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【结 构 式】 
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【分子编号】12856 【品名】4-(2-Hydroxyethyl)morpholine; 2-(4-Morpholinyl)-1-ethanol; N-(2-Hydroxyethyl)morpholine 【CA登记号】622-40-2 |
【 分 子 式 】C6H13NO2 【 分 子 量 】131.17476 【元素组成】C 54.94% H 9.99% N 10.68% O 24.39% |
合成路线1
该中间体在本合成路线中的序号：(III)Commercially available mycophelonic acid (I) is converted to its chloride (II) by means of thionyl chloride in dichloromethane/DMF and then esterified with 2-(4-morpholinyl)ethanol (III) in dichloromethane.
| 【1】 Robinson, C.; Castaner, J.; Mycophenolate Mofetil. Drugs Fut 1995, 20, 4, 356. |
| 【2】 Allison, A.C.; Eugui, E.M.; Nelson, P.H.; Gu, C.-L.L.; Lee, W.A. (Syntex (USA), Inc.); Treatment of allograft rejection with mycophenolic acid morpholinoethyl ester and derivs. Thereof. US 4786637 . |
| 【3】 Nelson, P.H.; Gu, C.-L.L.; Allison, A.C.; Eugui, E.M.; Lee, W.A. (Syntex (USA), Inc.); Morpholinoethylesters of mycophenolic acid and pharmaceutical compsns. AU 8782540; EP 0281713; JP 1988188672; US 4753935 . |
| 【4】 Leung, K.; Nelson, P.H.; Miksztal, A.R.; Lee, W.A.; Gu, L.; Chu, N.; Bioavailability improvement of mycophenolic acid through amino ester derivatization. Pharm Res 1990, 7, 2, 161-6. |
| 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) | 12854 | Mycophenolic acid; (E)-6-(4-Hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-2-benzofuran-5-yl)-4-methyl-4-hexenoic acid | 483-60-3 | C17H20O6 | 详情 | 详情 |
| (II) | 12855 | (E)-6-(4-Hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-2-benzofuran-5-yl)-4-methyl-4-hexenoyl chloride | C17H19ClO5 | 详情 | 详情 | |
| (III) | 12856 | 4-(2-Hydroxyethyl)morpholine; 2-(4-Morpholinyl)-1-ethanol; N-(2-Hydroxyethyl)morpholine | 622-40-2 | C6H13NO2 | 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 esterification of mycophenolic acid (I) with 2-(4-morpholinyl)ethanol (II) in refluxing dibutyl ether or refluxing dipentyl ether with azeotropic distillation of water gives the target mycophenolic ester.
| 【1】 Chudlik, M.; Husek, A. (Galena AS; Ivax Corp.); Method of mycophenolate mofetil preparation. WO 02100855 . |
合成路线3
该中间体在本合成路线中的序号：(V)In a different procedure, 2-chloronicotinic acid (III) was chlorinated to (IV) by means of boiling thionyl chloride. Condensation of acid chloride (IV) with 2-morpholinoethanol (V) gave rise to the morpholinoethyl chloronicotinate (VI). Finally, displacement of the 2-chloro with m-(trifluoromethyl)aniline (VII) in the presence of zinc oxide and iodine furnished the title compound.
| 【1】 Chiesi, P.; Servadio, V.; Pighi, R. (Chiesi Farmaceutici SpA); Processes for the preparation of morniflumate and analogous cpds.. EP 0349902 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (III) | 28824 | 2-Chloropyridine-3-carboxylic acid; 2-Chloronicotinic acid | 2942-59-8 | C6H4ClNO2 | 详情 | 详情 |
| (IV) | 15224 | 2-chloronicotinoyl chloride | 49609-84-9 | C6H3Cl2NO | 详情 | 详情 |
| (V) | 12856 | 4-(2-Hydroxyethyl)morpholine; 2-(4-Morpholinyl)-1-ethanol; N-(2-Hydroxyethyl)morpholine | 622-40-2 | C6H13NO2 | 详情 | 详情 |
| (VI) | 56318 | 2-(4-morpholinyl)ethyl 2-chloronicotinate | C12H15ClN2O3 | 详情 | 详情 | |
| (VII) | 26347 | 3-(trifluoromethyl)phenylamine; 3-(trifluoromethyl)aniline; 3-aminobenzotrifluoride | 98-16-8 | C7H6F3N | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(V)Alternatively, acid chloride (IV), prepared from 2-chloronicotinic acid (III), was treated with methanol and triethylamine to afford the methyl ester (VIII). Displacement of the 2-chloro with m-(trifluoromethyl)aniline (VII) yielded methyl niflumate (IX). Finally, transesterification of methyl ester (IX) with 2-morpholinoethanol (V) in the presence of sodium metal gave rise to the title compound.
