多靶点叶酸拮抗剂—培美曲唑的合成

Synthesis of a multitargeted antifolate—pemetrexed

目的改进多靶点叶酸拮抗剂-培美曲唑的合成工艺。方法以4-溴苯甲酸乙酯和3-丁炔-1-醇为起始原料,经钯(0)催化偶联、氧化、溴代,再同2,4-二氨基吡啶环合,得到4-[2-(2-氨基-4,7-二氢-4-氧代-1H-吡咯并[2,3-d]嘧啶-5-基)乙基]苯甲酸甲酯(4)。4经皂化、酸化,同L-谷氨酸二乙酯部分缩合,得到N-[4-[2-(2-氨基-4,7-二氢-4-氧代-1H-吡咯并[2,3-d]嘧啶-5-基)乙基]苯甲酰基]-L-谷氨酸二甲酯(2)。2和对甲苯磺酸成盐,再经皂化、酸化,得到培美曲唑(pemetrexed,1)。培美曲唑经中和,冷冻干燥,得到临床应用的培美曲唑二钠盐。结果与结论改进了培美曲唑的合成工艺,产物经1H-NMR、MS确证结构,总收率为39.2%(文献收率36.8%)。

Aim To improve the synthetic procedure of pemetrexed. Methods Methyl 4-bromobenzoate and 3- butyn-1-ol were used as starting material to give 4- [ 2-（2-amino-4, 7-dihydro-4-oxo-1 H-pyrrolo [ 2, 3-d ] pyrimidin-5-yl）ethyl]benzoic acid methyl ester （4） via palladium （0）-catalyzed coupling, reduction, oxidation, bromination and cyclocondensation with 2, 4-diamino-6-hydroxypyrimidine. 4 was saponificated, followed by acidification to give 4- [ 2- （ 2-amino-4, 7-dihydro-4-oxo- 1 H-pyrrolo [ 2, 3-d ] pyrimidin-5- yl） ethyl ] benzoic acid （3）. 3 was coupled with diethyl L-glutamate, reacted with p-toluene sulfonic acid to give N- [ 4- [ 2- （2-amino-4, 7- dihydro-4-oxo- 1H-pyrrolo [ 2, 3-d ]-pyrimidin-5-yl） ethyl ] benzoyl ]- L-glutamic acid diethyl ester 4-methyl benzenesulfonic acid salt （2 salt）. Pemetrexed（1）was obtained by the saponification and acidification of 2 salt. The disodium salt of pemetrexed was given by frozen drying of the neutralization of pemetrexed. Results and conclusion The structure of target compound was confirmed by MS and ^1H- NMR. The total yield was 39.2 % （lit. 36.8 % ）. The synthetic procedures of most intermediates were improved.