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【结 构 式】 
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【分子编号】27355 【品名】4-(2-chloroethyl)morpholine 【CA登记号】3647-69-6 |
【 分 子 式 】C6H12ClNO 【 分 子 量 】149.62012 【元素组成】C 48.17% H 8.08% Cl 23.7% N 9.36% O 10.69% |
合成路线1
该中间体在本合成路线中的序号：(III)Selenious acid (H2SeO3) is successfully reduced by sodium borohydride (in excess) to form NaHSe (II). After reacting with beta-morpholinoethyl chloride (III) the bis(beta-morpholinoethyl)selenide is the only product and no diselenide is isolated. The unreacted NaHSe is reoxidized during the workup to insoluble Sex, which is easily separated by filtration. The product is separated from unreduced H2SeO3 by chloroform extraction. This procedure is also useful for the preparation radioactive MOSE using Se-75 (t1/2 = 120 days). The purity of the extracted material is 95%.
| 【1】 Gandolfi, C.; Pellegata, R. Fumagalli, A. (Pharmacia & Upjohn SpA); 13,14-Dehydro-11-deoxy-prostaglandins and process for their preparation. US 4293705 . |
| 【2】 Kung, H.F.; Kostyniak, P.J.; Mose. Drugs Fut 1985, 10, 9, 748. |
合成路线2
该中间体在本合成路线中的序号：(II)This compound can be obtained by two related ways: 1) The condensation of 2-methylindole (I) with 2-morpholinoethyl chloride (II) by means of KOH in hot DMSO gives 1-(2-morpholinoethyl)-2-methylindole (III), which is then submitted to a Friedel-Craft's reaction with 4-methoxybenzoyl chloride (IV) by means of AlCl3 in dichloromethane or ethylene dichloride. 2) The condensation of indole (I) with acyl chloride (IV) by means of methylmagnesium bromide in anhydrous ethyl ether gives 2-methyl-3-(4-methoxy benzoyl)indole (V), which is then condensed with morpholine (II) by means of K2CO3 in DMF.
| 【1】 Bell, M.R. (Sanofi-Synthelabo); 3-Carbonyl-1-aminoalkyl-1H-indoles useful as analgesics and preparation thereof. AU 8545764; EP 0171037; ES 8609246; ES 8800149; ES 8800901; ES 8800902; ES 8801203; JP 1986047463 . |
| 【2】 Castaner, R.M.; Castaner, J.; Serradell, M.N.; WIN-48098. Drugs Fut 1987, 12, 9, 867. |
| 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) | 28747 | 2-methyl-1H-indole | 95-20-5 | C9H9N | 详情 | 详情 |
| (II) | 27355 | 4-(2-chloroethyl)morpholine | 3647-69-6 | C6H12ClNO | 详情 | 详情 |
| (III) | 28748 | 4-[2-(2-methyl-1H-inden-1-yl)ethyl]morpholine | C16H21NO | 详情 | 详情 | |
| (IV) | 22671 | 4-Methoxybenzoyl chloride; p-Methoxybenzoyl chloride; 4-Anisoyl chloride | 100-07-2 | C8H7ClO2 | 详情 | 详情 |
| (V) | 28749 | (4-methoxyphenyl)(2-methyl-1H-indol-3-yl)methanone | C17H15NO2 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(II)The title morpholinoethyl ester was prepared by reaction of niflumic acid (I) with N-(2-chloroethyl)morpholine (II) in refluxing isopropanol.