| 【1】 Chiesi, P.; Servadio, V.; Pighi, R. (Chiesi Farmaceutici SpA); Processes for the preparation of morniflumate and analogous cpds.. EP 0349902 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (III) | 28824 | 2-Chloropyridine-3-carboxylic acid; 2-Chloronicotinic acid | 2942-59-8 | C6H4ClNO2 | 详情 | 详情 |
| (IV) | 15224 | 2-chloronicotinoyl chloride | 49609-84-9 | C6H3Cl2NO | 详情 | 详情 |
| (V) | 12856 | 4-(2-Hydroxyethyl)morpholine; 2-(4-Morpholinyl)-1-ethanol; N-(2-Hydroxyethyl)morpholine | 622-40-2 | C6H13NO2 | 详情 | 详情 |
| (VII) | 26347 | 3-(trifluoromethyl)phenylamine; 3-(trifluoromethyl)aniline; 3-aminobenzotrifluoride | 98-16-8 | C7H6F3N | 详情 | 详情 |
| (VIII) | 56319 | methyl 2-chloronicotinate | C7H6ClNO2 | 详情 | 详情 | |
| (IX) | 56320 | methyl 2-[3-(trifluoromethyl)anilino]nicotinate | C14H11F3N2O2 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(VI)The cyclization of 4-methylphenylhydrazine (I) with pivaloylacetonitrile (II) in refluxing methanol gives the aminopyrazole (III), which is treated with Troc-Cl and NaOH in water/ethyl acetate to yield the carbamate (IV). Finally, this compound is condensed with 4-[2-(4-morpholinyl)ethoxy]naphthalene-1-amine (V) by means of DIEA in hot DMSO to afford the target urea. The intermediate 4-[2-(4-morpholinyl)ethoxy]naphthalene-1-amine (V) is obtained by condensation of 2-(4-morpholinyl)ethanol (VI) with 4-nitro-1-naphthol (VII) by means of NaOH and K2CO3 in hot 1-methyl-2-pyrrolidone to yield the corresponding ether (VIII), which is finally reduced with H2 over Pd/C in methanol.
| 【1】 Zhang, L.-H.; Zhu, L. (Boehringer Ingelheim Pharmaceuticals Inc.); Novel process for synthesis of heteroaryl-substd. urea cpds.. WO 0104115 . |
| 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) | 20387 | 1-(4-methylphenyl)hydrazine | C7H10N2 | 详情 | 详情 | |
| (II) | 44248 | 4,4-dimethyl-3-oxopentanenitrile | 59997-51-2 | C7H11NO | 详情 | 详情 |
| (III) | 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 | |
| (IV) | 55426 | 2,2,2-trichloroethyl 3-(tert-butyl)-1-(4-methylphenyl)-1H-pyrazol-5-ylcarbamate | C17H20Cl3N3O2 | 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) | 12856 | 4-(2-Hydroxyethyl)morpholine; 2-(4-Morpholinyl)-1-ethanol; N-(2-Hydroxyethyl)morpholine | 622-40-2 | C6H13NO2 | 详情 | 详情 |
| (VII) | 55428 | 4-nitro-1-naphthol | C10H7NO3 | 详情 | 详情 | |
| (VIII) | 55429 | 2-(4-morpholinyl)ethyl 4-nitro-1-naphthyl ether; 4-{2-[(4-nitro-1-naphthyl)oxy]ethyl}morpholine | C16H18N2O4 | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(XIII)Ether cleavage of methyl 5-methoxybenzofuran-2-carboxylate (XI) was achieved by treatment with aluminum chloride and ethanethiol to provide phenol (XII). Subsequent Mitsunobu coupling of the resulting phenol derivative (XII) with N-(2-hydroxyethyl)morpholine (XIII) gave ether (XIV). Basic hydrolysis of the ester group provided acid (XV), which was further coupled with the intermediate amine (X) to yield amide (XVI). Finally, oxidation of the alcohol function of (XVI) under Swern conditions gave rise to the title ketone derivative.
| 【1】 Bondinell, W.E.; Desjarlais, R.L.; Yamashita, D.S.; Veber, D.F. (GlaxoSmithKline Inc.); Protease inhibitors. WO 9959526 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (X) | 50909 | (2S)-2-amino-N-[(1S)-2-hydroxy-1-methyl-3-([2-[3-(2-pyridinyl)phenyl]acetyl]amino)propyl]-4-methylpentanamide | C23H32N4O3 | 详情 | 详情 | |
| (XI) | 50910 | methyl 5-methoxy-1-benzofuran-2-carboxylate | C11H10O4 | 详情 | 详情 | |
| (XII) | 50911 | methyl 5-hydroxy-1-benzofuran-2-carboxylate | C10H8O4 | 详情 | 详情 | |
| (XIII) | 12856 | 4-(2-Hydroxyethyl)morpholine; 2-(4-Morpholinyl)-1-ethanol; N-(2-Hydroxyethyl)morpholine | 622-40-2 | C6H13NO2 | 详情 | 详情 |
| (XIV) | 50912 | methyl 5-[2-(4-morpholinyl)ethoxy]-1-benzofuran-2-carboxylate | C16H19NO5 | 详情 | 详情 | |
| (XV) | 50913 | 5-[2-(4-morpholinyl)ethoxy]-1-benzofuran-2-carboxylic acid | C15H17NO5 | 详情 | 详情 | |
| (XVI) | 50914 | N-[(1S)-1-([[(1S)-2-hydroxy-1-methyl-3-([2-[3-(2-pyridinyl)phenyl]acetyl]amino)propyl]amino]carbonyl)-3-methylbutyl]-5-[2-(4-morpholinyl)ethoxy]-1-benzofuran-2-carboxamide | C38H47N5O7 | 详情 | 详情 |