Ethyl 2-[3-cyano-4-(2-methylpropoxy)phenyl]-4-methyl-5-thiazolecarboxylate

White crystalline powder

50 g of the compound II was added to a 500 ml reactor, and 66 g of anhydrous potassium carbonate was added thereto, and then 200 ml of N, N-dimethylformamide and 65 g of bromoisobutane were added thereto, and stirring was started.Heating to 90 ~ 95 ° C, the temperature is kept at this temperature for 2 ~ 3h;The TLC was subjected to central control (developing agent: PE: EA = 4:1), and TLC showed that the reaction was completely cooled to 40 to 45 ° C, and potassium carbonate was removed by suction filtration.The filtrate was transferred to a 1000 mL reaction kettle and the temperature was stirred.21 mL of phosphorus oxychloride was added dropwise at 0 ° C, followed by heating to 60 ° C and stirring for 2 h.Cool down to 10 ° C, add ammonia (25percent, 286ml), Subsequently, 53 g of elemental iodine was added, and the reaction temperature was controlled to be stirred at 20 ° C for 2 to 3 hours.TLC is controlled (developing agent: PE: EA=4:1), and saturated sodium sulfite water is added after the reaction is completed.50 mL of the solution was quenched.The reaction solution was diluted with 200 mL of purified water, and extracted three times with 300 mL of ethyl acetate.Washed with 200 mL of saturated saline solution, Dry anhydrous sodium sulfate 50g, filter, The filtrate was concentrated under reduced pressure at 50 ° C to give the crude ethyl bromide, ethyl 2-(3-cyano-4-isobutoxyphenyl)-4-methylthiazole-5-carboxylate 54 g, Yield 83percent, Purity HPLC: 96percent.At room temperature, 3000mL with mechanical stirring Four-necked flask Isobutoxy-5-bromobenzonitrile 200g (0.78 mol, 1.0 eq), Potassium carbonate 119 g (0.87 mol, 1.1 eq), Tetrakistriphenylphosphine palladium 45g (0.039mol, 0.05eq), 2-boronic acid-4-methyl-1, 3-thiazole-5-carboxylic acid ethyl ester 186 g (0.87 mol, 1.1 eq), 1.4-dioxane 2000 mL, 200mL of water, The temperature was raised to 80 ° C under nitrogen for 12 hours. The solution changes from yellow to black. Cool to room temperature, Pour into 2000mL water, Extracted with 500 mL * 3 ethyl acetate, Dry over anhydrous sodium sulfate, Concentrated to a crude product, Recrystallization from 2000 mL of ethyl acetate and 200 mL of petroleum ether gave 216 g of white solid. Melting point 162-164 ° C, The yield was 79percent and the purity was 99.2percent.At room temperature, Add in a 5000 mL four-necked flask equipped with mechanical stirring [3-Cyano-4-isobutoxyphenyl]-4-methylthiazole-5-carboxylic acid ethyl ester 200g (0.58 mol, 1.0 eq), 1200 mL of methanol, Tetrahydrofuran 800mL, 1.0 mol/L sodium hydroxide 700 mL (0.7 mol, 1.2 eq), The reaction was stirred at room temperature for 5 hours. TLC monitors the conversion of raw materials completely, The reaction solution was concentrated to dryness, and then water was added to 3000 mL. Washed with 500 mL*3 of dichloromethane, The aqueous phase is adjusted to a pH of about 2 with 36% concentrated hydrochloric acid. Extracted with 200 mL*3 of dichloromethane, Combine the organic phase, Dry over anhydrous sodium sulfate, filter, Concentrated to dry white solid febuxostat 176g, Melting point 202-204 C, The yield was 96% and the purity was 99.4%.Example - 4: Preparation of 2-(3-cyano-4-isobutoxy phenyl)-4-methyl thiozole -5- carboxylic acidA mixture of 10. Og of Ethyl-2-(3-cyano-4-isobutoxy phenyl)-4-methyl thiozole -5- carboxyltae, 2.0g of sodium hydroxide was heated at 45-60C in 75 ml of aqueous methanol for 1 hour. Reaction mass was cooled to ambient temperature and pH adjusted to 2.0 to 2.5 with dilute hydrochloric acid and precipitated crystal was collected by filtration to give 8.8g of 2-(3-cyano-4-isobutoxy