| 【1】 Hoffmann, C. (Hexachimie SA); 2-Anilino-nicotinic acid esters. US 3708481 . |
合成路线4
该中间体在本合成路线中的序号：(XXVI)Assembly of the target compound: The reaction of methyl 3-bromopropionate (XVII) with ethylmagnesium bromide (XVIII) and Ti(iPrO)4 gives 1-(2-bromoethyl)cyclopropan-1-ol (XIX), which is brominated by NBS in CCl4 to yield 1,5-dibromo-3-pentanone (XX). The reaction of (XX) with ethylene glycol (XXI), HC(OEt)3 and PPTS affords the cyclic ketal (XXII), which is cyclized with the indolinone intermediate (VII) by means of NaH in DMF to provide the spiro compound (XXIII). The deprotection of (XXIII) with PPTS in acetone/water gives the spiranic diketone (XXIV), which is selectively reduced with NaBH4 in methanol to yield the spiro cyclohexanol (XXV). The condensation of (XXV) with 4-(2-chloroethyl)morpholine (XXVI) by means of NaH in hot toluene affords the corresponding ether (XXVII), which is debenzylated by means of Li/NH3 to provide intermediate (XXVIII) with a free NH group. Finally, the sulfonation of (XXVIII) with intermediate chlorosulfonyl benzamide (XVI) by means of potassium tert-butoxide gives the target sulfonyl benzamide compound.
| 【1】 Venkatesan, H.; et al.; Total synthesis of SR 121463 A, a highly potent and selective vasopressin V2 receptor antagonist. J Org Chem 2001, 66, 11, 3653. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VII) | 50276 | 1-benzyl-5-ethoxy-1,3-dihydro-2H-indol-2-one | C17H17NO2 | 详情 | 详情 | |
| (XVI) | 50284 | 4-[(tert-butylamino)carbonyl]-2-methoxybenzenesulfonyl chloride | C12H16ClNO4S | 详情 | 详情 | |
| (XVII) | 50285 | 3-Bromopropionic acid methyl ester; Methyl 3-bromopropionate | 3395-91-3 | C4H7BrO2 | 详情 | 详情 |
| (XVIII) | 24239 | bromo(ethyl)magnesium；ethylmagnesium bromide | 925-90-6 | C2H5BrMg | 详情 | 详情 |
| (XIX) | 50286 | 1-(2-bromoethyl)cyclopropanol | C5H9BrO | 详情 | 详情 | |
| (XX) | 50287 | 1,5-dibromo-3-pentanone | C5H8Br2O | 详情 | 详情 | |
| (XXI) | 11295 | Polyethylene glycol;1,2-Ethanediol;Monoethylene glycol; Ethylene glycol | 107-21-1 | C2H6O2 | 详情 | 详情 |
| (XXII) | 50288 | 2,2-bis(2-bromoethyl)-1,3-dioxolane | C7H12Br2O2 | 详情 | 详情 | |
| (XXIII) | 50289 | C24H27NO4 | 详情 | 详情 | ||
| (XXIV) | 50290 | C22H23NO3 | 详情 | 详情 | ||
| (XXV) | 50291 | C22H25NO3 | 详情 | 详情 | ||
| (XXVI) | 27355 | 4-(2-chloroethyl)morpholine | 3647-69-6 | C6H12ClNO | 详情 | 详情 |
| (XXVII) | 50292 | C28H36N2O4 | 详情 | 详情 | ||
| (XXVIII) | 50293 | C21H30N2O4 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(III)The N-protection of 4-amino-1-naphthol (I) with Boc2O by means of BuLi in THF gives the carbamate (II), which is condensed with 4-(2-chloroethyl)morpholine (III) by means of K2CO3 in hot acetonitrile, yielding the corresponding aryl ether (IV). The deprotection of the amino group of (IV) with HCl in dioxane affords the naphthylamine (V), which is finally condensed with 3-(tert-butyl)-1-(4-methylphenyl)-1H-pyrazole-5-amine (VI) by means of COCl2 in toluene/dichloromethane and aq. NaHCO3 to provide the target urea. The intermediate 3-(tert-butyl)-1-(4-methylphenyl)-1H-pyrazole-5-amine (VI) is obtained by cyclization of 4-methylphenylhydrazine (VII) with 4,4-dimethyl-3-oxopentanenitrile (VIII) by means of HCl in refluxing ethanol.
| 【1】 Regan, J.R.; Zhang, L.-H.; Cirillo, P.F.; Hickey, E.R.; Gilmore, T.A. (Boehringer Ingelheim Pharmaceuticals Inc.); Aromatic heterocyclic cpds. as antiinflammatory agents. EP 1147104; US 6319921; WO 0043384 . |
| 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) | 55430 | 4-Amino-1-naphthol | C10H9NO | 详情 | 详情 | |
| (II) | 55431 | tert-butyl 4-hydroxy-1-naphthylcarbamate | C15H17NO3 | 详情 | 详情 | |
| (III) | 27355 | 4-(2-chloroethyl)morpholine | 3647-69-6 | C6H12ClNO | 详情 | 详情 |
| (IV) | 55432 | tert-butyl 4-[2-(4-morpholinyl)ethoxy]-1-naphthylcarbamate | C21H28N2O4 | 详情 | 详情 | |
| (V) | 55427 | 4-[2-(4-morpholinyl)ethoxy]-1-naphthalenamine; 4-[2-(4-morpholinyl)ethoxy]-1-naphthylamine | C16H20N2O2 | 详情 | 详情 | |
| (VI) | 55425 | 3-(tert-butyl)-1-(4-methylphenyl)-1H-pyrazol-5-amine; 3-(tert-butyl)-1-(4-methylphenyl)-1H-pyrazol-5-ylamine | C14H19N3 | 详情 | 详情 | |
| (VII) | 20387 | 1-(4-methylphenyl)hydrazine | C7H10N2 | 详情 | 详情 | |
| (VIII) | 44248 | 4,4-dimethyl-3-oxopentanenitrile | 59997-51-2 | C7H11NO | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(III)The reaction of 4-amino-1-naphthol (I) with Boc2O in THF gives the carbamate (II), which is condensed with 4-(2-chloroethyl)morpholine (III) by means of K2CO3 in hot acetonitrile to yield ether (IV). The hydrolysis of the carbamate group of (IV) by means of HCl in dioxane affords the naphthylamine (V), which is finally condensed with 3-tert-butyl-1-(4-methylphenyl)-1H-pyrazol-5-amine (VI) and phosgene (VII) in THF to provide the target urea. The intermediates 3-tert-butyl-1-(4-methylphenyl)-1H-pyrazol-5-amine (VI) and phosgene (VII) are obtained by cyclization of 4-methylphenylhydrazine (VIII) with 4,4-dimethyl-3-oxopentanenitrile (IX) in refluxing toluene or by means of HCl in refluxing ethanol.
| 【1】 Regan, J.; et al.; Pyrazole urea-based inhibtitors of p38 MAP kinase: From lead compound to clinical candidate. J Med Chem 2002, 45, 14, 2994. |
| 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) | 55430 | 4-Amino-1-naphthol | C10H9NO | 详情 | 详情 | |
| (II) | 55431 | tert-butyl 4-hydroxy-1-naphthylcarbamate | C15H17NO3 | 详情 | 详情 | |
| (III) | 27355 | 4-(2-chloroethyl)morpholine | 3647-69-6 | C6H12ClNO | 详情 | 详情 |
| (IV) | 55432 | tert-butyl 4-[2-(4-morpholinyl)ethoxy]-1-naphthylcarbamate | C21H28N2O4 | 详情 | 详情 | |
| (V) | 55427 | 4-[2-(4-morpholinyl)ethoxy]-1-naphthalenamine; 4-[2-(4-morpholinyl)ethoxy]-1-naphthylamine | C16H20N2O2 | 详情 | 详情 | |
| (VI) | 55425 | 3-(tert-butyl)-1-(4-methylphenyl)-1H-pyrazol-5-amine; 3-(tert-butyl)-1-(4-methylphenyl)-1H-pyrazol-5-ylamine | C14H19N3 | 详情 | 详情 | |
