4,6-Dichloro-2-(methylsulfonyl)pyrimidine

White solid

To a stirred solution of 4, 6-dichloro-2- (methylthio)pyrimidine (50 g, 0.26 mol) in dichloromethane (1 L) at 0To a stirred solution of 4, 6-dichloro- 2-(methylthio)pyrirnidine (50 g, 0.26 mol) in dichloromethane (1 L) at OTo a stirred solution of 4, 6-dichloro-2-(methylthio)pyrimidine (50 g, 0.26 mol) in dichloromethane (1 L) at 0To a stirred solution of 4, 6-dichloro-2- (methylthio)pyrirnidine (50 g, 0.26 mol) in dichloromethane (1 L) at 0Prepared by methods substantially similar to those set forth in Koppell et al, JOC, 26, 1961, 792, in the following manner. To a stirred solution of 4, 6-dichloro-2- (methylthio) pyrimidine (50 g, 0.26 mol) in dichloromethane [(1] L) at [0C] was added meta-chloroperoxybenzoic acid (143.6 g, 0.64 mol) over a period of 20 minutes. The solution was allowed to warm to room temperature and was stirred for 4 hours. The mixture was diluted with dichloromethane (1.5 L) and then treated sequentially with 50percent [NA2S203/NAHC03] solution (2 x 200 ml), sat. [NAHC03] solution (4 x 300 ml), and brine (200 ml) then dried [(MGS04).] The solvent was removed in vacuo to afford an off-white solid which was redissolved in EtOAc [(1 L)] and treated sequentially with sat. [NAHC03] solution (3 x [300] ml), and brine (100 [ML)] then dried (MgS04). The solvent was removed in vacuo to afford the title compound (A) as a white solid (55.6 g, 96percent yields NMR [CDC13] [5] 3.40 (3H, s, CH3), 7.75 [(1H.] s. ArH).In 250mL reaction flask equipped with a thermometer and a stirrer were added 39.0g of 2-methylthio-4, 6-dichloropyrimidine (0.2 mol), methanol and 1.8g of sodium tungstate 60.0g, stirring was warmed to 50 °C, concentration was added dropwise 68.0g of 30 wtpercent hydrogen peroxide (0.6mol), exothermic reaction. After incubation the reaction dropwise 1H, sample analysis, the starting material ≤0.5percent to stop the reaction. The reaction system was reduced to below 30 °C, then added to water, stirring cooled to 5 °C, filtered, the filter cake was washed with a small amount directly after drying, to give 2-methanesulfonyl-4, 6-dichloropyrimidine of 43.5g yield 95.8percent, purity 98.5percent (HPLC).EXAMPLE 274, 6-dichloro-2-(methylsulfonyl)pyrimidineCommercially available 4, 6-dichloro-2-methylthiopyrimidine (Aldrich, 21.0 g, 107.0 mmol, 1 equiv) was dissolved in dichloromethane and cooled with an ice-bath. 3-chlorobenzoyl peroxide (60.0 g, 77percent wt, 268.0 mmol, 2.5 equiv) was added in small portions. The resulting white suspension was stirred at room temperature for 4 hours, washed with 1 M sodium thiosulfate/saturated sodium bicarbonate (1:1, v/v, 200 mL x 3) and saturated sodium bicarbonate (100 mL x 3), and brine (100 mL x 1). The organic solution was dried and concentrated under reduced pressure. After drying under high vacuum for overnight Example EPO Method A: 4, 6-dichloro-2-(methylsulfonyl)pyrimidine Step 1:A mixture of 4, 6-dichloro-2-(methylsulfanyl)pyrimidine (1-180) (20.0 g, 102.53 mmol) and oxone (189.0 g, 308 mmol) in THF (450 mL) and H20 (150 mL) was stirred at room temperature for 16 hr. TLC (Petroluem ether : EtOAc = 1 : 1) showed the starting material had been consumed. The reaction mixture was filtered and washed with THF (100 mL). The combined filtrate was concentrated, dissolved in EtOAc (500 mL) and washed with H20 (2 x 300 mL) and brine (300 mL). The organic layer was dried over Na2S04 and concentrated. The residue was purified by silica gel chromatography (petroleum ether : EtOAc = 10 : 1 to pure EtOAc) to give 4, 6-dichloro- 2-(methylsulfonyl)pyrimidine (1-174) (20 g, 86 percent) as a white solid.General procedure: A mixture of 2-(methylthio)pyrimidines (5 mmol), tetrabutylammonium bromide (0.16 g, 0.5 mmol, 10 molpercent) and acetone (20 mL) was stirred at room temperature. The Oxone (12.5 mmol, 2.5 equiv) in water (20 mL) was added slowly to the vigorously stirred solution. After 4–6 h, TLC indicated the consumption of the starting material. The products 5 were isolated by filtering through a Buechner funnel and washed with water, and then dried to give the solid product. Yields, melting points and spectroscopic data for selected 2-(methylsulfonyl)pyrimidines are listed as follows. 4, 6-dichloro-2-(methylsulfonyl)pyrimidine (5a) White solid, yield 85percent, m.p. 130-131 °C; IR (KBr, cmExample 1To a stirred solution of 4, 6-Dichloro-2-methylsulfanyl-pyrimidine 0103 (5.0 g, 25.6 mmol) in CHA THF solution(5 ml) of 5-amino-2-ethoxypyridine(0.5 g, 3.6 mmol) was cooled to -78C, a THF solution of sodium bis(trimethylsilyl)amide(2M, 3 ml, 6.0 mmol) was added thereto and the mixture was stirred for 10 minutes. A THF solution(5 ml) of (2.00 g, 8.81 mmol) was dissolved in 60 ml of DCM, and isobutyl mercaptan (842 mg, 9.34 mmol) was added under dry ice acetone bath.After stirring for 5 minutes, triethylamine (891 mg, 8.81 mmol), the reaction was completed by TLC, and the dry ice acetone was removed.Quench the reaction with saturated ammonium chloride, layer with water and dichloromethane, and extract with dichloromethane.The organic layer was combined, washed with saturated brine, dried over anhydrous sodium sulfate and evaporated.Purification by column chromatography (petrole ether / ethyl acetate = 500/1)The yield is 99.5%.

Molecular Weight:227.07
XLogP3:1.7
Hydrogen Bond Acceptor Count:4
Rotatable Bond Count:1
Exact Mass:225.9370539
Monoisotopic Mass:225.9370539
Topological Polar Surface Area:68.3
Heavy Atom Count:12
Complexity:241
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes