Syntheses Of Antifolates Alimta And Its Analogs

Antifolate Alimta derived from pyrrolo[2,3-d]pyrimidine is a multitargeted antitumor agent, it can inhibit at least five major folate-dependent enzymes: thymidylate synthase(TS), dihydrofolate reductase(DHFR), glycinamide ribonucleo -tide formyltransferase(GARFT), aminoimidazole ribonucleotide formyl transferase (AICARFT) and C-1 tetrahydrofolate synthetase(C1-S).A novel synthetic route to Alimta was established by retrosynthetic analysis in this paper.The key intermediate, Ethyl 4-(4-ethoxy -4-oxobutyl) benzoate(6), was obtained from benzene via Friedel-Crafts acylation, Huang reduction, saponification followed by acidification and esterification in 36.6% yield. Selective reduction of 6 with KBH₄/LiBr afforded 4-(4-hydroxylbutyl)benzoic acid ethyl ester(7). (RS)-4-(3- bromo-4-oxobutyl)benzoic acid ethyl ester(9) could be obtained through PCC oxidation, DDBA bromination from 7. Cyclocondensation between 7 and commercially available 2,6-diamino-4-hydroxpyrimidine yielded 4-[2-(2- amino-4,7- dihydro-4-oxo -1H-pyrrolo[2,3-d]pyrimidine(10). Saphonification of 10 with aqueous NaOH afforded the carboxylic derivative 11. By means of DEPC, a peptide coupling reagent, treatment of 11 with diethyl L-glutamate afforded N-[4-[2-(2-amino -4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidine-5-yl)ethyl]benzoyl]-L-glutamic acid diethyl ester(12). Saphonification of 12 followed by acidification gave Alimta. in overall yield of 4.8%In addition, synthesis of Alimta the designed analogs was investigated.N-Cbz-oxazolidinone(13) was obtained from N-Cbz-L-glu by reaction with (CH₂O)m. Then it was coupled with p-amino benzoic acid methyl ester(14) using PCl₃ reagent to yield L-4-(3-(3-benzyloxyl)-5-oxo-1,3-oxazolidin-4-yl)propanamino) benzoic acid methyl ester(15a). Action of CH3ONa on 15a yielded N²-( benzyloxyl )...