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【结 构 式】

【分子编号】35243

【品名】methyl 4-(4-hydroxy-1-butynyl)benzoate

【CA登记号】

【 分 子 式 】C12H12O3

【 分 子 量 】204.22548

【元素组成】C 70.57% H 5.92% O 23.5%

与该中间体有关的原料药合成路线共 1 条

合成路线1

该中间体在本合成路线中的序号:(III)

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
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