A new and efficient synthesis of pyrrolo[2,3-d]pyrimidine anticancer agents:: Alimta (LY231514, MTA), homo-alimta, TNP-351, and some aryl 5-substituted pyrrolo[2,3-d]pyrimidines

被引:56
作者
Taylor, EC [1 ]
Liu, B [1 ]
机构
[1] Princeton Univ, Dept Chem, Princeton, NJ 08544 USA
关键词
D O I
10.1021/jo030248h
中图分类号
O62 [有机化学];
学科分类号
070303 ; 081704 ;
摘要
Alimta, as well as homo-Alimta, a nonbridged analogue of Alimta, and TNP-351 have been prepared by a new method that involves Michael addition of the appropriate 1-nitroalkene with 2,6-diamino-3H-pyrimidin-4-one or 2,4,6-triaminopyrimidine, followed by a Nef reaction of the resulting primary nitro Michael adduct. Spontaneous intramolecular cyclization of the resulting aldehyde with the pyrimidine 6-amino group yields the corresponding pyrrolo[2,3-d]pyrimidine. A series of previously unknown 5-arylpyrrolo[2,3-d]pyrimidines was prepared by the same methodology from the above pyrimidines and nitrostyrenes. It has been found that the intermediate primary nitro Michael adduct can be prepared in a single step by sonication of a mixture of an arylaldehyde, nitromethane, and the 6-aminopyrimidine in acetic acid containing ammonium acetate.
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收藏
页码:9938 / 9947
页数:10
相关论文
共 49 条
[1]   REGIOSELECTIVE SYNTHESIS OF PYRIDO[2,3-D]PYRIMIDINES [J].
ANDERSON, GL .
JOURNAL OF HETEROCYCLIC CHEMISTRY, 1985, 22 (05) :1469-1470
[2]   Microwave-assisted synthesis of 5-deaza-5,8-dihydropterins [J].
Bagley, MC ;
Singh, N .
SYNLETT, 2002, (10) :1718-1720
[3]  
Bagley MC, 2001, SYNLETT, P1523
[4]  
Barnett CJ, 1997, CHEMISTRY AND BIOLOGY OF PTERIDINES AND FOLATES 1997, P123
[5]   A CONVENIENT METHOD FOR REGIOSELECTIVE C-5 HALOGENATION OF 4(3H)-OXO-7H-PYRROLO[2,3-D]PYRIMIDINES [J].
BARNETT, CJ ;
KOBIERSKI, ME .
JOURNAL OF HETEROCYCLIC CHEMISTRY, 1994, 31 (05) :1181-1183
[6]   A practical synthesis of multitargeted antifolate LY231514 [J].
Barnett, CJ ;
Wilson, TM ;
Kobierski, ME .
ORGANIC PROCESS RESEARCH & DEVELOPMENT, 1999, 3 (03) :184-188
[7]  
BEARDSLEY GP, 1989, J BIOL CHEM, V264, P328
[8]   REGIOSELECTIVE BEHAVIOR OF UNSATURATED KETO ESTERS TOWARD VINYLOGOUS AMIDES [J].
BENNETT, GB ;
MASON, RB .
JOURNAL OF ORGANIC CHEMISTRY, 1977, 42 (11) :1919-1922
[9]  
BERTINO J, 1999, SEMINARS ONCOL S6, V26, P1
[10]   PYRIDO[2,3-D]PYRIMIDINES .4. SYNTHETIC STUDIES LEADING TO VARIOUS OXOPYRIDO[2,3-D]PYRIMIDINES [J].
BROOM, AD ;
SHIM, JL ;
ANDERSON, GL .
JOURNAL OF ORGANIC CHEMISTRY, 1976, 41 (07) :1095-1099