazole-5-carboxylic acid hydrochloride.
A round bottom flask was charged with acetic acid (700 ml), compound-5 (100 g) and iron powder (53.8 g) and raised the temperature to 75-85°C and stirred for 4 h. Cooled the reaction mass to 55-65°C, charged with ethyl acetate and stirred for 30 min. Filtered the reaction mass and washed with ethyl acetate and distilled-off the organic layer to obtain the solid compound. The obtain compound was charged with water, stirred for 2 h and filtered the reaction mass and washed with water. The obtain solid was charged with ethylene glycol, potassium hydroxide (109 g) and stirred for 6 h at 155-165°C. The reaction mass was cooled, charged with water and stirred for 15 min, and adjusted the pH of the reaction mass to 6.0 by using HCl solution. The reaction mass is stirred for 1 hr, filtered the solid obtain and washed with water and dried to obtain the title compound.
Yield: 78.6 g.
Example-19: Preparation of compound of formula-10 (4-hydroxy-N, N, 2-trimethyl-1-tosyl-1H-benzo[d]imidazole-6-carboxamide)
A round bottom flask was charged with DMF (500 ml), compound-7a (100 g), EDC-HCl (137.5 g), hydroxy benzotriazole (4.4 g), dimethylamine hydrochloride (142 g) and triethylamine (73 g) and stirred for 2 h at 25-35°C. The reaction mass was quenched with water, dichloromethane and stirred for 15 min at 25-35°C. Both layers were separated, and the aqueous layer was extracted with dichloride methane and the combined organic layer was dried over sodium sulfate and processed for next step.
The organic layer was charged with p-toluene sulfonyl chloride (135 g), triethyl amine (143.2 g) and stirred for 3 h at 35-45°C. The reaction mixture was cooled and charged with water and separated the layers. The organic layer was washed with sodium carbonate solution and distilled off completely. The obtained compound was charged with methyl tert-butyl ether and stirred for 2 h, filtered the solid compound and dried to get the compound of formula-9.
An autoclave was charged with the above compound of formula-9, methanol (1L) and Raney-nickel (80 g) and stirred under hydrogen gas pressure about (4-5 kg) at 55-65°C for 6 h. Cooled the reaction mixture, filtered through the hy-flow and washed with dichloromethane and distilled-off the solvent completely. The compound obtained was charged with isopropanol and stirred at 55-65°C, cooled the solution and filtered the solid material and washed with IPA and dried to get the title compound.
Yield: 65.2 g.
Example-20: Preparation of compound of formula-I ((S)-4-((5, 7-difluorochroman-4-yl) oxy)-N, N, 2-trimethyl-1H-benzo[d]imidazole-6-carboxamide)
A round bottom flask was charged with dichloromethane (1000 ml), compound-10 (100 g), compound-B [(R)-5,7-difluorochroman-4-ol, 75 g] and triphenyl phosphine (126.47 g) at 25-35°C. The reaction mass was cooled to 10-20°C, added diisopropyl azo dicarboxylate (97.46 g) and stirred for 3 h at 25-35°C.
The reaction mixture was quenched with 10 % sodium chloride solution and stirred for 15 min and separated into both layers. The organic layer was distilled off completely to get the residue compound.
The above residue compound was charged with a mixture of isopropanol, water and stirred for 1 h at 25-35°C, filtered the solid and washed with isopropanol. The obtained compound was charged with tetrahydrofuran, 2, 2, 2-trifluoroacetic acid (61.0 g) and heated the reaction mass to 50-60°C and stirred for 4 h. Cooled the reaction mass to 25-35°C, charged with dichloromethane, sodium carbonate solution and stirred the reaction mass for 15 min and separated layers. The organic layer was dried over sodium sulfate and distilled off completely. The obtained compound was charged with acetone and stirred for 10 min. Filtered the solid compound and washed with acetone and dried to get the title compound.
The PXRD of the compound is similar to the crystalline form-A.
Yield: 60 g. HPLC: 99.80 %, Chiral purity: 99.97 %
Example-21: Preparation of crystalline form-A of Tegoprazan
A round bottom flask was charged with formula-I (100 g), methanol (350 ml) followed by carbon and stirred for 10 min at 25-35°C. Filtered the reaction mixture and washed with methanol and distilled-off. The obtained compound was charged with acetone and stirred for 1 h. Filtered the compound obtained and washed with acetone and dried to obtain the title compound.
Yield: 60 g. HPLC: 99.80 %, Chiral purity: 99.97 %
,CLAIMS:We claim:
1. A compound of formula-4,


2. A process for N-(2-(benzyloxy)-4-cyano-6-nitrophenyl) acetamide the compound of formula-5. comprising of
a) reacting the compound of formula-3 with copper cyanide in presence of copper iodide in NMP, ammonia solution to provide compound of formula-4,


b) reacting the compound of formula-4 with acetic anhydride in presence of acetic acid, sulfuric acid to provide compound of formula-5,


3. An improved process for the preparation of (S)-7-((5,7-difluorochroman-4-yl)oxy)-N,N,2-trimethyl-1H-benzo[d] imidazole-5-carboxamide compound of formula-I,
comprising of:
a) reacting compound of formula-1 with benzyl chloride in presence of potassium carbonate in DMF to provide compound of formula-2,

b) brominating the compound of formula-2 with N-bromosuccinamide to provide compound of formula-3,

c) reacting the compound of formula-3 with copper cyanide in presence of copper iodide in NMP, ammonia solution to provide compound of formula-4,


d) reacting the compound of formula-4 with acetic anhydride in presence of acetic acid, sulfuric acid to provide compound of formula-5,


e) cyclizing the compound of formula-5 with iron powder in acetic acid to provide the compound of formula-6,

f) hydrolyzing the compound of formula-6 with potassium hydroxide in ethylene glycol followed by acidification to provide the compound of formula-7a,


g) reacting the compound of formula-7a with dimethylamine in presence of EDC-HCl, HOBt, triethylamine in DMF to provide the compound of formula-8,


h) reacting the compound of formula-8 with compound of formula-A in presence of triethyl amine in dichloromethane to provide the compound of formula-9,


i) deprotecting the compound of formula-9 using raney nickel in isopropanol under hydrogen gas pressure to provide compound of formula-10,

j) coupling the compound of formula-10 with compound of formula-B in presence of triphenylphosphine in DIAD in dichloromethane to provide compound of formula-11,

k) deprotecting the compound of formula-11 using trifluoroacetic acid in THF to provide compound of formula-I.

[I]
4. The compound of formula I, obtained according to the preceding claims having particle size distribution of D90 <300 pm, D50 <150 µm, D10 <75 µm.
5. The crystalline form-A of compound formula-1 obtained according to claim 3 having R-isomer less than 0.15% by HPLC.
6. A compound of formula having the structure,

Where R is mono or multi substitution with alkyl, alkoxy, halo, cyano, nitro or H.