(2S)-1-(1,3-benzodioxol-5-yl)-2-propanol -Drug Synthesis Database

【结构式】

【分子编号】29259

【品名】(2S)-1-(1,3-benzodioxol-5-yl)-2-propanol

【CA登记号】

【分子式】C₁₀H₁₂O₃

【分子量】180.20348

【元素组成】C 66.65% H 6.71% O 26.64%

与该中间体有关的原料药合成路线共 2 条

合成路线1 合成路线2

合成路线1

该中间体在本合成路线中的序号：(IV)

The reaction of 5-bromo-1,3-benzodioxole (I) with (S)-(-)-propylene oxide (II) by means of sec-butyllithium in THF gives the (S)-isopropanol derivative (IV) (also obtained by stereoselective reduction of 1-(1,3-benzodioxol-5-yl)-2-propanone (III) with Z. rouxii ATCC 14462 in a phosphate buffer). The cyclization of (IV) with 4-nitrobenzaldehyde (V) by means of HCl in hot toluene yields the benzopyran (VI), which is oxidized with air in aqueous NaOH affording the carbinol (VII). The reaction of (VII) with acetohydrazide (VIII) and HCl in refluxing ethanol gives the acetyl hydrazone (IX), which is mesylated at the secondary OH group with methanesulfonyl chloride and TEA in dichloromethane yielding the mesylate (X). The cyclization of (X) by means of NaOH in methanol provides the nitro benzodiazepine (XI), which is finally reduced with potassium formate and Pd/C in ethanol/water.

参考文献中间体

合成目标

【1】 Andrasi, F.; Talampanel. Drugs Fut 2001, 26, 8, 754.
【2】 Anderson, B.A.; et al.; Application of a practical biocatalytic reduction to an enantioselective synthesis of the 5H-2, 3-benzodiazepine LY300164. J Am Chem Soc 1995, 117, 49, 12358.
【3】 Andrasi, F.; Berzsenyi, P.; Botka, P.; Farkas, S.; Goldschmidt, K.; Hamori, T.; Korosi, J.; Moravcsik, I.; Tarnawa, I. (Gyogyszerkutato Intezet Kft.); N-Acyl-2,3-benzodiazepine derivs., pharmaceutical compsns. containing them and process for preparing same. EP 0492485; JP 1993070463; US 5519019; US 5521174; US 5536832; US 5604223; US 5639751 .
【4】 Varie, D.L.; Hansen, M.M.; Anderson, B.; Vicenzi, J.T.; Zmijewski, M.J. (Eli Lilly and Company); Stereoselective process for producing dihydro-2,3-benzodiazepine derivs.. EP 0699677; US 5665878 .
【5】 Zmijewski, M.J. Jr.; Varie, D.L.; Hansen, M.M.; Vicenzi, J.T.; Anderson, B.A. (Eli Lilly and Company); Physical form of dihidro-2,3-benzodiazepine deriv.. EP 0699676 .
【6】 Hansen, M.M.; Vicenzi, J.T.; Groleau, E.G.; Varie, D.L.; Zmijewski, M.J.; Anderson, B.A. (Eli Lilly and Company); Crystalline form of dihydro-2,3-benzodiazepine deriv.. EP 0699678 .
【7】 Anderson, B.A.; Varie, D.L.; Vicenzi, J.T.; Zmijewski, M.J.; Hansen, M.M. (Eli Lilly and Company); Stereoselective process for producing dihydro-2,3-benzodiazepine derivs.. US 5919954 .

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)	10124	5-Bromo-1,3-benzodioxole; 4-Bromo-1,2-(methylenedioxy)benzene	2635-13-4	C₇H₅BrO₂	详情	详情
(II)	29268	(2S)-2-methyloxirane	16088-62-3	C₃H₆O	详情	详情
(III)	28466	1-(1,3-benzodioxol-5-yl)acetone	4676-39-5	C₁₀H₁₀O₃	详情	详情
(IV)	29259	(2S)-1-(1,3-benzodioxol-5-yl)-2-propanol		C₁₀H₁₂O₃	详情	详情
(V)	18184	4-Nitrobenzaldehyde	555-16-8	C₇H₅NO₃	详情	详情
(VI)	29260	(7S)-7-methyl-5-(4-nitrophenyl)-7,8-dihydro-5H-[1,3]dioxolo[4,5-g]isochromene		C₁₇H₁₅NO₅	详情	详情
(VII)	29261	(7S)-7-methyl-5-(4-nitrophenyl)-7,8-dihydro-5H-[1,3]dioxolo[4,5-g]isochromen-5-ol		C₁₇H₁₅NO₆	详情	详情
(VIII)	29262	acetohydrazide	1068-57-1	C₂H₆N₂O	详情	详情
(IX)	29263	N'-[(E)-[6-[(2S)-2-hydroxypropyl]-1,3-benzodioxol-5-yl](4-nitrophenyl)methylidene]acetohydrazide		C₁₉H₁₉N₃O₆	详情	详情
(X)	29264	N'-[(E)-[6-((2S)-2-[[methyl(dimethylene)-lambda(6)-sulfanyl]oxy]propyl)-1,3-benzodioxol-5-yl](4-nitrophenyl)methylidene]acetohydrazide		C₂₂H₂₅N₃O₆S	详情	详情
(XI)	29265	1-[(8R)-8-methyl-5-(4-nitrophenyl)-8,9-dihydro-7H-[1,3]dioxolo[4,5-h][2,3]benzodiazepin-7-yl]-1-ethanone		C₁₉H₁₇N₃O₅	详情	详情

