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【结 构 式】 
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【分子编号】20635 【品名】N-[2-(benzyloxy)-5-[(1R)-1-hydroxy-2-iodoethyl]phenyl]methanesulfonamide 【CA登记号】 |
【 分 子 式 】C16H18INO4S 【 分 子 量 】447.29373 【元素组成】C 42.96% H 4.06% I 28.37% N 3.13% O 14.31% S 7.17% |
合成路线1
该中间体在本合成路线中的序号：(XI)Nitration of 4-hydroxyacetophenone with KNO3 in cold H2SO4 gave the 3-nitro derivative (II), which was protected as the benzyl ether (III) with benzyl bromide in DMF. Hydrogenation of the nitro group of (III) over PtO2 afforded aniline (IV), and further treatment of (IV) with methanesulfonyl chloride in pyridine provided sulfonamide (V). Subsequent alpha-bromination of the acetophenone (V) was achieved using CuBr2 in a refluxing mixture of EtOAc and CHCl3. Asymmetric reduction of the ketone with borane in the presence of the chiral oxazaborolidine (VII), (prepared in situ from (R)-a,a-diphenyl-2-pyrrolidinemethanol (VIII) and trimethylboroxine (IX) in boiling toluene), provided the (R)-alcohol (X). The bromo group of (X) was then substituted for a iodo group upon treatment with NaI in acetone, and the resulting (IX) was protected as the triethylsilyl ether (XII) with Et3SiCl in the presence of imidazole and dimethylaminopyridine. Reaction of 4,4'-dihydroxybenzophenone (XIII) with chlorodifluoromethane and t-BuOK yielded the bis(difluoromethyl) ether (XIV). The benzhydryl amine (XV) was then obtained by reductive amination with ammonium formate at 160 C, followed by acid hydrolysis of the intermediate formamide. Condensation of iodide (XII) with benzhydryl amine (XV) in the presence of diisopropyl ethylamine in THF at 110 C in a sealed flask provided the secondary amine (XVI). Finally, the target compound was obtained by desilylation with tetrabutylammonium fluoride, followed by hydrogenolysis of the benzyl protecting group.
| 【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) | 20631 | (R)-Methyl oxazaborolidine; (3aR)-1-methyl-3,3-diphenyltetrahydro-3H-pyrrolo[1,2-c][1,3,2]oxazaborole | 112022-83-0 | C18H20BNO | 详情 | 详情 |
| (VIII) | 20632 | diphenyl[(2R)pyrrolidinyl]methanol | C17H19NO | 详情 | 详情 | |
| (IX) | 20633 | 2,4,6-trimethylboroxin | 823-96-1 | C3H9B3O3 | 详情 | 详情 |
| (X) | 20634 | N-[2-(benzyloxy)-5-[(1R)-2-bromo-1-hydroxyethyl]phenyl]methanesulfonamide | C16H18BrNO4S | 详情 | 详情 | |
| (XI) | 20635 | N-[2-(benzyloxy)-5-[(1R)-1-hydroxy-2-iodoethyl]phenyl]methanesulfonamide | C16H18INO4S | 详情 | 详情 | |
| (XII) | 20636 | N-(2-(benzyloxy)-5-[(1R)-2-iodo-1-[(triethylsilyl)oxy]ethyl]phenyl)methanesulfonamide | C22H32INO4SSi | 详情 | 详情 | |
| (XIII) | 20637 | bis(4-hydroxyphenyl)methanone | 611-99-4 | C13H10O3 | 详情 | 详情 |
| (XIV) | 20638 | bis[4-(difluoromethoxy)phenyl]methanone | C15H10F4O3 | 详情 | 详情 | |
| (XV) | 20639 | bis[4-(difluoromethoxy)phenyl]methylamine; bis[4-(difluoromethoxy)phenyl]methanamine | C15H13F4NO2 | 详情 | 详情 | |
| (XVI) | 20640 | N-(2-(benzyloxy)-5-[(1R)-2-([bis[4-(difluoromethoxy)phenyl]methyl]amino)-1-[(triethylsilyl)oxy]ethyl]phenyl)methanesulfonamide | C37H44F4N2O6SSi | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(IX)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 |