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【结 构 式】

【药物名称】

【化学名称】N-[4-[N-(2-Methyl-4-oxo-3,4,7,8-tetrahydro-6H-cyclopenta[g]quinazolin-6(S)-yl)-N-(2-propynyl)amino]benzoyl]-L-glutamic

【CA登记号】

【 分 子 式 】C27H26N4O6

【 分 子 量 】502.53147

【开发单位】AstraZeneca (Originator), BTG (Originator)

【药理作用】ONCOLYTIC DRUGS, Antimetabolites, Thymidylate Synthase Inhibitors

合成路线1

The reaction of indan-5-amine (I) with acetic anhydride gives the acetamide (II), which is brominated with Br2 in acetic acid yielding the 6-bromo derivative (III). The reaction of (III) with CuCN in 1-methyl-2-pyrrolidone at 125 C affords the corresponding nitrile (IV), which is cyclized by means of H2O2 and NaOH in hot ethanol/water giving the tricyclic ketone (V). The reaction of (V) with chloromethyl pivalate (A) and potassium tert-butoxide in DMSO yields the pivaloyloxymethyl derivative (VI), which is oxidized with CrO3 and tert-butyl peroxide in dichloromethane affording the diketone (VII) (after chromatographic separation of the undesired regioisomer). The condensation of (VII) with N-(4-aminobenzoyl)-Lglutamic acid diethyl ester (VIII) by means of TsOH in refluxing DME gives the imino derivative (IX), which without isolation, is reduced to the secondary amine (X) (as a diastereomeric mixture) with NaBH3CN in methanol/acetic acid. The alkylation of the secondary amine group of (X) with propargyl bromide (XI) and CaCO3 in hot DMA yields the tertiary amine (XII), which is hydrolyzed and deprotected with first with NaOH in methanol/water, and then with aqueous HCl to provide the target compound as a diastereomeric mixture. Finally, this compound is resolved by a treatment with carboxypeptidase G2 and ZnCl2 in water that hydrolyzes selectively the undesired isomer.

1 Bavetsias, V.; Matusiak, Z.; Melin, C.; Neidle, S.; Marriott, J.H.; Boyle, F.T.; Jackman, A.L.; Chemoenzymatic preparation of the novel antifolate thymidylate synthase inhibitor N-(4-{N-[(6S)-2-methyl-4-oxo-3,4,7,8-tetrahydro-6H-cyclopenta[g]quinazolin-6-yl]-N-(prop-2-ynyl)amino}-benzoyl)-L-glutamic acid and its glutamyl cleavage product. J Chem Soc - Perkins Trans I 1999, 11, 1495.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(A) 16166 chloromethyl pivalate 18997-19-8 C6H11ClO2 详情 详情
(I) 21473 5-indanamine; 2,3-dihydro-1H-inden-5-ylamine 24425-40-9 C9H11N 详情 详情
(II) 21474 N-(2,3-dihydro-1H-inden-5-yl)acetamide C11H13NO 详情 详情
(III) 31073 N-(6-bromo-2,3-dihydro-1H-inden-5-yl)acetamide C11H12BrNO 详情 详情
(IV) 31074 N-(6-cyano-2,3-dihydro-1H-inden-5-yl)acetamide C12H12N2O 详情 详情
(V) 31075 2-methyl-3,6,7,8-tetrahydro-4H-cyclopenta[g]quinazolin-4-one C12H12N2O 详情 详情
(VI) 31076 (2-methyl-4-oxo-4,6,7,8-tetrahydro-3H-cyclopenta[g]quinazolin-3-yl)methyl pivalate C18H22N2O3 详情 详情
(VII) 31077 (2-methyl-4,6-dioxo-4,6,7,8-tetrahydro-3H-cyclopenta[g]quinazolin-3-yl)methyl pivalate C18H20N2O4 详情 详情
(VIII) 31078 diethyl (2S)-2-[(4-aminobenzoyl)amino]pentanedioate; Diethyl N-(4-aminobenzoyl)-L-glutamate 13726-52-8 C16H22N2O5 详情 详情
(IX) 31079 diethyl (2S)-2-([4-[(3-[[(2,2-dimethylpropanoyl)oxy]methyl]-2-methyl-4-oxo-3,4,7,8-tetrahydro-6H-cyclopenta[g]quinazolin-6-ylidene)amino]benzoyl]amino)pentanedioate C34H40N4O8 详情 详情
(X) 31080 diethyl (2S)-2-([4-[(3-[[(2,2-dimethylpropanoyl)oxy]methyl]-2-methyl-4-oxo-4,6,7,8-tetrahydro-3H-cyclopenta[g]quinazolin-6-yl)amino]benzoyl]amino)pentanedioate C34H42N4O8 详情 详情
(XI) 11176 3-Bromopropyne; 3-Bromo-1-propyne 106-96-7 C3H3Br 详情 详情
(XII) 31081 diethyl (2S)-2-([4-[(3-[[(2,2-dimethylpropanoyl)oxy]methyl]-2-methyl-4-oxo-4,6,7,8-tetrahydro-3H-cyclopenta[g]quinazolin-6-yl)(2-propynyl)amino]benzoyl]amino)pentanedioate C37H44N4O8 详情 详情
(XIII) 31082 (2S)-2-([4-[(2-methyl-4-oxo-4,6,7,8-tetrahydro-3H-cyclopenta[g]quinazolin-6-yl)(2-propynyl)amino]benzoyl]amino)pentanedioic acid C27H26N4O6 详情 详情
Extended Information