| (VII) | 56933 | carbonic dichloride | CCl2O | 详情 | 详情 | |
| (VIII) | 20387 | 1-(4-methylphenyl)hydrazine | C7H10N2 | 详情 | 详情 | |
| (IX) | 44248 | 4,4-dimethyl-3-oxopentanenitrile | 59997-51-2 | C7H11NO | 详情 | 详情 |
合成路线7
该中间体在本合成路线中的序号：(V)By condensation of diethyl 1,4-dihydro-4-(2-trifluoromethylphenyl)-2,6-dimethylpyridine-3,5-dicarboxylate (IV) with N-(2-chloroethyl)morpholine (V) by means of NaH in hot DMF - toluene
| 【1】 Loev, B.; Shroff, J.R. (USV Pharmaceutical Corp.); BE 888327; DE 3109794; FR 2480284; GB 2073739; JP 81158762; US 4258042 . |
| 【2】 Blancafort, P.; Serradell, M.N.; Castaner, J.; Thorpe, P.J.; Flordipine. Drugs Fut 1983, 8, 9, 770. |
合成路线8
该中间体在本合成路线中的序号：(VIII)The reaction of 2-(benzyloxy)aniline (I) with acetic anhydride and pyridine gives the acetanilide (II), which is treated with P2S5 in hot toluene to yield the thioacetamide (III). The reaction of (III) with methyl iodide and K2CO3 in hot acetonitrile affords the methylated thioimidate (IV), which is cyclized with biphenyl-4-carbohydrazide (V) in hot DMF to provide 4-(2-benzyloxyphenyl)-3-(4-biphenylyl)-5-methyl-4H-1,2,4-triazole (VI). The hydrogenation of (VI) with H2 over Pd/C in methanol gives the corresponding phenol (VII), which is finally alkylated by means of 4-(2-chloroethyl)morpholine (VIII) and NaH in hot DMF to yield the target triazole. (1,2)
| 【1】 Kakefuda, A.; Suzuki, T.; Tobe, T.; Tahara, A.; Sakamoto, S.; Tsukamoto, S.-I.; Discovery of 4,5-diphenyl-1,2,4-triazole derivatives as a novel class of selective antagonists for the human V1A receptor. Bioorg Med Chem 2002, 10, 6, 1905. |
| 【2】 Suzuki, T.; Murakami, T.; Tobe, T.; Tahara, A. (Yamanouchi Pharmaceutical Co., Ltd.); Novel triazole derivs.. WO 0158880 . |
| 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) | 18065 | 2-(benzyloxy)aniline; 2-(benzyloxy)phenylamine | C13H13NO | 详情 | 详情 | |
| (II) | 56977 | N-[2-(benzyloxy)phenyl]acetamide | C15H15NO2 | 详情 | 详情 | |
| (III) | 56978 | N-[2-(benzyloxy)phenyl]ethanethioamide | C15H15NOS | 详情 | 详情 | |
| (IV) | 56979 | methyl N-[2-(benzyloxy)phenyl]ethanimidothioate | C16H17NOS | 详情 | 详情 | |
| (V) | 56980 | 4-Biphenylcarboxylic acid hydrazide; 4-Phenylbenzhydrazide | 18622-23-6 | C13H12N2O | 详情 | 详情 |
| (VI) | 56981 | benzyl 2-(3-[1,1'-biphenyl]-4-yl-5-methyl-4H-1,2,4-triazol-4-yl)phenyl ether; 4-[2-(benzyloxy)phenyl]-3-[1,1'-biphenyl]-4-yl-5-methyl-4H-1,2,4-triazole | C28H23N3O | 详情 | 详情 | |
| (VII) | 56982 | 2-(3-[1,1'-biphenyl]-4-yl-5-methyl-4H-1,2,4-triazol-4-yl)phenol | C21H17N3O | 详情 | 详情 | |
| (VIII) | 27355 | 4-(2-chloroethyl)morpholine | 3647-69-6 | C6H12ClNO | 详情 | 详情 |