Ethyl 4-[[(3-chloro-4-methoxyphenyl)methyl]amino]-2-(methylthio)-5-pyrimidinecarboxylate

3-chloro-4-methoxybenzylamine (45.6 g, 0.27 mol) was dissolved in 180 mL of acetone, then triethylamine (40.4 g, 0.4 mol) was added.4-chloro-2-methylthiopyrimidine-5-carboxylic acid ethyl ester obtained in the step S2(53.3 g, 0.24 mol) dissolved in 250 mL of acetone and slowly dropped into the reaction solution.And reacted at room temperature for 3 h, and poured the reaction solution into the ice water mixture.Extracted with ethyl acetate, The combined organic phases were washed with 10percent aqueous citric acid (250 mL x 3).Dry the organic layer with anhydrous sodium sulfate.Evaporate the solvent under reduced pressure.Dry in vacuo to a white solid (86.0 g, 87.0percent).In DCM (100 mL) were dissolved ethyl 4-chloro-2-(methylthio) pyrimidine-5-carboxylate (5.0 g, 21.55 mmol), 3-chloro-4-methoxybenzylamine (4.0 g, 23.4 mmol) and triethylamine (4.35 g, 43.1 mmol). To 600ml of methylene dichloride was added lOOg of ethyl 4-chloro-2-(methylsulfanyl) pyrimidine-5-carboxylate and 91.2g of 3-chloro-4-methoxybenzylamine. The reaction mixture was stirred and 500m1 of water, 48g of sodium carbonate and Ig of tetra-butylammonium bromide were added to it. The reaction mixture was then maintained overnight at 25-30°C. After completion of reaction, methylene dichloride layer was separated, washed with water and evaporated to obtain 145g of ethyl 4-[(3-chloro-4-methoxybenzyl) amino]-2-(methyl sulfanyl) pyrimidine-5-carboxylate having 95percent of HPLC purity.After dissolving 50.0 g of 4-chloro-5-ethoxycarbonyl-2-methylthiopyrimidine and 59.9 ml of triethylamine into 430 ml of ethyl acetate, respectively, the mixture was cooled to 0 ° C, 44.7g of 3-chloro-4-methoxybenzylamine was added in portions, the reaction was carried out at 0-5 ° C for 30min and the reaction was continued at 20-30 ° C for 0.5-1h. The reaction was concentrated under reduced pressure, and then added ethyl acetate and citric acid solution 400ml each wash 2 times, the organic phase was washed with water and saturated brine each time, dried, filtered and concentrated under reduced pressure to give the crude 73.0g. Finally, with anhydrous ethanol at 55 ~ 60 ° C dissolved crude, stirring crystallization 12-18h, filtered and dried to give the product 42.3g.In a flask, tetrahydrofuran (4.5 L) was added, 3-chloro-4-methoxybenzylamine hydrochloride (500 g, 2.4 mol) was added under stirring, triethylamine (836 mL, 6.01 mol) was added dropwise, the mixture was stirred at room temperature for 30 min, cooled with ice-water, then ethyl 4-chloro-2-methylthiopyrimidine-5-carboxylate (466 g, 2.0 mol) was added, the reaction was stirred overnight at room temperature. TLC was used to monitor the reaction. Compound 13 (5 g, 21.86 mmole) and compound 18 (5.34 g, 25.4 mmol) were added to 75 ml of dry DMF 1 and dissolved with stirring. After stirring for 10 minutes, the reaction system was placed in an ice-water mixture. Triethylamine (21.4 g, 0.217 mole) was slowly added dropwise to the reaction flask and slowly warmed to room temperature. After 4 hours, TLC showed the reaction was completed. Dichloromethane was added, washed with water five times, dried and filtered, concentrated by rotary evaporation and passed through a column (PE: EA = 25: 1). Compound 19 (7.3 g, yield 78percent) was obtained as a white powder.In THF (150 mL) was suspended 3-chloro-4-methoxybenzylamine hydrochloride salt (16.0 g, 76.9 mmol). (3-Chloro-4-methoxyphenyl) methanamine hydrochloride compound of formula-6a (76.98 g) was added to the organic layer containing ethyl 4-chloro-2-(methylthio) pyrimidine-5-carboxylate compound of formula-5, which is obtained in step-b). Water (100 ml), followed by sodium carbonate (110.3 g) were added to the reaction mixture at 25-30°C and stirred for 4 hours at the same temperature. After completion of the reaction, water was added to it. Both the organic and aqueous layers were separated; the aqueous layer was extracted with toluene. All the organic layers were combined and washed with water. Distilled off the solvent from the organic layer under reduced pressure. The reaction mixture was cooled to 30-35°C. 700 ml of cyclohexane: ethyl acetate (in 9.5:5 ratio) was added to the reaction mixture. The reaction mixture was heated to 70-75°C and stirred until complete dissolution. The reaction mixture was cooled to 10-15°C and stirred for 3 hours. Filtered the precipitated solid, washed with cyclohexane and then dried to get title compound.Yield: 90 gms; Melting range: 81 -84°C; Purity by HPLC: 95.3percent.(3-Chloro-4-methoxyphenyl)methanamine malate compound of formula-6b (1 13.1 g) was added to the organic layer containing ethyl 4-chloro-2-(methylthio)pyrimidine-5- carboxylate compound of formula-5 obtained in step-(b). Water (200 ml), followed by sodium carbonate (147.06 g) and tetrabutyl ammonium bromide (4.47 g) were added to the reaction mixture at 25-30°C and stirred for 8 hours at the same temperature. Water was added to the reaction mixture at 25-30°C. The reaction mixture was heated to 40-45°C. Separated the both organic and aqueous layers. The organic layer was washed with water. Distilled off the solvent from the organic layer under reduced pressure and then co-distilled with cyclohexane. Cooled the obtained compound to 25-30°C and 600 ml of cyclohexane: ethyl acetate (in 9: 1 ratio) was added to it at the same temperature. The reaction mixture was heated to 65-70°C and stirred 15 minutes. The reaction mixture was cooled to 10-15°C and stirred for 3 hours. Filtered the precipitated solid and washed with cyclohexane. Water (1000 ml) was added to the wet solid. Heated the reaction mixture to 60-65°C and stirred for 30 minutes. Cooled the reaction mixture to 25-30°C and stirred for 60 minutes. Filtered the precipitated solid, washed with water and then dried to get the title compound.Yield: 102 gms; Melting range: 80-84°C; Purity by HPLC: 99.25percent

Molecular Weight:367.9
XLogP3:4.2
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:7
Rotatable Bond Count:8
Exact Mass:367.0757403
Monoisotopic Mass:367.0757403
Topological Polar Surface Area:98.6
Heavy Atom Count:24
Complexity:405
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes