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【结 构 式】 
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【分子编号】49681 【品名】4-anilino-N-methyl-N-phenyl-4-piperidinecarboxamide 【CA登记号】 |
【 分 子 式 】C19H23N3O 【 分 子 量 】309.41124 【元素组成】C 73.76% H 7.49% N 13.58% O 5.17% |
合成路线1
该中间体在本合成路线中的序号：(VI)The reaction of 4-oxopiperidine-1-carboxylic acid ethyl ester (I) with CHCl3, benzyl triethylammonium chloride and NaOH in THF/water gives the spirooxirane (II), which is treated with aniline (III) and NaOH to yield the anilide (IV). The methylation of the amide nitrogen by means of NaH and CH3I in THF affords the methylated anilide (V). The reaction of (V) with KOH in refluxing isopropanol causes elimination of its ethoxycarbonyl group, providing compound (VI), which is reduced with lithium triethylborohydride in THF to give 4-(hydroxymethyl)-4-(phenylamino)piperidine (VII). The condensation of (VII) with tetrazolone derivative (VIII) by means of KI in refluxing acetonitrile (or propionitrile) yields the adduct (XI), which is methylated with NaH and CH3I in THF to afford the methoxy derivative (XII). Finally, this compound is acylated with propionyl chloride (XIII) in chloroform to provide the target compound. The intermediate tetrazolone derivative (VIII) has been obtained by reaction of 1-ethyl-4,5-dihydro-1H-tetrazol-5-one (IX) with 1,2-dibromoethane (X) by means of TEA in acetonitrile.
| 【1】 Killgore, J.K.; Jacob, M. (Mallinckrodt Medical Inc.); New methods for the syntheses of alfentanil, sufentanil and remifentanil. WO 0140184 . |
| 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) | 49678 | ethyl 2,2-dichloro-1-oxa-6-azaspiro[2.5]octane-6-carboxylate | C9H13Cl2NO3 | 详情 | 详情 | |
| (III) | 12294 | Aniline; Phenylamine | 62-53-3 | C6H7N | 详情 | 详情 |
| (IV) | 49679 | ethyl 4-anilino-4-(anilinocarbonyl)-1-piperidinecarboxylate | C21H25N3O3 | 详情 | 详情 | |
| (V) | 49680 | ethyl 4-anilino-4-[(methylanilino)carbonyl]-1-piperidinecarboxylate | C22H27N3O3 | 详情 | 详情 | |
| (VI) | 49681 | 4-anilino-N-methyl-N-phenyl-4-piperidinecarboxamide | C19H23N3O | 详情 | 详情 | |
| (VII) | 49682 | (4-anilino-4-piperidinyl)methanol | C12H18N2O | 详情 | 详情 | |
| (VIII) | 14721 | 1-(2-bromoethyl)-4-ethyl-1,4-dihydro-5H-1,2,3,4-tetraazol-5-one | C5H9BrN4O | 详情 | 详情 | |
| (IX) | 32218 | 1-ethyl-1,4-dihydro-5H-1,2,3,4-tetraazol-5-one | 69048-98-2 | C3H6N4O | 详情 | 详情 |
| (X) | 10252 | 1,2-Dibromoethane; Ethylene dibromide | 106-93-4 | C2H4Br2 | 详情 | 详情 |
| (XI) | 49683 | 1-[2-[4-anilino-4-(hydroxymethyl)-1-piperidinyl]ethyl]-4-ethyl-1,4-dihydro-5H-1,2,3,4-tetraazol-5-one | C17H26N6O2 | 详情 | 详情 | |
| (XII) | 49684 | 1-[2-[4-anilino-4-(methoxymethyl)-1-piperidinyl]ethyl]-4-ethyl-1,4-dihydro-5H-1,2,3,4-tetraazol-5-one | C18H28N6O2 | 详情 | 详情 | |
| (XIII) | 15967 | propanoyl chloride; propionyl chloride | 79-03-8 | C3H5ClO | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(VI)The reaction of 4-oxopiperidine-1-carboxylic acid ethyl ester (I) with CHCl3, benzyl triethylammonium chloride and NaOH in THF/water gives the spirooxirane (II), which is treated with aniline (III) and NaOH to yield the anilide (IV). The methylation of the amide nitrogen by means of NaH and CH3I in THF affords the methylated anilide (V). The reaction of (V) with KOH in refluxing isopropanol causes elimination of its ethoxycarbonyl group, providing compound (VI), which is reduced with lithium triethylborohydride in THF to give 4-(hydroxymethyl)-4-(phenylamino)piperidine (VII). The condensation of (VII) with 2-(2-thienyl)ethyl mesylate (VIII) by means of K2CO3 in refluxing acetonitrile yields the adduct (XI), which is methylated with NaH and CH3I in THF to afford the methoxy derivative (X). Finally, this compound is acylated with propionyl chloride (XI) in chloroform to provide the target compound.
| 【1】 Killgore, J.K.; Jacob, M. (Mallinckrodt Medical Inc.); New methods for the syntheses of alfentanil, sufentanil and remifentanil. WO 0140184 . |
| 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) | 49678 | ethyl 2,2-dichloro-1-oxa-6-azaspiro[2.5]octane-6-carboxylate | C9H13Cl2NO3 | 详情 | 详情 | |
| (III) | 12294 | Aniline; Phenylamine | 62-53-3 | C6H7N | 详情 | 详情 |
| (IV) | 49679 | ethyl 4-anilino-4-(anilinocarbonyl)-1-piperidinecarboxylate | C21H25N3O3 | 详情 | 详情 | |
| (V) | 49680 | ethyl 4-anilino-4-[(methylanilino)carbonyl]-1-piperidinecarboxylate | C22H27N3O3 | 详情 | 详情 | |
| (VI) | 49681 | 4-anilino-N-methyl-N-phenyl-4-piperidinecarboxamide | C19H23N3O | 详情 | 详情 | |
| (VII) | 49682 | (4-anilino-4-piperidinyl)methanol | C12H18N2O | 详情 | 详情 | |
| (VIII) | 49685 | 2-(2-thienyl)ethyl methanesulfonate | C7H10O3S2 | 详情 | 详情 | |
| (IX) | 35257 | [4-anilino-1-[2-(2-thienyl)ethyl]-4-piperidinyl]methanol | C18H24N2OS | 详情 | 详情 | |
| (X) | 49686 | 1-[2-(5-ethyl-2-thienyl)ethyl]-4-(methoxymethyl)-N-phenyl-4-piperidinamine; N-[1-[2-(5-ethyl-2-thienyl)ethyl]-4-(methoxymethyl)-4-piperidinyl]-N-phenylamine | C21H30N2OS | 详情 | 详情 | |
| (XI) | 15967 | propanoyl chloride; propionyl chloride | 79-03-8 | C3H5ClO | 详情 | 详情 |