Patent GB-581334-A (GB)
Title: New pyrimidine compounds
Filed: 1943-09-29
Abstract: 2 - p - Nitrophenylguanidino-4-b -diethylamino-ethylamino-6 -methylpyrimidine is reduced with hydrogen in methanol in the presence of a Raney nickel catalyst to yield the corresponding amino compound.ALSO:Pyrimidine compounds, useful as chemotherapeutic agents, of the general formula <FORM:0581334/IV/1> wherein Ar represents an aryl group optionally bearing one or more non-acidic substituents such as hydrocarbon radicles (which themselves may bear substituents and which may be attached to the aryl group directly or through an oxygen, nitrogen or sulphur atom or a sulphonyl or carbonyl group), halogen atoms or cyano, nitro, amino, acylamino or esterified carboxyl groups, X and Y each represent hydrogen or a hydrocarbon radicle or together represent a divalent aliphatic hydrocarbon radicle forming with the 5- and 6-carbon atoms an alicylic ring, R11 is hydrogen or an alkyl or substituted alkyl (e.g. alkoxyalkyl or dialkylaminoalkyl) group, A represents a linking group which is aliphatic, alicyclic or aliphatic-carbo-cyclic and may be substituted (e.g. by hydrocarbon radicles, hydroxy, alkoxy or dialkylaminoalkyl groups), and which, when wholly or partly an aliphatic chain, may be interrupted by oxygen, nitrogen or sulphur atoms, and NRR1 represents a strongly basic amino or substituted amino group such as alkylamino, dialkylamino or piperidino or other strongly basic nitrogen-containing heterocyclic group, are manufactured by the interaction of a diamine NHR11-A-NRR1 with an appropriate 2 - arylguanidinopyrimidine - bearing groups Y and X in the 5- and 6-positions respectively and a labile group such as a halogen atom or a hydrocarbon radicle which is attached by means of an ether or thioether linkage (e.g. an alkoxy, aryloxy or alkylmercapto group) in the 4-position.  Alternatively, when NRR1 is a primary amino group, this is protected by acylation and the acyl group is split off after condensation with the pyrimidine compound, this precaution being essential when introducing a substituent of the type -N(Alkyl)-A-NH2. The reaction is effected by heating the reagents together, optionally in the presence of a solvent or diluent.  Either of the reagents may be used in the form of a salt, e.g. hydrochloride or acetate, and, if desired, an acid-binding agent such as sodium hydroxide may be present.  The products form salts with mineral and organic acids, e.g. hydrogen halides, sulphuric, phosphoric, acetic, lactic, tartaric, methanesulphonic, methylene-bis-2 : 3-hydroxynaphthoic and methylene-bis-salicylic acids.  In some cases, the substituent on the aryl radicle of the product may be chemically modified, e.g. 2 - p - nitrophenylananidino - 4 - b  - diethylaminoethylamino - 6 - methylpyrimidine may be reduced with hydrogen in methanol in the presence of a Raney nickel catalyst to yield the corresponding amino compound.  Also the terminal amino group of the 4-substituent may be modified, e.g. a primary amino group may be mono- or di-alkylated or converted to piperidino, pyrrolidino or other strongly basic nitrogen-containing heterocyclic group, or a monoalkylamino group may be converted to a dialkylamino group.  Many examples are given.  Specification 581,347 is referred to.  A sample has been furnished under Sect. 2 (5) of 2 - p - chlorophenylguanidino - 6 - methyl - 4 - (b  - aminoethylamino) - pyrimidine, prepared by heating 2 - p - chlorophenylguanidino - 4-chloro - 6 - methylpyrimidine with b  - acetylaminoethyl - amine in glacial acetic acid and hydrolysing the product by refluxing with dilute hydrochloric acid.  According to the Provisional Specifications, the linking group may be carbocyclic (not restricted to alicyclic).  The first Provisional Specification contains an additional example of the preparation of 2-p-methoxyphenylguanidino-4-(g -diethylaminopropylamino) -pyrimidine, the second Provisional Specification one of the preparation of 2-p-acetylaminophenylguanidino-6-methyl-4-(b -diethylaminoethylamino)-pyrimidine and the fourth Provisional Specification one of the preparation of 2-p-chlorophenylguanidino - 6 - methyl - 4 - (b  - diethylaminoethyl - methylamino)-pyrimidine, in each case from the corresponding 4-chloro-compound. 2-Arylguanidinopyrimidines containing an ether or thioether group in the 4-position are obtainable by interaction of the 4-halogen derivatives with appropriate hydroxy or mercapto compounds or alkali metal derivatives thereof.