(1R)-1-[(2R)-2-(2,4-difluorophenyl)oxiranyl]ethyl 3,5-dinitrobenzoate -Drug Synthesis Database

【结构式】

【分子编号】27874

【品名】(1R)-1-[(2R)-2-(2,4-difluorophenyl)oxiranyl]ethyl 3,5-dinitrobenzoate

【CA登记号】

【分子式】C₁₇H₁₂F₂N₂O₇

【分子量】394.2883664

【元素组成】C 51.79% H 3.07% F 9.64% N 7.1% O 28.4%

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：(XXXII)

Alternatively, derivative (XXIX) can be obtained in an analogous way as its enantiomer (XIX). Diastereoselective epoxidation of (XXIX) with trimethylsulfoxonium iodide and NaH in DMSO provides oxirane (XXX) (3). THP group removal by means of PPTS in EtOH, followed by reaction with 3,5-dinitrobenzoyl chloride (XXXI) and NaHCO3 in CH2Cl2, yields a diastereomeric mixture from which dinitrobenzoate derivative (2R,3R)-(XXXII) is obtained by recrystallization (1). Hydrolysis of (2R,3R)-(XXXII) in MeOH by treatment with aqueous NaOH gives compound (2R,3R)-(XXXIII), which is converted into ester (2R,3S)-(XXXIV) by Mitsunobu reaction with benzoic acid, Ph3P and DEAD in THF. Subsequent debenzoylation of (2R,3S)-(XXXIV) with NaOMe in MeOH affords oxiranyl ethanol derivative (2R,3R)-(XXXV), which is first converted into its triflate derivative by means of Tf2O and DIEA in CH2Cl2, and then into triazolone derivative (2S,3R)-(XXXVI) by reaction with intermediate (VII) and NaH in CH2Cl2/DMF. Finally, oxirane derivative (2S,3R)-(XXXVI) reacts with triazole (XXVI) and NaH in DMF to furnish the desired product.

参考文献中间体

合成目标

【1】 Tasaka, A.; Tamura, N.; Matsushita, Y.; Teranishi, K.; Hayashi, R.; Okonogi, K.; Itoh, K.; Optically active antifungal azoles. I. Synthesis and antifungal activity of (2R,3R)-2-(2,4-difluorophenyl)-3-mercapto-1-(1H-1,2,4-triazol-1-yl)-2-butanol and stereoisomers. Chem Pharm Bull 1993, 41, 6, 1035-42.
【2】 Tamura, N.; Okonogi, K.; Hayashi, R.; Matsushita, Y.; Kitazaki, T.; Tasaka, A.; Itoh, K.; Optically active antifungal azoles.VI. Synthesis and antifungal activity of N-[(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-N'-(4-substituted phenyl)-3(2H,4H)-1,2,4-triazolones and 5(1H,4H)-tetrazolones. Chem Pharm Bull 1996, 44, 2, 314.
【3】 Itoh, K.; Okonogi, K.; Tamura, N. (Takeda Chemical Industries, Ltd.); Azole cpds., their production and use. EP 0567982; US 5371101 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(XXXXIV)	43518	(1S)-1-[(2S)-2-(2,4-difluorophenyl)oxiranyl]ethyl benzoate		C₁₇H₁₄F₂O₃	详情	详情
(VII)	43502	4-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]-2,4-dihydro-3H-1,2,4-triazol-3-one		C₁₁H₉F₄N₃O₂	详情	详情
(XXVI)	13135	1H-1,2,4-Triazole; 1,2,4-Triazole	288-88-0	C₂H₃N₃	详情	详情
(XXIX)	13102	(2R)-1-(2,4-Difluorophenyl)-2-(tetrahydro-2H-pyran-2-yloxy)-1-propanone		C₁₄H₁₆F₂O₃	详情	详情
(XXX)	13103	(1R)-1-[(2R)-2-(2,4-Difluorophenyl)oxiranyl]ethyl tetrahydro-2H-pyran-2-yl ether; 2-([(1R)-1-[(2R)-2-(2,4-Difluorophenyl)oxiranyl]ethyl]oxy)tetrahydro-2H-pyran		C₁₅H₁₈F₂O₃	详情	详情
(XXXI)	12053	3,5-Dinitrobenzoyl chloride	99-33-2	C₇H₃ClN₂O₅	详情	详情
(XXXII)	27874	(1R)-1-[(2R)-2-(2,4-difluorophenyl)oxiranyl]ethyl 3,5-dinitrobenzoate		C₁₇H₁₂F₂N₂O₇	详情	详情
(XXXIII)	27875	(1R)-1-[(2R)-2-(2,4-difluorophenyl)oxiranyl]-1-ethanol		C₁₀H₁₀F₂O₂	详情	详情
(XXXV)	27877	(1S)-1-[(2R)-2-(2,4-difluorophenyl)oxiranyl]-1-ethanol		C₁₀H₁₀F₂O₂	详情	详情
(XXXVI)	43519	2-[(1R)-1-[(2R)-2-(2,4-difluorophenyl)oxiranyl]ethyl]-4-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]-2,4-dihydro-3H-1,2,4-triazol-3-one		C₂₁H₁₇F₆N₃O₃	详情	详情

