methyl 4-(4-oxobutyl)benzoate -Drug Synthesis Database

【结构式】

【分子编号】14808

【品名】methyl 4-(4-oxobutyl)benzoate

【CA登记号】

【分子式】C₁₂H₁₄O₃

【分子量】206.24136

【元素组成】C 69.89% H 6.84% O 23.27%

与该中间体有关的原料药合成路线共 2 条

合成路线1 合成路线2

合成路线1

该中间体在本合成路线中的序号：(XXIII)

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.

参考文献中间体

合成目标

【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：(V)

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.

参考文献中间体

合成目标

【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

Extended Information