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【结 构 式】

【分子编号】46871

【品名】tert-butyl 4-[[(7-chloro-3-methyl-2-[[(methylsulfonyl)oxy]methyl]-4-oxo-3,4-dihydro-6-quinazolinyl)methyl](2-propynyl)amino]benzoate

【CA登记号】

【 分 子 式 】C26H28ClN3O6S

【 分 子 量 】546.04364

【元素组成】C 57.19% H 5.17% Cl 6.49% N 7.7% O 17.58% S 5.87%

与该中间体有关的原料药合成路线共 2 条

合成路线1

该中间体在本合成路线中的序号:(XV)

Bromination of 3-chloro-4-methylaniline (I) in HOAc-Et2O afforded a mixture of the desired 2-bromo-5-chloro-4-methylaniline (II) and the dibromo derivative (III), which were separated by column chromatography. In an alternative procedure, aniline (I) was converted to the acetanilide (IV), which was then brominated to give (V). Subsequent acid hydrolysis of amide (V) provided the bromo aniline (II). Treatment of (II) with CuCN in hot NMP furnished nitrile (VI). This was hydrolyzed to the corresponding carboxylic acid (VII) using potassium hydroperoxide generated in situ. Cyclization of (VII) with chloroacetonitrile in the presence of NaOMe generated the quinazolinone system (VIII). The acetate ester (IX) was then obtained by displacement of the chloride group of (VIII) with cesium acetate in hot DMF. Further N-alkylation of quinazoline (IX) using methyl iodide and NaH produced (X). The bromomethyl derivative (XI) was prepared by benzylic bromination of (X) with N-bromosuccinimide in the presence of benzoyl peroxide. Condensation of bromide (XI) with tert-butyl 4-(N-propargylamino)benzoate (XII) yielded adduct (XIII). The acetate ester of (XIII) was then hydrolyzed with NaOH to give the hydroxymethyl quinazoline (XIV), which was subsequently converted to the mesylate (XV) upon treatment with methanesulfonic anhydride and Et3N.

1 Bavetsias, V.; et al.; The design and synthesis of water-soluble analogues of CB30865, a quinazolin-4-one-based antitumor agent. J Med Chem 2002, 45, 17, 3692.
2 Bavetsias, V.; Jackman, A.; Skelton, L. (Cancer Research Campaign Technology Ltd.); Anti-cancer dihydroquinazoline derivs.. WO 0050417 .
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) 26794 3-Chloro-4-methylaniline; 4-Amino-2-chlorotoluene 95-74-9 C7H8ClN 详情 详情
(II) 46858 2-bromo-5-chloro-4-methylaniline; 2-bromo-5-chloro-4-methylphenylamine C7H7BrClN 详情 详情
(III) 46859 2,6-dibromo-3-chloro-4-methylaniline; 2,6-dibromo-3-chloro-4-methylphenylamine 84483-22-7 C7H6Br2ClN 详情 详情
(IV) 46860 N-(3-chloro-4-methylphenyl)acetamide 7149-79-3 C9H10ClNO 详情 详情
(V) 46861 N-(2-bromo-5-chloro-4-methylphenyl)acetamide C9H9BrClNO 详情 详情
(VI) 46862 2-amino-4-chloro-5-methylbenzonitrile C8H7ClN2 详情 详情
(VII) 46863 2-amino-4-chloro-5-methylbenzoic acid C8H8ClNO2 详情 详情
(VIII) 46864 7-chloro-2-(chloromethyl)-6-methyl-4(3H)-quinazolinone C10H8Cl2N2O 详情 详情
(IX) 46865 (7-chloro-6-methyl-4-oxo-3,4-dihydro-2-quinazolinyl)methyl acetate C12H11ClN2O3 详情 详情
(X) 46866 (7-chloro-3,6-dimethyl-4-oxo-3,4-dihydro-2-quinazolinyl)methyl acetate C13H13ClN2O3 详情 详情
(XI) 46867 [6-(bromomethyl)-7-chloro-3-methyl-4-oxo-3,4-dihydro-2-quinazolinyl]methyl acetate C13H12BrClN2O3 详情 详情
(XII) 46868 tert-butyl 4-(2-propynylamino)benzoate C14H17NO2 详情 详情
(XIII) 46869 tert-butyl 4-[([2-[(acetoxy)methyl]-7-chloro-3-methyl-4-oxo-3,4-dihydro-6-quinazolinyl]methyl)(2-propynyl)amino]benzoate C27H28ClN3O5 详情 详情
(XIV) 46870 tert-butyl 4-[[[7-chloro-2-(hydroxymethyl)-3-methyl-4-oxo-3,4-dihydro-6-quinazolinyl]methyl](2-propynyl)amino]benzoate C25H26ClN3O4 详情 详情
(XV) 46871 tert-butyl 4-[[(7-chloro-3-methyl-2-[[(methylsulfonyl)oxy]methyl]-4-oxo-3,4-dihydro-6-quinazolinyl)methyl](2-propynyl)amino]benzoate C26H28ClN3O6S 详情 详情

合成路线2

该中间体在本合成路线中的序号:(XV)

Displacement of the mesylate group of (XV) with N-methylpiperazine (XVI) produced the disubstituted piperazine (XVII). The tert-butyl ester of (XVII) was cleaved to the corresponding carboxylic acid (XVIII) by means of trifluoroacetic acid in CH2Cl2. Then coupling of (XVIII) with 3-(aminomethyl)pyridine (XIX) gave rise to the title amide.

1 Bavetsias, V.; et al.; The design and synthesis of water-soluble analogues of CB30865, a quinazolin-4-one-based antitumor agent. J Med Chem 2002, 45, 17, 3692.
2 Bavetsias, V.; Jackman, A.; Skelton, L. (Cancer Research Campaign Technology Ltd.); Anti-cancer dihydroquinazoline derivs.. WO 0050417 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XV) 46871 tert-butyl 4-[[(7-chloro-3-methyl-2-[[(methylsulfonyl)oxy]methyl]-4-oxo-3,4-dihydro-6-quinazolinyl)methyl](2-propynyl)amino]benzoate C26H28ClN3O6S 详情 详情
(XVI) 10061 1-Methylpiperazine; 1-Methyl piperazine; N-Methylpiperazine 109-01-3 C5H12N2 详情 详情
(XVII) 46872 tert-butyl 4-[([7-chloro-3-methyl-2-[(4-methyl-1-piperazinyl)methyl]-4-oxo-3,4-dihydro-6-quinazolinyl]methyl)(2-propynyl)amino]benzoate C30H36ClN5O3 详情 详情
(XVIII) 46873 4-[([7-chloro-3-methyl-2-[(4-methyl-1-piperazinyl)methyl]-4-oxo-3,4-dihydro-6-quinazolinyl]methyl)(2-propynyl)amino]benzoic acid C26H28ClN5O3 详情 详情
(XIX) 18731 3-pyridinylmethanamine; 3-pyridinylmethylamine 3731-52-0 C6H8N2 详情 详情
Extended Information