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【结 构 式】 
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【分子编号】49554 【品名】(3S,4R)-1-[3-(4-fluorophenoxy)propyl]-3-methoxy-4-piperidinamine; (3S,4R)-1-[3-(4-fluorophenoxy)propyl]-3-methoxypiperidinylamine 【CA登记号】 |
【 分 子 式 】C15H23FN2O2 【 分 子 量 】282.3583032 【元素组成】C 63.81% H 8.21% F 6.73% N 9.92% O 11.33% |
合成路线1
该中间体在本合成路线中的序号：(IX)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.
| 【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2
该中间体在本合成路线中的序号：(II)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.
| 【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3
该中间体在本合成路线中的序号：(II)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.
| 【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 . |
合成路线4
该中间体在本合成路线中的序号：(III)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.
| 【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 |