|
【结 构 式】 
|
【分子编号】14770 【品名】2-methylbenzoyl chloride; o-Toluoyl chloride 【CA登记号】933-88-0 |
【 分 子 式 】C8H7ClO 【 分 子 量 】154.59568 【元素组成】C 62.15% H 4.56% Cl 22.93% O 10.35% |
合成路线1
该中间体在本合成路线中的序号：(V)Atofluding can be prepared by several similar ways: a) Acylation of 5-fluorouracil (I) with acetic anhydride in refluxing pyridine gives 1-acetyl-5-fluorouracil (II), which is then acylated with 2-methylbenzoyl chloride (V) by means of either TEA in dioxane at room temperature or pyridine in dioxane at 80 C. b) Acylation of 5-fluorouracil (I) with 2-methylbenzoyl chloride (V) in pyridine at room temperature yields 5-fluoro-3-(2-methylbenzoyl)uracil (III), which is then acylated with acetic anhydride at 80 C or with acetic anhydride by means of TEA in cooled dioxane. c) Acylation of 5-fluorouracil (I) with acetyl chloride by means of TEA in dioxane at room temperature provides 1,3-diacetyl-5-fluorouracil (IV), which is then acytated with 2-methylbenzoyl chloride (V) by means of TEA in dioxane.
| 【1】 Kametani, T.; Hiiragi, M.; Kigasawa, K.; et al.; Studies on the synthesis of chemotherapeutics. 10. Synthesis and antitumor activity of N-acyl- and N-(alkoxycarbonyl)-5-fluorouracil derivatives. J Med Chem 1980, 23, 12, 1324. |
| 【2】 Castaner, J.; Zhang, Z.; Xu, W.; Atofluding. Drugs Fut 2001, 26, 10, 935. |
| 【3】 Okada, T.; Uracil derivs., process for preparing the same, and oncotic preparation thereof. JP 1979135782; WO 7900922 . |
| 【4】 Palleja Martinez, J.; Okada, T.; Process to obtain new 5-fluorouracil derivs., specifically N1-acyl-substd.-N3-ortho-toluyl-5-fluorouracils. ES 2015772 . |
| 【5】 Hoffer, M. (Hoffmann-La Roche, Inc.); Preparation of thymidine and deoxyfluorouridine, and intermediates therefor. US 2949451 . |
| 【6】 Okada, T.; Palleja Martinez, J.; Process to obtain a new 5-fluorouracil deriv.. ES 2015151 . |
| 【7】 Hoffer, M. (Hoffmann-La Roche, Inc.); Mercury salts of nitrogen heterocyclics and preparation thereof. US 3041335 . |
| 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) | 29241 | 5-fluoro-2,4(1H,3H)-pyrimidinedione；5-fluorouracil；5-Fluoro-2,4-pyrimidinedione;5-Fluoropyrimidine-2,4-dione | 51-21-8 | C4H3FN2O2 | 详情 | 详情 |
| (II) | 48658 | 1-acetyl-5-methyl-2,4(1H,3H)-pyrimidinedione | C7H8N2O3 | 详情 | 详情 | |
| (III) | 48659 | 5-fluoro-3-(2-methylbenzoyl)-2,4(1H,3H)-pyrimidinedione | C12H9FN2O3 | 详情 | 详情 | |
| (IV) | 48660 | 1,3-diacetyl-5-fluoro-2,4(1H,3H)-pyrimidinedione | C8H7FN2O4 | 详情 | 详情 | |
| (V) | 14770 | 2-methylbenzoyl chloride; o-Toluoyl chloride | 933-88-0 | C8H7ClO | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(II)The condensation of 7-chloro-1,2,3,4-tetrahydroquinolin-4-one (I) with 2-methylbenzoyl chloride (II) by means of pyridine in dichloromethane gives the corresponding acyl quinolone (III), which is then treated with hydroxylamine-O-sulfonic acid (IV) and K2CO3 to yield the target oxime.
| 【1】 Uemura, A.; Mochida, E.; Haga, A.; Tokunaga, H.; Kato, K. (Mochida Pharmaceutical Co., Ltd.); 1-Acyl-2,3-dihydro-4(1H)-quinolinone-4-oxime derivs.. AU 9058618; EP 0243982; JP 1988239270; JP 1993262737; US 4739368; WO 8706580 . |
| 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) | 49524 | 7-chloro-2,3-dihydro-4(1H)-quinolinone | C9H8ClNO | 详情 | 详情 | |
| (II) | 14770 | 2-methylbenzoyl chloride; o-Toluoyl chloride | 933-88-0 | C8H7ClO | 详情 | 详情 |
| (III) | 49525 | 7-chloro-1-(2-methylbenzoyl)-2,3-dihydro-4(1H)-quinolinone | C17H14ClNO2 | 详情 | 详情 | |
| (IV) | 40596 | (aminooxy)(hydroxy)dioxo-lambda(6)-sulfane | 2950-43-8 | H3NO4S | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(VIII)A new synthesis of OPC-31260 has been published: The reductocondensation of 1-tosyl-2,3,4,5-tetrahydro-1-benzazepin-5-one (I) with methylamine and NaBH4 gives N-(1-tosyl-2,3,4,5-tetrahydro-1-benzazepin-5-yl)-N-methylamine (II), which is methylated with formaldehyde and sodium cyanoborohydride to yield N-(1-tosyl-2,3,4,5-tetrahydro-1-benzazepin-5-yl)-N,N-dimethylamine (III). The hydrolysis of (III) with polyphosphoric acid affords N-(2,3,4,5-tetrahydro-1-benzazepin-5-yl)-N,N-dimethylamine (IV), which is acylated with 4-nitrobenzoyl chloride to the expected benzoyl derivative (VI). The reduction of the nitro group of (VI) with H2 over Pd/C affords the corresponding 4-aminobenzoyl derivative (VII), which is finally acylated with 2-methylbenzoyl chloride by means of triethylamine in dichloromethane.
| 【1】 Ogawa, H.; Yamashita, H.; Kondo, K.; et al.; Orally active, nonpeptide vasopressin V2 receptor antagonists: A novel series of 1-[4-(benzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepines and related compounds. J Med Chem 1996, 39, 18, 3574. |
| 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) | 14763 | 1-[(4-methylphenyl)sulfonyl]-1,2,3,4-tetrahydro-5H-1-benzazepin-5-one | C17H17NO3S | 详情 | 详情 | |
| (II) | 14764 | N-methyl-1-[(4-methylphenyl)sulfonyl]-2,3,4,5-tetrahydro-1H-1-benzazepin-5-amine; N-methyl-N-[1-[(4-methylphenyl)sulfonyl]-2,3,4,5-tetrahydro-1H-1-benzazepin-5-yl]amine | C18H22N2O2S | 详情 | 详情 | |
| (III) | 14765 | N,N-dimethyl-1-[(4-methylphenyl)sulfonyl]-2,3,4,5-tetrahydro-1H-1-benzazepin-5-amine; N,N-dimethyl-N-[1-[(4-methylphenyl)sulfonyl]-2,3,4,5-tetrahydro-1H-1-benzazepin-5-yl]amine | C19H24N2O2S | 详情 | 详情 | |
| (IV) | 14762 | N,N-dimethyl-2,3,4,5-tetrahydro-1H-1-benzazepin-5-amine; N,N-dimethyl-N-(2,3,4,5-tetrahydro-1H-1-benzazepin-5-yl)amine | C12H18N2 | 详情 | 详情 | |
| (V) | 18941 | p-nitrobenzoyl chloride; 4-nitrobenzoyl chloride | 122-04-3 | C7H4ClNO3 | 详情 | 详情 |
| (VI) | 14768 | [5-(dimethylamino)-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl](4-nitrophenyl)methanone | C19H21N3O3 | 详情 | 详情 | |
| (VII) | 14769 | (4-aminophenyl)[5-(dimethylamino)-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl]methanone | C19H23N3O | 详情 | 详情 | |
| (VIII) | 14770 | 2-methylbenzoyl chloride; o-Toluoyl chloride | 933-88-0 | C8H7ClO | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(II)The required benzothiophenecarboxylic acid precursor (IV) was prepared by Friedel-Crafts acylation of 5-(methylthio)indan (I) with 2-methylbenzoyl chloride (II) followed by condensation of the resulting mercapto ketone (III) with hot chloroacetic acid. Curtius rearrangement of carboxylic acid (IV) using diphenylphosphoryl azide produced isocyanate (V), which was subsequently condensed with 2,6-diethylaniline (VI) to yield the title urea.
| 【1】 Nagamine, M.; Yamamoto, K.; Matsui, Y.; Horiuchi, K.; Yoshida, M. (Nihon Nohyaku Co., Ltd.); N-Heteroaryl-N'-phenylurea derivs., their production and use. CA 2116286; EP 0613894; JP 1994340647; US 5464863 . |
| 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) | 50709 | 2,3-dihydro-1H-inden-5-yl methyl sulfide; 5-(methylsulfanyl)indane | C10H12S | 详情 | 详情 | |
| (II) | 14770 | 2-methylbenzoyl chloride; o-Toluoyl chloride | 933-88-0 | C8H7ClO | 详情 | 详情 |
| (III) | 50710 | (2-methylphenyl)[6-(methylsulfanyl)-2,3-dihydro-1H-inden-5-yl]methanone | C18H18OS | 详情 | 详情 | |
| (IV) | 50711 | 3-(2-methylphenyl)-6,7-dihydro-5H-indeno[5,6-b]thiophene-2-carboxylic acid | C19H16O2S | 详情 | 详情 | |
| (V) | 50712 | 3-(2-methylphenyl)-6,7-dihydro-5H-indeno[5,6-b]thiophen-2-yl isocyanate; 2-isocyanato-3-(2-methylphenyl)-6,7-dihydro-5H-indeno[5,6-b]thiophene | C19H15NOS | 详情 | 详情 | |
| (VI) | 35058 | 2,6-diethylphenylamine; 2,6-diethylaniline | 579-66-8 | C10H15N | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(XIII)5-Chloro-2-nitrobenzoic acid (I) was converted into methyl ester (II) using dimethyl sulfate and K2CO3 in acetone. The nitro group of (II) was then reduced with SnCl2 to afford aniline (III), which was protected as the p-toluenesulfonamide (IV) with tosyl chloride in pyridine. Alkylation of (IV) with ethyl 4-bromobutyrate (V) yielded diester (VI). Subsequent Dieckmann cyclization of (VI) in the presence of potassium tert-butoxide provided benzazepinone (VIIa-b) as a mixture of ethyl and methyl esters, which was decarboxylated to (VIII) by heating with HCl in AcOH. Deprotection of the tosyl group of (VIII) was carried out in hot polyphosphoric acid. The resulting benzazepinone (IX) was condensed with 2-methyl-4-nitrobenzoyl chloride (X) to give amide (XI). After reduction of the nitro group of (XI) to the corresponding aniline (XII), condensation with 2-methylbenzoyl chloride (XIII) provided diamide (XIV). Finally, ketone reduction in (XIV) by means of NaBH4 led to the target compound.
| 【1】 Sorbera, L.A.; Silvestre, J.S.; Castañer, J.; Bayes, M.; Tolvaptan. Drugs Fut 2002, 27, 4, 350. |
| 【2】 Kondo, K.; Yamashita, H.; Ogawa, H.; et al.; 7-Chloro-5-hydroxy-1-[2-methyl-4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-1-benzazepine (OPC-41061): A potent, orally active nonpeptide arginine vasopressin V2 receptor antagonist. Bioorg Med Chem 1999, 7, 8, 1743. |
| 【3】 Yabuuchi, Y.; Kora, S.; Tanaka, M.; Miyamoto, H.; Komatsu, H.; Kondo, K.; Yamashita, H.; Tominaga, M.; Ogawa, H.; Nakaya, K. (Otsuka Pharmaceutical Co., Ltd.); Benzoheterocyclic cpds. US 5985869 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VIIa) | 33001 | methyl 7-chloro-1-[(4-methylphenyl)sulfonyl]-5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-4-carboxylate | C19H18ClNO5S | 详情 | 详情 | |
| (VIIb) | 33002 | ethyl 7-chloro-1-[(4-methylphenyl)sulfonyl]-5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-4-carboxylate | C20H20ClNO5S | 详情 | 详情 | |
| (I) | 32996 | 5-chloro-2-nitrobenzoic acid | 2516-95-2 | C7H4ClNO4 | 详情 | 详情 |
| (II) | 32997 | methyl 5-chloro-2-nitrobenzoate | 51282-49-6 | C8H6ClNO4 | 详情 | 详情 |
| (III) | 32998 | methyl 2-amino-5-chlorobenzoate | 5202-89-1 | C8H8ClNO2 | 详情 | 详情 |
| (IV) | 32999 | methyl 5-chloro-2-[[(4-methylphenyl)sulfonyl]amino]benzoate | C15H14ClNO4S | 详情 | 详情 | |
| (V) | 11263 | ethyl 4-bromobutanoate; Ethyl 4-bromobutyrate | 2969-81-5 | C6H11BrO2 | 详情 | 详情 |
| (VI) | 33000 | methyl 5-chloro-2-[(4-ethoxy-4-oxobutyl)[(4-methylphenyl)sulfonyl]amino]benzoate | C21H24ClNO6S | 详情 | 详情 | |
| (VIII) | 33003 | 7-chloro-1-[(4-methylphenyl)sulfonyl]-1,2,3,4-tetrahydro-5H-1-benzazepin-5-one | C17H16ClNO3S | 详情 | 详情 | |
| (IX) | 33004 | 7-chloro-1,2,3,4-tetrahydro-5H-1-benzazepin-5-one | C10H10ClNO | 详情 | 详情 | |
| (X) | 33005 | 2-methyl-4-nitrobenzoyl chloride | C8H6ClNO3 | 详情 | 详情 | |
| (XI) | 33006 | 7-chloro-1-(2-methyl-4-nitrobenzoyl)-1,2,3,4-tetrahydro-5H-1-benzazepin-5-one | C18H15ClN2O4 | 详情 | 详情 | |
| (XII) | 33007 | 1-(4-amino-2-methylbenzoyl)-7-chloro-1,2,3,4-tetrahydro-5H-1-benzazepin-5-one | C18H17ClN2O2 | 详情 | 详情 | |
| (XIII) | 14770 | 2-methylbenzoyl chloride; o-Toluoyl chloride | 933-88-0 | C8H7ClO | 详情 | 详情 |
| (XIV) | 33008 | N-[4-[(7-chloro-5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl)carbonyl]-3-methylphenyl]-2-methylbenzamide | C26H23ClN2O3 | 详情 | 详情 |