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【结 构 式】 
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【分子编号】15847 【品名】4-morpholinecarbonyl chloride; Morpholine-4-carbonyl chloride 【CA登记号】15159-40-7 |
【 分 子 式 】C5H8ClNO2 【 分 子 量 】149.57676 【元素组成】C 40.15% H 5.39% Cl 23.7% N 9.36% O 21.39% |
合成路线1
该中间体在本合成路线中的序号：(III)By condensation of 2(S)-[N-methyl-N-[2-[N-methyl-N-(morpholinocarbonyl)amino]ethyl]carbamoyloxy]-3-phenylpropanoic acid (I) with protected Nalpha-methyl-L-histidine 1(S)-(cyclohexylmethyl)-2(S)-hydroxy-5-methylhexylamide (II) by means of oxalyl chloride and DMF in dichloromethane. The starting compounds (I) and (II) are obtained as follows: 1) The reaction of morpholinocarbonyl chloride (III) with N-(tert-butoxycarbonyl)-N,N'-dimethylethylenediamine (IV) by means of triethylamine in dichloromethane gives the monoacylated diamine (V), which is deprotected with trifluoroacetic acid to yield N,N'-dimethyl-N-(morpholinocarbonyl)ethylenediamine (VI). The condensation of (VI) with 2(S)-hydroxy-3-phenylpropanoic acid benzyl ester (VII) by means of trichloromethyl chloroformate in refluxing THF affords 2(S)-[N-methyl-N-[2-[N-methyl-N-(morpholinocarbonyl)amino]ethyl]carbamoyloxy]propanoic acid benzyl ester (VIII), which is finally debenzylated by hydrogenation with H2 over Pd/C to give (I). 2) The Grignard reaction of tert-butoxycarbonyl-(3-cyclohexyl)-L-alaninal (IX) with 3-methylbutylmagnesium bromide (X) in THF gives 2(S)-(tert-butoxycarbonylamino)-1-cyclohexyl-3(S)-hydroxy-6-methylheptane (XI), which is deprotected with trifluoroacetic acid to yield the free amine derivative (XII). The condensation of (XII) with Nalpha-(tert-butoxycarbonyl)-Nalpha-methyl-Ntau-tosyl-L-histidine (XIII) by means of N-ethyl-N'-[3-(dimethylamino)propyl]carbodiimide (CDI) in dichloromethane affords the corresponding histidinamide (XIV), which is deprotected with trifluoroacetic acid to afford (II).
| 【1】 Hemmi, K.; Neya, M.; Marusawa, H.; Imai, K.; Kayakiri, N.; Hashimoto, M. (Fujisawa Pharmaceutical Co., Ltd.); New amino acid derivs. processes for the preparation thereof and pharmaceutical compsns. containing the same. AU 8818190; EP 0300189; JP 1989019071; US 4921855; US 5223489 . |
| 【2】 Prous, J.; Castaner, J.; FK-906. Drugs Fut 1993, 18, 4, 312. |
| 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) | 15845 | (2S)-2-[[(methyl[2-[methyl(morpholinocarbonyl)amino]ethyl]amino)carbonyl]oxy]-3-phenylpropionic acid | C19H27N3O6 | 详情 | 详情 | |
| (II) | 15846 | (2S)-N-[(1S,2S)-1-(cyclohexylmethyl)-2-hydroxy-5-methylhexyl]-2-(methylamino)-3-[1-[(4-methylphenyl)sulfonyl]-1H-imidazol-4-yl]propanamide | C28H44N4O4S | 详情 | 详情 | |
| (III) | 15847 | 4-morpholinecarbonyl chloride; Morpholine-4-carbonyl chloride | 15159-40-7 | C5H8ClNO2 | 详情 | 详情 |
| (IV) | 15848 | tert-butyl N-methyl-N-[2-(methylamino)ethyl]carbamate | C9H20N2O2 | 详情 | 详情 | |
