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【结 构 式】 
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【分子编号】49556 【品名】ethyl 3-hydroxy-4,4-dimethoxy-1-piperidinecarboxylate 【CA登记号】 |
【 分 子 式 】C10H19NO5 【 分 子 量 】233.2646 【元素组成】C 51.49% H 8.21% N 6% O 34.29% |
合成路线1
该中间体在本合成路线中的序号：(I)The decarboxylation of 3-hydroxy-4,4-dimethoxypiperidine-1-carboxylic acid ethyl ester (I) with KOH in refluxing isopropanol gives the piperidine (II), which is condensed with 3-(4-fluorophenoxy)propyl chloride (III) by means of K2CO3 in refluxing methyl isobutyl ketone to afford the alkylated piperidine (IV). The esterification of the OH group of (IV) with benzoyl chloride (V) and DMAP in dichloromethane provides the ester (VI), which is treated with sulfuric acid in dichloromethane to obtain the piperidinone (VII). The rearrangement of (VII) by means of ammonium acetate and acetic acid provides the amide (VIII), which is treated with TFA in dichloromethane to give the oxo amide (IX). The regioselective hydrogenation of the oxo group of (IX) with potassium selectride in THF affords the cis-hydroxyamide (X), which is hydrogenated with H2 over Pd/C in acetic acid to provide the 4-aminobenzamide (XI). Finally, the free OH group of (XI) is methylated with NaH and dimethyl sulfate in THF.
| 【1】 So, R.; Slemon, C.; Oudenes, J.; Ngooi, T.-K.; Lu, Y.-F. (Torcan Chemical Ltd.); Preparation of cisapride. WO 9611186 . |
| 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) | 49556 | ethyl 3-hydroxy-4,4-dimethoxy-1-piperidinecarboxylate | C10H19NO5 | 详情 | 详情 | |
| (II) | 49557 | 4,4-dimethoxy-3-piperidinol | C7H15NO3 | 详情 | 详情 | |
| (III) | 30524 | 3-chloropropyl 4-fluorophenyl ether; 1-(3-chloropropoxy)-4-fluorobenzene; 1-(4-Fluorophenoxy)-3-chloropropane | 1716-42-3 | C9H10ClFO | 详情 | 详情 |
| (IV) | 49558 | 1-[3-(4-fluorophenoxy)propyl]-4,4-dimethoxy-3-piperidinol | C16H24FNO4 | 详情 | 详情 | |
| (V) | 49559 | benzyl 2-chloro-4-(chlorocarbonyl)-5-methoxyphenylcarbamate | C16H13Cl2NO4 | 详情 | 详情 | |
| (VI) | 49560 | 1-[3-(4-fluorophenoxy)propyl]-4,4-dimethoxy-3-piperidinyl 4-[[(benzyloxy)carbonyl]amino]-5-chloro-2-methoxybenzoate | C32H36ClFN2O8 | 详情 | 详情 | |
| (VII) | 49561 | 1-[3-(4-fluorophenoxy)propyl]-4-oxo-3-piperidinyl 4-[[(benzyloxy)carbonyl]amino]-5-chloro-2-methoxybenzoate | C30H30ClFN2O7 | 详情 | 详情 | |
| (VIII) | 49562 | benzyl 2-chloro-4-[([1-[3-(4-fluorophenoxy)propyl]-3-hydroxy-4-methoxy-4-piperidinyl]amino)carbonyl]-5-methoxyphenylcarbamate | C31H35ClFN3O7 | 详情 | 详情 | |
| (IX) | 49563 | benzyl 2-chloro-4-[([1-[3-(4-fluorophenoxy)propyl]-3-oxo-4-piperidinyl]amino)carbonyl]-5-methoxyphenylcarbamate | C30H31ClFN3O6 | 详情 | 详情 | |
| (X) | 49564 | benzyl 2-chloro-4-[([(3S,4R)-1-[3-(4-fluorophenoxy)propyl]-3-hydroxypiperidinyl]amino)carbonyl]-5-methoxyphenylcarbamate | C30H33ClFN3O6 | 详情 | 详情 | |
