Patent GB-473193-A (GB)
Title: Improvements in or relating to the manufacture of pyrimidine compounds
Filed: 1936-04-03
Abstract: 2-Alkyl-(or 2-aralkyl)-4-amino-5-aminoalkylpyrimidines are prepared as follows.  An amidine of an aliphatic or araliphatic carboxylic acid is condensed with an acetic ester substituted in the acetic acid residue with (a) a hydroxymethylene group or the tautomeric formyl group or an etherified hydroxymethylene group, and (b) a protected aminoalkyl group or a group (as defined below) convertible into an aminoalkyl group; this condensation yields a 2-alkyl-(or 2-aralkyl)-4-hydroxypyrimidine substituted in the 5-position with a substituent as at (b) above, and this product is treated to replace the hydroxy group by an amino (including substituted amino) group and also to convert the substituent in the 5-position into an aminoalkyl group.  The initial condensation may be effected at atmospheric or raised temperature, preferably in a solvent or diluent and in the presence of an acid-binding agent, e.g. a metal alcoholate, carbonate or hydroxide; the substituted acetic esters may also be taken in the form of their metal compounds.  The conversion of the 4-hydroxypyrimidine derivatives into 4-aminopyrimidine derivatives may be effected by replacing the hydroxy group by halogen and then treating the halogen compound with ammonia or a primary or secondary amine. The substituent as at (b) above may be an acylaminoalkyl group, e.g. a phthalimidoalkyl group, or any of the following: a carboxylic or alkylcarboxylic ester or amide group, a cyanoalkyl group, or an alkoxyalkyl or aryloxyalkyl group.  An alkylcarboxylic ester group may be converted into an aminoalkyl group by way of the alkylcarboxylic amide or hydrazide group, which may then be degraded in known manner, e.g. by the Hoffmann or Curtius reaction, or may be dehydrated to yield a cyanoalkyl group, which is then reduced.  A carboxylic ester group may be converted into an aminomethyl group by way of the carboxylic amide group, which may be reduced directly or after conversion into a cyano group.  An alkoxyalkyl or aryloxyalkyl group may be converted into an aminoalkyl group by way of a halogenalkyl group. In the examples: (1) acetamidine hydrochloride and formylsuccinic acid diethyl ester yield 2-methyl-4-hydroxypyrimidine-5-acetic ester, which is treated with phosphorus oxychloride to yield 2-methyl-4-chloropyrimidine-5-acetic ester; the latter, by treatment with ammonia in methyl alcohol, yields 2 - methyl - 4 - aminopyrimidine - 5-acetamide, which by treatment with bromine in potassium hydroxide solution yields 2-methyl-4-amino-5-aminomethylpyrimidine; the same compound is obtained if the 2 - methyl - 4 - hydroxypyrimidine-5-acetic ester is converted into the 5-aminomethyl compound by way of the 5-acetic acid hydrazide and the Curtius reaction, and the hydroxy group in the 4-position is then replaced by an amino group, as described above; when the 2-methyl-4-chloropyrimidine-5-acetic ester is treated with methylamine in methyl alcohol, 2-methyl-4-methylaminopyrimidine-5-acetic acid methylamide is obtained, which yields 2-methyl-4-methylaminopyrimidine-5-acetic acid by saponification with baryta; the acid, by treatment with ammonia, yields 2-methyl-4-methylaminopyrimidine-5-acetamide, which is finally converted into 2-methyl-4-methylamino-5-aminomethylpyrimidine; if dimethylamine, ethylamine or diethylamine is used in place of methylamine, the corresponding 4-dimethylamino, 4-ethylamino or 4-diethylamino pyrimidine derivative is obtained; if propionamidine is used in place of acetamidine in the initial condensation, 2-ethyl-4-hydroxypyrimidine-5-acetic ester is obtained, and this may be converted