| (V) | 15849 | tert-butyl N-methyl-N-[2-[methyl(morpholinocarbonyl)amino]ethyl]carbamate | C14H27N3O4 | 详情 | 详情 | |
| (VI) | 15850 | N-methyl-N-[2-(methylamino)ethyl]-4-morpholinecarboxamide | C9H19N3O2 | 详情 | 详情 | |
| (VII) | 15851 | Benzyl (s)-(-)-2-hydroxy-3-phenylpropionate; benzyl (2S)-2-hydroxy-3-phenylpropanoate | 7622-21-1 | C16H16O3 | 详情 | 详情 |
| (VIII) | 15852 | benzyl (2S)-2-[[(methyl[2-[methyl(morpholinocarbonyl)amino]ethyl]amino)carbonyl]oxy]-3-phenylpropanoate | C26H33N3O6 | 详情 | 详情 | |
| (IX) | 15853 | tert-butyl N-[(1S)-2-cyclohexyl-1-formylethyl]carbamate | C14H25NO3 | 详情 | 详情 | |
| (X) | 13532 | Bromo(isopentyl)magnesium | C5H11BrMg | 详情 | 详情 | |
| (XI) | 15855 | tert-butyl N-[(1S,2S)-1-(cyclohexylmethyl)-2-hydroxy-5-methylhexyl]carbamate | C19H37NO3 | 详情 | 详情 | |
| (XII) | 15856 | (2S,3S)-2-amino-1-cyclohexyl-6-methyl-3-heptanol | C14H29NO | 详情 | 详情 | |
| (XIII) | 15857 | (2S)-2-[(tert-butoxycarbonyl)(methyl)amino]-3-[1-[(4-methylphenyl)sulfonyl]-1H-imidazol-4-yl]propionic acid | C19H25N3O6S | 详情 | 详情 | |
| (XIV) | 15858 | tert-butyl (1S)-2-[[(1S,2S)-1-(cyclohexylmethyl)-2-hydroxy-5-methylhexyl]amino]-1-([1-[(4-methylphenyl)sulfonyl]-1H-imidazol-4-yl]methyl)-2-oxoethyl(methyl)carbamate | C33H52N4O6S | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XIII)3,4-Dimethoxybenzoic acid (I) is converted into oxazoline (II) by known methods. This compound is treated with BuLi and I2 in ethyl ether to yield the 2-iodo derivative (III), which is treated with POCl3 in hot pyridine to afford 2-iodo-3,4-dimethoxybenzonitrile (IV). The nitration of (IV) by means of nitronium tetrafluoroborate in acetonitrile provides 2-iodo-3,4-dimethoxy-6-nitrobenzonitrile (V), which is condensed with 4-fluorophenylboronic acid (VI) by means of Pd(PPh3)4 in toluene/ethanol to give the biphenyl derivative (VII). The reduction of the nitro group of (VII) by means of sodium dithionite in DMF/water yields the corresponding amino derivative (VIII), which is condensed with 1-acetyl-4-(morpholin-4-ylcarbonyl)perhydro-1,4-diazepine (IX) by means of POCl3 in dichloromethane to afford the adduct (X). Finally, this compound is cyclized by means of LDA in THF to provide the target quinoline derivative. The intermediate 1-acetyl-4-(morpholin-4-ylcarbonyl)perhydro-1,4-diazepine (IX) has been obtained as follows: The reaction of perhydro-1,4-diazepine (XI) with Boc2O in dichloromethane gives the monoprotected diazepine (XII), which is condensed with morpholin-4-yl-carbonyl chloride (XIII) by means of TEA in dichloromethane to yield the acylated diazepine (XIV). The deprotection of (XIV) by means of HCl in dichloromethane/methanol affords the deprotected diazepine (XV), which is finally acylated with acetic anhydride and TEA in dichloromethane to provide the target intermediate (IX).
