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【结 构 式】

【分子编号】20628

【品名】1-[3-amino-4-(benzyloxy)phenyl]-1-ethanone

【CA登记号】

【 分 子 式 】C15H15NO2

【 分 子 量 】241.28964

【元素组成】C 74.67% H 6.27% N 5.8% O 13.26%

与该中间体有关的原料药合成路线共 4 条

合成路线1

该中间体在本合成路线中的序号:(IV)

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:(IV)

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3

该中间体在本合成路线中的序号:(VII)

The condensation of benzaldehyde (I) with thiazolidine-2,4-dione (II) by means of piperidine in ethanol gives the benzylidene-thiazolidinedione (III), which is reduced with H2 over Pd/C in methanol to yield the benzyl derivative (IV). The cleavage of the cyclic ketal group of (IV) with HCl affords the piperidone (V), which is finally reductocondensed with the chiral ethanolamine (VI) by means of sodium triacetoxyborohydride in DMF to provide the target compound. The intermediate ethanolamine (VI) has been obtained as follows: The reaction of 3-amino-4-(benzyloxy)acetophenone (VII) with Ms-Cl and pyridine in dichloromethane gives the expected sulfonamide (VIII), which is brominated with CuBr2 in chloroform to yield the phenacyl bromide (IX). Enantioselective reduction with the Corey's chiral oxazaborolidine catalyst affords the (R)-bromoethanol derivative (X), which is treated with NaN3 in DMSO to provide the azido compound (XI). Finally, this compound is reduced and debenzylated by hydrogenation with H2 over Pd/C in methanol to furnish the desired ethanolamine intermediate (VI).

1 Gunawan, I.; Ellingboe, J.; Hu, B.; et al.; 2,4-Thiazolidinediones as potent and selective human beta3 agonists. Bioorg Med Chem Lett 2001, 11, 6, 757.
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) 49400 4-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)benzaldehyde C14H17NO3 详情 详情
(II) 10883 1,3-Thiazolane-2,4-dione; 2,4-Thiazolidinedione 2295-31-0 C3H3NO2S 详情 详情
(III) 49401 5-[(E)-[4-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)phenyl]methylidene]-1,3-thiazolidine-2,4-dione C17H18N2O4S 详情 详情
(IV) 49402 5-[4-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)benzyl]-1,3-thiazolidine-2,4-dione C17H20N2O4S 详情 详情
(V) 49403 5-[4-(4-oxo-1-piperidinyl)benzyl]-1,3-thiazolidine-2,4-dione C15H16N2O3S 详情 详情
(VI) 49404 N-[5-[(1R)-2-amino-1-hydroxyethyl]-2-hydroxyphenyl]methanesulfonamide C9H14N2O4S 详情 详情
(VII) 20628 1-[3-amino-4-(benzyloxy)phenyl]-1-ethanone C15H15NO2 详情 详情
(VIII) 20629 N-[5-acetyl-2-(benzyloxy)phenyl]methanesulfonamide C16H17NO4S 详情 详情
(IX) 20630 N-[2-(benzyloxy)-5-(2-bromoacetyl)phenyl]methanesulfonamide C16H16BrNO4S 详情 详情
(X) 20634 N-[2-(benzyloxy)-5-[(1R)-2-bromo-1-hydroxyethyl]phenyl]methanesulfonamide C16H18BrNO4S 详情 详情
(XI) 49405 N-[5-[(1R)-2-azido-1-hydroxyethyl]-2-(benzyloxy)phenyl]methanesulfonamide C16H18N4O4S 详情 详情

合成路线4

该中间体在本合成路线中的序号:(I)

The reaction of 3-amino-4-benzyloxyacetophenone (I) with phosgene in toluene gives 3-isocyanate-4-benzyloxyacetophenone (II), which by reaction with ammonia in benzene yields 4-benzyloxy-3-ureidoacetophenone (III). The bromination of this product with Br2 in CHCl3 affords 4-benzyloxy-3-ureidophenacyl bromide (IV), amorphous product that is condensed with N-benzyl-N-tert-butylamine (V) in acetonitrile giving 4-benzyloxy-3-ureido-alpha-(N-benzyl-N-tert-butylamine)acetophenone hydrochloride (VI), m.p. 220-1 C. This product is finally hydrogenated with H2 over Pd/C in methanol

1 Castaner, J.; Sungurbey, K.; Carbuterol. Drugs Fut 1976, 1, 9, 412.
2 Kaiser C.; et al. (Smith Kline French); DE 2106620 .
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) 20628 1-[3-amino-4-(benzyloxy)phenyl]-1-ethanone C15H15NO2 详情 详情
(II) 60749 1-[4-(benzyloxy)-3-isocyanatophenyl]-1-ethanone C16H13NO3 详情 详情
(III) 60750 N-[5-acetyl-2-(benzyloxy)phenyl]urea C16H16N2O3 详情 详情
(IV) 60751 N-[2-(benzyloxy)-5-(2-bromoacetyl)phenyl]urea hydrobromide C16H16Br2N2O3 详情 详情
(V) 24700 N-benzyl-2-methyl-2-propanamine 3378-72-1 C11H17N 详情 详情
(VI) 60752 N-[5-{2-[benzyl(tert-butyl)amino]acetyl}-2-(benzyloxy)phenyl]urea C27H31N3O3 详情 详情
Extended Information