Patent GB-806584-A (GB)
Title: Novel pyrimidine derivatives and a process for the manufacture thereof
IPC: C07D239/56
Filed: 1957-05-08
Abstract: The invention comprises 5-fluoro-uracil, 5-fluoro-thiouracil, their 6-carboxy derivatives, salts thereof, also 2-ethers of 5-fluoro-uracil and 5 - fluoro - thiouracil, their 6 - alkoxy - carbonyl derivatives and their salts, together with a process for their preparation by reacting an alkali metal fluoro-acetate with an alkylating agent, condensing the alkyl fluoro-acetate with an alkyl formate or dialkyl oxalate in the presence of an alkali metal condensing agent, reacting the resulting alkali metal enolate of an alkyl fluoro-malonaldehydate or dialkyl fluoro-oxalacetate with a 2-ether of pseudo-urea or isothiourea, and, where the product is a 2-ether of 5-fluoro-uracil or thiouracil, hydrolysing the 2-ether group to a hydroxyl group with acid or, where the product is a 2-ether of a 5-fluoro-orotic acid ester of thio-orotic acid ester, hydrolysing the 6-ester group with acid or alkali and the 2-ether group with acid and, if desired, decarboxylating the resulting 6-carboxy-5-fluoro-uracil by heating, or alternatively, where the product is a 2-ether of 5-fluoro-thiouracil or a 6-alkoxycarbonylthiouracil, either hydrolysing the ester group if present and splitting the ether group with anhydrous hydrogen halide (or for benzyl ethers with aluminium bromide) and if desired, oxidizing the resulting 5-fluorothiouracil or 5-fluoro-thio-orotic acid with hydrogen peroxide to give 5-fluoro-uracil or 5-fluoro-orotic acid and, if desired, decarboxylating the latter, or replacing the 4-hydroxyl group by halogen using a phosphorus pentahalide, reacting the resulting 2-ether of a 5-fluoro-4-halogeno - 2 - mercaptopyrimidine or 6 - alkoxy carbonyl derivative thereof with ammonia, hydrolysing the ether and ester groups of the resulting 2-ether of 2-thio-4-amino-5-fluoro-pyrimidine or 6-alkoxycarbonyl derivative thereof, treating the product with nitrous acid to give 5-fluorouracil or 5-fluoro-orotic acid, and if desired decarboxylating the latter.  In an example: sodium fluoro-acetate and diethyl sulphate are refluxed giving ethyl fluoroacetate, which is reacted with (a) ethyl formate, or (b) diethyl oxalate in the presence of potassium ethoxide yielding the potassium enolate of ethyl fluoro-malonaldehydrate (I), or of diethyl fluoro-oxalacetate (II) respectively; (I) O-methylpseudourea hydrochloride and sodium methoxide are refluxed in methanol giving the 2-methyl ether of 5-fluorouracil; similarly (I) and S-methyl-isothiouronium sulphate give 2-methylmercapto-5-fluoro-uracil (the S-ethyl and S-benzyl ethers are also described); (II) with S-ethyl-isothiouronium bromide or S-methyl-isothiouronium sulphate give the S-ethyl and S-methyl ethers of 5-fluoro-thio-orotic ethyl ester (or methyl ester using sodium methoxide) respectively; 5-fluoro-uracil 2-methyl ether with HCl gives 5-fluoro-uracil, also obtained from 5-fluoro-uracil S-methyl and S-ethyl ether, while hydrolysis of the S-ethyl ether of 5-fluoro-thio-orotic acid ethyl ester gives 5-fluoro-oritic acid monohydrate; the S-methyl ether of 5-fluoro-thiouracil is heated with HI in acetic acid-acetic anhydride, giving 5-fluoro-thiouracil (also prepared from the S-benzyl ether and AlBr3 in toluene) which on oxidation with alkaline H2O2 gives 5-fluoro-uracil; the S-ethyl ether of 5-fluoro-thiouracil is reacted with PCl5, the resulting 2-ethylmercapto-4-chloro-5-fluoropyrimidine autoclaved with liquid ammonia and the 2-ethylmercapto-4-amino-5-fluoropyrimidine obtained refluxed with HBr yielding 5-fluoro-cytosine, which with nitrous acid gives 5-fluoro-uracil; 5-fluoro-orotic acid is decarboxylated by heating above its m. pt. or in diphenyl-diphenyl oxide to give 5-fluoro-uracil.