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【结 构 式】

【药物名称】Cisapride hydrate, R-51619(anhydrous), Arcasin, Alimix, Propulsin, Propulsid, Acenalin, Risamol, Prepulsid

【化学名称】cis-4-Amino-5-chloro-N-[1-[3-(4-fluorophenoxy)propyl]-3-methoxypiperidin-4-yl]-2-methoxybenzamide monohydrate
　　　　　　cis-4-Amino-5-chloro-N-[1-[3-(4-fluorophenoxy)propyl]-3-methoxypiperidin-4-yl]-o-anisamide monohydrate

【CA登记号】81098-60-4 (anhydrous)

【 分 子 式 】C23H31ClFN3O5

【 分 子 量 】483.97202

【开发单位】Janssen (Originator), Janssen-Cilag (Originator), Esteve (Licensee), Mitsubishi Pharma (Licensee)

【药理作用】Esophageal Diseases, Treatment of, Gastric Emptying Disorders,Treatment of of, Gastroesophageal Reflux Disease, Agents for, GASTROINTESTINAL DRUGS, Non-Ulcer Dyspepsia, Agents for, Prokinetic Agents

合成路线1合成路线2合成路线3合成路线4合成路线5合成路线6合成路线7合成路线8合成路线9合成路线10合成路线11合成路线12合成路线13合成路线14合成路线15

合成路线1

By condensation of cis-4-amino-5-chloro-2-methoxy-N-(3-methoxy-4-piperidyl)benzamide (I) with 1-(3-chloropropoxy)-4-fluorobenzene (II) by means of KI and triethylamine in hot DMF.

参考文献 中间体
【1】 Van Daele, G. (Janssen Pharmaceutica NV); Novel N-(3-hydroxy-4-piperidinyl)benzamide derivs.. US 4962115 .
【2】 Neuman, M.; Serradell, M.N.; Castaner, J.; Cisapride. Drugs Fut 1984, 9, 7, 497.
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) 30523 4-amino-5-chloro-2-methoxy-N-(3-methoxy-4-piperidinyl)benzamide C14H20ClN3O3 详情 详情
(II) 30524 3-chloropropyl 4-fluorophenyl ether; 1-(3-chloropropoxy)-4-fluorobenzene; 1-(4-Fluorophenoxy)-3-chloropropane 1716-42-3 C9H10ClFO 详情 详情

合成路线2

By condensation of 4-amino-5-chloro-2-methoxybenzoyl chloride (III) with 4-amino-1-[3-(fluorophenoxy)propyl]-3-methoxypiperidine (IV) by means of triethylamine in CHCl3.

参考文献 中间体
【1】 Van Daele, G. (Janssen Pharmaceutica NV); Novel N-(3-hydroxy-4-piperidinyl)benzamide derivs.. US 4962115 .
【2】 Neuman, M.; Serradell, M.N.; Castaner, J.; Cisapride. Drugs Fut 1984, 9, 7, 497.
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) 28152 4-amino-5-chloro-2-methoxybenzoyl chloride C8H7Cl2NO2 详情 详情
(IV) 30525 1-[3-(4-fluorophenoxy)propyl]-3-methoxy-4-piperidinamine; 1-[3-(4-fluorophenoxy)propyl]-3-methoxy-4-piperidinylamine C15H23FN2O2 详情 详情

合成路线3

The condensation of 3-(4-fluorophenoxy)propionic acid (I) with 4-piperidone (II) by means of pivaloyl chloride and TEA in refluxing toluene gives the amide (III), which is submitted to oxidation with diacetoxyiodobenzene and KOH in methanol, yielding the hydroxy-dimethoxyketal (IV). The methylation of the OH group of (IV) with Me-I and Ag2O in DMF affords the corresponding methoxy compound (V), which is hydrolyzed with HOAc to provide the methoxypiperidone (VI). The reaction of (VI) with O-benzylhydroxylamine (VII) and pyridine in refluxing toluene gives the oxime (VIII), which is diastereoselectively reduced with BH3 in THF, yielding the cis-isomer (IX). Finally, this amine is condensed with 4-amino-5-chloro-2-methoxybenzoic acid (X) by means of ethyl chloroformate, TEA and HOBt in DMF to afford the target amide.

