[5-(benzyloxy)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-3-yl]methanol -Drug Synthesis Database

【结构式】

【分子编号】30773

【品名】[5-(benzyloxy)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-3-yl]methanol

【CA登记号】

【分子式】C₂₁H₂₆O₃

【分子量】326.43564

【元素组成】C 77.27% H 8.03% O 14.7%

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：(VII)

The cyclization of 2,5-dimethoxy-1,3,4-trimethylbenzene (I) with 2-bromo-2-methylpropionyl bromide (II) by means of FeCl3 and NaOH in methanol/water gives 5-hydroxy-2,2,4,6,7-pentamethyl-2,3-dihydrobenzofuran-3-one (III), which is treated with benzyl bromide (IV) and K2CO3 to yield the benzyl ether (V). The reaction of (V) with methylmagnesium bromide, followed by dehydration of the intermediate carbinol affords the methylene derivative (VI), which is hydroxylated with borane / dimethylsulfide and NaOH/H2O2 to furnish the hydroxymethyl compound (VII). The reaction of (VII) with MsCl and TEA gives the mesylate (VIII), which is finally condensed with 1-methylpiperazine (IX) by means of K2CO3 and debenzylated by hydrogenation with H2 over Pd/C in ethanol/HOAc to afford the target compound as a racemic mixture.

参考文献中间体

合成目标

【1】 Petty, M.A.; Marciniak, G.; Design and biological evaluation of new antioxidants for use in cerebrovascular disorders. Drugs Fut 1996, 21, 10, 1037.
【2】 Ayers, T.A.; Schnettler, R.A.; Marciniak, G.; Krysan, D.J. (Hoechst Marion Roussel Inc.); Novel process for preparing derivatives of 2,2,4,6,7-pentaalkyl-2,2-dihydrobenzofuranols. EP 0813530 .

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)	41220	1,4-dimethoxy-2,3,5-trimethylbenzene; 4-methoxy-2,3,5-trimethylphenyl methyl ether		C₁₁H₁₆O₂	详情	详情
(II)	19367	2-bromo-2-methylpropanoyl bromide	20769-85-1	C₄H₆Br₂O	详情	详情
(III)	41221	5-hydroxy-2,2,4,6,7-pentamethyl-1-benzofuran-3(2H)-one		C₁₃H₁₆O₃	详情	详情
(IV)	12912	1-(Bromomethyl)benzene; Alpha-bromotoluene	100-39-0	C₇H₇Br	详情	详情
(V)	41222	5-(benzyloxy)-2,2,4,6,7-pentamethyl-1-benzofuran-3(2H)-one		C₂₀H₂₂O₃	详情	详情
(VI)	41223	5-(benzyloxy)-2,2,4,6,7-pentamethyl-3-methylene-2,3-dihydro-1-benzofuran; benzyl 2,2,4,6,7-pentamethyl-3-methylene-2,3-dihydro-1-benzofuran-5-yl ether		C₂₁H₂₄O₂	详情	详情
(VII)	30773	[5-(benzyloxy)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-3-yl]methanol		C₂₁H₂₆O₃	详情	详情
(VIII)	26455	5-(benzyloxy)-2,2,4,6,7-pentamethyl-3-([[methyl(dimethylene)-lambda(6)-sulfanyl]oxy]methyl)-2,3-dihydro-1-benzofuran		C₂₄H₃₂O₃S	详情	详情
(IX)	10061	1-Methylpiperazine; 1-Methyl piperazine; N-Methylpiperazine	109-01-3	C₅H₁₂N₂	详情	详情

合成路线2

该中间体在本合成路线中的序号：(rac)-(VII)

The enantiomers of the title product have been obtained by optical resolution of the racemic hydroxymethyl compound (rac)-(VII) by means of "Candida cylindracea" and vinyl acetate to give (S)-(VII) and (R)-(VII). Finally both chiral intermediates are condensed with 1-methylpiperazine (IX) and debenzylated by hydrogenation with H2 over Pd/C in ethanol/HOAc for the racemic mixture (rac)-(VII).

