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【结 构 式】

【分子编号】19825

【品名】dimethyl (2S)-2-[([4-[(2,4-diamino-6-pteridinyl)methyl]-3,4-dihydro-2H-1,4-benzothiazin-7-yl]carbonyl)amino]hexanedioate

【CA登记号】

【 分 子 式 】C24H28N8O5S

【 分 子 量 】540.60324

【元素组成】C 53.32% H 5.22% N 20.73% O 14.8% S 5.93%

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:(VII)

Carboxilic acid (I) is converted to the correspondig acid chloride (II) and and amidated with dimethyl homoglutamate (III) to give the amide (IV). The benzyloxycarbonyl grouo of the amide (IV) is removed with H2 over Pd/C to give the amide (V), which is effectively alkylated with 6-(bromomethyl)-2,4-diaminopteridine (VI) to produce compound (VII). Finally, compound (VII) is hydrolyzed with 1N NaoH to yield MX-68.

1 Maruyama, N.; et al.; Antirheumatic agents. Novel methotrexate derivatives which are resistant to polyglutamation. 213th ACS Natl Meet (April 13-17, San Francisco) 1997, Abst MEDI 090.
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) 19819 4-[(benzyloxy)carbonyl]-3,4-dihydro-2H-1,4-benzothiazine-7-carboxylic acid C17H15NO4S 详情 详情
(II) 19820 benzyl 7-(chlorocarbonyl)-2,3-dihydro-4H-1,4-benzothiazine-4-carboxylate C17H14ClNO3S 详情 详情
(III) 19821 dimethyl (2S)-2-aminohexanedioate C8H15NO4 详情 详情
(IV) 19822 dimethyl (2S)-2-[([4-[(benzyloxy)carbonyl]-3,4-dihydro-2H-1,4-benzothiazin-7-yl]carbonyl)amino]hexanedioate C25H28N2O7S 详情 详情
(V) 19823 dimethyl (2S)-2-[(3,4-dihydro-2H-1,4-benzothiazin-7-ylcarbonyl)amino]hexanedioate C17H22N2O5S 详情 详情
(VI) 11006 2-Amino-6-(bromomethyl)-4-pteridinylamine; 6-(Bromomethyl)-2,4-pteridinediamine 52853-40-4 C7H7BrN6 详情 详情
(VII) 19825 dimethyl (2S)-2-[([4-[(2,4-diamino-6-pteridinyl)methyl]-3,4-dihydro-2H-1,4-benzothiazin-7-yl]carbonyl)amino]hexanedioate C24H28N8O5S 详情 详情

合成路线2

该中间体在本合成路线中的序号:(X)

As shown in Scheme 22540502a, initially, starting material (I) is converted to benzothiazol (II) by treatment of sodium thiocyanate in the presence of bromine. Alkali hydrolysis of compound (II) gives thiol (III), which is immediatly submitted to S-alkylation with 1-bromo-2-chloroethane, followed by acid esterification, which gives thioether (IV). After protection of the amino group of compound (IV) with tosyl chloride, treatment of NaOH affords benzothiazine ester (V), and next hydrolysis produces the key intermediate (VI). Subsequently, compound (VI) is converted to the corresponding acid chloride and amidated with dimethyl homoglutamate to give the amide (VII). The tosyl group of the amide (VII) is removed with HBr-AcOH to give the amine (VIII), which is effectively alkilated with 6-(bromomethyl)-,4-diaminopteridine (IX) to produce (X). Finally, compound (X) is hydrolyzed with 1N NaOH to yield MX-68.

1 Matsuoka, H.; et al.; Antirheumatic agents: Novel methotrexate derivatives bearing a benzoxazine or benzothiazine moiety. J Med Chem 1997, 40, 1, 105.
2 Mihara, M.; Matsuoka, H.; The synthesis and biological evaluation of new methotrexate derivatives in rheumatoid arthritis. Drugs Fut 1998, 23, 9, 1015.
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) 20004 p-aminobenzoic acid; 4-aminobenzoic acid 150-13-0 C7H7NO2 详情 详情
(II) 25039 2-amino-1,3-benzothiazole-6-carboxylic acid C8H6N2O2S 详情 详情
(III) 25040 4-amino-3-sulfanylbenzoic acid hydrochloride C7H8ClNO2S 详情 详情
(IV) 25041 methyl 4-amino-3-[(2-chloroethyl)sulfanyl]benzoate hydrochloride C10H13Cl2NO2S 详情 详情
(V) 25042 methyl 4-[(4-methylphenyl)sulfonyl]-3,4-dihydro-2H-1,4-benzothiazine-7-carboxylate C17H17NO4S2 详情 详情
(VI) 25043 4-[(4-methylphenyl)sulfonyl]-3,4-dihydro-2H-1,4-benzothiazine-7-carboxylic acid C16H15NO4S2 详情 详情
(VII) 25044 dimethyl 2-[([4-[(4-methylphenyl)sulfonyl]-3,4-dihydro-2H-1,4-benzothiazin-7-yl]carbonyl)amino]hexanedioate C24H28N2O7S2 详情 详情
(VIII) 19823 dimethyl (2S)-2-[(3,4-dihydro-2H-1,4-benzothiazin-7-ylcarbonyl)amino]hexanedioate C17H22N2O5S 详情 详情
(IX) 11006 2-Amino-6-(bromomethyl)-4-pteridinylamine; 6-(Bromomethyl)-2,4-pteridinediamine 52853-40-4 C7H7BrN6 详情 详情
(X) 19825 dimethyl (2S)-2-[([4-[(2,4-diamino-6-pteridinyl)methyl]-3,4-dihydro-2H-1,4-benzothiazin-7-yl]carbonyl)amino]hexanedioate C24H28N8O5S 详情 详情
Extended Information