ETHYL 2-(METHYLSULFONYL)PYRIMIDINE-5-CARBOXYLATE

Step 2: Ethyl 2-(methylsulfonyl)pyrimidine-5-carboxylate (121); [0725] A solution of sulfide 120 (0.424 g, 2.14 mmol) in DCM (9 rnL) was treated with a solution of 3-chloroperoxybenzoic acid (mCPBA) (2.0 g) in DCM (9 rnL) then the reaction mixture was stirred at room temperature for 100 min, quenched with a solution OfNa0 ° C conditions, M-CPBA (458 mg, 2.65 mmol)In CH2Cl2 (18 mL) was added dropwise to a solution of compound 12 (210 mg, 1.06 mmol)In CH2Cl2 (18 mL)Stirring at room temperature for 30 minutes, The reaction solution was allowed to stand at room temperature for 6 hours, Followed by saturated NaHSO3 (18 mL), Saturated NaHCO3 (3 x 18 mL) and saturated brine (18 mL)Na2SO4 dried, The product was thawed under reduced pressure. Yield 76percentStep B: Ethyl 2-(methylsulfonyl)pyrimidine-5-carboxylateEthyl 2-(methylthio)pyrimidine-5-carboxylate (2.2 g, 11 mmol) was dissolved in DCM at 0 °C and stirred at room temperature for 15 minutes, followed by addition of /w-chloroperbenzoic acid (mCPBA) (5.75 g, 33 mmol). The reaction mixture was stirred for 1 hour. Saturated NaHC0Step 2: Ethyl 2-(methylsulfonyl)pyrimidine-5-carboxylate (149)A suspension of mCPBA (5.47 g, 31.68 mmol) in dichloromethane (30 ml) was added to a solution of 148 (1.57 g, 7.92 mmol) in dichloromethane (20 ml) at 0° C. The reaction mixture was allowed to warm to room temperature, stirred for an additional 3 h and quenched with an aqueous solution of NaStage 2 - Sulfide oxidation to yield ethyl 2-(methylsulfonyl)pyrimidine-5-carboxylate (Intermediate F); To a stirred solution of stage 1 product (13g, 47.59mmol) in dry THF (25OmL) was slowly added over 30 minutes a solution of mCPBA (47.59g, 275.76mmol) in THF (15OmL) at OTo a stirred solution of ethyl 2-(methylthio)pyrimidine-5-carboxylate (13g, 47.59mmol) in dry THF (250ml) was slowly added over 30 min a solution of mCPBA (47.59g, 275.76mmol) in THF (150ml) at OEthyl 2-(methylsulfonyl)pyrimidine-5-carboxylate To a stirred solution of ethyl 2-(methylthio)pyrimidine-5-carboxylate (2.8 g, 14.2 mmol) in tetrahydrofuran at 0 °C, 3-chloroperbenzoic acid (7.8 g, 60.7mmol, spectrochem) was added and the resulting solution was stirred at rt for 3 h. It was concentrated. DCM was added and was washed with water (25 mL) and 10percent sodium bicarbonate solution (20 mL) and dried over NaTo a stirred solution of ethyl 2-(methylthio)pyrimidine-5-carboxylate (2.8 g, 14.2 mmol) in tetrahydrofuran at 0 °C 3-chloroperbenzoic acid (7.8 g, 60.7mmol, spectrochem) was added and the resulting solution was stirred at rt for 3 h. It was concentrated. DCM was added and was washed with water (25 mL) and 10percent sodium bicarbonate solution (20 mL) and dried over Na2SO4. After evaporation of the solvents, the crude product was purified by flash chromatography to afford the titled product. Yield: 50.7 percent (1.65 g, off white solid). 1H NMR (400 MHz, DMSO-d6): 9.48 (s, 2H), 4.43 (q, J = 7.0 Hz, 2H), 3.48 (s, 3H), 1.37 (t, J = 7.1 Hz, 3H), LCMS: (Method A) 230.9 (M+H), Rt. 2.33 min, 97.48percent (Max).To a stirred solution of ethyl 2-(methylthio)pyrimidine-5-carboxylate (2.8 g, 14.2 mmol)in tetrahydrofuran at 0 °C, 3-chloroperbenzoic acid (7.8 g, 60.7mmol, spectrochem)was added and the resulting solution was stirred at rt for 3 h. It was concentrated. DCM was added and was washed with water (25 mL) and 10percent sodium bicarbonate solution (20 mL) and dried over Na2SO4. After evaporation of the solvents, the crude product was purified by flash chromatography to afford the titled product. Yield: 50.7 percent (1 .65 g, off white solid).1H NMR (400 MHz, DMSO-d6): 9.48 (s, 2H), 4.43 (q, J = 7.0 Hz, 2H), 3.48 (s, 3H), 1.37 (t, J= 7.1 Hz, 3H), LCMS: (Method A) 230.9 (M+H), Rt. 2.33 mm, 97.48percent (Max).Ethyl 4-chloro-2-(methylthio)pyrimidine-5-carboxylate (10 g, 43.0 mmol) was suspended in dry THF (50 ml), and zinc powder (8.43 g, 129 mmol) was carefully added. The suspension was heated to reflux in a previously heated bath, and then acetic acid (2.460 ml, 43.0 mmol) was