合成路线2

该中间体在本合成路线中的序号：(VIII)

The diastereomeric mixture of tetrahydropyranyl-protected compounds (VI) was hydrolyzed with pyridinium p-toluenesulfonate to furnish the epoxyalcohols (VII). Subsequent coupling of (VIII) with 3,5-dinitrobenzoyl chloride produced a mixture of diastereomeric esters, from which the required isomer (VIII) was isolated by recrystallization from EtOAc. Hydrolysis with methanolic NaOH yielded the R,R-epoxyalcohol (IX). Inversion of configuration was then achieved by Mitsunobu coupling with benzoic acid, followed by hydrolysis of the resulting benzoate ester (X).

参考文献中间体

合成目标

【1】 Itoh, K.; Tamura, N.; Matsushita, Y.; Hososno, H.; Hayashi, R.; Okonogi, K.; Kitazaki, T.; Tasaka, A.; Optically active antifungal azoles. VIII. Synthesis and antifungal activity of 1-[(1R,2R)-2-(2,4-difluoro- and 2-fluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-3-(4-substituted phenyl)-2(1H,3H)-imidazolones and 2-imidazolidinones. Chem Pharm Bull 1999, 47, 3, 351.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(VIIa)	27873	(1R)-1-[2-(2,4-difluorophenyl)-2-oxiranyl]-1-ethanol		C₁₀H₁₀F₂O₂	详情	详情
(VIa)	27882	2-([(1R)-1-[2-(2,4-difluorophenyl)-2-oxiranyl]ethyl]oxy)tetrahydro-2H-pyran		C₁₅H₁₈F₂O₃	详情	详情
(VIIb)	53869	(1R)-1-[(2R)-2-(2,4-difluorophenyl)oxiranyl]-1-ethanol	n/a	C₁₀H₁₀F₂O₂	详情	详情
(VIb)	53870	2-({(1R)-1-[(2R)-2-(2,4-difluorophenyl)oxiranyl]ethyl}oxy)tetrahydro-2H-pyran; (1R)-1-[(2R)-2-(2,4-difluorophenyl)oxiranyl]ethyl tetrahydro-2H-pyran-2-yl ether	n/a	C₁₅H₁₈F₂O₃	详情	详情
(VIII)	27874	(1R)-1-[(2R)-2-(2,4-difluorophenyl)oxiranyl]ethyl 3,5-dinitrobenzoate		C₁₇H₁₂F₂N₂O₇	详情	详情
(IX)	27875	(1R)-1-[(2R)-2-(2,4-difluorophenyl)oxiranyl]-1-ethanol		C₁₀H₁₀F₂O₂	详情	详情
(X)	27876	(1S)-1-[(2R)-2-(2,4-difluorophenyl)oxiranyl]ethyl benzoate		C₁₇H₁₄F₂O₃	详情	详情
(XI)	27877	(1S)-1-[(2R)-2-(2,4-difluorophenyl)oxiranyl]-1-ethanol		C₁₀H₁₀F₂O₂	详情	详情

Extended Information