| (XI) | 49565 | 4-amino-5-chloro-N-[(3S,4R)-1-[3-(4-fluorophenoxy)propyl]-3-hydroxypiperidinyl]-2-methoxybenzamide | C22H27ClFN3O4 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(VI)This compound has been obtained by two related ways: 1. The reaction of 1-benzyl-3-bromopiperidin-4-one (I) with sodium methoxide in methanol gives the intermediate epoxide, which in the reaction medium yields 1-benzyl-3-hydroxypiperidin-4-one dimethylacetal (III). The hydrogenation of (III) with H2 over Pd/C in methanol affords 3-hydroxypiperidin-4-one dimethylacetal (IV), which is condensed with ethyl chloroformate (V) by means of NaOH in THF to provide 3-hydroxy-4,4-dimethoxypiperidine-1-carboxylic acid ethyl ester (VI), which is methylated with methyl iodide and NaH in DMF to give the 3,4,4-trimethoxy compound (VII). The hydrolysis of the acetal group of (VII) by means of H2SO4 in refluxing water yields the piperidinone (VIII), which by reductocondensation with benzylamine and H2 over Pd/C in methanol affords the cis- 4-(benzylamino)-3-methoxypiperidine-1-carboxylic acid ethyl ester (IX). The decarboxylation of (IX) by means of KOH in refluxing isopropanol provides the cis-4-(benzyloxy)-3-methoxypiperidine (X), which is alkylated with 3-(4-fluorophenoxy)propyl chloride (XI) by means of TEA in DMF, giving the N-substituted piperidine (XII). The deprotection of the amino group of (XII) by hydrogenation with H2 over Pd/C in methanol yields the 4-aminopiperidine (XIII), which is finally condensed with 4-amino-5-chloro-2-methoxybenzoic acid (XIV) by means of ethyl chloroformate and TEA in chloroform to obtain the target carboxamide. 2. The debenzylation of the cis- 4-(benzylamino)-3-methoxypiperidine-1-carboxylic acid ethyl ester (IX) with H2 over Pd/C in methanol gives the cis-4-amino-3-methoxypiperidine-1-carboxylic acid ethyl ester (XV), which is condensed with 4-amino-5-chloro-2-methoxybenzoic acid (XIV) by means of ethyl chloroformate and TEA in chloroform to yield the corresponding amide (XVI). The decarboxylation of (XVI) with KOH in refluxing isopropanol affords (XVII), with a free NH group that is alkylated with 3-(4-fluorophenoxy)propyl chloride (XI) by means of TEA in DMF to obtain the target carboxamide.
| 【1】 Van Daele, G.H.P.; et al.; Synthesis of cisapride, a gastrointestinal stimulant derived from cis-4-amino-3-methoxypiperidine. Drug Dev Res 1986, 8, 225. |
| 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) | 49566 | 1-benzyl-3-bromo-4-piperidinone | C12H14BrNO | 详情 | 详情 | |
| (II) | 49567 | 3-benzyl-6-methoxy-7-oxa-3-azabicyclo[4.1.0]heptane; 3-benzyl-7-oxa-3-azabicyclo[4.1.0]hept-6-yl methyl ether | C13H17NO2 | 详情 | 详情 | |
| (III) | 49568 | 1-benzyl-4,4-dimethoxy-3-piperidinol | C14H21NO3 | 详情 | 详情 | |
| (IV) | 49557 | 4,4-dimethoxy-3-piperidinol | C7H15NO3 | 详情 | 详情 | |
| (V) | 11229 | 1-[(Chlorocarbonyl)oxy]ethane;ethyl carbonochloridate; Carbonchloridic acid ethyl ester;Ethyl chloroformate;Ethyl chlorocarbonate | 541-41-3 | C3H5ClO2 | 详情 | 详情 |
| (VI) | 49556 | ethyl 3-hydroxy-4,4-dimethoxy-1-piperidinecarboxylate | C10H19NO5 | 详情 | 详情 | |
| (VII) | 49569 | ethyl 3,4,4-trimethoxy-1-piperidinecarboxylate | C11H21NO5 | 详情 | 详情 | |
| (VIII) | 49570 | ethyl 3-methoxy-4-oxo-1-piperidinecarboxylate | C9H15NO4 | 详情 | 详情 | |
| (IX) | 49571 | ethyl (3S,4R)-4-(benzylamino)-3-methoxy-1-piperidinecarboxylate | C16H24N2O3 | 详情 | 详情 | |
| (X) | 49572 | (3S,4R)-N-benzyl-3-methoxy-4-piperidinamine; N-benzyl-N-[(3S,4R)-3-methoxypiperidinyl]amine | C13H20N2O | 详情 | 详情 | |
| (XI) | 30524 | 3-chloropropyl 4-fluorophenyl ether; 1-(3-chloropropoxy)-4-fluorobenzene; 1-(4-Fluorophenoxy)-3-chloropropane | 1716-42-3 | C9H10ClFO | 详情 | 详情 |
