Methyl 4-(4-Fluorophenyl)-6-isopropyl-2-(methylsulfonyl)pyrimidine- 5-carboxylate synthesis

Yield:799842-06-1 90.92%

Reaction Conditions:

with ammonium peroxomolybdate;dihydrogen peroxide;Aliquat 336 in dichloromethane;water at 20 - 35; for 19 - 21.5 h;Product distribution / selectivity;

Steps:

1.B; 3.B; II

Step -B: PREPARATION OF METHYL-4- (4-FLUOROPHENYL)-6-ISOPROPYL-2-METHYL SULFONYL PYRIMIDINE-5-CARBOXYLATE (FORMULA VII) To a four neck clean RB flask, charged dichloromethane (1500.0 ml), Methyl -4- (4-fluorophenyl)-6-isopropyl-2-methylthio-pyrimidine-5-carboxylate (150.0gm,0.468 moles),ammonium heptamolybdate tetrahydrate (8.62 gm,0.00697 moles) and tricaprylyl methyl ammonium chloride (Aliquat336) (21.0 gm,0.047 moles) were stirred at 25 to 30⁰C. This was followed by the slow addition of 50 % hydrogen peroxide solution (96.5 gm, 1.42 moles) at 20 to 35⁰C over period of 1 to 1.5 hrs. Reaction mass were further stirred at 25 to 30 C for 18 to 20 hours. After the completion of reaction charged water (450.0 ml) and continued stirring for 10 min. This was followed by layer separation. The aqueous layer was extracted with 130.0 ml dichloromethane. Combined all organic layers and Washed with water (2 x 500.0 ml). Dichloromethane was distilled under reduced pressure at 40 to 45⁰C and followed by degassing for 30 min at 50 to 55⁰C under reduced pressure. Isopropyl alcohol (175.0 ml) was added and distilled out under vacuum at 50 to 55 ⁰C, followed by the addition of isopropyl alcohol (350.0 ml) and heat to 60 to 65⁰C to get clear solution. Cooled solution to 25 to 30⁰C and stirred for 2.0 hrs at 25 to 30⁰C .Further cooled to 0 to 5 ⁰C and stirred for 2.0 hrs at 0 to 5 ⁰C. Filtered and washed with chilled (0 ⁰C) isopropyl alcohol (100.0 ml). The wet product was dried at 40 to 45⁰C under reduced pressure to obtain Methyl-4- (4-fluorophenyl)-6-isopropyl-2- methylsulfonyl pyrimidine-5-carboxylate (150.0 g, 90.92%).; Step -B: PREPARATION OF METHYL-4- (4-FLUOROPHENYL)-6-ISOPROPYL-2- METHYL SULFONYL PYRIMIDINE-5-CARBOXYLATE (FORMULA VII) To a four neck clean RB flask, charged dichloromethane (2530.0ml), Methyl-4- (4-fluorophenyl)-6-isopropyl-2-methylthio-pyrimidine-5-carboxylate(225.0gm,0.7022 moles),ammonium heptamolybdate tetrahydrate (12.93 gm,.01046moles) and tricaprylyl methyl ammonium chloride (Aliquat336) (28.44 gm,0.0703 moles) were stirred at 25 to 30⁰C. This was followed by the slow addition of 50 % hydrogen peroxide solution (145.15 gm, 2.1393 moles) at 20 tq 35⁰C over period of 1 to 1.5 hrs. Reaction mass were further stirred at 25 to 30⁰C for 18 to 20 hours. After the completion of reaction charged water (700.0ml) and continued stirring for 10 min. This was followed by layer separation. The aqueous layer was extracted with 330.0 ml dichloromethane. Combined all organic layers and Washed with water (2 x 750.0 ml). Dichloromethane was distilled under reduced pressure at 40 to 45⁰C and followed by degassing for 30 min at 50 to 55⁰C under reduced pressure. Isopropyl alcohol (225.0 ml) was added and distilled out under vacuum at 50 to 55 ⁰C, followed by the addition of isopropyl alcohol (900.0 ml) and heat to 60 to 65⁰C to get clear solution. Cooled solution to 25 to 30⁰C and stirred for 2.0 hrs at 25 to 30⁰C .Further cooled to 0 to 5 ⁰C and stirred for 2.0 hrs at 0 to 5 ⁰C. Filtered and washed with chilled (0 ⁰C) isopropyl alcohol (110.0 ml). The wet product was dried at 40 to 45⁰C under reduced pressure to obtain 213.0 gm Methyl-4- (4-fluorophenyl)-6-isopropyl-2- methylsulfonyl pyrimidine-5-carboxylate . Purity by HPLC: 98.34%Melting point : 115.9.O⁰C to 117.5°C

References:

WO2008/59519,2008,A2 Location in patent:Page/Page column 8; 15-16; 20