title: Approaches to the preparation of 6- and 7-methyl-8-substituted pterins: Part 1. The effect of reaction conditions on isomer distribution and a novel approach to isomer separation.
abstract: A new approach to the preparation of 6- and 7-methyl-8-alkylpterins is reported. This procedure relies primarily on the separation of the isomers due to their different propensities to form adducts with hydrogensulfite. The primary synthesis of 6-methyl-8-propylpterin was achieved by the condensation of 2,5-diamino-6-(propylamino)pyrimidin-4(3H)- one with pyruvic aldehyde in the presence of NaHSO3 at pH 4. This results in a solid product which was found to be > 98% pure 6-isomer in the form of the HSO3- adduct. Further treatment by a simple procedure gave the final product as the pterin hydrochloride greater than 99.5% isomer pure. The 7-methyl isomer was obtained from the filtrate of the primary synthesis by a cation exchange chromatographic procedure, again exploiting the different propensities of the two isomers to form adduct. The effect of reaction conditions and the nature of the 8-substituent on the proportions of the isomeric products produced by the above condensation reaction was investigated by a series of small scale syntheses. It was found that the proportion of the two isomeric products was dependent on the size of the 8-substituent and, to a lesser extent, the pH of the reaction mixture. For large 8-substituents such as n-propyl, isopropyl and 2-hydroxyethyl, 6-methyl isomer was the predominant product under all conditions. The presence of HSO3 [symbol: see text] did not generate any significant regioselective effect toward further formation of 6-isomer but had either negligible effect on the product distribution or increased the amount of 7-isomer formed. For the small methyl 8-substituent, the major product in the absence of HSO3 [symbol: see text] was found to be 7-isomer at all pH values. However, in the presence of HSO3 [symbol: see text] the major product became the 6-isomer. A 1H-NMR study of the nature of pyruvic aldehyde in acidic water solution is reported which shows that pyruvic aldehyde exists primarily as the monohydrated geminal ketodiol with a lesser proportion of the bishydrated vicinal diol. No free aldehyde was observed by 1H-NMR. The implications of these findings and the product distribution experiments are discussed in relation to the mechanism of the reaction and the role of HSO3 [symbol: see text] within this mechanism.
authors: Department of Biochemistry, University of Sydney, Australia.
authors: M T
authors: MT
authors: Ivery
authors: J E
authors: JE
authors: Gready
mesh_terms: D006863:Hydrogen-Ion Concentration; D007202:Indicators and Reagents; D007536:Isomerism; D009682:Magnetic Resonance Spectroscopy; D011622:Pterins / Q000138:chemical synthesis* / Q000737:chemistry / Q000302:isolation & purification; D011765:Pyruvaldehyde / Q000737:chemistry; D013447:Sulfites / Q000737:chemistry
chemical_list: D007202:Indicators and Reagents; D011622:Pterins; D013447:Sulfites; D011765:Pyruvaldehyde; C042345:hydrogen sulfite