参考文献 中间体
【1】 Cossy, J.; et al.; A short synthesis of cisapride: A gastrointestinal stimulant derived from cis-4-amino-3-methoxypiperidine. Tetrahedron Lett 2001, 42, 33, 5713.
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) 39121 3-(4-fluorophenoxy)propionic acid 2967-70-6 C9H9FO3 详情 详情
(II) 27115 4-piperidinone 40064-34-4 C5H9NO 详情 详情
(III) 49549 1-[3-(4-fluorophenoxy)propanoyl]-4-piperidinone C14H16FNO3 详情 详情
(IV) 49550 3-(4-fluorophenoxy)-1-(3-hydroxy-4,4-dimethoxy-1-piperidinyl)-1-propanone C16H22FNO5 详情 详情
(V) 49551 3-(4-fluorophenoxy)-1-(3,4,4-trimethoxy-1-piperidinyl)-1-propanone C17H24FNO5 详情 详情
(VI) 49552 　 C15H18FNO4 详情 详情
(VII) 14640 O-benzylhydroxylamine; 1-[(aminooxy)methyl]benzene 622-33-3 C7H9NO 详情 详情
(VIII) 49553 1-[3-(4-fluorophenoxy)propanoyl]-3-methoxy-4-piperidinone O-benzyloxime C22H25FN2O4 详情 详情
(IX) 49554 (3S,4R)-1-[3-(4-fluorophenoxy)propyl]-3-methoxy-4-piperidinamine; (3S,4R)-1-[3-(4-fluorophenoxy)propyl]-3-methoxypiperidinylamine C15H23FN2O2 详情 详情
(X) 12419 4-Amino-5-chloro-2-methoxybenzoic acid 7206-70-4 C8H8ClNO3 详情 详情

合成路线4

The reductive amination of 1-[3-(4-fluorophenoxy)propyl]-3-methoxypiperidin-4-one (I) with benzylamine by hydrogenation with H2 over Pd/C, followed by crystallization of the HCl or HNO3 salts, gives cis-1-[3-(4-fluorophenyl)propyl]-3-methoxypiperidine-4-amine (II). This compound is condensed with 4-amino-5-chloro-2-methoxybenzoic acid (III) by means of ethyl chloroformate, TEA and HOBt to afford the target amide.

参考文献 中间体
【1】 Moens, L.J.R.; Rey, M.; De Knaep, A.G.M. (Janssen Pharmaceutica NV); Synthesis of cisapride. WO 9816511 .
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) 49555 1-[3-(4-fluorophenoxy)propyl]-3-methoxy-4-piperidinone C15H20FNO3 详情 详情
(II) 49554 (3S,4R)-1-[3-(4-fluorophenoxy)propyl]-3-methoxy-4-piperidinamine; (3S,4R)-1-[3-(4-fluorophenoxy)propyl]-3-methoxypiperidinylamine C15H23FN2O2 详情 详情
(III) 12419 4-Amino-5-chloro-2-methoxybenzoic acid 7206-70-4 C8H8ClNO3 详情 详情

合成路线5

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.

参考文献 中间体
【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6

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.

参考文献 中间体
【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7

The title compound has been obtained by hydrogenation of 4-(4-amino-5-chloro-2-methoxybenzamido)-1-[3-(4-fluorophenoxy)propyl]-3-methoxypyridinium iodide (I) with H2 over PtO2 in methanol, or with NaBH4 and RhCl3 or NiCl2 in methanol.

参考文献 中间体
【1】 Caldero Ges, J.M.; Huguet Clotet, J.; Process for obtaining cis-4-amino-5-chloro-2-methoxy-N-[1-[3-(4-fluorophenoxy)propyl]-3-methoxy-4-piperidinyl]benzamide. ES 2019234 .
【2】 Huguet Clotet, J.; Caldero Ges, J.M.; Process for obtaining cis-4-amino-5-chloro-2-methoxy-N-[1-[3-(4-fluorophenoxy)propyl]-3-methoxy-4-piperidinyl]benzamide. ES 2020128 .
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) 49577 4-[(4-amino-5-chloro-2-methoxybenzoyl)amino]-1-[3-(4-fluorophenoxy)propyl]-3-methoxypyridinium iodide C23H24ClFIN3O4 详情 详情

合成路线8

The title compound has been obtained by hydrogenation of 4-amino-5-chloro-N-[1-[3-(4-fluorophenoxy)propyl]-3-methoxy-1,2,5,6-tetrahydropyridin-4-yl]-2-methoxybenzamide (I) with H2 over Pt/C or Rh/Al2O3 in methanol.

参考文献 中间体
【1】 Huguet Clotet, J.; Caldero Ges, J.M.; Process for obtaining cis-4-amino-5-chloro-2-methoxy-N-[1-[3-(4-fluorophenoxy)propyl]-3-methoxy-4-piperidinyl]benzamide. ES 2019235 .
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) 49578 4-amino-5-chloro-N-[1-[3-(4-fluorophenoxy)propyl]-5-methoxy-1,2,3,6-tetrahydro-4-pyridinyl]-2-methoxybenzamide C23H27ClFN3O4 详情 详情

合成路线9

The title compound has been obtained by condensation of 4-amino-5-chloro-2-methoxybenzoic acid (I) with cis-1-[3-(4-fluorophenoxy)propyl]-3-methoxypiperidine-4-amine (II) by means of DCC in dichloromethane or PCl3 in benzene.

