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【结 构 式】 
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【分子编号】17123 【品名】(2S,3R)-3-(2,4-difluorophenyl)-3-hydroxy-2-methyl-4-(1H-1,2,4-triazol-1-yl)butanenitrile 【CA登记号】 |
【 分 子 式 】C13H12F2N4O 【 分 子 量 】278.2614464 【元素组成】C 56.11% H 4.35% F 13.66% N 20.13% O 5.75% |
合成路线1
该中间体在本合成路线中的序号：(III)ER-30346 is synthesized by thiazole ring formation of (2R,3R)-3-(2,4-difluorophenyl)-3-hydroxy-2-methyl-4-(1H-1,2,4-triazol-1-yl)thiobutanamide (I) and 4-bromoacetylbenzonitrile (II) by means of reflux in methanol. The thioamide (I) is obtained with excellent yield from a chiral nitrile (III) by heating with diethyl dithiophosphate in aqueous medium.
| 【1】 Saji, I.; Tamoto, K.; Tanaka, Y.; Fujimoto, K.; Ohashi, N.; Stereoselective synthesis of antifungal agent threo-2-(2,4-difluorophenyl)-3-methylsulfonyl-1-(1H-1,2,4-triazol-1-yl)-2-butanol (SM-8668). Bull Chem Soc Jpn 1994, 67, 1427-33. |
| 【2】 Konos, T.; Miyaoka, T.; Tajima, Y.; Oida, S.; Triazole antifungals. III. Stereocontrolled synthesis of an optically active triazolylmethyloxirane precursor to antifungal oxazolodine derivatives. Chem Pharm Bull 1991, 39, 9, 2241. |
| 【3】 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. |
| 【4】 Naito, T.; Hata, K.; Tsuruoka, A.; ER-30346. Drugs Fut 1996, 21, 1, 20. |
| 【5】 Naito, T.; Hata, K.; Kaku, Y.; Tsuruoka, A.; Tsukada, I.; Yanagisawa, M.; Toyosawa, T.; Nara, K. (Eisai Co., Ltd.); Azole antifungal agents, process for the preparation thereof and intermediates. CA 2141731; EP 0667346; JP 1995223950; JP 1996020578; JP 1996053426; US 5648372; US 5789429; US 5792781 . |
| 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) | 17121 | (2R,3R)-3-(2,4-difluorophenyl)-3-hydroxy-2-methyl-4-(1H-1,2,4-triazol-1-yl)butanethioamide | C13H14F2N4OS | 详情 | 详情 | |
| (II) | 17122 | 4-(2-bromoacetyl)benzonitrile; 4-Cyanophenacyl bromide | 20099-89-2 | C9H6BrNO | 详情 | 详情 |
| (III) | 17123 | (2S,3R)-3-(2,4-difluorophenyl)-3-hydroxy-2-methyl-4-(1H-1,2,4-triazol-1-yl)butanenitrile | C13H12F2N4O | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(III)The nitrile (III), a chiral key intermediate of this synthesis, can be obtained by two different synthetic routes as follows: Route-a: The key step of this route is ring opening reaction of the trisubstituted oxirane (VII) by cyanide anion leading to the nitrile (III). The chiral oxirane (VII) is synthesized from (R)-lactic acid derivatives as already reported. The reaction of (VII) with diethylaluminum cyanide in toluene or lithium cyanide in tetrahydrofuran gives the nitrile (III) with high yield without any epimerization reaction.
| 【1】 Saji, I.; Tamoto, K.; Tanaka, Y.; Fujimoto, K.; Ohashi, N.; Stereoselective synthesis of antifungal agent threo-2-(2,4-difluorophenyl)-3-methylsulfonyl-1-(1H-1,2,4-triazol-1-yl)-2-butanol (SM-8668). Bull Chem Soc Jpn 1994, 67, 1427-33. |
| 【2】 Konos, T.; Miyaoka, T.; Tajima, Y.; Oida, S.; Triazole antifungals. III. Stereocontrolled synthesis of an optically active triazolylmethyloxirane precursor to antifungal oxazolodine derivatives. Chem Pharm Bull 1991, 39, 9, 2241. |
| 【3】 Naito, T.; Hata, K.; Tsuruoka, A.; ER-30346. Drugs Fut 1996, 21, 1, 20. |
| 【4】 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. |
| 【5】 Naito, T.; Hata, K.; Kaku, Y.; Tsuruoka, A.; Tsukada, I.; Yanagisawa, M.; Toyosawa, T.; Nara, K. (Eisai Co., Ltd.); Azole antifungal agents, process for the preparation thereof and intermediates. CA 2141731; EP 0667346; JP 1995223950; JP 1996020578; JP 1996053426; US 5648372; US 5789429; US 5792781 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (III) | 17123 | (2S,3R)-3-(2,4-difluorophenyl)-3-hydroxy-2-methyl-4-(1H-1,2,4-triazol-1-yl)butanenitrile | C13H12F2N4O | 详情 | 详情 | |
| (IV) | 13100 | (2R)-1-(2,4-Difluorophenyl)-2-hydroxy-1-propanone | C9H8F2O2 | 详情 | 详情 | |
| (V) | 17125 | (2S)-2-[(2S)-2-(2,4-difluorophenyl)oxiranyl]propyl tetrahydro-2H-pyran-2-yl ether; 2-([(2S)-2-[(2S)-2-(2,4-difluorophenyl)oxiranyl]propyl]oxy)tetrahydro-2H-pyran | C16H20F2O3 | 详情 | 详情 | |
| (VI) | 13106 | (2R,3R)-2-(2,4-Difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2,3-butanediol | C12H13F2N3O2 | 详情 | 详情 | |
| (VII) | 13114 | 1-[[(2S,3S)-2-(2,4-Difluorophenyl)-3-methyloxiranyl]methyl]-1H-1,2,4-triazole | C12H11F2N3O | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(II)The nitrile (III), a chiral key intermediate of this synthesis, can be obtained by two different synthetic routes as follows: Route-b: The starting material of this route is methyl (S)-3-hydroxy-2-methylpropionate (VIII), which contains one additional carbon between the hydroxyl group and the 2-position carbon of (R)-lactate, the starting material of route-a. The hydroxyl group of (VIII) is protected by triphenylmethyl group. Then, 2,4-difluorophenyl moiety is introduced to give the ketone (X). Direct conversion of the ketone (X) to the oxirane (XIV) by dimethylsulfoxonium methylide, the same condition for compound (IV) in route-a, does not proceed. The oxirane (XIV) having desired stereochemistry is obtained via oxidation reaction. The ketone (X) is converted to the exomethylene (XI) by Wittig reaction. The stereoselective oxidation of (XI) is achieved by means of osmium tetroxide in the presence of 4-methylmorpholine N-oxide to give the diol (XII) in 58% yield after separation of its epimer by column chromatography. After methanesulfonylation of the primary alcohol of (XII), a triazole moiety is introduced and the triphenylmethyl group is deprotected. Then, the primary hydroxyl group of (XVI) is oxidized under Swern oxidation condition to give the aldehyde (XVII), which is converted to the chiral nitrile intermediate (III) by means of heating with hydroxylamine-O-sulfonic acid.
