Improved process for preparing a statin precursor

Oxo-Pyrimidine-Carbonitrile Formation

[0062]This example shows the preparation of 4-(4-fluorophenyl)-6-isopropyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carbonitrile from p-fluorobenzaldehyde, 4-methyl-3-oxopentanenitrile and urea conducted in methanol. The example corresponds to step 1 of WO 2008 / 151510. The reaction mechanism is as follows.

To a reactor of 2 L was added p-fluorobenzaldehyde (156 g, 1.26 mol), 4-methyl-3-oxopentanenitrile (140 g, 1.26 mol) and MeOH (330 mL). To the clear mixture was added urea (151 g, 2.52 mol) and Cu(I)Cl (1.25 g, 12.6 mmol), followed by addition of concentrated H2SO4 in 5 min (10.07 mL, 0.19 mol). The reaction mixture was heated in 30 min to 65° C. The now clear brownish solution was stirred and kept at 65° C. for 64 h. The reaction mixture was cooled to 20° C. in 3 h and stirred for 2 h at this temperature.

[0063]The precipitated solid was filtered and washed with MeOH (2×60 mL). The crude solid was suspended in 135 mL of MeOH and 470 mL of water. The...

Oxo-Pyrimidine-Carbonitrile Oxidation with HNO3

[0064]This example shows the preparation of 4-(4-fluorophenyl)-2-hydroxy-6-isopropylpyrimidine-5-carbonitrile from 4-(4-fluorophenyl)-6-isopropyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carbonitrile using HNO3 as an oxidizing agent. The example corresponds to step 2 of WO 2008 / 151510. The reaction mechanism is as follows.

To a reactor is added an aqueous solution of 65% conc. HNO3 (129.2 g, 1.38 mol). The reaction mixture is cooled to 10° C. and NaNO2 (0.92 g, 0.013 mol) was added. Then 4-(4-fluorophenyl)-6-isopropyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carbonitrile (40 g, 0.15 mol) is dosed in 80 min keeping the temperature below 10° C. The reaction is stirred for 3 h at 10° C. Then water (360 mL) is added and the pH adjusted to 5 with 50% aqueous NaOH keeping the temperature below 15° C. The precipitated solid was isolated by filtration and washed with water (2×50 mL). After drying, 4-(4-fluorophenyl)-2-hydroxy-6-isopropylpyrimidine-5-ca...

Oxo-Pyrimidine-Carbonitrile Oxidation with TBHP

[0065]This Example shows the preparation of 4-(4-fluorophenyl)-2-hydroxy-6-isopropylpyrimidine-5-carbonitrile from 4-(4-fluorophenyl)-6-isopropyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carbonitrile using tert-butylhydroperoxide (TBHP) as an oxidizing agent. The reaction mechanism is as follows.

To a reactor is added CH2Cl2 (150 mL), 4-(4-fluorophenyl)-6-isopropyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carbonitrile (16.2 g, 62.5 mmol), K2CO3 (0.6 g, 4.4 mol) and CuCl (0.06 g, 0.6 mmol). The reaction mixture is heated to 35° C. under stirring, whereupon a clear solution is obtained. Next, TBHP (14.6 mL tert-butylhydroperoxide, 70% in water, 106.2 mmol) is dosed during 3 h. When dosing is completed, the reaction mixture is stirred for 1 h at 35° C., cooled and stirred for 16 h at 20° C., whereupon the color of the reaction mixture has changed from clear yellow to turbid greenish. Next the reaction mixture is quenched by addition of 0.5 M aqueou...