phenyl)-4-methyl thiozole -5-carboxylic acid (yield 95.8%).Example-4 Preparation of 2-(3-cyano-4-isobutoxy phenyl)-4-methyl thiozole-5-carboxylic acid A mixture of 10.0 g of Ethyl-2-(3-cyano-4-isobutoxy phenyl)-4-methyl thiozole-5-carboxylate, 2.0 g of sodium hydroxide was heated at 45-60 C. in 75 ml of aqueous methanol for 1 hour. Reaction mass was cooled to ambient temperature and pH adjusted to 2.0 to 2.5 with dilute hydrochloric acid and precipitated crystal was collected by filtration to give 8.8 g of 2-(3-cyano-4-isobutoxy phenyl)-4-methyl thiozole-5-carboxylic acid (yield 95.8%). Preparation of pure 2-(3-cyano-4-isobutoxy phenyl)-4-methyl thiozole-5-carboxylic acid; 10.0 g of 2-(3-cyano-4-isobutoxy phenyl)-4-methyl thiozole-5-carboxylic acid was dissolved in 100 ml of ethanol at reflux temperature. After dissolution reaction mass was cooled and precipitated crystal was collected by filtration to give 9.6 g of pure 2-(3-cyano-4-isobutoxy phenyl)-4-methyl thiozole-5-carboxylic acid (yield 96%).Example 4 - Preparation of Febuxostat and isolation from Ethanol[0092] A compound of formula VI (10.0 gr, 29 mmol) was hydro lysed under anhydrous conditions using solid sodium hydroxide (1.9 gr, 48 mmol) in 50 ml ethanol (95%)). The reaction was performed at 40C during 6 hours. Concentrated aqueous HC1 solution (4.5 ml) was added to the reaction mixture to get pH~3. The resulting mixture was heated to reflux (~78C). A hot filtration of inorganic salts was performed. The filtrate was heated to reflux again in order to complete product dissolution. The mixture was cooled slowly to obtain precipitation. After cooling to about 5C, the Febuxostat suspension was filtered and the separated crude product was dried at 75 C under reduced pressure to provide Febuxostat (8.64 gr, yield - 94%>; purity - 99.33%>).20 g of the compound of formula (II) was dissolved in 150 g of acetone, Then add 33g sodium hydroxide solution (2.5mol / L), After heating to reflux reaction for 2 h, the acetone solution was distilled off under reduced pressure (to no continuous condensate);160 g of ethyl acetate was added to the system.Warming up to reflux, Adjust the pH to 2.0 with hydrochloric acid and reflux for 1 h;Naturally cool down to 40 C and add 0.5 g of seed crystals.After stirring for 0.5 h, the temperature was lowered to -10 C for 3 h.After suction filtration, the filter cake was dried at 80 C for 3 h to obtain 19.9 g of the non-Butstat A crystal product.The product yield is 94.7%.The purity is 99.912%.The 100mg (0. 29mmol) having the formula (VIII) dissolved in a mixture of a compound of methanol and tetrahydrofuran was added 0. 6mL, IN Na0H (0. 58mmol), was heated to 70 C, stirred for 3 hours. The mixture was concentrated to dryness, added10mL water, extracted three times with 20mL of dichloromethane, the organic phase discarded, the aqueous phase was adjusted to pH 1-2 with 1N hydrochloric acid, extracted three times with dichloromethane 0mL, the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to give 85mg white solid, febuxostat is a yield of 93%.FebuxostatTo a suspension of compound 2 (28 Kg, 82 mol) in Tetrahydrofuran (140 L) was added a KOH aqueous solution (11.1 Kg / 196 mol and water 73L). The mixture was heated at 60-65C until the reaction was finished (around 2 hours). The reaction mixture was treated with methylene chloride (56L) and the pH was adjusted to 1-2 with a 6 N hydrochloric acid aqueous solution. The organic phase was separated and the water layer was extracted with methylene chloride (23 L). The organic phases were combined and the solvents (about 30 %) were distilled in order to reduce its volume.The suspension was treated with methanol (112L) and the