培美曲塞二钠重结晶文献 J. Med. Chem. 1992,35,4450-4454

关于培美曲塞二钠重结晶的文献，1992年
N-  [4-  [  2-(  2-Amino-3,4-dihydro-4-oxo-7H-pyrrolo  [  2,343  pyrimidin-5-yl)ethyl]  benzoyl]    glutam am-
ic acid (lS),  prepared  in  five  steps  from 2-pivaloyl-7-deazaguanine,  has  been  found  to be  an  antitumor
agent with ita primary site of action at  thymidylate synthase rather than purine synthesis.  This
compound appears to be a promising candidate for clinical evaluation.
Introduction
6,10-Dideaza-5,6,7,&tetrahydrofolic  acid (DDATHF,
Lometrexol, 1) was synthesized  in 1985l  and  immediately
recognized as  the fist representative of  a new  class of
potent folate antimetabolites that were active antitumor
agents due to their effects on de novo purine synthesis.2
Ita  target has  been  shown  to  be glycinamide  ribonucleotide
formyltransferase (GARFT, EC 2.1.2.1),  the first folate
cofactor-dependent  formyl transfer  step in the de novo
purine biosynthetic pathway.3  Because DDATHF  is not
advanced  to clinical trial on  the basis  of  its profile  of
therapeutic activity against several murine solid tumors
and  human  tumor  xenografts.  It  has  demonstrated  activity
against  human  disease in  the  course  of four Phase  1  clinical
trials.5
The penultimate step  in the majority of  the DDATHF
syntheses described thus far is reduction of  an aromatic
pyridine  intermediate  such  as  2 (X  =  -CHzCHr),  resulting
in a mixture of  two DDATHF diastereomers  differing in
chirality  at  C-6.'  Subsequent  resolution  of these mixtures
2
n
a dihydrofolate reductase  (DHFR) inhibitor, it is fully
active against tumors resistant  to methotrexate  due to
amplification  of  the  DHFR  gene.2bv4  DDATHF  was1429