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【结 构 式】 
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【分子编号】16053 【品名】2-[(4-chlorophenyl)(4-piperidinyloxy)methyl]pyridine; (4-chlorophenyl)(2-pyridinyl)methyl 4-piperidinyl ether 【CA登记号】 |
【 分 子 式 】C17H19ClN2O 【 分 子 量 】302.80344 【元素组成】C 67.43% H 6.32% Cl 11.71% N 9.25% O 5.28% |
合成路线1
该中间体在本合成路线中的序号：(I)The reaction of 4-[1-(4-chlorophenyl)-1-(2-pyridyl)methoxy]piperidine (I) with ethyl 4-bromobutyrate (II) by means of K2CO3 in refluxing acetone gives the corresponding condensation product (III), which is then hydrolyzed with NaOH in ethanol/water yielding compound (IV).
| 【1】 Castaner, J.; Graul, A.; Betotastine besilate. Drugs Fut 1998, 23, 3, 256. |
| 【2】 Koda, A.; Kuroki, Y.; Fujiwara, H.; Takamura, S.; Yamano, K. (Ube Industries, Ltd.); Piperidine and piperazine derivs., process for preparing the same and pharmaceutical compsns. containing them. EP 0335586; JP 1989242574; JP 1990025465; JP 1993294929; US 4929618 . |
| 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) | 16053 | 2-[(4-chlorophenyl)(4-piperidinyloxy)methyl]pyridine; (4-chlorophenyl)(2-pyridinyl)methyl 4-piperidinyl ether | C17H19ClN2O | 详情 | 详情 | |
| (II) | 11263 | ethyl 4-bromobutanoate; Ethyl 4-bromobutyrate | 2969-81-5 | C6H11BrO2 | 详情 | 详情 |
| (III) | 16055 | ethyl 4-[4-[(4-chlorophenyl)(2-pyridinyl)methoxy]piperidino]butanoate | C23H29ClN2O3 | 详情 | 详情 | |
| (IV) | 16056 | 4-[4-[(4-chlorophenyl)(2-pyridinyl)methoxy]piperidino]butyric acid | C21H25ClN2O3 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(I)A new synthesis of betotastine has been developed: The racemic 4-[1-(4-chlorophenyl)-1-(2-pyridyl)methoxy]piperidine (I) is submitted to optical resolution with N-acyl amino acids such as N-acetyl-L-phenylalanine (preferred), N-acetyl-L-leucine, N-(benzyloxycarbonyl)-L-phenylalanine, N-(benzyloxycarbonyl)-L-valine, N-(benzyloxycarbonyl)-L-threonine, N-(benzyloxycarbonyl)-L-serine or with (2R,3R)-3-(5-chloro-2-nitrophenylsulfanyl)-2-hydroxy-3-(4-methoxyphenyl)propionic acid (preferred) or (2R,3R)-2-hydroxy-3-(4-methoxyphenyl)-3-(2-nitrophenylsulfanyl)propionic acid as chiral intermediates, yielding the (S)-isomer (II). The condensation of (II) with ethyl 4-bromobutyrate (III) by means of a base such as Na2CO3, NaHCO3, K2CO3 or KHCO3 gives the expected 4-(1-piperidinyl)butyric acid ester (IV), which is finally hydrolyzed with NaOH or KOH in aqueous ethanol or methanol.
| 【1】 Kita, J.; Yoshioka, R.; Ozaki, Y.; Takemura, S.; Fujiwara, H.; Yamada, S. (Tanabe Seiyaku Co., Ltd.; Ube Industries, Ltd.); Acid-addition salts of optically active piperidine cpd. and process for producing the same. JP 1998237070; JP 2000198784; WO 9829409 . |
| 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) | 16053 | 2-[(4-chlorophenyl)(4-piperidinyloxy)methyl]pyridine; (4-chlorophenyl)(2-pyridinyl)methyl 4-piperidinyl ether | C17H19ClN2O | 详情 | 详情 | |
| (II) | 22441 | (S)-(4-chlorophenyl)(2-pyridinyl)methyl 4-piperidinyl ether | C17H19ClN2O | 详情 | 详情 | |
| (III) | 11263 | ethyl 4-bromobutanoate; Ethyl 4-bromobutyrate | 2969-81-5 | C6H11BrO2 | 详情 | 详情 |
| (IV) | 22443 | ethyl 4-(4-[[(S)-(4-chlorophenyl)(2-pyridinyl)methyl]oxy]-1-piperidinyl)butanoate | C23H29ClN2O3 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(IV)
| 【1】 Ha TH, Parks CH, Kim WJ, et al. 2008. Process for preparing bepotastine and intermediates used therein. WO 2008153289 (Hanmi Pharm Co Ltd, S Korea). Krueger W, Krueger G. 1983. 4-[1-methyl-5-bis[(2-chloroethyl) amino] -2-benzimidazolyl] butyric acid. Ger, (East)DD 159877. |
| 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) | 67057 | (2R,5R)-2-isopropyl-5-methylcyclohexyl 4-(4-((S)-(4-chlorophenyl)(pyridin-2-yl)methoxy)piperidin-1-yl)butanoate (R)-2-(((benzyloxy)carbonyl)amino)succinate | C31H43ClN2O3.C12H13NO6 | 详情 | 详情 | |
| (I) | 11265 | 4-Chlorobutanoyl chloride; 4-Chlorobutyric acid chloride | 4635-59-0 | C4H6Cl2O | 详情 | 详情 |
| (II) | 67053 | (1R,5R)-2-isopropyl-5-methylcyclohexanol | C10H20O | 详情 | 详情 | |
| (III) | 67054 | (1S,5S)-2-isopropyl-5-methylcyclohexyl 4-chlorobutanoate | C14H25ClO2 | 详情 | 详情 | |
| (IV) | 16053 | 2-[(4-chlorophenyl)(4-piperidinyloxy)methyl]pyridine; (4-chlorophenyl)(2-pyridinyl)methyl 4-piperidinyl ether | C17H19ClN2O | 详情 | 详情 | |
| (V) | 67055 | (1S,2R)-2-isopropyl-5-methylcyclohexyl 4-(4-((4-chlorophenyl)(pyridin-2-yl)methoxy)piperidin-1-yl)butanoate | C31H43ClN2O3 | 详情 | 详情 | |
| (VI) | 67056 | (S)-2-(((benzyloxy)carbonyl)amino)succinic acid | C12H13NO6 | 详情 | 详情 | |
| (VIII) | 67058 | (2R,5R)-2-isopropyl-5- methylcyclohexyl 4-(4-((S)-(4-chlorophenyl)(pyridin-2 -yl)methoxy)piperidin-1-yl)butanoate | C31H43ClN2O3 | 详情 | 详情 | |
| (IX) | 67059 | C21H25ClN2O3 | 详情 | 详情 |