distillation was continued until the internal volume was around 150L. The resulting suspension was cooled during 30 minutes at 0-5C. The suspension was filtered and the solid obtained was dried at 60C in a flow air oven until constant weight.Yield: 24 Kg. (92 %)Ethyl 2-(3- cyano-4-isobutyloxyphenyl)-4-methylthiazole-5-carboxylate ( 17.0g, 0.045mol) was hydrolyzed using aqueous (4.0%) sodium hydroxide (4.08g, 0.102mol) solution in THF( 170ml)and methanol( 127ml). The reaction was performed at 60-65C for 30minutes. After reaction completion water (340ml) was added to the reaction mixture at room temperature, which then was acidified to about pH 2-3 with IN HC1 (90ml). The precipitated febuxostat was separated by filtration to yield crude wet product (23g, purity by HPLC-99.55%). The crude wet product was dissolved in THF(72ml) at 50-55C. Activated carbon(0.5) was charged to the clear solution and maintained at 50-55C for 30minutes. The reaction mass was filtered and washed with THF(29ml). The filtrate was brought to room temperature and added slowly during one hour to the mixture of methanol( 17ml) and water( 100ml) and stirred for 6hours . The product was filtered and washed with water(80ml) and vacuum dried at 60-65C to yield Febuxostat ( 13g, 92%) of 99.92% HPLC purity. The product was identified as polymorphic form FC- 1 by XRD, IR, DSC, TGA, crystal morphology (Figures- 1 to 5). Water by arl-fischer: 1.9%A four-necked flask containing 1 L of the above solid was charged with 200 mL of anhydrous ethanol and 5.1 g of sodium hydroxide with stirring. T =60 , heat reflux 2h. A solution prepared from 20.0 g of purified hydrochloric acid and 50.0 g of water was added dropwise to adjust the pH to about 6. Filtration, adding 60mL water beating 1.5h, filtered to get wet compounds I compounds. Optional use of ethanol recrystallization, solid 60 C blast drying to constant weight, (HPLC): 97.4%, single-impurity (HPLC): 1.6%, total miscellaneous (HPLC): 2.6% in a total amount of 28.4 g, yield: 92.0%. After recrystallization using ethanol, it is still difficult to meet the purity (HPLC) 99.0%, single impurity ' 0.5% and ' 1.0% of the total impurity quality indicators.(1) Compound 6 (5 g, 14.5 mmol); ethanol (25 ml); tetrahydrofuran (25 ml), Mix 1mol/L sodium hydroxide solution (25ml), heat to 40~70C, TLC monitoring, It takes 1 hour to complete the reaction, and it is cooled. The appropriate amount of hydrochloric acid is slowly added to the reaction solution and stirred.Adding an appropriate amount of water, stirring, filtering, and drying to obtain a compound 7 4.0 g yield of 87.2%. (1) Compound 7 (5 g, 15.8 mmol); methanol (50 ml) was mixed, heated to reflux to dissolve, cooled and stirred.Filtration and drying gave Compound 4.8 g, Compound 7 (4.8 g, 15.2 mmol);Mix with methanol (50ml), heat to reflux to dissolve, cool, stir, filter, dry, Compound 7 4.6 g yield 92%; HPLC ' 99.8%, The isomer (Compound 4) <0.01%A solution of ethyl 2- (3-cyano-4-isobutyloxyphenyl) -4-methylthiazole-5-carboxylate (0.1 g, 0.29 mmol) in methanol (5 mL) Sodium hydroxide solution (lmL). The reaction solution was stirred at 80 C for 3 hours and then concentrated under reduced pressure. The resulting residue was dispersed in water (10 ml) and dichloromethane (20 mL), separated from the aqueous phase and adjusted to pH 1 to 2 with 1 M hydrochloric acid. The mixture was extracted with dichloromethane (20 mL x3) and the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated to give the title compound as a white solid (82 mg, 90%). Synthesis of 2-[3-Cvano-4-(2-Methyrpropoxy) Phenyl1-4-Methylthiazole-5- Carboxylic Acid (Febuxosta )Aqueous barium hydroxide octahydrate solution (prepared by dissolving 55 g, 0.174 mol of barium hydroxide octahydrate in 350 mL water) was added to a solution of ethyl-2-(3-cyano-4-isobutyloxyphenyl)-4-methyl-5-thiazole carboxylate (100 g, 0.29 mol) in tetrahydrofuran (1000 mL) and denatured spirit (300 mL). The reaction mixture was stirred at a temperature of about 60C for about 90 minutes to about 120 minutes. After completion of reaction, the mixture was cooled to a temperature of about 45C and diluted with ethyl acetate and water. The pH of the reaction mixture was adjusted to 0.5-0.8 with 6N HC1 at about 35C. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic layer was treated with activated carbon (10 g) and filtered through hyflobed. The hyflobed was washed with ethyl acetate. The combined filtrate was concentrated at a temperature of about 45C under reduced pressure. The residue thus obtained was dissolved in a mixture of dichloromethane (400 mL) and methanol (1000 mL) and the solution was cooled to about 0C, stirred for about 1 hour. The solid thus obtained was filtered, washed with a precooled mixture of methanol and methylene chloride, dried under reduced pressure to give febuxostat. (Yield: 81 g, 88%)HPLC purity: 99.93%Amide by-product: 0.07%.In a 500 ml round bottom flask, 114.0 g of absolute ethanol, 6.0 g of purified water and 1.6 g of sodium hydroxide were added, and the mixture was stirred for 0.5 h to dissolve, and 12.0 g of ethyl 2-(3-cyano-4-isobutoxy) phenyl)-4-methyl-thiazole-5-carboxylic acid ethyl ester (FBT-2) prepared in Example 4 was added, and the temperature was raised to 65-75 C, and the reaction was kept for 5 hours. After the reaction was completed, the temperature was lowered to 20-30 C, and 5.0 g concentrated hydrochloric acid was added dropwise, adjust the pH to 2 ~ 3, incubated at 20 ~ 30 C for 2h, filtered and dried to give 9.7g 2-(3-cyano-4-isobutoxy-phenyl)-4-methyl-thiazole -5-formic acid (FBT) finished product, the yield is 88.0%, the febuxostat content is 99.86%, and the maximum single impurity is 0.05%, which meets the quality requirements of the finished product in the API declaration standard, and no additional refining was required.Add 28g of intermediate 2, 168ml of ethanol to the three-necked flask. 260 ml of a 1 mol/L sodium hydroxide solution was added dropwise with stirring. The reaction solution is yellow-green slurry, reacted at 45±2 C for 4 h, after the reaction is completed, Yellow transparent solution, reduced to room temperature, and then dropped to 0 ~ 10 C, Add 1M hydrochloric acid dropwise to adjust pH=2~3, A white solid precipitated. Directly filter the reaction solution, The reaction vessel was rinsed with purified water and dried to give a white solid (23.4 g). The yield was 91%. (4) crude refining: synthesis of febuxostat Dissolve 100 g of febuxostat in 1000 ml of 80% ethanol. Raise to reflux for 1 h, reduce to room temperature, suction filtration, Drying the initial refined product of febuxostat 92g, purity 99.4%, yield 92%; Dissolve the preliminary preparation of febuxostat in 920 ml of acetone. The temperature was raised to reflux for 1 h, filtered while hot, and the filtrate was collected. It was cooled to 5 C for crystallization. Filtered and dried to obtain 70g of white febuxostat. The purity was 99.7%, and the yield was 76.1%.Preparation of Febuxostat To a solution of ethyl-2-(3-cyano-4-isobutoxyphenyl)-4-methylthiazole-5-carboxylate (2.0 gms/0.006035 moles) in 15 ml of THF was added 4.3ml of 2N NaOH slowly under nitrogen atmosphere at 25-30C. The resultant mixture was stirred at reflux for 5 hour. The reaction mass was cooled to 25C and filtered through celite. To the reaction mass concentrated HCI was added followed by 50ml of distilled water. The reaction mass was further stirred for 30 minutes. The resulting solid was isolated by filtration, washed with water until a neutral pH and dried under vacuum to yield 1.3 gms of the titled compound. Efficiency: 72%Ethyl 2-(3-cyano-4-isobutoxyphenyl)-4-methylthiazole-5-carboxylate (8.0 Kg), acetone (80 L), lithium hydroxide monohydrate (1 .2 Kg), and water (12 L) were mixed and heated to reflux. The mixture was maintained under reflux until reaction completion. After the reaction was complete, the mass was cooled to about 25C, ethyl acetate (120 L) was added, and pH was adjusted to about 1 to 2 with hydrochloric acid (3.2 L). The organic layer was separated and the aqueous layer was extracted with ethyl acetate (80 L). The combined organic material was washed with water (3^80 L), and treated with activated carbon at about 50C. The combined organic material was filtered, and the filtrate was evaporated completely under vacuum below 45C. Acetonitrile (16 L) was added to the residue and the solvent was distilled. Acetonitrile (80 L) was added to the residue and the mixture was heated to about 65C and maintained for about 1 hour. The mass was cooled to about 30C and maintained for about 1 hour. The formed solid was filtered and washed with acetonitrile (32 L). The wet solid was dried at about 60C to a constant weight to yield 5.2 Kg of the title compound.Purity by HPLC: 99.9 %.IN sodium hydroxide (2 ml) was added to a solution of ethyl 2-[3-cyano-4-(2- methyl propoxy)phenyl]-4-methylthiazole-5-carboxylate (400 mg) in ethanol (3 ml) and tetrahydrofuran (4 ml) and heated to 60C for about 1 hour. After completion of the reaction, distilled off the solvent completely and the residue obtained was neutralized with IN hydrochloric acid. The reaction mixture was extracted with ethyl acetate. The organic layer was concentrated to get the crystalline febuxostat. Yield: 121 mgd) Preparation of 2-(3-cvano-4-isobutyloxyphenyl)-4-methyl-5-thiazole carboxylic acid (Febuxostat) [Compound of formula Pi.250.0gm of Ethyl 2-(3-cyano-4-isobutoxyphenyl)-4-methyl-5-thiazolecarboxylate, [Compound of formula V] and then 200.0gm of potassium carbonate were added to the mixture of 7.51tr of methanol and 250.0ml water. Heated the solution to reflux under stirring for 3hr to complete the reaction. Cooled the clear solution formed and applied vacuum to distill out the solvent to maximum extent below 40C. To the residue 5.01tr of water was added and stirred to obtain solution. Added 2.51tr of ethyl acetate, stirred and layers separated. pH of aqueous solution adjusted to 2.5 +/- 0.2 by addition of dil. hydrochloric acid solution at 40C and stirred for about l.Ohr. Slurry of the product was filtered, washed with water and dried under vacuum to give 215.0gm of Febuxostat.Analytical Data- · ^NMR (CDCI3, 400 MHz): delta 0.992-1.067 (doublet, 6H); delta 2.029-2.117(multiplet, 1H); delta 2.636 (singlet, 3H); delta 3.963-3.985 (doublet, 2H); delta 7.317-7.347 (doublet, 1H); delta 8.160-8.197 (doublet of doublet, 1H); delta 8.238-8.245 (doublet, 1H); delta 13.397 (Broad singlet, 1H).? Mass (m/e) : 317.1Preparation of febuxostat2-(3-Cyano-4-isobutoxyphenyl)-4-methylthiazole-5-carboxylic acid ethyl ester (100 gm) was dissolved in ethanol (500 ml) at room temperature and then added a solution of sodium hydroxide (13 gm) in water. (250 ml) slowly for 30 minutes. The contents were heated to 65C and maintained for 1 hour. The reaction mass was then cooled to 50C and pH of the reaction mass was adjusted to 2.0 with hydrochloric acid solution (15%). The reaction mass was stirred for 15 minutes at 50C and then cooled to room temperature. The contents were maintained for 3 hours at room temperature and filtered. The solid