2-Methoxy-5-fluoro-4-aminopyrimidine

The 32.5g formula III compound are added 170g10wt percent of the isopropyl alcohol solution of ammonia, heating to 40-60°C, stirring reaction 3-5 hours, natural cooling to room temperature, filtered, collecting solid, washing with isopropyl alcohol, drying, the compound of formula II is obtained (kind of white solid) 27.2g, molar yield is 95.0percent, HPLC purity of 99.0percent.The compound was synthesized after a modified procedure by Dietz et al. [1]. Potassium-(Z)-2-cyano-2-fluoroethenolate (8) (0.766 g, 6.12 mmol, 1.0 eq, corrected for formate content) was added to a suspension of O-methylisourea hemisulfate (1.130 g, 9.18 mmol, 1.5 eq) in dry methanol (15 mL) under argon atmosphere. The mixture was stirred for 14 h and the solvent was removed in vacuo. The residue was taken up in water and ethyl acetate, the phases were separated and the aqueous phase was extracted three times with ethyl acetate. The organic layers were combined, washed with brine, dried over sodium sulfate and all volatiles were removed in vacuo. The crude product was purified by column chromatography (cHex/EtOAc, Isolera Flash Purification System, gradient from 0 to 100% EtOAc). Yield: 0.584 g (4.08 mmol, 67%), colorless solid, Rf = 0.27 (cHex/EtOAc 1:1). M.p. 190.4-191.3 C. 1H-NMR, COSY (300 MHz, [D6]DMSO): delta/ppm = 7.93 (d, 1H, J = 3.5 Hz, H-6), 7.27 (s, 2H, NH2), 3.74 (s, 3H, CH3). 13C-NMR, HSQC, HMBC (75 MHz, [D6]DMSO): delta/ppm = 160.5 (d, J = 1.5 Hz, C-2), 154.9 (d, J = 13.7 Hz, C-4), 142.1 (d, J = 245.3 Hz, C-5), 139.7 (d, J = 20.4 Hz, C-6), 54.1 (s, CH3). 19F-NMR (282 MHz, [D6]DMSO): delta/ppm = -165.9 (d, J = 3.5 Hz). IR (ATR): nu[cm-1] = 3361, 3314, 3143, 165, 1456, 1392, 1352, 777. MS (ESI): m/z (%) = 144.0 (100) [M+H]+. HR-MS (ESI): 144.0566 ([M+H]+, calc.: 144.0568). The analytical data are consistent with those reported in the literature [1].Take 27.2kg of Intermediate 5 prepared in the previous step and mix with sulfuric acid, raise the temperature to 95-105 C, maintain the temperature for 1.5h, and then lower the temperature. Then add the mixture to water, adjust the pH to 8-9, cool, and stand still. Set, filter, and dry to obtain 23.3 kg of crude product with a yield of 95.0%. Step 6: Take 20.5 kg of the crude product prepared in the previous step and mix it with 200 kg of water, add 0.6 kg of activated carbon, stir and raise the temperature, maintain the temperature for 1 h, and filter. The resulting mother liquor is cooled and crystallized, filtered, and dried to obtain 19.7 kg of 5-fluorocytosine. The yield is 96.1%, and the purity of HPLC is 99.9% or more. According to the reaction yield of each step, the total yield of the process route provided by the present invention is 57.3%.1 Added 14.3 g to the reaction deviceThe 24.0g formula II compound are added 102g30wt % hydrogen chloride in methanol solution, heating to 40-60C, stirring reaction 5-7 hours, concentrating the reaction solution under reduced pressure, the concentrated residual liquid cooling to room temperature, add water (the heating volume is residual liquid volume of 2 times), slowly dropping 50 wt % of sodium hydroxide aqueous solution, the reaction system is adjusted to pH 8.0-8.5, precipitated solid, is continuously stirred for 0.5 hours, filtering, collecting solid, ice water washing, drying, namely type I compound (white solid) 20.6g, molar yield is 95.0%, HPLC purity of 99.6%.The 32.5g formula III compound are added 170g10wt percent of the isopropyl alcohol solution of ammonia, heating to 40-60°C, stirring reaction 3-5 hours, natural cooling to room temperature, filtered, collecting solid, washing with isopropyl alcohol, drying, the compound of formula II is obtained (kind of white solid) 27.2g, molar yield is 95.0percent, HPLC purity of 99.0percent.

Fluorocytosine intermediate.

Molecular Weight:143.12
XLogP3:0.3
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:5
Rotatable Bond Count:1
Exact Mass:143.04948999
Monoisotopic Mass:143.04948999
Topological Polar Surface Area:61
Heavy Atom Count:10
Complexity:113
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes