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【结 构 式】 
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【药物名称】Saredutant, SR-489686, SR-48965 (R-isomer), SR-48968 【化学名称】(S)-N-[4-(4-Acetamido-4-phenylpiperidin-1-yl)-2-(3,4-dichlorophenyl)butyl]-N-methylbenzamide 【CA登记号】142001-63-6 【 分 子 式 】C31H35Cl2N3O2 【 分 子 量 】552.5495 |
【开发单位】Sanofi-synthélabo (Originator) 【药理作用】Antiallergy/Antiasthmatic Drugs, Antidepressants, Antipsychotic Drugs, Anxiolytics, Asthma Therapy, GASTROINTESTINAL DRUGS, Irritable Bowel Syndrome, Agents for, Mood Disorders, Treatment of, PSYCHOPHARMACOLOGIC DRUGS, RENAL-UROLOGIC DRUGS, RESPIRATORY DRUGS, Urinary Incontinence Therapy, Tachykinin NK2 Antagonists |
合成路线1
The intermediate piperidine (III) was prepared from 1-benzyl-4-hydroxy-4-phenylpiperidine (I) via conversion to acetamide (II) by means of a Ritter reaction with acetonitrile and H2SO4, followed by hydrogenolysis of the N-benzyl protecting group
| 【1】 Hale, J.J.; Finke, P.E.; MacCross, M.; A facile synthesis of the novel neurokinin A antagonist SR 48968. Bioorg Med Chem Lett 1993, 3, 2, 319. |
| 【2】 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 . |
| 【3】 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 . |
| 【4】 Finke, P.E.; Mills, S.G.; Hale, J.J.; MacCoss, M. (Merck & Co., Inc.); Process of making chiral 2-aryl-1,4-butanediamine derivs.. WO 9407839 . |
| 【5】 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. |
合成路线2
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3
In a different procedure, 3,4-dichlorophenylacetic acid (XIV) was condensed with the lithiated chiral oxazolidinone (XV), via activation as the mixed anhydride with pivaloyl chloride, to afford the N-acyl oxazolidinone (XVI). Diastereoselective alkylation of the sodium enolate of (XVI) with allyl iodide (XVII) afforded the (S)-pentenyl oxazolidinone (XVIII), which was further hydrolyzed to the chiral acid (XIX) by means of lithium peroxide. Alternatively, acid (XIX) was obtained by alkylation of the lithium dianion of 3,4-dichlorophenylacetic acid (XIV) with allyl bromide (XX), followed by resolution of the resultant racemic acid (XXI) with (S)-1-phenylethylamine. Acid (XIX) was converted to the amide (XXII) via the corresponding acid chloride. Reduction of amide (XXII) with DIBAL gave the secondary amine (XXIII), which was subsequently acylated with benzoyl chloride, yielding benzamide (XXIV). Dihydroxylation of the olefin double bond with N-methylmorpholine-N-oxide in the presence of OsO4, followed by oxidative cleavage of the resultant diol (XXV) with sodium periodate furnished aldehyde (XXVI). Finally, reductive amination of aldehyde (XXVI) with piperidine (III) in the presence of NaBH3CN provided the title compound
| 【1】 Hale, J.J.; Finke, P.E.; MacCross, M.; A facile synthesis of the novel neurokinin A antagonist SR 48968. Bioorg Med Chem Lett 1993, 3, 2, 319. |
| 【2】 Finke, P.E.; Mills, S.G.; Hale, J.J.; MacCoss, M. (Merck & Co., Inc.); Process of making chiral 2-aryl-1,4-butanediamine derivs.. WO 9407839 . |
| 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 | |
| (XIV) | 30414 | 2-(3,4-dichlorophenyl)acetic acid；2-(3,4-Dichlorophenyl)acetic acid | 5807-30-7 | C8H6Cl2O2 | 详情 | 详情 |
| (XV) | 58942 | C10H10LiNO2 | 详情 | 详情 | ||
| (XVI) | 62381 | (4S)-4-benzyl-3-[2-(3,4-dichlorophenyl)acetyl]-1,3-oxazolidin-2-one | C18H15Cl2NO3 | 详情 | 详情 | |
| (XVII) | 32112 | 3-iodo-1-propene;3-iodo-propen;allyl iodide | 556-56-9 | C3H5I | 详情 | 详情 |
| (XVIII) | 62382 | (4S)-4-benzyl-3-[(2S)-2-(3,4-dichlorophenyl)-4-pentenoyl]-1,3-oxazolidin-2-one | C21H19Cl2NO3 | 详情 | 详情 | |
| (XIX) | 62383 | (2S)-2-(3,4-dichlorophenyl)-4-pentenoic acid | C11H10Cl2O2 | 详情 | 详情 | |
| (XX) | 11463 | 3-Bromo-1-propene; 3-Bromopropene；allyl bromide | 106-95-6 | C3H5Br | 详情 | 详情 |
| (XXI) | 50421 | 2-(3,4-dichlorophenyl)-4-pentenoic acid | C11H10Cl2O2 | 详情 | 详情 | |
| (XXII) | 62384 | (2S)-2-(3,4-dichlorophenyl)-N-methyl-4-pentenamide | C12H13Cl2NO | 详情 | 详情 | |
| (XXIII) | 62385 | (2S)-2-(3,4-dichlorophenyl)-N-methyl-4-penten-1-amine; N-[(2S)-2-(3,4-dichlorophenyl)-4-pentenyl]-N-methylamine | C12H15Cl2N | 详情 | 详情 | |
| (XXIV) | 62386 | N-[(2S)-2-(3,4-dichlorophenyl)-4-pentenyl]-N-methylbenzamide | C19H19Cl2NO | 详情 | 详情 | |
| (XXV) | 62387 | N-[(2S)-2-(3,4-dichlorophenyl)-4,5-dihydroxypentyl]-N-methylbenzamide | C19H21Cl2NO3 | 详情 | 详情 | |
| (XXVI) | 26943 | N-[(2S)-2-(3,4-dichlorophenyl)-4-oxobutyl]-N-methylbenzamide | C18H17Cl2NO2 | 详情 | 详情 |
合成路线4
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 |