Patent GB-600337-A (GB)
Title: New pyrimidine compounds
IPC: C07D239/46
Filed: 1945-11-12
Abstract: Pyrimidine compounds, useful as chemotherapeutic agents or as intermediates therefor, and of the general formula <FORM:0600337/IV(b)/1> wherein X represents hydrogen or a hydrocarbon radical and Y hydrogen or a neutral substituent, or X and Y together form an alkylene chain, R11 represents hydrogen or an alkyl or substituted alkyl (e.g. alkoxyalkyl or dialkylaminoalkyl) group, A represents an aliphatic or alicyclic linking group, which may be substituted by hydroxy, alkoxy or dialkylaminoalkyl groups, and, when an aliphatic chain, may be interrupted by oxygen, sulphur or nitrogen atoms, and NRR1 represents an amino or substituted amino group such as acylamino, alkylamino, dialkylamino or piperidino or other strongly basic nitrogen-containing heterocyclic group, are manufactured by the interaction of a diamine NHN11-A-NRR1 with an appropriate pyrimidine derivative containing in the 2-position a labile substituent such as a halogen atom or a hydrocarbon radical attached by an ether or thioether linkage, e.g. an alkoxy, aryloxy or alkylmercapto group. The reaction may be effected by heating the reagents together, optionally in the presence of a solvent or diluent.  One or other of the reagents may be employed in the form of a salt, e.g. hydrochloride or acetate, and if desired an acid-bonding agent, e.g. sodium hydroxide, may be present.  When R1 represents hydrogen, it is usually necessary to employ an acylated diamine NHN11-A-NRAc and subsequently to hydrolyse the acylamino group. Another modification consists in introducing the substituent -NR11-A-NRN1 in stages by reacting the 4 - aminopyrimidine derivative carrying a labile substituent with an amino compound NHN11-A1-B, where A1 represents the whole or a part of the linking group A, and B represents a reactive group (e.g. a hydroxy group or a derivative thereof which is, or is readily convertible to, a reactive ester thereof, such as a halide), which group is then converted directly or indirectly by methods involving the step of reaction with ammonia or a compound containing an amino group into the amino group NRR1 or a group A11-NRN1 such that A1 and A11 together constitute the group A, e.g. by reaction with an amine NHRR1 or a substituted amine NH2-A111-NRR1, HO-A111-NRN1 or HS-A111-NRR1 (or an alkali metal derivative of the hydroxy or mercapto compound) such that A1-NH-A111, A1-O-A111 or A1-S-A111 constitutes the group A.  A terminal amino group, when unsubstituted, may, if desired, be modified, e.g. by alkylation, conversion to a heterocyclic group such as piperidino, or reaction with a halogen-substituted amine Hal-A111-NRR1 so as to extend the linking group A to A-NH-A111.  In examples: (1) 4-amino-2-methylmercapto-5 : 6-dimethylpyrimidine is heated in an autoclave with g -diethylaminopropylamine to produce 4-amino-2-g -diethylaminopropylamino - 5 : 6 - dimethylpyrimidine; (2) the diamine in (1) is replaced by b -diethylaminoethylamine; (3) 2 - chloro - 4 - amino - 6 - methyl - pyrimidine and b -diethylaminoethylamine are refluxed together to form 2-b -diethylaminoethylamino-4-amino-6-methylpyrimidine; (4) the diamine in (3) is replaced by d -diethylamino-a -methylbutylamine; (5) by g -diethylaminopropylamine; and (6) by g -dibutylaminopropylamine; (7) 4 - amino - 2 - methylmercapto - 6 - methylpyrimidine is heated in an autoclave with g -dimethylaminopropylamine to yield 4 - amino - 2 - g - dimethylaminopropylamino-6-methylpyrimidine.  Specifications 605,784 and 606,181 are referred to. 2-Ethylmercapto-4-amino-5-methylpyrimidine and 2 - methylmercapto - 4 - amino - 5 : 6 - dimethyl - pyrimidine are obtainable by the action of alcoholic ammonia on the corresponding 4-chloro compounds, which in turn may be made by chlorination of the 4-hydroxy compounds.