-Drug Synthesis Database

【结构式】

【药物名称】

【化学名称】(1R,2R)-1-[2-(2-Fluorophenyl)-2-hydroxy-1-methyl-3-(1,2,4-triazol-1-yl)propyl]-3-[4-(1,1,2,2-tetrafluoroethoxy)phenyl]imidazolidin-2-one

【CA登记号】

【分子式】C₂₃H₂₂F₅N₅O₃

【分子量】511.45549

【开发单位】Takeda (Originator)

【药理作用】Antifungal Agents, ANTIINFECTIVE THERAPY

合成路线1 合成路线2 合成路线3

合成路线1

Aniline (I) was converted to phenyl carbamate (II) by treatment with phenyl chloroformate. Subsequent condensation of (II) with 2,2-diethoxyethylamine provided urea (III), which was cyclized under acidic conditions to give imidazolone (IV). Optionally, imidazolidinone (V) was obtained by catalytic hydrogenation of (IV).

参考文献中间体

【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
	10331	2,2-Diethoxy-1-ethanamine; 2,2-Diethoxyethylamine; Aminoacetaldehyde diethyl acetal	645-36-3	C₆H₁₅NO₂	详情	详情
	13580	1-[(Chlorocarbonyl)oxy]benzene; phenyl chloroformate	1885-14-9	C₇H₅ClO₂	详情	详情
(I)	27857	4-(1,1,2,2-tetrafluoroethoxy)aniline	713-62-2	C₈H₇F₄NO	详情	详情
(II)	27858	phenyl 4-(1,1,2,2-tetrafluoroethoxy)phenylcarbamate		C₁₅H₁₁F₄NO₃	详情	详情
(III)	27859	N-(2,2-diethoxyethyl)-N'-[4-(1,1,2,2-tetrafluoroethoxy)phenyl]urea		C₁₅H₂₀F₄N₂O₄	详情	详情
(IV)	27860	1-[4-(1,1,2,2-tetrafluoroethoxy)phenyl]-1,3-dihydro-2H-imidazol-2-one		C₁₁H₈F₄N₂O₂	详情	详情
(V)	27861	1-[4-(1,1,2,2-tetrafluoroethoxy)phenyl]-2-imidazolidinone		C₁₁H₁₀F₄N₂O₂	详情	详情

合成路线2

The diastereomeric mixture of tetrahydropyranyl-protected compounds (VI) was hydrolyzed with pyridinium p-toluenesulfonate to furnish the epoxyalcohols (VII). From this mixture, the target isomer (IX) was obtained by two alternative procedures. Condensation of (VII) with 3,5-dinitrobenzoic acid under Mitsunobu conditions proceeded with inversion of configuration. Further recrystallization of the resulting diastereomeric esters from EtOAc provided isomer (VIII). This was hydrolyzed with NaOH to yield the S,R-epoxyalcohol (IX). Alternatively, the diasteremeric epoxyalcohols (VII) were coupled with 3,5-dinitrobenzoyl chloride with retention of configuration. Recrystallization furnished isomer (X), which was subsequently hydrolyzed to the R,R-epoxyalcohol (XI). Inversion of configuration was then achieved by Mitsunobu coupling with benzoic acid, followed by hydrolysis of the resulting benzoate ester (XII).

