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【结 构 式】

【分子编号】43502

【品名】4-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]-2,4-dihydro-3H-1,2,4-triazol-3-one

【CA登记号】

【 分 子 式 】C11H9F4N3O2

【 分 子 量 】291.2050928

【元素组成】C 45.37% H 3.12% F 26.1% N 14.43% O 10.99%
与该中间体有关的原料药合成路线共 4 条
合成路线1合成路线2合成路线3合成路线4

合成路线1

该中间体在本合成路线中的序号：(VII)

Treatment of 4-nitrophenol (I) with propyl iodide derivative (II) and K2CO3 in DMF, followed by reduction with hydrazine hydrate, FeCl3 and activated carbon affords (III). Conversion of aniline derivative (III) into phenylcarbamate (IV) by means of PhOCOCl and treatment of (IV) with hydrazine hydrate yields semicarbazide (V), which is then subjected to cyclization with formamidine (VI) to give triazolone derivative (VII). Benzyl (S)-lactate (VIII) is converted to triflate (IX) by means of Tf2O in the presence of DIEA and its reaction with triazolone (VII) and NaH in DMF provides derivative (X). Debenzylation of (X) by hydrogenolysis over Pd/C followed by treatment with oxalyl chloride in CH2Cl2/DMF furnishes chloride (XI), which reacts with 1,3-difluorobenzene (XII) in CH2Cl2 in the presence of AlCl3 to yield intermediate (XIII).

参考文献 中间体
合成目标
【1】 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.
【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
(I) 11236 4-Nitrophenol; p-Nitrophenol 100-02-7 C6H5NO3 详情 详情
(II) 43498 1,1,2,2-tetrafluoro-1-iodopropane C3H3F4I 详情 详情
(III) 43499 4-(2,2,3,3-tetrafluoropropoxy)phenylamine; 4-(2,2,3,3-tetrafluoropropoxy)aniline C9H9F4NO 详情 详情
(IV) 43500 phenyl 4-(2,2,3,3-tetrafluoropropoxy)phenylcarbamate C16H13F4NO3 详情 详情
(V) 43501 N-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]-1-hydrazinecarboxamide C10H11F4N3O2 详情 详情
(VI) 15369 Iminoformamide; Methanimidamide 463-52-5 CH4N2 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
(VIII) 43503 benzyl (2S)-2-hydroxypropanoate 56777-24-3 C10H12O3 详情 详情
(IX) 43504 benzyl (2S)-2-[[(trifluoromethyl)sulfonyl]oxy]propanoate C11H11F3O5S 详情 详情
(X) 43505 benzyl (2R)-2-[5-oxo-4-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl]propanoate C21H19F4N3O4 详情 详情
(XI) 43506 (2R)-2-[5-oxo-4-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl]propanoyl chloride C14H12ClF4N3O3 详情 详情
(XII) 13095 m-Difluorobenzene; 1,3-Difluorobenzene 372-18-9 C6H4F2 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

合成路线2

该中间体在本合成路线中的序号：(VII)

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3

该中间体在本合成路线中的序号：(VII)

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4

该中间体在本合成路线中的序号：(VII)

Alternatively, oxirane derivative (XXX) reacts with 1H-1,2,4-triazole (XXVI) and NaH in DMF to yield butanol derivative (XXXVII), which is treated with p-TsOH for THP removal followed by recrystallization to obtain diastereomer (2R,3R)-(XXXVIII). Conversion of (2R,3R)-(XXXVIII) into the corresponding mesylate derivative by means of MsCl and Et3N in AcOEt, followed by treatment with NaOMe in MeOH, gives oxirane (2R,3S)-(XXXIX), which is finally condensed with (VII) by means of K2CO3 or KHCO3 or LiOH in DMF. Alternatively, (2R,3R)-(XXXVIII) can be converted into p-toluenesulfonyloxy derivative (2R,3R)-(XL) (or, alternatively, its mesylate derivative), which is finally condensed with (VII) and K2CO3 in DMF.

参考文献 中间体
合成目标
【1】 Tasaka, A.; et al.; Optically active antifungal azoles. IV. Synthesis and antifungal activity of (2R,3R)-3-azolyl-2-(substituted phenyl)-1-(1H-1,2,4-triazol-1-yl)-2-butanols. Chem Pharm Bull 1995, 43, 3, 432.
【2】 Itoh, K.; Tasaka, A.; Matsushita, Y. (Takeda Chemical Industries, Ltd.); Optically active azole derivs., their production and use. CA 2134417; EP 0659751; JP 1995228574 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(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
(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
(XXXVII) 43520 (2S,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
(XXXVIII) 43521 (2S,3R)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2,3-butanediol C12H13F2N3O2 详情 详情
(XXXIX) 13114 1-[[(2S,3S)-2-(2,4-Difluorophenyl)-3-methyloxiranyl]methyl]-1H-1,2,4-triazole C12H11F2N3O 详情 详情
(XL) 43522 (1R,2S)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl 4-methylbenzenesulfonate C19H19F2N3O4S 详情 详情
Extended Information