thus obtained was dissolved in ethanol (500 ml) and then heated to 60C. The reaction mass was treated with carbon at 60C and filtered. The filtrate obtained was then cooled to room temperature and stirred for 2 hours. The reaction mass was further cooled to 10C and maintained for 1 hour. The solid obtained was collected by filtration and washed with chilled ethanol to obtain a wet solid. To the wet solid was added a mixture of ethanol and water (9: 1 ; 500 ml) at room temperature and then heated to 60C to obtain a solution. The solution was stirred for 30 minutes at 60C and then cooled to 25C. The reaction mass was maintained for 1 hour at 25C and the mass was further cooled to 10C. The solid obtained was collected by filtration and dried with vacuum sucking for 15 minutes to obtain 65 gm of febuxostat.20g of ethyl ester of Febuxostat [ethyl 2-(3-cyano-4-isobutyloxyphenyl)-4-methyl-5- thiazolecarboxylate] was suspended in EtOH (160 mL) and of THF (220 mL) at 25-30C and stirred for 10 - 15 min to obtain clear solution. To this clear solution, aqueous NaOH solution (IN, 108 mL) was added slowly at 25 - 30C, raised the temperature to 60C and stirred the reaction mass at 60C for lh. The solvent was distilled out completely under reduced pressure at 60 - 70C. The reaction mass was cooled to 25 - 30C, added water (100 mL) and neutralized with IN HC1. Then ethyl acetate (400 mL) was added to the reaction mass and stirred for 10 - 15 minutes at 25 - 30C. The aqueous layer was extracted using ethyl acetate (100 mL) and dried over anhydrous Na2S04. The reaction mass was distilled out completely at 75 - 80 C under reduced pressure and cooled to 25- 30 C. To the resulting solid mass, cyclohexane (100 mL) was added, slurred for 2 hours at 25 - 30 C and filtered. The isolated solid was dried at 60 C under vacuum for 12 - 15 h. The product obtained was identified as crystalline Febuxostat Form K.Example-5 Preparation of Febuxostat (I) [0124] 3.2 N sodium hydroxide solution was added to a reaction mass containing (50.0 g) Example-14 Process for the Preparation of Febuxostat Crystal Form-K 20 g of ethyl ester of Febuxostat [In a 100 ml 2-neck round-bottomed flask charge 2.407g of ethyl-2-(3-cyano-4-isobutoxyphenyl)- 4-methylhiazole-carboxylate in 20ml tetrahydrofuran under stirring, at 25-35 C, 0.748g of sodium hydroxide and heat reaction mass to 60-65 C for approximately 8 hrs. Check the progress of the reaction by TLC (cyclohexane:ethyl acetate 3:1). Cool reaction mass to 0-5 C and add 50 ml process water keeping temperature within 0-5 C. Adjust pH to 1-2 with 4.5 ml 6 N hydrochloric acid, keeping temperature within 0-5 C. Warm up reaction mass to 25-30 C and stir reaction mass at the above temperature for 15 min. Filter off the precipitated solid through Buchner funnel under reduced pressure, spray wash with 2 ml process water and suck dry for 20- 30 min. Transfer the crude solid in a 50 ml round-bottomed flask, charge 12 ml process water and 12 ml acetone at 25-30C. Heat the reaction mass to 50-60 C for 60 min. Cool down reaction mass to 0-5 C and stir for 60 min at the above temperature. Filter off the precipitated solid though Buchner funnel under reduced pressure, spray wash with 2 ml of a 1 : 1 mixture of acetone and process water and suck dry for 30-45 min. Dry under vacuum at 60 C. 1.821g of (compound I) Febuxostat are collected, Purity: 82.6%, Yield: 0.62w/w.Add 400 kg of DMAC, 100 kg of 2- (3-formyl-4-hydroxyphenyl) -4-methylthiazole-5-carboxylic acid ethyl ester to the reaction tank, 50kg bromoisobutane, 35kg triethylamine, The temperature was raised to 75 C for 15h.Then, 25 kg of hydroxylamine hydrochloride was added at a reduced temperature, and reacted at 75 C