| (XII) | 49573 | (3S,4R)-N-benzyl-1-[3-(4-fluorophenoxy)propyl]-3-methoxy-4-piperidinamine; N-benzyl-N-[(3S,4R)-1-[3-(4-fluorophenoxy)propyl]-3-methoxypiperidinyl]amine | C22H29FN2O2 | 详情 | 详情 | |
| (XIII) | 49574 | ethyl (3S,4R)-4-amino-3-methoxy-1-piperidinecarboxylate | C9H18N2O3 | 详情 | 详情 | |
| (XIV) | 12419 | 4-Amino-5-chloro-2-methoxybenzoic acid | 7206-70-4 | C8H8ClNO3 | 详情 | 详情 |
| (XV) | 49574 | ethyl (3S,4R)-4-amino-3-methoxy-1-piperidinecarboxylate | C9H18N2O3 | 详情 | 详情 | |
| (XVI) | 49575 | ethyl (3S,4R)-4-[(4-amino-5-chloro-2-methoxybenzoyl)amino]-3-methoxy-1-piperidinecarboxylate | C17H24ClN3O5 | 详情 | 详情 | |
| (XVII) | 49576 | 4-amino-5-chloro-2-methoxy-N-[(3S,4R)-3-methoxypiperidinyl]benzamide | C14H20ClN3O3 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(III)The bromination of 4-oxopiperidine-1-carboxylic acid ethyl ester (I) with Br2 in chloroform gives 3-bromo-4-oxopiperidine-1-carboxylic acid ethyl ester (II), which is treated with NaOMe in methanol to yield 3-hydroxy-4,4-dimethoxypiperidine-1-carboxylic acid ethyl ester (III). The methylation of (III) with NaH and MeI in DMF affords 3,4,4-trimethoxypiperidine-1-carboxylic acid ethyl ester (IV), which is hydrolyzed with refluxing 1% aq. H2SO4 to provide 3-methoxy-4-oxopiperidine-1-carboxylic acid ethyl ester (V). The reductocondensation of (V) with benzylamine and H2 over Pd/C in methanol in the presence of thiophene gives cis-4-amino-3-methoxypiperidine-1-carboxylic acid ethyl ester (VI), which is condensed with 4-amino-5-chloro-2-methoxybenzoic acid (VII) by means of ethyl chloroformate and TEA in chloroform to yield the benzamide (VIII). The hydrolysis of the carbamate group of (VIII) with KOH in refluxing isopropanol affords the free piperidine derivative (IX), which is finally condensed with 3-(4-fluorophenoxy)propyl chloride (X) by means of TEA and KI in hot DMF to provide the target, cisapride.
| 【1】 Van Daele, G. (Janssen Pharmaceutica NV); Novel N-(3-hydroxy-4-piperidinyl)benzamide derivs.. US 4962115 . |
| 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) | 13486 | Ethyl 4-oxo-1-piperidinecarboxylate; N-Carbethoxy-4-piperidone | 29976-53-2 | C8H13NO3 | 详情 | 详情 |
| (II) | 53112 | ethyl 3-bromo-4-oxo-1-piperidinecarboxylate | 95629-02-0 | C8H12BrNO3 | 详情 | 详情 |
| (III) | 49556 | ethyl 3-hydroxy-4,4-dimethoxy-1-piperidinecarboxylate | C10H19NO5 | 详情 | 详情 | |
| (IV) | 49569 | ethyl 3,4,4-trimethoxy-1-piperidinecarboxylate | C11H21NO5 | 详情 | 详情 | |
| (V) | 49570 | ethyl 3-methoxy-4-oxo-1-piperidinecarboxylate | C9H15NO4 | 详情 | 详情 | |
| (VI) | 49574 | ethyl (3S,4R)-4-amino-3-methoxy-1-piperidinecarboxylate | C9H18N2O3 | 详情 | 详情 | |
| (VII) | 12419 | 4-Amino-5-chloro-2-methoxybenzoic acid | 7206-70-4 | C8H8ClNO3 | 详情 | 详情 |
| (VIII) | 49575 | ethyl (3S,4R)-4-[(4-amino-5-chloro-2-methoxybenzoyl)amino]-3-methoxy-1-piperidinecarboxylate | C17H24ClN3O5 | 详情 | 详情 | |
| (IX) | 49576 | 4-amino-5-chloro-2-methoxy-N-[(3S,4R)-3-methoxypiperidinyl]benzamide | C14H20ClN3O3 | 详情 | 详情 | |
| (X) | 30524 | 3-chloropropyl 4-fluorophenyl ether; 1-(3-chloropropoxy)-4-fluorobenzene; 1-(4-Fluorophenoxy)-3-chloropropane | 1716-42-3 | C9H10ClFO | 详情 | 详情 |