参考文献中间体

合成目标

【1】 Petty, M.A.; Marciniak, G.; Design and biological evaluation of new antioxidants for use in cerebrovascular disorders. Drugs Fut 1996, 21, 10, 1037.
【2】 Ayers, T.A.; Schnettler, R.A.; Marciniak, G.; Krysan, D.J. (Hoechst Marion Roussel Inc.); Novel process for preparing derivatives of 2,2,4,6,7-pentaalkyl-2,2-dihydrobenzofuranols. EP 0813530 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(rac)-(VII)	30773	[5-(benzyloxy)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-3-yl]methanol		C₂₁H₂₆O₃	详情	详情
(S)-(VII)	41224	[(3S)-5-(benzyloxy)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-3-yl]methanol		C₂₁H₂₆O₃	详情	详情
(R)-(VII)	41225	[(3R)-5-(benzyloxy)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-3-yl]methanol		C₂₁H₂₆O₃	详情	详情
(IX)	10061	1-Methylpiperazine; 1-Methyl piperazine; N-Methylpiperazine	109-01-3	C₅H₁₂N₂	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 known benzofuran carbinol (I) was converted to mesylate (II) upon treatment with methanesulfonyl chloride and triethylamine and then condensed with (S)-prolinol (III) at 120 C to afford adduct (IV). Subsequent chlorination of (IV) with concomitant rearrangement by means of thionyl chloride in benzene produced the 3-chloropiperidine derivative (V). The reaction of (V) with 4-hydroxybenzaldehyde (VI) in the presence of K2CO3 in DMF at 80 C furnished a mixture of six- and five-membered ring products (VII) and (VIII), which were separated by column chromatography. Condensation of the required aldehyde (VIII) with thiazolidinedione (IX) using piperidinium benzoate in refluxing toluene provided the target benzylidene thiazolidine, which was finally converted to the corresponding maleate salt.

参考文献中间体

合成目标

【1】 Reddy, K.A.; Lohray, B.B.; Brushan, V.; et al.; Novel antidiabetic and hypolipidemic agents. 3. Benzofuran-containing thiazolidinediones. J Med Chem 1999, 42, 11, 1927.
【2】 Ramanujam, R.; Chakrabarti, R.; Lohray, B.B.; Bajji, A.C.; Lohray, V.B.; Alla, S.R. (Dr. Reddy's Research Foundation); Heterocyclic cpds. having antidiabetic, hypolipidaemic, antihypertensive properties, process for their preparation and pharmaceutical compsns. containing them. US 5889032 .

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)	30773	[5-(benzyloxy)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-3-yl]methanol		C₂₁H₂₆O₃	详情	详情
(II)	30774	[5-(benzyloxy)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-3-yl]methyl methanesulfonate		C₂₂H₂₈O₅S	详情	详情
(III)	21347	(2S)pyrrolidinylmethanol	23356-96-9	C₅H₁₁NO	详情	详情
(IV)	30775	((2S)-1-[[5-(benzyloxy)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-3-yl]methyl]pyrrolidinyl)methanol		C₂₆H₃₅NO₃	详情	详情
(V)	30776	(3R)-1-[[5-(benzyloxy)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-3-yl]methyl]-3-chloropiperidine; benzyl 3-[[(3R)-3-chloropiperidinyl]methyl]-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-yl ether		C₂₆H₃₄ClNO₂	详情	详情
(VI)	13433	4-Hydroxybenzaldehyde; p-Hydroxybenzaldehyde	123-08-0	C₇H₆O₂	详情	详情
(VII)	30777	4-[((3R)-1-[[5-(benzyloxy)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-3-yl]methyl]piperidinyl)oxy]benzaldehyde		C₃₃H₃₉NO₄	详情	详情
(VIII)	30778	4-[((2S)-1-[[5-(benzyloxy)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-3-yl]methyl]pyrrolidinyl)methoxy]benzaldehyde		C₃₃H₃₉NO₄	详情	详情
(IX)	10883	1,3-Thiazolane-2,4-dione; 2,4-Thiazolidinedione	2295-31-0	C₃H₃NO₂S	详情	详情

Extended Information