A SIAN J OURNAL OF C HEMISTRY A SIAN J OURNAL OF C HEMISTRY Synthesis, Characterization and Crystal Structure of N -(4-(4-Fluorophenyl)-5-(hydroxymethyl)-6-isopropylpyrimidin-2-yl)- N -methylmethanesulfonamide

N -[4-(4-Fluorophenyl)-5-(hydroxymethyl)-6-isopropylpyrimidin-2-yl]- N -methylmethane sulfonamide ( I ), an important intermediate to synthesize rosuvastatin, an HMG-CoA reductase inhibitor. It was prepared from methyl 4-(4-fluorophenyl)-6-isopropyl-2-(methylamino)pyrimidine-5-carboxylate ( 1 ) via mesylation by mesyl chloride and sodium tert -pentoxide, then reduction by DIBAL/HCl. The product was characterized by NMR and LC-MS. The crystal structure of compound I was investigated using X-ray diffraction and SHELXTL-97 software. The result indicated that compound I crystallized in the monoclinic system, space group C2/C with a = 29.683(6), b = 7.6290 (15), c = 18.215(4) Å, V = 3451.1 (16) Å 3 ; Z 8.


INTRODUCTION
Pyrimidine derivatives are known as pharmaceutical active ingredients or as precursors for the preparation. An important pyrimidine derivative is rosuvastatin, an HMG-CoA reductase inhibitor 1 , that is to say an inhibitor of cholesterol biosynthesis, which is used in the treatment of hyperlipoprote-inaemia and arteriosclerosis. It was proved to be a kind of long duration, good tolerance and high security drug to treat hyperlipidemia and high cholesterol statins, which have a broad market prospect.
In other literatures, the compound I was prepared by methyl 4-(4-fluorophenyl)-6-isopropyl-2-(methylthio) pyrimidine-5carboxylate through hydrolysis by LiOH and then reduction by NaBH4/BF3·Et2O. The disadvantage of this route is that the BF3·Et2O is toxic and it is not friendly to the environment.

EXPERIMENTAL
Methyl 4-(4-fluorophenyl)-6-isopropyl-2-(methylamino) pyrimidine-5-carboxylate (1) was supplied by Well Chemical Co. Ltd. of Jiangsu (Yancheng, People's Republic of China), its mass content is 98.5 % determined by LC. DIBAL solution, mesyl chloride and sodium tert-pentoxide was supplied by Sinopharm Chemical Reagent Co. Ltd. of China. All other chemicals were of reagent grade and used without purification as received. 1 H NMR spectrum was obtained with Bruker AV-300 spectrometer at 300.13 MHz and measured in CDCl3 solution at 25 ± 0.5 °C. The sample was dissolved in a 5 mm diameter tube at a concentration of 20 mg/mL. X-ray diffraction was Asian Journal of Chemistry; Vol. 26, No. 22 (2014), 7766-7768 performed on a Bruker APEXII CCD diffractometer. Mass spectrum of (I) was analyzed using Trace DSQ LC/MS (Thermo Electron Co., USA).

Synthesis of compound 2:
In a 1 L four-necked flask, sodium tert-pentoxide (11.2 g, 0.1 mol) is added into dimethoxyethane (130 mL) under argon and the compound 1 (15.1 g, 0.05 mol) is then added. Stirring is carried out at room temperature for 1.5 h, cooling to -10 °C is then carried out and mesyl chloride (11.5 g, 0.2 mol) is added. Stirring is carried out at that temperature for a further 1 h and the reaction mixture is then added to 150 mL of water. The mixture is diluted with ether and the organic phase is separated off. The organic phase is washed twice with water and then dried using Na2SO4. The salt mixture is filtered off and the filtrate is concentrated by evaporation. The residue is suspended in a mixture of hexane/acetone (6:1, 35mL). The yellow powder is filtered off and dried. In this manner, 15 g of compound 2 (78 %) are obtained.
Synthesis of compound I: In a 1 L four-necked flask, DIBAL solution (1 M in hexane, 135 mL, 0.135 mol) is added dropwise at -10 °C to a solution of the compound 2 (14.5 g, 0.038 mol) in toluene (130 mL). The mixture is subsequently stirred at -10 °C for a further 1.5 h. After adding 1 mL of methanol, the mixture is warmed to room temperature and is added dropwise to a warm solution of HCl (37 %, 50 mL) and water (60 mL). Stirring is carried out at 45 °C for 0.5 h, followed by cooling to room temperature, separating off the organic phase and drying. The salt mixture is filtered off and the filtrate is concentrated by evaporation. The residue is concentrated by evaporation. In this manner, 13.5 g (m.p. 145-146 °C) of the compound I are obtained in the form of a yellow oil which crystallizes at room temperature.
Crystals of (I) that suitable for X-ray diffraction were obtained by slow evaporation of 1,2-dichloroethane solution of compound I. X-ray crystallography: A colorless block-like crystal of compound I grown in 1,2-dichloroethane with dimensions of 0.30 mm × 0.20 mm × 0.20 mm was used for structural determination. Diffraction data were collected on a Bruker APEX-II CCD diffractometer by using graphite monochromated MoKα radiation (λ = 0.71073 Å). The structure was solved by direct methods with SHELXS-97 and refined on the F 2 by full-matrix least-squares method with SHELXL-97. All nonhydrogen atoms were refined anisotropically [10][11][12][13] .