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【结 构 式】 
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【分子编号】35242 【品名】methyl 4-(3-bromo-4-oxobutyl)benzoate 【CA登记号】 |
【 分 子 式 】C12H13BrO3 【 分 子 量 】285.13742 【元素组成】C 50.55% H 4.6% Br 28.02% O 16.83% |
合成路线1
该中间体在本合成路线中的序号：(VI)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 |
合成路线2
该中间体在本合成路线中的序号：(IV)The Heck coupling of 4-bromobenzoic acid methyl ester (I) with 3-buten-1-ol (II) by means of Pd(OAc)2, LiOAc, LiCl and Bu4NBr in hot DMF, followed by reaction with NaHSO3 in ethanol/water/ethyl acetate, gives the bisulfite adduct (III), which is treated with Tms-Cl in acetonitrile and brominated with Br2 to yield the desired intermediate, the 2-bromo-4-[4-methoxycarbonyl)phenyl]butyraldehyde (IV).
| 【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. |