参考文献中间体

【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
(VIa)	27862	(1R)-1-[2-(2-fluorophenyl)-2-oxiranyl]ethyl tetrahydro-2H-pyran-2-yl ether		C₁₅H₁₉FO₃	详情	详情
(VIIa)	27863	(1R)-1-[2-(2-fluorophenyl)-2-oxiranyl]-1-ethanol		C₁₀H₁₁FO₂	详情	详情
(VIb)	53867	(1R)-1-[(2R)-2-(2-fluorophenyl)oxiranyl]ethyl tetrahydro-2H-pyran-2-yl ether; 2-({(1R)-1-[(2R)-2-(2-fluorophenyl)oxiranyl]ethyl}oxy)tetrahydro-2H-pyran	n/a	C₁₅H₁₉FO₃	详情	详情
(VIIb)	53868	(1R)-1-[(2R)-2-(2-fluorophenyl)oxiranyl]-1-ethanol	n/a	C₁₀H₁₁FO₂	详情	详情
(VIII)	27864	(1S)-1-[(2R)-2-(2-fluorophenyl)oxiranyl]ethyl 3,5-dinitrobenzoate		C₁₇H₁₃FN₂O₇	详情	详情
(IX)	27865	(1S)-1-[(2R)-2-(2-fluorophenyl)oxiranyl]-1-ethanol		C₁₀H₁₁FO₂	详情	详情
(X)	27866	(1R)-1-[(2R)-2-(2-fluorophenyl)oxiranyl]ethyl 3,5-dinitrobenzoate		C₁₇H₁₃FN₂O₇	详情	详情
(XI)	27867	(1R)-1-[(2R)-2-(2-fluorophenyl)oxiranyl]-1-ethanol		C₁₀H₁₁FO₂	详情	详情
(XII)	27868	(1S)-1-[(2R)-2-(2-fluorophenyl)oxiranyl]ethyl benzoate		C₁₇H₁₅FO₃	详情	详情

合成路线3

Treatment of epoxyalcohol (IX) with trifluoromethanesulfonic anhydride and diisopropyl ethylamine gave triflate (XIII). Condensation of (XIII) with imidazolone (IV) provided the required N-alkylated compound (XIV) along with some O-alkylated isomer, which were separated by column chromatography. Epoxide opening with triazole (XV) afforded the imidazolone (XVI), which was finally hydrogenated to produce the target imidazolidinone. Alternatively, condensation of triflate (XIII) with imidazolidinone (V) furnished, after chromatographic separation of some O-alkylated isomer, imidazolidinone (XVII). Finally, the reaction of (XVII) with triazole (XV) then provided an alternative route to the target compound.

参考文献中间体

【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
(IV)	27860	1-[4-(1,1,2,2-tetrafluoroethoxy)phenyl]-1,3-dihydro-2H-imidazol-2-one		C₁₁H₈F₄N₂O₂	详情	详情
(V)	27861	1-[4-(1,1,2,2-tetrafluoroethoxy)phenyl]-2-imidazolidinone		C₁₁H₁₀F₄N₂O₂	详情	详情
(IX)	27865	(1S)-1-[(2R)-2-(2-fluorophenyl)oxiranyl]-1-ethanol		C₁₀H₁₁FO₂	详情	详情
(XIII)	27869	(1S)-1-[(2R)-2-(2-fluorophenyl)oxiranyl]ethyl trifluoromethanesulfonate		C₁₁H₁₀F₄O₄S	详情	详情
(XIV)	27870	1-[(1R)-1-[(2S)-2-(2-fluorophenyl)oxiranyl]ethyl]-3-[4-(1,1,2,2-tetrafluoroethoxy)phenyl]-1,3-dihydro-2H-imidazol-2-one		C₂₁H₁₇F₅N₂O₃	详情	详情
(XV)	13135	1H-1,2,4-Triazole; 1,2,4-Triazole	288-88-0	C₂H₃N₃	详情	详情
(XVI)	27871	1-[(1R,2R)-2-(2-fluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-3-[4-(1,1,2,2-tetrafluoroethoxy)phenyl]-1,3-dihydro-2H-imidazol-2-one		C₂₃H₂₀F₅N₅O₃	详情	详情
(XVII)	27872	1-[(1R)-1-[(2S)-2-(2-fluorophenyl)oxiranyl]ethyl]-3-[4-(1,1,2,2-tetrafluoroethoxy)phenyl]-2-imidazolidinone		C₂₁H₁₉F₅N₂O₃	详情	详情

Extended Information