Patent GB-683523-A (GB)
Title: The manufacture of purine derivatives
Inventor: HEILBRON IAN MORRIS
IPC: C07D473/28
Filed: 1948-08-18
Abstract: Purine compounds of formula (I) or (II) <FORM:0683523/IV (b)/1> <FORM:0683523/IV (b)/2> are made by reacting compounds of formula (III) or (IV) <FORM:0683523/IV (b)/3> <FORM:0683523/IV (b)/4> with an organic or inorganic basic medium preferably pyridine or an alkali hydroxide.  When inorganic bases e.g. alkali hydroxides are used, subsequent acidification is necessary.  Compounds (III) and (IV) are made by reacting compounds of formula (V) or (VI) <FORM:0683523/IV (b)/5> <FORM:0683523/IV (b)/6> with an isocyanate, an isothiocyanate, a urea, a thiourea or N-substituted derivative thereof, using, for example, a basic medium such as pyridine.  Compounds (V) or (VI) are made by condensing compounds of formula <FORM:0683523/IV (b)/7> <FORM:0683523/IV (b)/8> with an iminoether, a thioiminoether or an amidine such as compounds of formula <FORM:0683523/IV (b)/9> <FORM:0683523/IV (b)/100> <FORM:0683523/IV (b)/111> <FORM:0683523/IV (b)/122> <FORM:0683523/IV (b)/133> In the above formul  R1, R2, R3 and R4 may be the same or different and represent H, alkyl, aryl or aralkyl groups which may contain inert substituents, X may be O or S and R is H or preferably hydrocarbon such as ethyl.  When R3 is H (i) and (ii) are tautomers and when R1 and R4 are H further tautomers of (i) and (ii) may be obtained. In examples: (1) ethyl aminocyanacetate is refluxed in alcoholic-chloroform solution with formamidine hydrochloride to yield 4-amino-5-carbethoxy-iminazole which is refluxed in pyridine with methyl isothiocyanate to give 4-N1-methylthioureido-5-carbethoxy-iminazole which on dissolving in 2N NaOH and acidifying with acetic acid gives 2-thio-1-methylxanthine which may also be made without isolation of the intermediates; (2) ethyl aminocyanacetate refluxed in CHCl3 with thioacetiminobenzyl ether hydrochloride yields 4-amino-5-carbethoxy-2-methyliminazole hydrochloride which is converted by the method of (i) to 4-N1-methyl-thiomido-5-carbethoxy-2-methyliminazole and to 2-thio-1 : 8-dimethylxanthine; (3) 4-amino-5-carbethoxy-2-methyliminazole is refluxed in pyridine with methyl isocyanate, dissolved in hot 10 per cent NaOH after removal of the pyridine, and acidified with acetic acid to give 1 : 8-dimethylxanthine; (4) ethyl aminocyanacetate and thiobenziminobenzyl ether hydrochloride yield 4-amino-5-carbethoxy - 2 - phenyliminazole hydrochloride which with methyl isothiocyanate gives 4-N1-methylthioureido-5-carbethoxy-2-phenyliminazole converted by dissolution in 2N NaOH and acidification to 2 - thio - 8 - phenyl - 1 - methylxanthine; (5) 4-amino-5-carbethoxy-2-phenyliminazole with methylisocyanate yields the corresponding methylureido derivative which on warming with 2N NaOH and acidification yields 1-methyl-8-phenylxanthine; (6) the iminazole of (5) with urea forms 4-ureido-5-carbethoxy-2-phenyliminazole which on treatment with 5 per cent NaOH at 80 DEG  C. and subsequent acidification yields 2 : 6-dihydroxy-8-phenylpurine; (7) 4 - amino - 5 - carbethoxy-1-methyl-2-phenyliminazole is refluxed with urea in pyridine and the solid obtained on pouring into water dissolved in 2N NaOH at 80 DEG  C. when on acidification 2 : 4-dihydroxy-9-methyl-8-phenylpurine is obtained; (8) the iminazole of (5) and acetylisothiocyanate yields an acetythioureido compound which is hydrolysed with 2N HCl in ethanol to the thioureidoiminazole which on warming in 2N NaOH and acidifying yields 2 - thio - 8 - phenylxanthine; (9) ethyl aminocyanacetate with phenylacetiminoethylthioether hydrochloride yields 4-amino-5-carbethoxy-2-benzyliminazole hydrochloride which with phenylisocyanate gives 4 - N1 - phenylureido - 5 - carbethoxy - 2 - benzyliminazole converted to 8-benzyl-1-phenyl-xanthine on boiling in 2N NaOH and acidifying; (10) 4-amino-5-carbethoxy-2-benzyliminazole with phenylisothiocyanate yields a phenylthioureido compound which with 2N NaOH at 90 DEG  C. and acidification yields 2-thio-1-phenyl-8-benzylxanthine; (11) the same benzyliminazole is methylated either with diazomethane in methanol or dimethyl sulphate and refluxed with pyridine and methyl isothiocyanate to give a methylthioureido compound which is converted to 2-thio-1 : 7-dimethyl-8-benzylxanthine; (12) the iminazole of (5) is methylated with ethanol diazomethane to the 2-phenyl-1-methyliminazole which is converted to 4-N1-methylthioureido-5-carbethoxy-2-phenyl-1-methyl-imina zole and then to 2-thio-8-phenyl-1 : 7-dimethylxanthine as in (1); (13) ethyl aminocyanacetate with p - nitrophenylacetiminobenzylthioether hydrochloride gives 4-amino-5-carbethoxy-2-(p1-nitrobenzyl)-iminazole hydrochloride which with methylisocyanate yields 4-N1-methylureido-5-carbethoxy-2-(p1-nitrobenzyl) -iminazole converted to 8-(p1-nitrobenzyl)-1-methylxantine on boiling with 5 per cent NaOH and acidifying.  Specifications 683,593 and 683,594 are referred to.