Patent GB-877318-A (GB)
Title: The manufacture of cytidines
IPC: C07F3/10
Filed: 1960-05-18
Abstract: The invention comprises 1-(21-deoxy-31, 51-diaroyl - D - ribofuranosyl)-5-fluoro-cytosines, especially the di(p-toluoyl) and di(p-chlorobenzoyl) derivatives; and a process for the manufacture of 5 - fluoro - 21 - deoxy-cytidine which comprises reacting 5-fluoro-cytosine with a mercuric salt (e.g. the acetate), reacting the resulting (5-fluoro-cytosine)-monomercury (which may be more or less hydrated) with a 2-deoxy-3,5-diaroyl-D-ribofuranosyl halide, and dearoylating the resulting 1-(D-21-deoxy-31, 51 - diaroyl - ribofuranosyl)-5-fluoro-cytosine.  The 5-fluoro-cytosine may be prepared by chlorinating 5-fluoro-uracil, reacting the resulting 2,4-dichloro-5-fluoro-pyrimidine with ammonia, and hydrolysing the resulting 2-chloro-4-amino-5-fluoro-pyrimidine.  The chlorination is suitably effected with POCl3 in the presence of an acid acceptor. Specified aroyl groups are benzoyl, chlorobenzoyl, bromobenzoyl, nitrobenzoyl, and alkyl- or alkoxybenzoyl containing up to 11 carbon atoms.  Specified mercuric salts are the formate, acetate, benzoate and chloride.  The final dearoylation can be effected by conventional saponification with alcoholic alkalies, e.g. ethanolic and methanolic NaOH, ethanolic ammonia, and ethanolic barium ethoxide. 2-Deoxy-3,5-di(p-toluoyl)- and -di(p-chloro-benzoyl)-D-ribofuranosyl chlorides are prepared by methylating 2-deoxy-D-ribose with methanol containing anhydrous hydrogen chloride to give 1-methyl-2-deoxy-D-ribofuranoside, treating this with the appropriate aroyl chloride, and converting the methyl group to chloromethyl by means of anhydrous hydrogen chloride in acetic acid.  Specification 859,245 is referred to.ALSO:The invention comprises 1-phenyl-3,6-dioxo-1,2,3,6- tetrahydropyridazines having in the 2-position a low alkyl radical and in one of the positions 4 and 5 a low aliphatically etherified hydroxy or mercapto group or a benzyloxy group, the phenyl radicals being unsubstituted or substituted by low alkyl or alkoxy groups or halogen atoms and the term "low" denoting the presence of 1-8 carbon atoms; the preparation thereof by the action of (a) a sulphuric acid diester of a lower alkanol on the corresponding 2-unsubstituted compounds (or their 3-enol ethers or acylates) or (b) a low aliphatic alcohol or mercaptan or benzyl alcohol on a 2-alkyl compound containing a chlorine or bromine atom instead of an etherified hydroxy or mercapto group in position 4 or 5 (whereby the etherified hydroxy or mercapto group is introduced into the 4-position irrespective of the position of the halogen atom replaced) or on the corresponding 4,5-dihalo-1,2,3,4,5,6-hexahydro compounds in the presence of a basic condensing agent (whereby dehydrohalogenation and replacement of the remaining halogen atom occur simultaneously); and pharmaceutical preparations containing the products (see Group VI).  Acid addition and quaternary ammonium salts of the products are mentioned.  1 - Phenyl - 3, 5 - dimethoxy - 6 - oxo - 1, 6 - dihydropyridazine and 1-phenyl-4- and -5-methoxy-3,6-dioxo-1,2,3,6-tetrahydropyridazine are prepared by heating 1-phenyl-3,5-dichloro-6-oxo-1,6-dihydropyridazine and 1-phenyl-4- and -5-chloro - 3, 6 - dioxo - 1, 2, 3, 6 - tetrahydropyrid - azine, respectively, with a solution of sodium methoxide in methanol.  1 -o - Chlorophenyl - 2 - methyl - 5 - bromo - 3, 6 - dioxo-1,2,3,6-tetrahydropyridazine is prepared by heating 1-o-chlorophenyl-3,6-dioxo-1,2,3,6-tetrahydropyridazine with dimethyl sulphate to produce 1-o-chlorophenyl-2-methyl-3,6-dioxo-1,2,3,6-tetrahydropyridazine, heating this with bromine in glacial acetic acid, and boiling the resulting 1 - o - chlorophenyl - 2 - methyl - 4, 5 - dibromo - 3, 6 - dioxo - 1, 2, 3, 4, 5, 6 - hexahydropyridazine with pyridine in chloroform.  Specification 880,016 is referred to.