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Synthesis and biological properties of 3‐methyl‐10‐propargyl‐5,8‐dideazafolic acid
Author(s) -
Jones Terence R.,
Betteridge Richard F.,
Newell David R.,
Jackman Ann L.
Publication year - 1989
Publication title -
journal of heterocyclic chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.321
H-Index - 59
eISSN - 1943-5193
pISSN - 0022-152X
DOI - 10.1002/jhet.5570260548
Subject(s) - chemistry , hydrobromide , methylamine , propargyl , hydrochloride , methyl group , tosyl , quinazoline , deamination , bromide , methyl iodide , medicinal chemistry , organic chemistry , alkyl , enzyme , catalysis
The synthesis of N 3 ‐methyl‐10‐propargyl‐5,8‐dideazafolic acid ( 1b ) is described. Ring closure of methyl‐5‐methylanthranilate with chloroformamidine hydrochloride gave a high yield of pure 2‐amino‐4‐hydroxy‐6‐methylquinazoline treatment of which with iodomethane/sodium hydroxide provided the corresponding 3‐methylquinazoline (6) which was converted to its 2‐pivaloylamino derivative. This synthetic approach, next involving functionalisation of the 6‐methyl group, was not further pursued because of difficulty encountered in removing the pivaloyl group. Methyl 5‐methylanthranilate was treated with p ‐toluenesulfonyl chloride and the product then N ‐methylated. The tosyl group was cleaved with hydrogen bromide/phenol and the resulting methylamine ring‐closed with chloroformamidine hydrochloride to provide 2‐amino‐1,4‐dihydro‐1,6‐dimethyl‐4‐oxoquinazoline ( 11 ). The 2‐pivaloylamino derivative of 11 was prone to hydrolytic deamination when attempts were made to remove the pivaloyl group and further elaboration of this heterocycle, with the intention of obtaining N 1 ‐methyl‐10‐propargyl‐5,8‐dideazafolic acid was, too, not attempted. Di‐ t ‐butyl N ‐(4‐propargylamino)benzoyl)‐L‐glutamate was therefore prepared and coupled with 2‐amino‐6‐bromomethyl‐4‐hydroxyquinazoline hydrobromide. The resulting antifolate diester was N ‐monomethylated. Removal of the t ‐butyl groups with trifluoracetic acid afforded the target compound 1b and its structure was proved by degradation to the quinazoline 6 . Its IC 50 for L1210 thymidylate synthase (TS) was 26 μ M ; the control value for 10‐propargyl‐5,8‐dideazafolic acid ( 1a ) was 0.02 μM. Thus the substitution of the lactam hydrogen in 1a by a methyl group reduced the TS inhibition by 1300‐fold. Compound 1b was poorly cytotoxic to L1210 cells in culture (ID 50 > 100 μM). An unperturbed lactam group in this class of antifolate is important for binding to TS.