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【结 构 式】 
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【分子编号】14812 【品名】methyl 4-[2-(2-amino-4-oxo-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoate 【CA登记号】 |
【 分 子 式 】C16H16N4O3 【 分 子 量 】312.3282 【元素组成】C 61.53% H 5.16% N 17.94% O 15.37% |
合成路线1
该中间体在本合成路线中的序号：(XXVII)3) The silylation of 4-(3-formylpropyl)benzoic acid methyl ester (XXIII) with hexamethyldisilazane (HMSAZ) and trimethylsilyl iodide in dichloromethane gives the 4-(trimethylsilyloxy)-3-butenyl derivative (XXIV), which is brominated with Br2 in CCl4 yielding the 2-bromo-3-formylpropyl derivative (XXV). The cyclization of (XXV) with 2,4-diamino-6-hydroxypyrimidine (XXVI) by means of sodium acetate in methanol/water affords the 4-[2-(2-amino-4-oxo-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl] benzoic acid methyl ester (XXVII), which is saponified with NaOH to the corresponding free acid (XX) already obtained. The synthesis is then continued as in scheme 1735602a. 4) The benzoic ester (XXVII) can also be obtained by condensation of 4-(2-formylethyl)benzoic acid methyl ester (XIV) with methoxymethyltriphenylphosphonium bromide by means of potassium tert-butoxide in toluene giving 4-(4-methoxy-3-butenyl)benzoic acid methyl ester (XXVIII), which is then cyclized with 2,4-diamino-6-hydroxypyrimidine (XXVI) by means of Br2 in acetonitrile.
| 【1】 Castaner, J.; Graul, A.; Tracy, M.; Penetrexed Disodium. Drugs Fut 1998, 23, 5, 498. |
| 【2】 Barnett, C.J.; Wilson, T.M. (Eli Lilly and Company); Process for preparing 5-substd. pyrrolo[2,3-d]pyrimidines. EP 0589720; US 5416211 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XIV) | 63842 | methyl 4-(3-oxopropyl)benzoate | C11H12O3 | 详情 | 详情 | |
| (XX) | 14805 | 4-[2-(2-amino-4-oxo-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoic acid | C15H14N4O3 | 详情 | 详情 | |
| (XXIII) | 14808 | methyl 4-(4-oxobutyl)benzoate | C12H14O3 | 详情 | 详情 | |
| (XXIV) | 14809 | methyl 4-[(E)-4-[(trimethylsilyl)oxy]-3-butenyl]benzoate | C15H22O3Si | 详情 | 详情 | |
| (XXV) | 14810 | methyl 4-(2-bromo-4-oxobutyl)benzoate | C12H13BrO3 | 详情 | 详情 | |
| (XXVI) | 14811 | 2,4-Diamino-6-hydroxypyrimidine; 2,6-diamino-4-pyrimidinol | 56-06-4 | C4H6N4O | 详情 | 详情 |
| (XXVII) | 14812 | methyl 4-[2-(2-amino-4-oxo-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoate | C16H16N4O3 | 详情 | 详情 | |
| (XXVIII) | 14813 | methyl 4-[(E)-4-methoxy-3-butenyl]benzoate | C13H16O3 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(VIII)A concise and scalable synthesis of pemetrexed disodium has been presented: The alkylation of methyl 4-bromobenzoate (I) with 3-butyn-1-ol (II) by means of Pd(0) gives methyl 4-(4-hydroxy-1-butynyl)benzoate (III), which is reduced with H2 over Pd/C to the 4-hydroxybutyl derivative (IV). The oxidation of (IV) with NaOCl and 2,2,6,6-tetramethyl-1-piperidinyloxy free radical (TEMPO) yields the corresponding aldehyde (V), which is brominated with 5,5-dibromobarbituric acid (DBBA) and HBr in acetic acid/dichloromethane affording the alpha-bromoaldehyde (VI). The cyclization of (VI) with 2,6-diaminopyrimidin-4(3H)-one (VII) by means of NaOAc in acetonitrile/water gives the pyrrolopyrimidine (VIII), which is hydrolyzed with aqueous NaOH and acidified with aqueous HCl yielding the benzoic acid derivative (IX). The condensation of (IX) with L-glutamic acid diethyl ester (X) by means of 2-chloro-4,6-dimethoxy-1,3,5-triazine (CDMT) and NMM in DMF affords the diethyl ester (XI) of pemetrexed, which is finally hydrolyzed with aqueous NaOH.
| 【1】 Kjell, D.P.; Slattery, B.J.; Improved route to multitargeted antifolate LY231514. 218th ACS Natl Meet (Aug 22 1999, New Orleans) 1999, Abst ORG 130. |
| 【2】 Kobierski, M.E.; Wilson, T.M.; Barnett, C.J.; A practical synthesis of multitargeted antifolate LY231514. Org Process Res Dev 1999, 3, 3, 184. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (I) | 10168 | 4-Bromobenzoic acid methyl ester; methyl 4-bromobenzoate | 619-42-1 | C8H7BrO2 | 详情 | 详情 |
| (II) | 32507 | 3-butyn-1-ol | 927-74-2 | C4H6O | 详情 | 详情 |
| (III) | 35243 | methyl 4-(4-hydroxy-1-butynyl)benzoate | C12H12O3 | 详情 | 详情 | |
| (IV) | 35241 | methyl 4-(4-hydroxybutyl)benzoate | C12H16O3 | 详情 | 详情 | |
| (V) | 14808 | methyl 4-(4-oxobutyl)benzoate | C12H14O3 | 详情 | 详情 | |
| (VI) | 35242 | methyl 4-(3-bromo-4-oxobutyl)benzoate | C12H13BrO3 | 详情 | 详情 | |
| (VII) | 14277 | 2,6-Diamino-4(3H)-pyrimidinone | C4H6N4O | 详情 | 详情 | |
| (VIII) | 14812 | methyl 4-[2-(2-amino-4-oxo-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoate | C16H16N4O3 | 详情 | 详情 | |
| (IX) | 14805 | 4-[2-(2-amino-4-oxo-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoic acid | C15H14N4O3 | 详情 | 详情 | |
| (X) | 11013 | diethyl (2S)-2-aminopentanedioate | C9H17NO4 | 详情 | 详情 | |
| (XI) | 14807 | diethyl (2S)-2-([4-[2-(2-amino-4-oxo-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]amino)pentanedioate | C24H29N5O6 | 详情 | 详情 |