| 【1】 Collis, A.J.; Fox, D.N.A.; Newman, J. (Pfizer Inc.); Quinoline and quinazoline cpds. useful in therapy. EP 0877734; JP 1999501668; US 6103738; WO 9723462 . |
| 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) | 13439 | 3,4-Dimethoxybenzoic acid | 93-07-2 | C9H10O4 | 详情 | 详情 |
| (II) | 54071 | 2-(3,4-dimethoxyphenyl)-4,4-dimethyl-4,5-dihydro-1,3-oxazole; 4-(4,4-dimethyl-4,5-dihydro-1,3-oxazol-2-yl)-2-methoxyphenyl methyl ether | n/a | C13H17NO3 | 详情 | 详情 |
| (III) | 54072 | 2-(2-iodo-3,4-dimethoxyphenyl)-4,4-dimethyl-4,5-dihydro-1,3-oxazole; 3-(4,4-dimethyl-4,5-dihydro-1,3-oxazol-2-yl)-2-iodo-6-methoxyphenyl methyl ether | n/a | C13H16INO3 | 详情 | 详情 |
| (IV) | 54073 | 2-iodo-3,4-dimethoxybenzonitrile | n/a | C9H8INO2 | 详情 | 详情 |
| (V) | 54074 | 2-iodo-3,4-dimethoxy-6-nitrobenzonitrile | n/a | C9H7IN2O4 | 详情 | 详情 |
| (VI) | 38403 | 4-fluorophenylboronic acid | 1765-93-1 | C6H6BFO2 | 详情 | 详情 |
| (VII) | 54075 | 4'-fluoro-5,6-dimethoxy-3-nitro[1,1'-biphenyl]-2-carbonitrile | n/a | C15H11FN2O4 | 详情 | 详情 |
| (VIII) | 54076 | 3-amino-4'-fluoro-5,6-dimethoxy[1,1'-biphenyl]-2-carbonitrile | n/a | C15H13FN2O2 | 详情 | 详情 |
| (IX) | 54077 | 1-[4-(4-morpholinylcarbonyl)-1,4-diazepan-1-yl]-1-ethanone | n/a | C12H21N3O3 | 详情 | 详情 |
| (X) | 54078 | 4'-fluoro-5,6-dimethoxy-3-({(E)-1-[4-(4-morpholinylcarbonyl)-1,4-diazepan-1-yl]ethylidene}amino)[1,1'-biphenyl]-2-carbonitrile | n/a | C27H32FN5O4 | 详情 | 详情 |
| (XI) | 25030 | 1,4-diazepane | 505-66-8 | C5H12N2 | 详情 | 详情 |
| (XII) | 54079 | tert-Butyl 1-homopiperazine carboxylate | n/a | C10H20N2O2 | 详情 | 详情 |
| (XIII) | 15847 | 4-morpholinecarbonyl chloride; Morpholine-4-carbonyl chloride | 15159-40-7 | C5H8ClNO2 | 详情 | 详情 |
| (XIV) | 54080 | tert-butyl 4-(4-morpholinylcarbonyl)-1,4-diazepane-1-carboxylate | n/a | C15H27N3O4 | 详情 | 详情 |
| (XV) | 54081 | 1,4-diazepan-1-yl(4-morpholinyl)methanone | n/a | C10H19N3O2 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(II)Cyclohexylalanine benzyl ester (I) is acylated by 4-morpholinecarbonyl chloride (II) to furnish the urea derivative (III). The benzyl ester group of (III) is then removed by transfer hydrogenolysis, yielding N-(4-morpholinecarbonyl)-L-cyclohexylalanine (IV).
| 【1】 Frye, L.L.; Cywin, C.L.; Morwick, T.; Spero, D.M.; Thomson, D.; Ward, Y. (Boehringer Ingelheim Pharmaceuticals Inc.); Cpds. useful as reversible inhibitors of cathepsin S. JP 2002538151; US 6395897; WO 0051998 . |
| 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) | 63389 | phenylmethyl 2-amino-3-cyclohexylpropanoate | C16H23NO2 | 详情 | 详情 | |
| (II) | 15847 | 4-morpholinecarbonyl chloride; Morpholine-4-carbonyl chloride | 15159-40-7 | C5H8ClNO2 | 详情 | 详情 |
| (III) | 63390 | phenylmethyl 3-cyclohexyl-2-[(4-morpholinylcarbonyl)amino]propanoate | C21H30N2O4 | 详情 | 详情 | |
| (IV) | 63391 | 3-cyclohexyl-N-(4-morpholinylcarbonyl)alanine | C14H24N2O4 | 详情 | 详情 |