added drop wise. The mixture was reacted at the same temperature overnight. The suspension was filtered through a celite pad washing with DCM and MeOH; the filtrate was evaporated and the residue was triturated with DCM:EtA mixture of ethyl 2-(methylthio)pyrimidine-5-carboxylate and ethyl 2, 4-bis(methylthio)pyrimidine-5-carboxylate (about 1 : 1 ratio; 3.47 g) was dissolved in DCM (78 ml) and m-CPBA (77percent w/w; 10.54 g, 47.0 mmol) was added portion wise stirring at room temperature. The reaction was stirred at the same temperature overnight. The obtained suspension was filtered washing with DCM and the filtrate was evaporated. The crude was dissolved in ethyl acetate (250 ml) and washed twice with a sat. NaHC0To a stirred solution of (1.87 g, 6.94mmol) in dry acetonitrile (10 mL), potassium carbonate (2.87 g, 20.8 mmol, Spectrochem) and To a stirred solution of Intermediate 2 (1 .87 g, 6.94 mmol) in dry acetonitrile, potassium carbonate (2.87g, 20.8 mmol, spectrochem) and ethyl 2- (methylsulfonyl)pyrimidine-5-carboxylate were added and the resulting mixure was at rt for 12 h. It was filtered through celite and concentrated. Dichloromethane (25 mL) was added and the solution was washed with water, brine and dried over Na2SO4. Afterevaporation of the solvents, the crude product was purified by flash column chromatography to afford the title compound (white solid).1H NMR (400 MHz, DMSO87 d6): 8.74 (s, 2H), 6.85 (t, J = 7.8 Hz, 2H), 6.75 (d, J = 7.8 Hz, I H), 5.98 (s, 2H), 4.25 (q, J= 6.8 Hz, 2H), 3.81 (s, 4H), 3.32 (s, IH), 2.37-2.42 (m, 4H), 1.28 (d, J= 6.6 Hz, 6H).LCMS: (Method A) 385.2 (M+H), Rt. 3.22 mm, 98.88percent (Max).To a stirred solution of (1.87 g, 6.94 mmol) in dry acetonitrile, potassium carbonate (2.87g, 20.8 mmol, spectrochem) and Ethyl 2-[(3, 4, 4, 7, 7-pentamethyl-4, 5, 6, 7-tetrahydro-1-benzothiophen-2-yl)amino]pyrimidine-5-carboxylate To a stirred solution of NaH (0.31 g, 12.5 mmol) in THF (10.0 mL), 3, 4, 4, 7, 7-pentamethyl-4, 5, 6, 7-tetrahydro-1-benzothiophen-2-amine (2.0 g, 8.6 mmol) and Example 18A Ethyl 2-[(2R)-2-(methoxymethyl)pyrrolidin-1-yl]pyrimidine-5-carboxylate (0370) (0371) 450 mg (3.91 mmol) of (R)-(+)-2-(methoxymethyl)pyrrolidine were added to a suspension of 818 mg (3.52 mmol) of ethyl 2-(methylsulphonyl)pyrimidine-5-carboxylate and 1.47 g (10.7 mmol) of potassium carbonate in 9.0 ml of acetonitrile. The mixture was stirred at RT for 18 h. The reaction mixture was then diluted with ethyl acetate and filtered off, the residue was washed with ethyl acetate/dichloromethane and the filtrate was concentrated. The crude product was purified on silica gel (elution: cyclohexane/ ethyl acetate 8:1-5:1), which gave 558 mg (59percent of theory) of the title compound. (0372) LC-MS [Method 8]: Rt=2.75 min; MS (ESIpos): m/z=266 (M+H)+ (0373) 1H-NMR (400 MHz, DMSO-d6): delta [ppm]=1.29 (t, 3H), 1.86-2.09 (m, 4H), 3.26 (s, 3H), 3.36 (dd, 1H), 3.46-3.63 (m, 3H), 4.22-4.35 (m, 3H), 8.79 (s, 2H).Example 16A Ethyl 2-(4, 4-difluoropiperidin-1-yl)pyrimidine-5-carboxylate (0362) (0363) 579 mg (4.78 mmol) of 4, 4-difluoropiperidine were added to a suspension of 1.00 g (4.34 mmol) of ethyl 2-(methylsulphonyl)pyrimidine-5-carboxylate and 1.80 g (13.0 mmol) of potassium carbonate in 10 ml of acetonitrile. The mixture was stirred at RT for 18 h. The reaction mixture was then diluted with ethyl acetate and filtered off, the residue was washed with ethyl acetate/dichloromethane and the filtrate was concentrated. The crude product was purified on silica gel (elution: cyclohexane/ ethyl acetate 8:1-5:1), which gave 500 mg (42percent of theory) of the product. (0364) LC-MS [Method 1]: Rt=1.08 min; MS (ESIpos): m/z=272 (M+H)+ (0365) 1H-NMR (400 MHz, DMSO-d6): delta [ppm]=1.29 (t, 3H), 1.97-2.11 (m, 4H), 3.96-4.03 (m, 4H), 4.28 (q, 2H), 8.82 (s, 2H).

Molecular Weight:230.24
Hydrogen Bond Acceptor Count:6
Rotatable Bond Count:4
Exact Mass:230.03612798
Monoisotopic Mass:230.03612798
Topological Polar Surface Area:94.6
Heavy Atom Count:15
Complexity:314
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes