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【结 构 式】

【分子编号】20636

【品名】N-(2-(benzyloxy)-5-[(1R)-2-iodo-1-[(triethylsilyl)oxy]ethyl]phenyl)methanesulfonamide

【CA登记号】

【 分 子 式 】C22H32INO4SSi

【 分 子 量 】561.55639

【元素组成】C 47.06% H 5.74% I 22.6% N 2.49% O 11.4% S 5.71% Si 5%
与该中间体有关的原料药合成路线共 3 条
合成路线1合成路线2合成路线3

合成路线1

该中间体在本合成路线中的序号：(XII)

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.

参考文献 中间体
合成目标
【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：(X)

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.

参考文献 中间体
合成目标
【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3

该中间体在本合成路线中的序号：(X)

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.

参考文献 中间体
合成目标
【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
Extended Information