(1S)-2-(2,4-difluorophenyl)-1-methyl-2-oxoethyl trifluoromethanesulfonate -Drug Synthesis Database

【结构式】

【分子编号】43510

【品名】(1S)-2-(2,4-difluorophenyl)-1-methyl-2-oxoethyl trifluoromethanesulfonate

【CA登记号】

【分子式】C₁₀H₇F₅O₄S

【分子量】318.221196

【元素组成】C 37.74% H 2.22% F 29.85% O 20.11% S 10.08%

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：(XX)

Alternatively, intermediate (XIII) can be obtained as follows: Heating of ethyl (S)-lactate (XIV) with morpholine affords amide (XVI), which then reacts with 3,4-dihydro-2H-pyran (A) in the presence of p-TsOH to give protected derivative (XVII). Grignard reaction between (XVII), bromo derivative (XVIII) and Mg turnings in THF yields protected ketone (XIX), which is treated with pyridinium p-toluenesulfonate (PPTS) (THP group removal) and reprotected by means of Tf2O and DIEA to give triflate derivative (XX). Conversion of (XX) into intermediate (XIII) is achieved by reaction with triazolone (VII) and NaH in THF.

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】 Kitazaki, T.; et al.; Optically active antifungal azoles. IX. An alternative synthetic route for 2-[(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-4-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]-3(2H,4H)-1,2,4-triazolone and its analogs. Chem Pharm Bull 1999, 47, 3, 360.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(A)	13684	3,4-Dihydro-2H-pyran;2,3-Dihydro-4H-pyran; 5,6-Dihydro-4H-pyran;Dihydropyran	110-87-2	C₅H₈O	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
(XIII)	43507	2-[(1R)-2-(2,4-difluorophenyl)-1-methyl-2-oxoethyl]-4-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]-2,4-dihydro-3H-1,2,4-triazol-3-one		C₂₀H₁₅F₆N₃O₃	详情	详情
(XIV)	43508	propyl (2S)-2-hydroxypropanoate	616-09-1	C₆H₁₂O₃	详情	详情
(XV)	10388	Morpholine	110-91-8	C₄H₉NO	详情	详情
(XVI)	41498	(2S)-2-hydroxy-1-(4-morpholinyl)-1-propanone		C₇H₁₃NO₃	详情	详情
(XVII)	43509	(2S)-1-(4-morpholinyl)-2-(tetrahydro-2H-pyran-2-yloxy)-1-propanone		C₁₂H₂₁NO₄	详情	详情
(XVIII)	15488	1-bromo-2,4-difluorobenzene	348-57-2	C₆H₃BrF₂	详情	详情
(XIX)	43511	(2S)-1-(2,4-difluorophenyl)-2-(tetrahydro-2H-pyran-2-yloxy)-1-propanone		C₁₄H₁₆F₂O₃	详情	详情
(XX)	43510	(1S)-2-(2,4-difluorophenyl)-1-methyl-2-oxoethyl trifluoromethanesulfonate		C₁₀H₇F₅O₄S	详情	详情

合成路线2

该中间体在本合成路线中的序号：(XIX)

The preparation of the epoxide precursor (XV) can also be carried out by an alternative route starting from the chiral hydroxypropiophenone (XVIII), obtained from ethyl (S)-lactate. Hydroxy ketone (XVIII) was converted to triflate (XIX), which was condensed with the sodium salt of imidazolone (XII), yielding adduct (XX). Addition of (dimethylisopropoxysilyl)methylmagnesium chloride to the propiophenone (XX) furnished carbinol (XIX). Oxidative desilylation of (XIX) with H2O2 in the presence of NaHCO3 afforded diol (XXII). This was converted to the corresponding mesylate (XXIII) and then cyclized to oxirane (XV) in the presence of K2CO3.

参考文献中间体

合成目标

【2】 Itoh, K.; Okonogi, K.; Tasaka, A. (Takeda Chemical Industries, Ltd.); Azole cpds., their production and use. EP 0809640; JP 1997183769; WO 9625410 .
【1】 Hosono, H.; Itoh, K.; Kitazaki, T.; Ichikawa, T.; Okonogi, K.; Tasaka, A.; Matsushita, Y.; Hayashi, R.; Optically active antifungal azoles. X. Synthesis and antifungal activity of N-[4-(azolyl)phenyl] and N-[4-(azolylmethyl)phenyl]-N'[(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H,1,2,4-triazol-1-yl)propyl]-azolones. Chem Pharm Bull 2000, 48, 12, 1935.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(XII)	45562	1-[4-(1H-1,2,3,4-tetraazol-1-yl)phenyl]-1,3-dihydro-2H-imidazol-2-one	C₁₀H₈N₆O	详情	详情
(XV)	45565	1-[(1R)-1-[(2R)-2-(2,4-difluorophenyl)oxiranyl]ethyl]-3-[4-(1H-1,2,3,4-tetraazol-1-yl)phenyl]-1,3-dihydro-2H-imidazol-2-one	C₂₀H₁₆F₂N₆O₂	详情	详情
(XVIII)	45571	(2S)-1-(2,4-difluorophenyl)-2-hydroxy-1-propanone	C₉H₈F₂O₂	详情	详情
(XIX)	43510	(1S)-2-(2,4-difluorophenyl)-1-methyl-2-oxoethyl trifluoromethanesulfonate	C₁₀H₇F₅O₄S	详情	详情
(XIX)	45568	1-[(1R,2S)-2-(2,4-difluorophenyl)-2-hydroxy-3-[isopropoxy(dimethyl)silyl]-1-methylpropyl]-3-[4-(1H-1,2,3,4-tetraazol-1-yl)phenyl]-1,3-dihydro-2H-imidazol-2-one	C₂₅H₃₀F₂N₆O₃Si	详情	详情
(XX)	45567	1-[(1R)-2-(2,4-difluorophenyl)-1-methyl-2-oxoethyl]-3-[4-(1H-1,2,3,4-tetraazol-1-yl)phenyl]-1,3-dihydro-2H-imidazol-2-one	C₁₉H₁₄F₂N₆O₂	详情	详情
(XXII)	45569	1-[(1R,2S)-2-(2,4-difluorophenyl)-2,3-dihydroxy-1-methylpropyl]-3-[4-(1H-1,2,3,4-tetraazol-1-yl)phenyl]-1,3-dihydro-2H-imidazol-2-one	C₂₀H₁₈F₂N₆O₃	详情	详情
(XXIII)	45570	(2S,3R)-2-(2,4-difluorophenyl)-2-hydroxy-3-[2-oxo-3-[4-(1H-1,2,3,4-tetraazol-1-yl)phenyl]-2,3-dihydro-1H-imidazol-1-yl]butyl methanesulfonate	C₂₁H₂₀F₂N₆O₅S	详情	详情

Extended Information