1-(4-hydroxy-3-nitrophenyl)-1-ethanone -Drug Synthesis Database

【结构式】

【分子编号】20626

【品名】1-(4-hydroxy-3-nitrophenyl)-1-ethanone

【CA登记号】6322-56-1

【分子式】C₈H₇NO₄

【分子量】181.14792

【元素组成】C 53.04% H 3.89% N 7.73% O 35.33%

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：(II)

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：(II)

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：(I)

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).

参考文献中间体

合成目标

【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

Extended Information