successively into 2-ethyl-4-chloropyrimidine-5-acetic ester, 2-ethyl-4-aminopyrimidine-5 - acetamide, and 2 - ethyl - 4 - amino - 5 - aminomethylpyrimidine; (2) acetamidine hydrochloride and the sodium salt of a -formyl-b -benzoylaminopropionic acid ethyl ester yield 2 - methyl - 4 - hydroxy - 5 - benzoylaminomethylpyrimidine, which by reaction with phosphorus oxychloride yields 2-methyl-4-chloro-5-benzoylaminomethylpyrimidine; the latter is heated with ammonia in methyl alcohol to yield 2-methyl-4-amino-5-benzoylaminomethylpyrimidine, and from this product, by alkaline saponification, 2 - methyl - 4 - amino - 5 - aminomethylpyrimidine is obtained; (3) acetamidine hydrochloride and ethoxymethylenemalonic acid diethyl ester yield 2-methyl-4-hydroxy-5-carbethoxypyrimidine, which by reaction with phosphorus oxychloride yields 2-methyl-4-chloro-5-carbethoxypyrimidine; the latter, on treatment with ammonia in methyl alcohol, yields 2-methyl-4-aminopyrimidine-5-carboxylic amide, from which, by catalytic reduction with hydrogen, 2-methyl-4-amino-5-aminomethylpyrimidine is obtained; (4) acetamidine hydrochloride and formylglutaric acid diethyl ester yield 2 - methyl - 4 - hydroxypyrimidine - 5 - propionic ester, which, by successive reactions with phosphorus oxychloride and ammonia, yields 2 - methyl - 4 - aminopyrimidine - 5 - propionamide, the latter, subjected to the Hoffmann degradation as in example 1, yields 2-methyl-4-amino-5-aminoethylpyrimidine; (5) acetamidine hydrochloride and a -formyl-g -phenoxybutyric acid ethyl ester yield 2-methyl - 4 - hydroxy - 5 - (b -phenoxyethyl)-pyrimidine, which is heated successively with hydrobromic acid and phosphorus oxychloride to yield 2-methyl-4-chloro-5-bromoethylpyrimidine; from this product, by treatment with ammonia in methyl alcohol, 2 - methyl - 4 - amino - 5 - aminoethylpyrimidine is obtained; (6) phenylacetamidine and formylsuccinic acid diethyl ester yield 2-benzyl-4-hydroxypyrimidine-5-acetic ester, which by reaction with phosphorus oxychloride yields 2 - benzyl - 4 - chloropyrimidine - 5 - acetic ester; this product, by reaction with ammonia, yields 2-benzyl-4-aminopyrimidine-5-acetamide, which is subjected to the Hoffmann degradation, as in example 1, to yield 2-benzyl-4-amino-5-aminomethylpyrimidine; the product is isolated by way of its benzylidene compound; (7) acetamidine hydrochloride and a -formyl-b -cyanopropionic acid ethyl ester yield 2-methyl-4-hydroxy-5-cyanomethylpyrimidine, which is saponified to yield 2-methyl-4-hydroxypyrimidine-5-acetic acid; the latter may be converted into its ethyl ester, from which 2-methyl-4-amino - 5 - aminomethylpyrimidine may be obtained as described in example 1; alternatively, the 2-methyl-4-hydroxy-5-cyanomethylpyrimidine may be treated with phosphorus oxychloride to yield 2-methyl-4-chloro-5-cyanomethylpyrimidine, which is treated with ammonia in methyl alcohol to yield 2-methyl-4-amino-5-cyanomethylpyrimidine; the latter yields 2-methyl-4-amino-5-aminoethylpyrimidine by catalytic reduction with hydrogen.  a -Formyl-b -benzoylaminopropionic acid ethyl ester, used in example 2, is obtained from b -benzoylaminopropionic acid ethyl ester and ethyl formate in the presence of sodium ethylate. Formylglutaric acid diethyl ester, used in example 4, is obtained by treating glutaric acid diethyl ester with ethyl formate in ethereal solution in the presence of sodium.  a -Formyl-g -phenoxybutyric acid ethyl ester, used in example 5, is obtained by treating g -phenoxybutyric acid ethyl ester with ethyl formate in ethereal solution in the presence of sodium.  a -Formyl-b -cyanopropionic acid ethyl ester, used in example 7, is obtained similarly from b -cyanopropionic acid ethyl ester and ethyl formate.