参考文献 中间体
【1】 Izquierdo Sanjose, M.; Martin Escudero, U.; Process for obtaining a 4-amino-5-chloro-2-methoxybenzoic acid deriv.. ES 2002640 .
【2】 Alonso Cires, L.; Process for the preparation of substd. benzamides. ES 8605768 .
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) 12419 4-Amino-5-chloro-2-methoxybenzoic acid 7206-70-4 C8H8ClNO3 详情 详情
(II) 49554 (3S,4R)-1-[3-(4-fluorophenoxy)propyl]-3-methoxy-4-piperidinamine; (3S,4R)-1-[3-(4-fluorophenoxy)propyl]-3-methoxypiperidinylamine C15H23FN2O2 详情 详情

合成路线10

The title compound has been obtained by condensation of methanesulfonate (I) with 4-fluorophenol (II) by means of NaNH2 in DMF.

参考文献 中间体
【1】 Gallardo Carrera, A. (Fordonal SL); Process for the preparation of 4-aminopiperidine derivs.. ES 8601133 .
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) 49579 3-[(3S,4R)-4-[(4-amino-5-chloro-2-methoxybenzoyl)amino]-3-methoxypiperidinyl]propyl methanesulfonate C18H28ClN3O6S 详情 详情
(II) 19639 4-fluorophenol 371-41-5 C6H5FO 详情 详情

合成路线11

The reaction of 4-amino-5-chloro-2-methoxybenzoic acid (I) with benzyl chloride (II) and NaHCO3 in refluxing water gives the N-benzyl protected compound (III), which is condensed with cis-4-amino-3-methoxypiperidine-1-carboxylic acid ethyl ester (IV) by means of methyl chloroformate and TEA in dichloromethane to yield the benzamide (V). The deprotection of (V) with KOH in refluxing isopropanol affords compound (VI) with a free piperidinic NH group that is acylated with 3-(4-fluorophenoxy)propyl chloride (VII) by means of Na2CO3 in refluxing methylisobutylketone to provide the protected adduct (VIII). Finally, this compound is debenzylated by hydrogenation with H2 over Pd/C in hot methanol to give the target compound. Alternatively, the piperidine derivative (VI) is treated with p-toluenesulfonic acid in refluxing toluene and then debenzylated and simultaneously reductocondensed with 3-(4-fluorophenoxy)propionaldehyde (IX) by means of H2 over Pd/C in methanol to give the target compound.

参考文献 中间体
【1】 Gutierrez Fuentes, L.G.; Process for the preparation of benzamides. ES 2019047 .
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) 12419 4-Amino-5-chloro-2-methoxybenzoic acid 7206-70-4 C8H8ClNO3 详情 详情
(II) 19171 1-(Chloromethyl)benzene; Benzyl chloride 100-44-7 C7H7Cl 详情 详情
(III) 49580 4-(benzylamino)-5-chloro-2-methoxybenzoic acid C15H14ClNO3 详情 详情
(IV) 19574 (4-carboxybutyl)(triphenyl)phosphonium chloride C23H24ClO2P 详情 详情
(V) 19581 trans-4-Aminocyclohexanol；trans-4-Amino-1-cyclohexanol;trans-4-Amino-1-cyclohexanol; 27489-62-9 C6H13NO 详情 详情
(VI) 49582 4-(benzylamino)-5-chloro-2-methoxy-N-[(3S,4R)-3-methoxypiperidinyl]benzamide C21H26ClN3O3 详情 详情
(VII) 30524 3-chloropropyl 4-fluorophenyl ether; 1-(3-chloropropoxy)-4-fluorobenzene; 1-(4-Fluorophenoxy)-3-chloropropane 1716-42-3 C9H10ClFO 详情 详情
(VIII) 49583 4-(benzylamino)-5-chloro-N-[(3S,4R)-1-[3-(4-fluorophenoxy)propyl]-3-methoxypiperidinyl]-2-methoxybenzamide C30H35ClFN3O4 详情 详情
(IX) 49584 3-(4-fluorophenoxy)propanal C9H9FO2 详情 详情

合成路线12

Saponification of 4-acetylamino-2-methoxybenzoate methyl ester (I) with NaOH in MeOH provides carboxylic acid (II), which is then coupled to cis-4-amino-1-[3-(fluorophenoxy)propyl]-3-methoxypiperidine (III) by means of ethyl chloroformate and Et3N in chloroform, affording benzamide (IV). Removal of the acetyl group either by means of HCl at reflux or with NaOH in refluxing MeOH furnishes derivative (V), which is finally converted into the desired product by chlorination with N-chlorosuccinimide (NCS) in acetic acid. Alternatively, compound (IV) can be converted into the target compound by first chlorination with NCS in HOAc, providing chloro derivative (VI), followed by acetyl removal either with HCl at 90 C or with NaOH in refluxing MeOH.

参考文献 中间体
【1】 Serra i Masia, J.; Montserrat Vidal, C.; Process for obtaining cis-4-amino-5-chloro-N-[1-[3-(4-fluorophenoxy)propyl]-3-methoxy-4-piperidinyl]-2-methoxybenzamide. ES 2019011 .
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) 12417 methyl 4-(acetamido)-2-methoxybenzoate; Methyl 4-acetamido-2-methoxybenzoate 4093-28-1 C11H13NO4 详情 详情
(II) 17956 4-(acetamido)-2-methoxybenzoic acid 4093-29-2 C10H11NO4 详情 详情
(III) 49554 (3S,4R)-1-[3-(4-fluorophenoxy)propyl]-3-methoxy-4-piperidinamine; (3S,4R)-1-[3-(4-fluorophenoxy)propyl]-3-methoxypiperidinylamine C15H23FN2O2 详情 详情
(IV) 50814 4-(acetamido)-N-[(3S,4R)-1-[3-(4-fluorophenoxy)propyl]-3-methoxypiperidinyl]-2-methoxybenzamide C25H32FN3O5 详情 详情
(V) 50815 4-amino-N-[(3S,4R)-1-[3-(4-fluorophenoxy)propyl]-3-methoxypiperidinyl]-2-methoxybenzamide C23H30FN3O4 详情 详情
(VI) 50816 4-(acetamido)-5-chloro-N-[(3S,4R)-1-[3-(4-fluorophenoxy)propyl]-3-methoxypiperidinyl]-2-methoxybenzamide C25H31ClFN3O5 详情 详情

合成路线13

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.

参考文献 中间体
【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

合成路线14

The 3-bromo-4-oxopiperidine-1-carboxylic acid ethyl ester (III), an intermediate in the synthesis of cisapride, has been obtained as follows: The bromination of 4-oxopiperidine-1-carboxylic acid ethyl ester (I) with Br2 in methanol followed by neutralization of the resulting HBr with NaOMe in the same solvent gives 3-bromo-4,4-dimethoxypiperidine-1-carboxylic acid ethyl ester (II), which is finally hydrolyzed with aq. 2N HBr or HCl to afford the target intermediate 3-bromo-4-oxopiperidine-1-carboxylic acid ethyl ester (III).

参考文献 中间体
【1】 Serra Masia, J.; Lombardero Fernandez, J.; Montserrat, Vidal, C. (Laboratorios Salvat SA); Ethyl 3-bromo-4-oxo-1-piperidinecarboxylate, process for obtaining it and novel intermediates for its preparation. ES 2053394 .
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) 53113 ethyl 3-bromo-4,4-dimethoxy-1-piperidinecarboxylate n/a C10H18BrNO4 详情 详情
(III) 53112 ethyl 3-bromo-4-oxo-1-piperidinecarboxylate 95629-02-0 C8H12BrNO3 详情 详情

合成路线15

The condensation of 4-amino-5-chloro-2-methoxybenzoic acid (I) with 3-methoxypyridine-4-amine (II) by means of ethyl chloroformate and DEA in chloroform gives the corresponding amide (III), which is condensed with 3-(4-fluorophenoxy)propyl chloride (IV) by means of phenol in hot toluene to yield the pyridinium chloride (V). Finally, this compound is hydrogenated with H2 over PtO2/C in ethanol containing NaHCO3 to afford the target cisapride.

参考文献 中间体
【1】 Van Daele, G.H.P. (Janssen Pharmaceutica NV); ES 2007259 .
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) 12419 4-Amino-5-chloro-2-methoxybenzoic acid 7206-70-4 C8H8ClNO3 详情 详情
(II) 53287 3-methoxy-4-pyridinylamine; 3-methoxy-4-pyridinamine n/a C6H8N2O 详情 详情
(III) 53288 4-amino-5-chloro-2-methoxy-N-(3-methoxy-4-pyridinyl)benzamide n/a C14H14ClN3O3 详情 详情
(IV) 30524 3-chloropropyl 4-fluorophenyl ether; 1-(3-chloropropoxy)-4-fluorobenzene; 1-(4-Fluorophenoxy)-3-chloropropane 1716-42-3 C9H10ClFO 详情 详情
(V) 53289 4-[(4-amino-5-chloro-2-methoxybenzoyl)amino]-1-[3-(4-fluorophenoxy)propyl]-3-methoxypyridinium chloride n/a C23H24Cl2FN3O4 详情 详情
Extended Information