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【结 构 式】 
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【分子编号】26942 【品名】N-[(2S)-2-(3,4-dichlorophenyl)-4-hydroxybutyl]-N-methylbenzamide 【CA登记号】 |
【 分 子 式 】C18H19Cl2NO2 【 分 子 量 】352.2598 【元素组成】C 61.37% H 5.44% Cl 20.13% N 3.98% O 9.08% |
合成路线1
该中间体在本合成路线中的序号：(XII)Alkylation of 3,4-dichlorophenylacetonitrile (VI) with (tetrahydropyranyloxy)ethyl bromide (V) (prepared by protection of 2-bromoethanol (IV) with dihydropyran) furnished nitrile (VII). Catalytic hydrogenation of (VII) in the presence of Raney-Ni and Et3N gave the primary amine (VIII). After acidic hydrolysis of the tetrahydropyranyl group of (VIII), the resultant amino alcohol was resolved by means of D-tartaric acid providing the (S)-enantiomer (IX). Reaction of amine (IX) with ethyl chloroformate afforded carbamate (X), which was further reduced to the N-methyl amine (XI) employing LiAlH4. Subsequent acylation of (XI) with benzoyl chloride furnished benzamide (XII). Mesylate (XIII) was then prepared by treatment of alcohol (XII) with methanesulfonyl chloride and triethylamine. Finally, condensation between piperidine (III) and mesylate (XIII) led to the title compound
| 【1】 Emonds-Alt, X.; Goulaouic, P.; Proietto, V.; Van Broeck, D. (Sanofi-Synthelabo); Arylalkylamines, process for their preparation and pharmaceutical compsns. containing them. EP 0474561; FR 2666335; FR 2678267; JP 1992261155; US 5236921; US 5350852 . |
| 【2】 Emonds-Alt, X.; Proietto, V.; Van Broeck, D.; Vilain, P.; Advenier, C.; Neliat, G.; Le Fur, G.; Breliere, J.-C.; Pharmacological profile and chemical synthesis of SR 48968, a non-peptide antagonist of the neurokinin A (NK2) receptor. Bioorg Med Chem Lett 1993, 3, 5, 925. |
| 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) | 59283 | N-(4-phenyl-4-piperidinyl)acetamide | C13H18N2O | 详情 | 详情 | |
| (IV) | 10059 | Ethylene bromohydrin; 2-Bromo-1-ethanol | 540-51-2 | C2H5BrO | 详情 | 详情 |
| (V) | 26934 | 2-bromoethyl tetrahydro-2H-pyran-2-yl ether | C7H13BrO2 | 详情 | 详情 | |
| (VI) | 26935 | 2-(3,4-dichlorophenyl)acetonitrile | 3218-49-3 | C8H5Cl2N | 详情 | 详情 |
| (VII) | 26936 | 2-(3,4-dichlorophenyl)-4-(tetrahydro-2H-pyran-2-yloxy)butanenitrile | C15H17Cl2NO2 | 详情 | 详情 | |
| (VIII) | 26937 | 2-(3,4-dichlorophenyl)-4-(tetrahydro-2H-pyran-2-yloxy)-1-butanamine | C15H21Cl2NO2 | 详情 | 详情 | |
| (IX) | 26939 | (3S)-4-amino-3-(3,4-dichlorophenyl)-1-butanol | C10H13Cl2NO | 详情 | 详情 | |
| (X) | 26940 | ethyl (2S)-2-(3,4-dichlorophenyl)-4-hydroxybutylcarbamate | C13H17Cl2NO3 | 详情 | 详情 | |
| (XI) | 26941 | (3S)-3-(3,4-dichlorophenyl)-4-(methylamino)-1-butanol | C11H15Cl2NO | 详情 | 详情 | |
| (XII) | 26942 | N-[(2S)-2-(3,4-dichlorophenyl)-4-hydroxybutyl]-N-methylbenzamide | C18H19Cl2NO2 | 详情 | 详情 | |
| (XIII) | 62380 | (3S)-4-(benzoylamino)-3-(3,4-dichlorophenyl)butyl methanesulfonate | C18H19Cl2NO4S | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XII)In a further method, the chiral amino alcohol (IX) was acylated with benzoyl chloride to afford the benzamide (XXVII). Subsequent protection of the hydroxyl group of (XXVII) with dihydropyran provided the tetrahydropyranyl ether (XXVIII). Alternatively, amino alcohol (IX) was initially protected as the tetrahydropyranyl derivative (XXIX), which was subsequently acylated with benzoyl chloride . N-Alkylation of amide (XXVIII) to give (XXX) was either performed with dimethyl sulfate or with methyl iodide in the presence of NaH. Subsequent deprotection of the tetrahydropyranyl ether (XXX) in acidic medium furnished alcohol (XII). This was converted to the sulfonate ester (XXXI) upon treatment with benzenesulfonyl chloride and Et3N. Alternatively, alcohol (XII) was converted to the corresponding mesylate as shown in Scheme 1 (5). Finally, condensation of the benzenesulfonate (XXXI) with piperidine (III) in the presence of K2CO3 in refluxing acetonitrile yielded the title compound
| 【1】 Descamps, M.; Radisson, J.; Anne-Archard, G. (Sanofi-Synthélabo); Process for the preparation of the (-)-N-methyl-N-[4-(4-phenyl-4-acetyl-aminopiperidin-1-yl)-2-(3,4-dichlorophenyl)butyl]-benzamide and its pharmaceutically acceptable salts. EP 0698601 . |
| 【2】 Emonds-Alt, X.; Proietto, V.; Van Broeck, D.; Vilain, P.; Advenier, C.; Neliat, G.; Le Fur, G.; Breliere, J.-C.; Pharmacological profile and chemical synthesis of SR 48968, a non-peptide antagonist of the neurokinin A (NK2) receptor. Bioorg Med Chem Lett 1993, 3, 5, 925. |
| 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) | 59283 | N-(4-phenyl-4-piperidinyl)acetamide | C13H18N2O | 详情 | 详情 | |
| (IX) | 26939 | (3S)-4-amino-3-(3,4-dichlorophenyl)-1-butanol | C10H13Cl2NO | 详情 | 详情 | |
| (XII) | 26942 | N-[(2S)-2-(3,4-dichlorophenyl)-4-hydroxybutyl]-N-methylbenzamide | C18H19Cl2NO2 | 详情 | 详情 | |
| (XXVII) | 62388 | N-[(2S)-2-(3,4-dichlorophenyl)-4-hydroxybutyl]benzamide | C17H17Cl2NO2 | 详情 | 详情 | |
| (XXVIII) | 62389 | N-[(2S)-2-(3,4-dichlorophenyl)-4-(tetrahydro-2H-pyran-2-yloxy)butyl]benzamide | C22H25Cl2NO3 | 详情 | 详情 | |
| (XXIX) | 62390 | (2S)-2-(3,4-dichlorophenyl)-4-(tetrahydro-2H-pyran-2-yloxy)butylamine; (2S)-2-(3,4-dichlorophenyl)-4-(tetrahydro-2H-pyran-2-yloxy)-1-butanamine | C15H21Cl2NO2 | 详情 | 详情 | |
| (XXX) | 62391 | N-[(2S)-2-(3,4-dichlorophenyl)-4-(tetrahydro-2H-pyran-2-yloxy)butyl]-N-methylbenzamide | C23H27Cl2NO3 | 详情 | 详情 | |
| (XXXI) | 49143 | (3S)-4-[benzoyl(methyl)amino]-3-(3,4-dichlorophenyl)butyl benzenesulfonate | C24H23Cl2NO4S | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(XI)The reaction of 2-bromoethanol (I) with dihydropyran by means of a strong acid ion exchange resin gives the tetrahydropyranyl ether (II), which is condensed with 2-(3,4-dichlorophenyl)acetonitrile (III) by means of NaH in THF yielding thebutyronitrile (IV). The reduction of (IV) with H2 over RaNi in ethanol/NH4OH affords the butylamine (V), which is deprotected with HCl in methanol providing racemic 2-(3,4-dichlorophenyl)-4-hydroxybutylamine (VI). The optical resolution of (VI) with D-tartaric acid affords the corresponding (S) isomer (VII), which is treated with ethyl chloroformate and triethylamine in dichloromethane to give the carbamate (VIII). The reduction of (VIII) with LiAlH4 in THF yields N-[2(S)-(3,4-dichlorophenyl)-4-hydroxybutyl]-N-methylamine (IX), which is acylated with benzoyl chloride (X) and triethylamine in dichloromethane to affords the amide (XI). Oxidation of the hydroxyl group of (XI) with Dess-Martin periodinane yields the corresponding aldehyde (XII), which is reductocondensed with 4-[N-(trifluoroacetyl)-N-[3-(trifluoroacetamido)propyl]amino]piperidine (XIII) by means of NaBH3CN in methanol/acetic acid providing the bis(trifluoroacetylated) intermediate (XIV). The deprotection of (XIV) with KOH in methanol/water gives the diamine intermediate (XV), which is finally cyclized with carbonyldiimidazole (CDI) in chloroform.
| 【1】 Miller, S.C. (AstraZeneca plc); Therapeutic heterocycles which antagonize neurokinin receptors. JP 1997501439; US 5567700; US 5990130; US 6124279; WO 9505377 . |
| 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) | 10059 | Ethylene bromohydrin; 2-Bromo-1-ethanol | 540-51-2 | C2H5BrO | 详情 | 详情 |
| (II) | 26934 | 2-bromoethyl tetrahydro-2H-pyran-2-yl ether | C7H13BrO2 | 详情 | 详情 | |
| (III) | 26935 | 2-(3,4-dichlorophenyl)acetonitrile | 3218-49-3 | C8H5Cl2N | 详情 | 详情 |
| (IV) | 26936 | 2-(3,4-dichlorophenyl)-4-(tetrahydro-2H-pyran-2-yloxy)butanenitrile | C15H17Cl2NO2 | 详情 | 详情 | |
| (V) | 26937 | 2-(3,4-dichlorophenyl)-4-(tetrahydro-2H-pyran-2-yloxy)-1-butanamine | C15H21Cl2NO2 | 详情 | 详情 | |
| (VI) | 26938 | 4-amino-3-(3,4-dichlorophenyl)-1-butanol | C10H13Cl2NO | 详情 | 详情 | |
| (VII) | 26939 | (3S)-4-amino-3-(3,4-dichlorophenyl)-1-butanol | C10H13Cl2NO | 详情 | 详情 | |
| (VIII) | 26940 | ethyl (2S)-2-(3,4-dichlorophenyl)-4-hydroxybutylcarbamate | C13H17Cl2NO3 | 详情 | 详情 | |
| (IX) | 26941 | (3S)-3-(3,4-dichlorophenyl)-4-(methylamino)-1-butanol | C11H15Cl2NO | 详情 | 详情 | |
| (X) | 10463 | Benzoyl chloride | 98-88-4 | C7H5ClO | 详情 | 详情 |
| (XI) | 26942 | N-[(2S)-2-(3,4-dichlorophenyl)-4-hydroxybutyl]-N-methylbenzamide | C18H19Cl2NO2 | 详情 | 详情 | |
| (XII) | 26943 | N-[(2S)-2-(3,4-dichlorophenyl)-4-oxobutyl]-N-methylbenzamide | C18H17Cl2NO2 | 详情 | 详情 | |
| (XIII) | 26944 | 2,2,2-trifluoro-N-(4-piperidinyl)-N-[3-[(2,2,2-trifluoroacetyl)amino]propyl]acetamide | C12H17F6N3O2 | 详情 | 详情 | |
| (XIV) | 26945 | N-[(2S)-2-(3,4-dichlorophenyl)-4-[4-((2,2,2-trifluoroacetyl)[3-[(2,2,2-trifluoroacetyl)amino]propyl]amino)-1-piperidinyl]butyl]-N-methylbenzamide | C30H34Cl2F6N4O3 | 详情 | 详情 | |
| (XV) | 26946 | N-[(2S)-4-[4-[(3-aminopropyl)amino]-1-piperidinyl]-2-(3,4-dichlorophenyl)butyl]-N-methylbenzamide | C26H36Cl2N4O | 详情 | 详情 |