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【结 构 式】 
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【分子编号】13103 【品名】(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 【CA登记号】 |
【 分 子 式 】C15H18F2O3 【 分 子 量 】284.3029264 【元素组成】C 63.37% H 6.38% F 13.36% O 16.88% |
合成路线1
该中间体在本合成路线中的序号：(IX)A synthesis of Sch-42427, the active (RR)-enantiomer of Sch-39304, has been published: The condensation of 1,3-difluorobenzene (I) with (S)-2-chloropropionyl chloride (II) by means of AlCl3 gives 2(S)-chloro-1-(2,4-difluorophenyl)-1-propanone (III), which is reduced with NaCNBH3 to the corresponding alcohol (IV). Epoxidation of (IV) with K2CO3 in methanol yields the chiral epoxide (V). The oxidative opening of (V) by means of BF3 in DMSO affords (R)-1-(2,4-difluorophenyl)-2-hydroxypropanone (VI), which is protected with dihydropyran (DHP) and p-toluenesulfonic acid to the tetrahydropyranyl ether (VIII). Alternatively, the treatment of (V) with trimethylsilyl bromide and dihydropyran gives the (R)-bromo-tetrahydropyranyl ether (VII), which can be oxidized to (VIII) with silver benzoate. The reaction of (VIII) with sodium dimethylsulfoxonium methylide in THF gives the epoxide (IX), which is opened with sodium 1,2,4-triazole (X) to yield the semi-protected diol (XI). Hydrolysis of (XI) in acidic medium affords the diol (XII), which is treated with methanesulfonyl chloride and triethylamine to afford the mono methanesulfonyl ester (XIII). The reaction of (XIII) with sodium methyl mercaptane gives the thioether (XIV), which is finally oxidized with peracetic acid.
| 【1】 Girijavallabhan, V.M.; Pinto, P.A.; Ganguly, A.K.; Sarre, O.Z.; Synthesis of the antifungal agent SCH 42427 (SM 9164). Bioorg Med Chem Lett 1992, 1, 7, 349. |
| 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) | 13095 | m-Difluorobenzene; 1,3-Difluorobenzene | 372-18-9 | C6H4F2 | 详情 | 详情 |
| (II) | 13096 | (2S)-2-Chloropropanoyl chloride | C3H4Cl2O | 详情 | 详情 | |
| (III) | 13097 | (2S)-2-Chloro-1-(2,4-difluorophenyl)-1-propanone | C9H7ClF2O | 详情 | 详情 | |
| (IV) | 13098 | (2S)-2-Chloro-1-(2,4-difluorophenyl)-1-propanol | C9H9ClF2O | 详情 | 详情 | |
| (V) | 13099 | (3R)-2-(2,4-Difluorophenyl)-3-methyloxirane | C9H8F2O | 详情 | 详情 | |
| (VI) | 13100 | (2R)-1-(2,4-Difluorophenyl)-2-hydroxy-1-propanone | C9H8F2O2 | 详情 | 详情 | |
| (VII) | 13101 | 2-[[(1R)-2-Bromo-2-(2,4-difluorophenyl)-1-methylethyl]oxy]tetrahydro-2H-pyran; (1R)-2-Bromo-2-(2,4-difluorophenyl)-1-methylethyl tetrahydro-2H-pyran-2-yl ether | C14H17BrF2O2 | 详情 | 详情 | |
| (VIII) | 13102 | (2R)-1-(2,4-Difluorophenyl)-2-(tetrahydro-2H-pyran-2-yloxy)-1-propanone | C14H16F2O3 | 详情 | 详情 | |
| (IX) | 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 | |
| (X) | 13104 | 1,2,4-Triazole, sodium derivative | 41253-21-8 | C2H2N3Na | 详情 | 详情 |
| (XI) | 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 | |
| (XII) | 13106 | (2R,3R)-2-(2,4-Difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2,3-butanediol | C12H13F2N3O2 | 详情 | 详情 | |
| (XIII) | 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 | |