合成路线2

该中间体在本合成路线中的序号：(IV)

The chiral intermediate (S)-alpha-methyl-1,3-benzodioxole-5-ethanol (IV) was prepared by microbiological reduction of 3,4-methylenedioxyphenyl acetone (I) or, alternatively, by lithiation of 4-bromo-1,2-(methylenedioxy)benzene (II) with sec-butyllithium, followed by addition to (S)-propylene oxide (III). Hydrochloric acid-promoted condensation of (IV) with p-nitrobenzaldehyde (V) in hot toluene gave rise to the dioxolobenzopyran system (VIa-b), which was hydroxylated to (VIIa-b) by air oxidation under alkaline conditions. Hydrazone (IXa-b) was obtained as a mixture of E,Z isomers upon treatment of (VIIa-b) with 2-hydrazinopyridine (VIII) in refluxing EtOH. After mesylation of the alcohol group of (IXa-b) with methanesulfonyl chloride and triethylamine, the resulting mesylate (Xa-b) was cyclized to the dioxolo benzodiazepine (XI) using lithium tert-butoxide in THF. The nitro group of (XI) was finally reduced to the target aniline by transfer hydrogenation with potassium formate in the presence of Pd/C.

参考文献中间体

合成目标

【1】 Anderson, B.A.; Harkness, A.R.; Hansen, M.V.; Harn, N.K.; Lodge, D.; Leander, J.D.; Synthesis and anticonvulsant activity of 3-aryl-5H-2,3-benzodiazepine AMPA antagonists. Bioorg Med Chem Lett 1999, 9, 14, 1953.
【2】 Anderson, B.A.; Hansen, M.M.; Vicenzi, J.T.; Varie, D.L.; Zmijewski, M.J. Jr.; Harkness, A.R. (Eli Lilly and Company); Physical form of dihydro-2,3-benzodiazepine deriv.. EP 0699676; JP 1996081468; JP 1996081469; JP 1996092255; JP 1998505066; US 5795886 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(VIa)	34410	(5R,7S)-7-methyl-5-(4-nitrophenyl)-7,8-dihydro-5H-[1,3]dioxolo[4,5-g]isochromene		C₁₇H₁₅NO₅	详情	详情
(VIb)	34411	(5S,7S)-7-methyl-5-(4-nitrophenyl)-7,8-dihydro-5H-[1,3]dioxolo[4,5-g]isochromene		C₁₇H₁₅NO₅	详情	详情
(VIIa)	34412	(5R,7S)-7-methyl-5-(4-nitrophenyl)-7,8-dihydro-5H-[1,3]dioxolo[4,5-g]isochromen-5-ol		C₁₇H₁₅NO₆	详情	详情
(VIIb)	34413	(5S,7S)-7-methyl-5-(4-nitrophenyl)-7,8-dihydro-5H-[1,3]dioxolo[4,5-g]isochromen-5-ol		C₁₇H₁₅NO₆	详情	详情
(IXa)	34415	[6-[(2S)-2-hydroxypropyl]-1,3-benzodioxol-5-yl](4-nitrophenyl)methanone N-(2-pyridinyl)hydrazone		C₂₂H₂₀N₄O₅	详情	详情
(IXb)	34416	[6-[(2S)-2-hydroxypropyl]-1,3-benzodioxol-5-yl](4-nitrophenyl)methanone N-phenylhydrazone		C₂₃H₂₁N₃O₅	详情	详情
(Xa)	34417	(1S)-1-methyl-2-(6-[(4-nitrophenyl)[(E)-2-(2-pyridinyl)hydrazono]methyl]-1,3-benzodioxol-5-yl)ethyl methanesulfonate		C₂₃H₂₂N₄O₇S	详情	详情
(Xb)	34418	(1S)-1-methyl-2-(6-[(4-nitrophenyl)[(Z)-2-phenylhydrazono]methyl]-1,3-benzodioxol-5-yl)ethyl methanesulfonate		C₂₄H₂₃N₃O₇S	详情	详情
(I)	28466	1-(1,3-benzodioxol-5-yl)acetone	4676-39-5	C₁₀H₁₀O₃	详情	详情
(II)	10124	5-Bromo-1,3-benzodioxole; 4-Bromo-1,2-(methylenedioxy)benzene	2635-13-4	C₇H₅BrO₂	详情	详情
(III)	29268	(2S)-2-methyloxirane	16088-62-3	C₃H₆O	详情	详情
(IV)	29259	(2S)-1-(1,3-benzodioxol-5-yl)-2-propanol		C₁₀H₁₂O₃	详情	详情
(V)	18184	4-Nitrobenzaldehyde	555-16-8	C₇H₅NO₃	详情	详情
(VIII)	34414	2-hydrazinopyridine		C₅H₇N₃	详情	详情
(XI)	34419	(8R)-8-methyl-5-(4-nitrophenyl)-7-(2-pyridinyl)-8,9-dihydro-7H-[1,3]dioxolo[4,5-h][2,3]benzodiazepine		C₂₂H₁₈N₄O₄	详情	详情

Extended Information