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【结 构 式】 
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【分子编号】19823 【品名】dimethyl (2S)-2-[(3,4-dihydro-2H-1,4-benzothiazin-7-ylcarbonyl)amino]hexanedioate 【CA登记号】 |
【 分 子 式 】C17H22N2O5S 【 分 子 量 】366.43816 【元素组成】C 55.72% H 6.05% N 7.64% O 21.83% S 8.75% |
合成路线1
该中间体在本合成路线中的序号：(V)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：(VIII)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 |
合成路线3
该中间体在本合成路线中的序号：(IX)The synthetic scheme of tritiated MX-68 ia also presented in Scheme 22540503a. Treatment of compound (I) with triphenylphosphine, followed by Wittig reaction with 4-ethylbenzoic aldehyde (II) yields an olefin (III). To improve the solubility of (III) in routine organic solvents, the amino group of compound (III) is acylated with anhydride (IV) to give a lipophilic olefin (V). The olefin moiety is next oxidized by treatment of ozone to give an aldehyde (VI). Reduction of compound (VI) with NaBT4 is performed in isopropanol to give the corresponding tritiated alcohol (VII). The alohol (VII) is deacylated to yield acyl-free pteridine (VIII). The conversion of compound (VIII) to HBr salt, followed by bromination of alcohol with dibromotriphenylphosphorane, amination with compound (IX) and alkali hydrolysis produces [9-3H]-MX-68.
| 【1】 Matsuoka, H.; et al.; Synthesis of tritiated N-[4-(2, 4-diaminopteridine-6-methyl)-3,4-dihydro-2H-1, 4-benzothiazine-7-carbonyl]-L-homo glutamic acid (MX-68). J Label Compd Radiopharm 1997, 39, 5, 363. |
| 【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) | 11006 | 2-Amino-6-(bromomethyl)-4-pteridinylamine; 6-(Bromomethyl)-2,4-pteridinediamine | 52853-40-4 | C7H7BrN6 | 详情 | 详情 |
| (II) | 25045 | 4-ethylbenzaldehyde | 4748-78-1 | C9H10O | 详情 | 详情 |
| (III) | 25046 | 6-(4-ethylstyryl)-2,4-pteridinediamine | C16H16N6 | 详情 | 详情 | |
| (IV) | 25047 | butyric anhydride | 106-31-0 | C8H14O3 | 详情 | 详情 |
| (V) | 25048 | N-[2-(butyrylamino)-6-(4-ethylstyryl)-4-pteridinyl]butanamide | C24H28N6O2 | 详情 | 详情 | |
| (VI) | 25049 | N-[2-(butyrylamino)-6-formyl-4-pteridinyl]butanamide | C15H18N6O3 | 详情 | 详情 | |
| (VII) | 25050 | N-[2-(butyrylamino)-6-(hydroxymethyl)-4-pteridinyl]butanamide | C15H20N6O3 | 详情 | 详情 | |
| (VIII) | 20068 | (2,4-diamino-6-pteridinyl)methanol | 945-24-4 | C7H8N6O | 详情 | 详情 |
| (IX) | 19823 | dimethyl (2S)-2-[(3,4-dihydro-2H-1,4-benzothiazin-7-ylcarbonyl)amino]hexanedioate | C17H22N2O5S | 详情 | 详情 |