6-(Chloromethyl)-2,4(1H,3H)-pyrimidinedione

In a 250 mL three-necked flask, Compound 2 (11.5 g, 0.081 mol) was added, Then, 115 mL of dichloromethane was added successively, Thionyl chloride (17.6 mL, 0.24 mol) and a catalytic amount of N, N-dimethylformamide, Add the temperature to reflux and stir the reaction for 2 hours.Cooled to room temperature, Filter, Dichloromethane wash, dry, 11.8 g of 6-chloromethyluracil was obtained in a yield of 90.8percent.In a 500 L reactor, compound 2 (8.0 kg, 56.29 mol) was added to 80 L of methylene chloride, stirred and 8 L of dichlorosulfoxide was added at room temperature (20 C)Keep slowly at room temperature dropwise 4L DMF, the solution becomes clear, the reaction 3h, a large number of white solid precipitation.The 2-point reaction of the TLC following compound disappeared (dichloromethane: methanol = 5: 1) and the reaction was completed. The reaction solution was centrifuged, The filter cake was air-dried for 6 hours at 60 ° C to afford SM1 as an off-white solid (5.0 kg, 55.56percent yield).At room temperature, The 500mL of tetrahydrofuran and 50g compound IV 'has added to the three bottles, After sufficiently stirring, the mixture was replaced with nitrogen three times, Ethanol bath temperature of liquid nitrogen in the range of -80 ~ -75 , 80 mL of a n-butyllithium n-hexane solution (2.5 M) was slowly added under the condition of securing the gas-tightness, The reaction was stirred at a temperature of 2 h, And then gradually increased to room temperature reaction 1h.The reaction was quenched with an appropriate amount of saturated ammonium chloride solution, And then extracted with methyl tert-butyl ether, Washed repeatedly with purified water and then with absolute ethanol, Drying after blowing a yellow-white solid 21.8g, I.e. Compound IV, Yield 78percent.Referential Example 7 Synthesis of 6-(1-pyrrolidinylmethyl)uracil To a solution of 1.78 g of pyrrolidine in water (20 ml), 1.33 g of Referential Example 7 Synthesis of 6-(1-pyrrolidinylmethyl)uracil To a solution of 1.78 g of pyrrolidine in water (20 ml), 1.33 g of A mixture of ethyl 4-chloro-3-oxobutanoate (100 gm), polyphosphoric acid (400 gm) and urea (109.4 gm) was heated to 90-95C and stirred the reaction mixture for 3 hr at the same temperature. Further heated the reaction mixture to i20-i25C and stirred for iO hr at the same temperature. Reduced the temperature of the reaction mixture to 90-95C and chilled water was slowly added to it at the same temperature. Cooled the reaction mixture to 0-5C and stirred for 3 hr at the same temperature. Filtered the solid and washed with chilled water. Methanol (500 ml) and water (500 ml) were added to the obtained compound at 25-30C. Heated the reaction mixture to 70-75C and stirred for 40 mm at the same temperature. Charcoal (8 gm) was added to the reaction mixture at 70-75C and stirred for 40 mm at the same temperature. Filtered the reaction mixture through hyflow bed and washed the hyflow bed with methanol. Cooled the filtrate to 0-5C and stirred for 3 hr at the same temperature. Filtered the precipitated solid, washed with chilled water and dried the material to get the title compound.Yield: 23.0 gm; M.R.: 253-255C.Step 1: Preparation of 5-Bromo-6-(Chloromethyl)uracil (1) To a solution of 6-(chloromethyl)uracil (2.0 g, 12.5 mmol) in DMF (15 mL) at 0 C. was added NBS (recrystallized, 2.44 g, 13.7 mmol). The mixture was stirred at 0 C. for 1.5 h, and then quenched by ice water. The precipitate was collected by filtration and washed with AcOH and water to give the title compound (2.35 g, 69%) as a white solid. 1H NMR (DMSO, 500 MHz) delta 1.66 (s, 1H), delta 11.61 (s, 1H), delta 4.47 (s, 2H). MS (Multimode, M+H+) C5H5BrClN2O2, calcd. 238.9. found 238.9.1)10.0 g of REFERENCE Synthesis of 5-Chloro-6-(2-iminopyrrolidin-1-yl)methyl-2, 4(1H, 3H)-pyrimidinedione Hydrochloride (Compound 1) Sulfulyl chloride (120 ml) was added dropwise to a suspension of 163 g of Referential Synthesis of 5-chloro-Referential Synthesis of 5-chloro-To 20.0g 6 - chloro methyl uracil is added in 100 ml acetic acid, stirring 20 minutes into the 22 ml chloride, dropwise, 30 - 35 C stirring reaction, TLC monitoring raw material of reaction, the reaction liquid slowly putting into 200 ml ice water, filtered, 10 - 15ml methanol washing, 50 C drying by blowing, getting white solid 16.0g, yield 66.0%.50 g of In a 20 L reaction flask, compound SM1 (1000.0 g, 6.23 mol) was added to 5000 mL of acetic acid. Mechanical stirring was started and an ice bath was added. Sulfonyl chloride (1000 mL, 12.37 mol) was added dropwise keeping the temperature of the addition below 30 C. Canada completed at room temperature (20 ) reaction 6h, a large number of white solid precipitation. TLC trace compound SM1 point reaction disappeared (dichloromethane: methanol = 10: 1), the reaction was completed. The reaction mixture was suction filtered, and the resulting solid was air-dried for 12 hours at 60 C to give 5-chloro-Sulfuryl chloride (302 ml) was slowly added to a pre-cooled mixture of 6- (chloromethyl)pyrimidine-2, 4(1H, 3H)-dione compound of formula-2a (200 gm) and acetic acid (1400 i-ni) at 15-20C under nitrogen atmosphere. Raised the temperature of the reaction mixture to 25-30C and stined for 7 hrs at same temperature. Filtered the solid, washed with ethyl acetate and suck dried the material to get the title compound.Yield: 180 gm.Synthesis of 5-chloro-6-(chloromethyl)- l, 2, 3, 4-tetrahydropyrimidine-2, 4-dione: Into a 1- L round-bottom flask, was placed 6-(chloromethyl)- l, 2, 3, 4-tetrahydropyrimidine-2, 4-dione (15 g, 93.42 mmol, 1 equiv), acetic acid (225 mL), acetyl acetate (15 mL). The resulting solution was stirred for 30 min at 80 C in an oil bath. Then NCS (16.2 g, 121.32 mmol, 1.30 equiv) was added at 60 C. The resulting solution was stirred for 3h at 60 C in an oil bath. The reaction was then quenched by the addition of 500 mL of water/ice. The solids were collected by filtration. The solid was dried in an oven under reduced pressure. This resulted in 10.1 g of 5- chloro-6-(chloromethyl)- l, 2, 3, 4-tetrahydropyrimidine-2, 4-dione as an off-white solid. LC-MS- BLV-CY-202- 1 : (ES, m/z): 195[M+H]+. H-NMR- BLV-CY-202- 1 : (300 MHz, OMSO, ppm): delta 11.71 (s, 1H), 11.56 (s, 1H), 4.47 (s, 2H).

Molecular Weight:160.56
XLogP3:-0.7
Hydrogen Bond Donor Count:2
Hydrogen Bond Acceptor Count:2
Rotatable Bond Count:1
Exact Mass:160.0039551
Monoisotopic Mass:160.0039551
Topological Polar Surface Area:58.2
Heavy Atom Count:10
Complexity:212
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes