N-[5-acetyl-2-(benzyloxy)phenyl]methanesulfonamide -Drug Synthesis Database

【结构式】

【分子编号】20629

【品名】N-[5-acetyl-2-(benzyloxy)phenyl]methanesulfonamide

【CA登记号】

【分子式】C₁₆H₁₇NO₄S

【分子量】319.38132

【元素组成】C 60.17% H 5.37% N 4.39% O 20.04% S 10.04%

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：(V)

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：(V)

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：(VIII)

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).

参考文献中间体

合成目标

【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

Extended Information