| (XIV) | 13108 | (2R,3R)-2-(2,4-Difluorophenyl)-3-(methylsulfanyl)-1-(1H-1,2,4-triazol-1-yl)-2-butanol | C13H15F2N3OS | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(II)The synthesis of [14C]-labeled Sch-42427 labeled in two different positions, i.e., threo-2(R)-(2,4-difluorophenyl)-3(R)-(methylsulfonyl)-1-(1H-1,2,4-triaz ol-1-yl)[1-14C]-butan-2-ol and threo-2(R)-(2,4-difluorophenyl)-3(R)-[[14C]-methylsulfonyl]-1-(1H-1,2,4-triazol-1-yl)butan-2-ol, has been reported: The condensation of 2,4-difluoro-alpha-(tetrahydroypranyloxy)propiophenone (I) with [14C]-trimethylsulfoxonium iodide by means of NaH in DMSO yields the labeled epoxide (II), which is condensed with sodium 1,2,4-triazole (III) in hot DMF yielding 2-(2,4-difluorophenyl)-3-(tetrahydropyranyloxy)-1-(1,2,4-triazol-1-yl)b utan-2-ol (IV). The acidic hydrolysis of (IV) affords the diol (V), which is cyclized to the epoxide (VI) with triethylamine and NaOH. Ring opening of (VI) with sodium methylmercaptane in methanol gives the thio ether (VII), which is finally oxidized with peracetic acid in dichloromethane (scheme 14695202a).
| 【1】 Koharski, D.; Saluja, S.; Hesk, D.; Bowlen, C.; Duelfer, T.; McNamara, P.; Synthesis of SCH 42427 labelled with 14C in two different positions. J Label Compd Radiopharm 1992, 31, 6, 445. |
| 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) | 13102 | (2R)-1-(2,4-Difluorophenyl)-2-(tetrahydro-2H-pyran-2-yloxy)-1-propanone | C14H16F2O3 | 详情 | 详情 | |
| (II) | 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 | |
| (II) | 45160 | 2-([(2S)-2-[(2R)-2-(2,4-difluorophenyl)oxiranyl]propyl]oxy)tetrahydro-2H-pyran; (2S)-2-[(2R)-2-(2,4-difluorophenyl)oxiranyl]propyl tetrahydro-2H-pyran-2-yl ether | C16H20F2O3 | 详情 | 详情 | |
| (III) | 13104 | 1,2,4-Triazole, sodium derivative | 41253-21-8 | C2H2N3Na | 详情 | 详情 |
| (IV) | 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 | |
| (IV) | 45161 | (2R,3S)-2-(2,4-difluorophenyl)-3-methyl-4-(tetrahydro-2H-pyran-2-yloxy)-1-(1H-1,2,4-triazol-1-yl)-2-butanol | C18H23F2N3O3 | 详情 | 详情 | |
| (V) | 13106 | (2R,3R)-2-(2,4-Difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2,3-butanediol | C12H13F2N3O2 | 详情 | 详情 | |
| (V) | 45162 | (2R,3R)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2,3-butanediol | C12H13F2N3O2 | 详情 | 详情 | |
| (VI) | 13114 | 1-[[(2S,3S)-2-(2,4-Difluorophenyl)-3-methyloxiranyl]methyl]-1H-1,2,4-triazole | C12H11F2N3O | 详情 | 详情 | |
| (VI) | 45163 | 1-[[(2S,3S)-2-(2,4-difluorophenyl)-3-methyloxiranyl]methyl]-1H-1,2,4-triazole | C12H11F2N3O | 详情 | 详情 | |
| (VII) | 13108 | (2R,3R)-2-(2,4-Difluorophenyl)-3-(methylsulfanyl)-1-(1H-1,2,4-triazol-1-yl)-2-butanol | C13H15F2N3OS | 详情 | 详情 | |
| (VII) | 45164 | (2R,3R)-2-(2,4-difluorophenyl)-3-(methylsulfanyl)-1-(1H-1,2,4-triazol-1-yl)-2-butanol | C13H15F2N3OS | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(XXX)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.
| 【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：(XXX)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.
| 【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 |
合成路线5
该中间体在本合成路线中的序号：(XXVIII)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.
| 【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 |