1-[(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-3-[4-(1H-1,2,3,4-tetraazol-1-yl)phenyl]-1,3-dihydro-2H-imidazol-2-one -Drug Synthesis Database

【结构式】

【分子编号】45566

【品名】1-[(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-3-[4-(1H-1,2,3,4-tetraazol-1-yl)phenyl]-1,3-dihydro-2H-imidazol-2-one

【CA登记号】

【分子式】C₂₂H₁₉F₂N₉O₂

【分子量】479.4491264

【元素组成】C 55.11% H 3.99% F 7.93% N 26.29% O 6.67%

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：(XVII)

The chiral epoxy alcohol (XIII), prepared from methyl (R)-lactate, was converted to triflate (XIV) by treatment with trifluoromethanesulfonic anhydride in the presence of diisopropylethylamine. Condensation of triflate (XIV) with the sodium salt of imidazolone (XII) afforded (XV). Subsequent oxirane ring opening with 1,2,4-triazole (XVI) in the presence of NaH gave the triazolyl alcohol (XVII). The title imidazolidinone was then obtained by catalytic hydrogenation of imidazolone (XVII).

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	CAS号	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
(XIII)	45563	(1S)-1-[(2S)-2-(2,4-difluorophenyl)oxiranyl]-1-ethanol		C₁₀H₁₀F₂O₂	详情	详情
(XIV)	45564	(1S)-1-[(2S)-2-(2,4-difluorophenyl)oxiranyl]ethyl trifluoromethanesulfonate		C₁₁H₉F₅O₄S	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
(XVI)	13135	1H-1,2,4-Triazole; 1,2,4-Triazole	288-88-0	C₂H₃N₃	详情	详情
(XVII)	45566	1-[(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-3-[4-(1H-1,2,3,4-tetraazol-1-yl)phenyl]-1,3-dihydro-2H-imidazol-2-one		C₂₂H₁₉F₂N₉O₂	详情	详情

合成路线2

该中间体在本合成路线中的序号：(XVII)

In a related procedure, protection of methyl (R)-lactate (XXIV) as the corresponding tetrahydropyranyl ether, followed by treatment with morpholine, gave amide (XXV). Subsequent addition of 2,4-difluorophenylmagnesium bromide (XXVI) to (XXV) afforded propiophenone (XXVII), which was converted into epoxide (XXVIII) by reaction with the ylide resulting from trimethylsulfoxonium iodide. Epoxide ring opening with 1,2,4-triazole (XVI) produced the triazolyl alcohol (XXIX). After acid cleavage of the tetrahydropyranyl protecting group of (XXIX), recrystallization of the diastereomeric mixture provided diol (XXX). Mesylation of the secondary hydroxyl group of (XXX), followed by basic cyclization of the resulting hydroxy mesylate (XXXI), produced epoxide (XXXII). Epoxide (XXXII) was reacted with 2,2-diethoxyethylamine (X) in the presence of Ti(iPrO)4 to give the amino alcohol (XXXIII). Condensation of amine (XXXIII) with carbamate (IX) generated urea (XXXIV), which was then cyclized to imidazolone (XVII) in the presence of HCl. This was finally converted to the title imidazolidinone by catalytic hydrogenation as above.

参考文献中间体

合成目标

【3】 Kitazaki, T.; Matsushita, Y.; Hosono, H.; Itoh, K.; Mitsudera, H. (Takeda Chemical Industries, Ltd.); Triazole derivs. and their production. EP 0884311 .
【1】 Ichikawa, T.; Matsushita, Y.; Yamada, M.; Tasaka, A.; Yamaguchi, M.; Itoh, K.; Okonogi, K.; Kitazaki, T.; TAK-456 and the water-soluble prodrug TAK-457, new antifungal triazoles: Synthesis and in vitro antifungal activity. 40th Intersci Conf Antimicrob Agents Chemother (Sept 17 2000, Toronto) 2000, Abst F-1085.
【2】 Ichikawa, T.; et al.; Optically active antifungal azoles. XI. An alternative synthetic route for 1-[(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-3-[4-(1H-1-tetrazolyl)phenyl]-2-imidazolidinone (TAK-456) and its analog. Chem Pharm Bull 2000, 48, 12, 1947.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(IX)	45560	phenyl 4-(1H-1,2,3,4-tetraazol-1-yl)phenylcarbamate		C₁₄H₁₁N₅O₂	详情	详情
(X)	10331	2,2-Diethoxy-1-ethanamine; 2,2-Diethoxyethylamine; Aminoacetaldehyde diethyl acetal	645-36-3	C₆H₁₅NO₂	详情	详情
(XVI)	13135	1H-1,2,4-Triazole; 1,2,4-Triazole	288-88-0	C₂H₃N₃	详情	详情
(XVII)	45566	1-[(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-3-[4-(1H-1,2,3,4-tetraazol-1-yl)phenyl]-1,3-dihydro-2H-imidazol-2-one		C₂₂H₁₉F₂N₉O₂	详情	详情
(XXIV)	11591	methyl (2R)-2-hydroxypropanoate	17392-83-5	C₄H₈O₃	详情	详情
(XXV)	45574	(2R)-1-(4-morpholinyl)-2-(tetrahydro-2H-pyran-2-yloxy)-1-propanone		C₁₂H₂₁NO₄	详情	详情
(XXVI)	20262	bromo(2,4-difluorophenyl)magnesium		C₆H₃BrF₂Mg	详情	详情
(XXVII)	13102	(2R)-1-(2,4-Difluorophenyl)-2-(tetrahydro-2H-pyran-2-yloxy)-1-propanone		C₁₄H₁₆F₂O₃	详情	详情
(XXVIII)	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
(XXIX)	13105	(2R,3R)-2-(2,4-Difluorophenyl)-3-(tetrahydro-2H-pyran-2-yloxy)-1-(1H-1,2,4-triazol-1-yl)-2-butanol		C₁₇H₂₁F₂N₃O₃	详情	详情
(XXX)	13106	(2R,3R)-2-(2,4-Difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2,3-butanediol		C₁₂H₁₃F₂N₃O₂	详情	详情
(XXXI)	13107	(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl methanesulfonate		C₁₃H₁₅F₂N₃O₄S	详情	详情
(XXXII)	13114	1-[[(2S,3S)-2-(2,4-Difluorophenyl)-3-methyloxiranyl]methyl]-1H-1,2,4-triazole		C₁₂H₁₁F₂N₃O	详情	详情
(XXXIII)	45572	(2R,3R)-3-[(2,2-diethoxyethyl)amino]-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-butanol		C₁₈H₂₆F₂N₄O₃	详情	详情
(XXXIV)	45573	N-(2,2-diethoxyethyl)-N-[(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-N'-[4-(1H-1,2,3,4-tetraazol-1-yl)phenyl]urea		C₂₆H₃₁F₂N₉O₄	详情	详情

Extended Information