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【结 构 式】 
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【药物名称】 【化学名称】N-(2,5-Difluorobenzyl)-4-[4-[2-[2(S)-hydroxy-3-[4-hydroxy-3-(methylsulfonamido)phenoxy]propylamino]ethyl]phenylamino]piperidine-1-carboxamide 【CA登记号】392630-57-8 【 分 子 式 】C31H39F2N5O6S 【 分 子 量 】647.74718 |
【开发单位】Wyeth Pharmaceuticals (Originator) 【药理作用】Antidiabetic Drugs, Antiobesity Drugs, ENDOCRINE DRUGS, METABOLIC DRUGS, RENAL-UROLOGIC DRUGS, Treatment of Nutritional Disorders, Type 2 Diabetes Mellitus, Agents for, Urinary Incontinence Therapy, beta3-Adrenoceptor Agonists |
合成路线1
The chiral epoxide (VIII) was prepared as follows. 4-Hydroxy-3-nitroacetophenone (I) was protected as the silyl derivative (II) and then subjected to a Baeyer-Villiger rearrangement to afford the phenol acetate ester (III). Hydrogenation of the nitro group of (III) over Raney nickel provided aniline (IV), which was acylated by methanesulfonyl chloride producing sulfonamide (V). After protection of the sulfonamide NH of (V) with Boc2O, basic hydrolysis of the acetate ester furnished phenol (VI). Mitsunobu coupling between phenol (VI) and (R)-glycidol (VII) led to the glycidyl ether (VIII).
| 【1】 Mulvey, R.; Ashwell, M.A.; Solvibile, W.R. Jr.; Han, S.; Tillet, J.; Largis, E.; 4-Aminopiperidine ureas as potent selective agonists of the human beta3-adrenergic receptor. Bioorg Med Chem Lett 2001, 11, 24, 3123. |
| 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) | 20626 | 1-(4-hydroxy-3-nitrophenyl)-1-ethanone | 6322-56-1 | C8H7NO4 | 详情 | 详情 |
| (II) | 59660 | 1-(4-{[tert-butyl(diphenyl)silyl]oxy}-3-nitrophenyl)-1-ethanone | C24H25NO4Si | 详情 | 详情 | |
| (III) | 59661 | 4-{[tert-butyl(diphenyl)silyl]oxy}-3-nitrophenyl acetate | C24H25NO5Si | 详情 | 详情 | |
| (IV) | 59662 | 3-amino-4-{[tert-butyl(diphenyl)silyl]oxy}phenyl acetate | C24H27NO3Si | 详情 | 详情 | |
| (V) | 59663 | 4-{[tert-butyl(diphenyl)silyl]oxy}-3-[(methylsulfonyl)amino]phenyl acetate | C25H29NO5SSi | 详情 | 详情 | |
| (VI) | 59664 | tert-butyl 2-{[tert-butyl(diphenyl)silyl]oxy}-5-hydroxyphenyl(methylsulfonyl)carbamate | C28H35NO6SSi | 详情 | 详情 | |
| (VII) | 16206 | (4R,5R,6S)-6-[(1R)-1-hydroxyethyl]-4-methyl-2-[2-(4-nitrobenzyloxy)acetyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-en-3-yl diphenylphosphinate | C29H27N2O8P | 详情 | 详情 | |
| (VIII) | 59665 | tert-butyl 2-{[tert-butyl(diphenyl)silyl]oxy}-5-[(2S)oxiranylmethoxy]phenyl(methylsulfonyl)carbamate | C31H39NO7SSi | 详情 | 详情 |
合成路线2
4-Aminophenethylamine (IX) was selectively protected at the aliphatic amino group by means of Boc2O to afford (X). Reductive alkylation of aniline (X) with N-benzyl-4-piperidone (XI) in the presence of NaBH(OAc)3 furnished the secondary amine (XII). Subsequent N-benzyl group cleavage in (XI) by transfer hydrogenolysis gave rise to diamine (XIII), which was further converted to urea (XV) by coupling with isocyanate (XIV). The N-Boc group of (XV) was then cleaved by means of formic acid, yielding amine (XVI). The title compound was then obtained by condensation of amine (XVI) with epoxide (VIII), followed by removal of the N-Boc and silyl protecting groups.
| 【1】 Mulvey, R.; Ashwell, M.A.; Solvibile, W.R. Jr.; Han, S.; Tillet, J.; Largis, E.; 4-Aminopiperidine ureas as potent selective agonists of the human beta3-adrenergic receptor. Bioorg Med Chem Lett 2001, 11, 24, 3123. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VIII) | 59665 | tert-butyl 2-{[tert-butyl(diphenyl)silyl]oxy}-5-[(2S)oxiranylmethoxy]phenyl(methylsulfonyl)carbamate | C31H39NO7SSi | 详情 | 详情 | |
| (IX) | 18961 | 4-(2-aminoethyl)aniline; 4-(2-aminoethyl)phenylamine | 13472-00-9 | C8H12N2 | 详情 | 详情 |
| (X) | 18966 | tert-butyl 4-aminophenethylcarbamate | C13H20N2O2 | 详情 | 详情 | |
| (XI) | 15720 | 1-benzyltetrahydro-4(1H)-pyridinone; 1-Benzyl-4-piperidone; N-Benzyl-4-piperidone; 1-(benzyl)-4-piperidinone; 1-benzylpiperidin-4-one; 1-(benzyl)piperidin-4-one | 3612-20-2 | C12H15NO | 详情 | 详情 |
| (XII) | 52065 | tert-butyl 4-[(1-benzyl-4-piperidinyl)amino]phenethylcarbamate | C25H35N3O2 | 详情 | 详情 | |
| (XIII) | 52066 | tert-butyl 4-(4-piperidinylamino)phenethylcarbamate | C18H29N3O2 | 详情 | 详情 | |
| (XIV) | 59666 | 1,4-difluoro-2-(isocyanatomethyl)benzene; 2,5-difluorobenzyl isocyanate | C8H5F2NO | 详情 | 详情 | |
| (XV) | 59667 | tert-butyl 4-[(1-{[(2,5-difluorobenzyl)amino]carbonyl}-4-piperidinyl)amino]phenethylcarbamate | C26H34F2N4O3 | 详情 | 详情 | |
| (XVI) | 59668 | 4-[4-(2-aminoethyl)anilino]-N-(2,5-difluorobenzyl)-1-piperidinecarboxamide | C21H26F2N4O | 详情 | 详情 |