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【结 构 式】 
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【药物名称】BMS-196085 【化学名称】N-[5-[2-[1(R)-[4-(Difluoromethoxy)phenyl]-2-phenylethylamino]-1(R)-hydroxyethyl]-2-hydroxyphenyl]methanesulfonamide 【CA登记号】170686-10-9, 170687-20-4 (trifluoroacetate) 【 分 子 式 】C24H26F2N2O5S 【 分 子 量 】492.54602 |
【开发单位】Bristol-Myers Squibb (Originator) 【药理作用】Antidiabetic Drugs, Antiobesity Drugs, ENDOCRINE DRUGS, METABOLIC DRUGS, Treatment of Nutritional Disorders, beta3-Adrenoceptor Agonists |
合成路线1
4-Hydroxyacetophenone (I) was nitrated with KNO3 in H2SO4 to give (II). Alkylation of the phenolic hydroxyl of (II) with benzyl bromide afforded benzyl ether (III). The nitro group of (III) was then reduced by catalytic hydrogenation to yield aniline (IV), which was converted to sulfonamide (V) upon treatment with mesyl chloride and pyridine. Bromination of (V) with CuBr2 produced the bromoacetophenone (VI), which by reduction with BH3-Me2S in the presence of the chiral auxiliary agent (VII) furnished the (R)-alcohol (VIII). After displacement of the bromo group of (VIII) with NaI, the resulting iodoalcohol (IX) was protected as the silyl ether (X) by treatment with triethyl chlorosilane and imidazole.
| 【1】 Washburn, W.N.; Girotra, R.N.; Sher, P.M.; Mikkilineni, A.B.; Poss, K.M.; Mathur, A.; Gavai, A.; Bisacchi, G.S. (Bristol-Myers Squibb Co.); Catecholamine surrogates useful as B3 agonists. CA 2138675; EP 0659737; JP 1995206806; US 5776983 . |
| 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) | 18123 | 1-(4-hydroxyphenyl)-1-ethanone; 4'-Hydroxyacetophenone | 99-93-4 | C8H8O2 | 详情 | 详情 |
| (II) | 20626 | 1-(4-hydroxy-3-nitrophenyl)-1-ethanone | 6322-56-1 | C8H7NO4 | 详情 | 详情 |
| (III) | 20627 | 1-[4-(benzyloxy)-3-nitrophenyl]-1-ethanone | C15H13NO4 | 详情 | 详情 | |
| (IV) | 20628 | 1-[3-amino-4-(benzyloxy)phenyl]-1-ethanone | C15H15NO2 | 详情 | 详情 | |
| (V) | 20629 | N-[5-acetyl-2-(benzyloxy)phenyl]methanesulfonamide | C16H17NO4S | 详情 | 详情 | |
| (VI) | 20630 | N-[2-(benzyloxy)-5-(2-bromoacetyl)phenyl]methanesulfonamide | C16H16BrNO4S | 详情 | 详情 | |
| (VII) | 28292 | (S)-Methyl oxazaborolidine; (3aS)-1-methyl-3,3-diphenyltetrahydro-3H-pyrrolo[1,2-c][1,3,2]oxazaborole | 112022-81-8 | C18H20BNO | 详情 | 详情 |
| (VIII) | 20634 | N-[2-(benzyloxy)-5-[(1R)-2-bromo-1-hydroxyethyl]phenyl]methanesulfonamide | C16H18BrNO4S | 详情 | 详情 | |
| (IX) | 20635 | N-[2-(benzyloxy)-5-[(1R)-1-hydroxy-2-iodoethyl]phenyl]methanesulfonamide | C16H18INO4S | 详情 | 详情 | |
| (X) | 20636 | N-(2-(benzyloxy)-5-[(1R)-2-iodo-1-[(triethylsilyl)oxy]ethyl]phenyl)methanesulfonamide | C22H32INO4SSi | 详情 | 详情 |
合成路线2
Reaction of methyl 4-hydroxybenzoate (XI) with difluorochloromethane and potassium tert-butoxide provided difluoromethyl ether (XII). After basic hydrolysis of the methyl ester of (XII), the resulting carboxylic acid (XIII) was converted to acid chloride (XIV) by means of refluxing SOCl2. Subsequent coupling of (XIV) with benzyl bromide in the presence of Zn and palladium catalyst produced the diaryl ethanone (XV). Reductive amination of (XV) with ammonium formate at 160 C gave formamide (XVI), which was hydrolyzed to racemic amine (XVII) with boiling HCl. Alkylation of this amine with the intermediate iodide (X) in THF at 110 C in a sealed flask yielded a diastereomeric mixture of secondary amines (XVIII), which were separated by column chromatography. The required (R,R)-isomer was desilylated employing tetrabutylammonium fluoride and AcOH to produce aminoalcohol (XIX). Finally, hydrogenolytic cleavage of the benzyl ether of (XIX) furnished the title compound.
| 【1】 Washburn, W.N.; Girotra, R.N.; Sher, P.M.; Mikkilineni, A.B.; Poss, K.M.; Mathur, A.; Gavai, A.; Bisacchi, G.S. (Bristol-Myers Squibb Co.); Catecholamine surrogates useful as B3 agonists. CA 2138675; EP 0659737; JP 1995206806; US 5776983 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (X) | 20636 | N-(2-(benzyloxy)-5-[(1R)-2-iodo-1-[(triethylsilyl)oxy]ethyl]phenyl)methanesulfonamide | C22H32INO4SSi | 详情 | 详情 | |
| (XI) | 10251 | methyl 4-hydroxybenzoate; Methyl p-hydroxybenzoate | 99-76-3 | C8H8O3 | 详情 | 详情 |
| (XII) | 28293 | methyl 4-(difluoromethoxy)benzoate | C9H8F2O3 | 详情 | 详情 | |
| (XIII) | 28294 | 4-(difluoromethoxy)benzoic acid | 4837-20-1 | C8H6F2O3 | 详情 | 详情 |
| (XIV) | 28295 | 4-(difluoromethoxy)benzoyl chloride | C8H5ClF2O2 | 详情 | 详情 | |
| (XV) | 28296 | 1-[4-(difluoromethoxy)phenyl]-2-phenyl-1-ethanone | C15H12F2O2 | 详情 | 详情 | |
| (XVI) | 28297 | 1-[4-(difluoromethoxy)phenyl]-2-phenylethylformamide | C16H15F2NO2 | 详情 | 详情 | |
| (XVII) | 28298 | 1-[4-(difluoromethoxy)phenyl]-2-phenyl-1-ethanamine | C15H15F2NO | 详情 | 详情 | |
| (XVIII) | 28299 | N-(2-(benzyloxy)-5-[(1R)-2-([1-[4-(difluoromethoxy)phenyl]-2-phenylethyl]amino)-1-[(triethylsilyl)oxy]ethyl]phenyl)methanesulfonamide | C37H46F2N2O5SSi | 详情 | 详情 | |
| (XIX) | 28300 | N-[2-(benzyloxy)-5-[(1R)-2-([(1R)-1-[4-(difluoromethoxy)phenyl]-2-phenylethyl]amino)-1-hydroxyethyl]phenyl]methanesulfonamide | C31H32F2N2O5S | 详情 | 详情 |