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【结 构 式】 
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【分子编号】45866 【品名】ethyl (2R)-4-[(6-chloro-2-naphthyl)sulfonyl]-6-oxo-1-[[1-(4-pyridinyl)-4-piperidinyl]methyl]-2-piperazinecarboxylate 【CA登记号】 |
【 分 子 式 】C28H31ClN4O5S 【 分 子 量 】571.0968 【元素组成】C 58.89% H 5.47% Cl 6.21% N 9.81% O 14.01% S 5.61% |
合成路线1
该中间体在本合成路线中的序号：(IX)Swern oxidation of 1-(4-pyridinyl)-4-piperidinemethanol (I) affords aldehyde (II). Reductive amination of (II) with the (R)-diaminopropionic acid derivative (III) in the presence of NaBH(OAc)3 yields (IV). Subsequent acylation of (IV) with bromoacetyl chloride (V) provides bromoacetamide (VI). Acidic cleavage of the N-Boc group of (VI), followed by cyclization in the presence of triethylamine leads to piperazinone (VII). Sulfonylation of amine (VII) with 6-chloro-2-naphthalenesulfonyl chloride (VIII) gives (IX). Finally, the target carboxylic acid is obtained by hydrolysis of ethyl ester (IX) under acidic conditions.
| 【1】 Nishida, H.; Miyazaki, Y.; Mukaihira, T.; Saitoh, F.; Fukui, M.; Harada, K.; Itoh, M.; Muraoka, A.; Matsusue, T.; Okamoto, A.; Hosaka, Y.; Matsumoto, M.; Ohnishi, S.; Mochizuki, H.; Synthesis and evaluation of 1-arylsulfonyl-3-piperazinone derivatives as a factor Xa inhibitor II. Substituent effect on biological activities. Chem Pharm Bull 2002, 50, 9, 1187. |
| 【2】 Miyazaki, Y.; Mukaihira, T.; Nishida, H.; Hosaka, Y.; Matsusue, T. (Mochida Pharmaceutical Co., Ltd.); Aromatic cpds. having cyclic amino or salts thereof. EP 1048652; WO 9933805 . |
| 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) | 45860 | [1-(4-pyridinyl)-4-piperidinyl]methanol | C11H16N2O | 详情 | 详情 | |
| (II) | 52205 | 1-(4-pyridinyl)-4-piperidinecarbaldehyde | C11H14N2O | 详情 | 详情 | |
| (III) | 45862 | ethyl (2R)-2-amino-3-[(tert-butoxycarbonyl)amino]propanoate | C10H20N2O4 | 详情 | 详情 | |
| (IV) | 45863 | ethyl (2R)-3-[(tert-butoxycarbonyl)amino]-2-([[1-(4-pyridinyl)-4-piperidinyl]methyl]amino)propanoate | C21H34N4O4 | 详情 | 详情 | |
| (V) | 27903 | 2-Bromoacetyl chloride | 22118-09-8 | C2H2BrClO | 详情 | 详情 |
| (VI) | 45864 | ethyl (2R)-2-((2-bromoacetyl)[[1-(4-pyridinyl)-4-piperidinyl]methyl]amino)-3-[(tert-butoxycarbonyl)amino]propanoate | C23H35BrN4O5 | 详情 | 详情 | |
| (VII) | 61247 | ethyl (2R)-6-oxo-1-{[1-(4-pyridinyl)-4-piperidinyl]methyl}-2-piperazinecarboxylate | C18H26N4O3 | 详情 | 详情 | |
| (VIII) | 45865 | 6-chloro-2-naphthalenesulfonyl chloride | C10H6Cl2O2S | 详情 | 详情 | |
| (IX) | 45866 | ethyl (2R)-4-[(6-chloro-2-naphthyl)sulfonyl]-6-oxo-1-[[1-(4-pyridinyl)-4-piperidinyl]methyl]-2-piperazinecarboxylate | C28H31ClN4O5S | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(VIII)Oxidation of 1-(4-pyridyl)piperidin-4-yl methanol (I) with oxalyl chloride and DMSO in dichloromethane provides carbaldehyde (II), which is then subjected to a reductive amination with amino acid (III) by means of HOAc and triacetoxyborohydride (Na(OAc)3BH) in dichloromethane to provide compound (IV). Condensation of (IV) with bromoacetyl chloride (V) in dichloromethane in the presence of Et3N furnishes derivative (VI), which is converted into compound (VIII) by first removal of the Boc group with HCl in MeOH followed by condensation with 6-chloronaphthalen-2-ylsulfonyl chloride (VII) in dichloromethane/DMF in the presence of Et3N. Finally, the target compound is obtained by treatment of (VIII) with methanesulfonic acid (CH3SO3H) in MeOH.
| 【1】 Miyazaki, Y.; Mukaihira, T.; Nishida, H.; Hosaka, Y.; Matsusue, T. (Mochida Pharmaceutical Co., Ltd.); Aromatic cpds. having cyclic amino or salts thereof. EP 1048652; WO 9933805 . |
| 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) | 45860 | [1-(4-pyridinyl)-4-piperidinyl]methanol | C11H16N2O | 详情 | 详情 | |
| (II) | 45861 | 1-(4-pyridinyl)-4-piperidinecarboxylic acid | C11H14N2O2 | 详情 | 详情 | |
| (III) | 45862 | ethyl (2R)-2-amino-3-[(tert-butoxycarbonyl)amino]propanoate | C10H20N2O4 | 详情 | 详情 | |
| (IV) | 45863 | ethyl (2R)-3-[(tert-butoxycarbonyl)amino]-2-([[1-(4-pyridinyl)-4-piperidinyl]methyl]amino)propanoate | C21H34N4O4 | 详情 | 详情 | |
| (V) | 27903 | 2-Bromoacetyl chloride | 22118-09-8 | C2H2BrClO | 详情 | 详情 |
| (VI) | 45864 | ethyl (2R)-2-((2-bromoacetyl)[[1-(4-pyridinyl)-4-piperidinyl]methyl]amino)-3-[(tert-butoxycarbonyl)amino]propanoate | C23H35BrN4O5 | 详情 | 详情 | |
| (VII) | 45865 | 6-chloro-2-naphthalenesulfonyl chloride | C10H6Cl2O2S | 详情 | 详情 | |
| (VIII) | 45866 | ethyl (2R)-4-[(6-chloro-2-naphthyl)sulfonyl]-6-oxo-1-[[1-(4-pyridinyl)-4-piperidinyl]methyl]-2-piperazinecarboxylate | C28H31ClN4O5S | 详情 | 详情 |