for 3 hours.Then 30 kg of acetyl chloride was added dropwise and reacted at 80 C for 7 hours.After the reaction was completed, the temperature was lowered to 20-30 C, water was added, 20 kg of sodium hydroxide was added, and hydrolysis was performed at 45 C for 6 hours.Then add hydrochloric acid dropwise to adjust the pH to 6.0-7.0. Reduce the temperature to 0-5 C, then add water and crystallize for 2h.After centrifugation, a white solid powder was obtained, and the obtained powder was crude febuxostat with a wet weight of 128 kg. 2. Preparation of febuxostat The crude febuxostat is dissolved in 90% methanol, and the activated carbon is decolorized and filtered through a 0.45um filter into a crystallizing tank in a Class D clean zone. Then, the temperature is reduced to 0-5 C, and purified water is added for crystallization. White solid powder, vacuum-dried at 70 C for 12 h to moisture ' 1.0%. The powder obtained was 98.5kg and the molar yield was 90.7%. The HPLC test results are shown in Figure 2: purity (HPLC) '99.96%, single impurity (HPLC) '0.05%, total impurity (HPLC) '0.1 %; Residual solvent DMAC was not detected, 13 genotoxic impurities were not detected (standard ' 15 ppm).Toluene (50 mL) was placed into a round bottom flask and 3-cyano-4- isobutoxybenzothioamide (5.0 g) was added, followed by addition of ethyl-2- chloroacetoacetate (4.25 g). The mixture was heated to reflux and maintained until reaction completion. After the reaction was completed, the mass was cooled to about 25°C and maintained at that temperature for about 20 minutes. The reaction mass was then filtered and the solid was washed with toluene (10 mL).The wet solid was dried at about 75°C to a constant weight to yield 4.0 g of the title compound. Purity by HPLC: 99.41 percent.A mixture of 3-cyano-4-(2-methylpropoxy)benzothiamide compound of formula-3 (25 g), ethyl 2-chloroacetoacetate compound of formula-4 (17.5 g), ethylacetate (75 ml) and dimethylformamide (13 ml) was heated to 80-85°C and stirred for 22 hours. After completion of the reaction, the reaction mixture was cooled to 25-30°C and stirred for 3 hours. The obtained residue was filtered and washed with ethylacetate. Ethylacetate (75 ml) was added to the obtained wet residue, heated to 70-75°C and stirred for 45 minutes. Cooled the reaction mixture to 25-30°C and stirred for 45 minutes. Filtered the obtained solid, washed with ethylacetate and dried to get the title compound. Yield: 20 grams.14 g (1 eq) of the compound of formula III prepared according to the method described in was dissolved in 200 ml of ethanol.28.7 g (3 eq) of ethyl 2-chloroacetoacetate was added.The temperature was raised to 100 ° C and stirred for 2 hours.Down to -10 ° C, A large amount of solid was precipitated, filtered, and the cake was dried to give the title compound 16.7 g, white solid, yield 85percent, purity 99.The above prepared mixture was added to ethyl 2-bromo-4-methylthiazole-5-carboxylate (249 mg, 1 mmol) under anhydrous anaerobic conditions, And Pd (PPh3) 4 (116 mg, 0.1 mmol).Stirring at room temperature, TLC monitoring reaction.After completion of the reaction, brine (20 mL) was added and extracted with ethyl acetate (100 mL x3).The combined organic phases were dried over anhydrous sodium sulfate, filtered, concentrated and chromatographed (petroleum ether: ethyl acetate (v / v) = 10: 1) to give the title compound as a white solid (0.21 g, 61percent)

Febuxostat intermediate

Molecular Weight:344.4
XLogP3:4.6
Hydrogen Bond Acceptor Count:6
Rotatable Bond Count:7
Exact Mass:344.11946368
Monoisotopic Mass:344.11946368
Topological Polar Surface Area:100
Heavy Atom Count:24
Complexity:476
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes