Patent GB-858635-A (GB)
Title: Novel pteridine derivatives and a process for the preparation thereof
Filed: 1958-06-12
Abstract: The invention comprises substituted pteridines of the general formula:  <FORM:0858635/IV(b)/1> wherein one of the substituents R1 to R4 represents the nitrogen atom of a saturated heterocyclic ring which may contain a further hetero atom and if desired further substituents, two more substituents R1 to R4 represent either nitrogen atoms of saturated heterocyclic rings (which may be substituted and/or contain other hetero atoms) or substituted or unsubstituted amino groups, and the last of substituents R1 to R4 represents a hydrogen or halogen atom, a substituted or unsubstituted alkyl, aryl, aralkyl, hydroxy, thiol or amino group or a nitrogen atom of a saturated heterocyclic ring (which may be substituted and/or contain further hetero atoms) and their non-toxic acid addition salts, and the preparation thereof by reacting a compound of the general formula:  <FORM:0858635/IV(b)/2> wherein at most three of the groups Z1 to Z4 correspond to the groups R1 to R4 defined above and the remaining 1 to 4 Z group(s) not corresponding to R1 to R4 are halogen atoms, with a heterocyclic compound containing an active hydrogen atom and at least nitrogen as a heterocyclic element, or a primary or secondary amine, an alcohol such as ethanol or b -ethoxy-ethanol, phenol, thiol such as ethylmercaptan or thiophenol, if desired in the presence of an added acid-binding agent, e.g. on alkali metal hydroxide, carbonate, or alcoholate or a tertiary amine, or an excess of amine reactant.  The process may be carried out at a temperature between - 20 and 250 DEG C. preferably in an inert solvent such as benzene, acetone, dioxane or dimethyl formamide, but where one of the reactants is liquid at the reaction temperature, for example, a cyclic amine, an excess of this type of reactant may be used. The process may be carried out in the absence of alkali at a low temperature and water or an aliphatic alcohol may be used as solvent.  The reaction proceeds more readily in the presence of a condensation catalyst, such as copper, copper salts and alkali metal iodides, particularly where the halogen atoms are difficult to replace as is often the case in the 2- and 4-positions. Suitable pteridine eactants are 2 : 4 : 6 : 7-tetrachloro(bromo)-, 2 : 4 : 7-trichloro-, 2 : 4 : 6-trichloro-, 2 : 4 : 7-trichloro-6-phenyl-, 2 : 4 : 7-trichloro-6-carboxymethyl-, 2-benzyl-4 : 6 : 7-trichloro-, 6-methyl-2 : 4 : 7-trichloro-, 2-methylamino-4 : 6 : 7-trichloro-, 2 : 4-dichloro-6 : 7-bis-(diethylamino)-, 2-ethylthio-4-chloro-6 : 7-dimorpholino-, and 2-phenoxy-4-chloro-6 : 7-dimorpholino-pteridines.  The compound which is reacted with the pteridine reactant may be an alkyl substituted primary or seondary amine, heterocyclic amine such as morpholine, piperidine, pyrrolidine and hexahydropyrazine, dialkylaminoalkylamine or an amino-alcohol. In the case where a pteridine reactant contains more than one halogen atom, the halogen atoms may be reacted in a step-wise manner. Non-toxic acid addition salts may be derived from hydrochloric, hydrobromic, sulphuric, phosphoric, acetic, lactic, fumaric, maleic, succinic, tartaric, citric, malonic, salicylic, nicotinic, ascorbic and camphorsulphonic.  A large number of compounds falling within the scope of the above formula are prepared in the example.  2 : 4-Dichloro-6, 7-dimorpholino-pteridine is prepared by reacting 2 : 4 : 6 : 7-tetrachloro-pteridine and morpholine.  2 : 4 : 7-Trichloro-6-phenyl-pteridine is prepared by reacting 2 : 4 : 7-trihydroxy-6-phenylpteridine with phosphorous pentachloride and phosphorous oxychloride.  2-Phenyl-4 : 6 : 7-trichloro-pteridine is prepared in a similar manner.  2 : 7-Dimorpholino-4-chloro-6-carboxymethyl - pteridine is prepared by reacting 2 : 4 : 7-trichloro-6-carboxymethyl-pteridine and morpholine.  2 : 4-Dimorpholino-7-dimethylamino-pteridine is prepared by reacting 2 : 4 : 7-trichloro-pteridine and dimethylamine.