| 【1】 Saji, I.; Tamoto, K.; Tanaka, Y.; Fujimoto, K.; Ohashi, N.; Stereoselective synthesis of antifungal agent threo-2-(2,4-difluorophenyl)-3-methylsulfonyl-1-(1H-1,2,4-triazol-1-yl)-2-butanol (SM-8668). Bull Chem Soc Jpn 1994, 67, 1427-33. |
| 【2】 Konos, T.; Miyaoka, T.; Tajima, Y.; Oida, S.; Triazole antifungals. III. Stereocontrolled synthesis of an optically active triazolylmethyloxirane precursor to antifungal oxazolodine derivatives. Chem Pharm Bull 1991, 39, 9, 2241. |
| 【3】 Naito, T.; Hata, K.; Tsuruoka, A.; ER-30346. Drugs Fut 1996, 21, 1, 20. |
| 【4】 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. |
| 【5】 Naito, T.; Hata, K.; Kaku, Y.; Tsuruoka, A.; Tsukada, I.; Yanagisawa, M.; Toyosawa, T.; Nara, K. (Eisai Co., Ltd.); Azole antifungal agents, process for the preparation thereof and intermediates. CA 2141731; EP 0667346; JP 1995223950; JP 1996020578; JP 1996053426; US 5648372; US 5789429; US 5792781 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (II) | 17123 | (2S,3R)-3-(2,4-difluorophenyl)-3-hydroxy-2-methyl-4-(1H-1,2,4-triazol-1-yl)butanenitrile | C13H12F2N4O | 详情 | 详情 | |
| (VIII) | 17128 | Methyl (2S)-3-hydroxy-2-methylpropanoate | 72657-23-9 | C5H10O3 | 详情 | 详情 |
| (IX) | 17129 | Methyl (2S)-2-methyl-3-(trityloxy)propanoate | C24H24O3 | 详情 | 详情 | |
| (X) | 17130 | (2S)-1-(2,4-difluorophenyl)-2-methyl-3-(trityloxy)-1-propanone | C29H24F2O2 | 详情 | 详情 | |
| (XI) | 17131 | (2R)-3-(2,4-difluorophenyl)-2-methyl-3-butenyl trityl ether; 2,4-difluoro-1-[1-[(1R)-1-methyl-2-(trityloxy)ethyl]vinyl]benzene | C30H26F2O | 详情 | 详情 | |
| (XII) | 17132 | (2R,3S)-2-(2,4-difluorophenyl)-3-methyl-4-(trityloxy)-1,2-butanediol | C30H28F2O3 | 详情 | 详情 | |
| (XIII) | 17133 | (2R,3S)-2-(2,4-difluorophenyl)-3-methyl-1-[[methyl(dimethylene)-lambda(6)-sulfanyl]oxy]-4-(trityloxy)-2-butanol | C33H34F2O3S | 详情 | 详情 | |
| (XIV) | 17134 | (2R)-2-(2,4-difluorophenyl)-2-[(1S)-1-methyl-2-(trityloxy)ethyl]oxirane; (2S)-2-[(2R)-2-(2,4-difluorophenyl)oxiranyl]propyl trityl ether | C30H26F2O2 | 详情 | 详情 | |
| (XV) | 17135 | (2R,3S)-2-(2,4-difluorophenyl)-3-methyl-1-(1H-1,2,4-triazol-1-yl)-4-(trityloxy)-2-butanol | C32H29F2N3O2 | 详情 | 详情 | |
| (XVI) | 17136 | (2S,3R)-3-(2,4-difluorophenyl)-2-methyl-4-(1H-1,2,4-triazol-1-yl)-1,3-butanediol | C13H15F2N3O2 | 详情 | 详情 | |
| (XVII) | 17137 | (2R,3R)-3-(2,4-difluorophenyl)-3-hydroxy-2-methyl-4-(1H-1,2,4-triazol-1-yl)butanal | C13H13F2N3O2 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(XV)The synthesis of (2S,3S)-3-(2,4-difluorophenyl)-3-hydroxy-2-methyl-4-(1,2,4-triazol-1-yl)butyronitrile (XV), a key intermediate the synthesis of ER-30346 has been described: The tritylation of 3-hydroxy-2(S)-methylpropionic acid methyl ester (I) with trityl chloride in hot pyridine gives the trityl ether (II), which is hydrolyzed with LiOH in H2O/THF/methanol yielding the free acid (III). The esterification of (III) with 2-mercaptopyridine (IV) by means of dicyclohexylcarbodiimide (DCC) in dichloromethane gives the thioester (V), which is treated with 2,4-difluorophenylmagnesium bromide (VI) in THF yielding the propiophenone (VII), which by treatment with methyltriphenylphosphonium bromide/NaH in THF is converted into the methylene derivative (VIII). The oxidation of (VIII) with OsO4 and N-methylmorpholine oxide in acetone affords, after column chromatography, the chiral diol (IX), which is monomesylated with mesyl chloride/triethylamine in dichlormethane giving the monoester (X). The reaction of (X) with 1,2,4-triazol (XI) and NaH in DMF yields (2R,3S)-2-(2,4-difluorophenyl)-3-methyl-1-(1,2,4-triazol-1-yl)-4-(triphenylmethoxy)-2-butanol (XII), which is detritylated with p-toluenesulfonic acid in methanol affording the diol (XIII). The oxidation of (XIII) with oxalyl chloride/DMSO in dichloromethane gives the aldehyde (XIV), which is finally treated with hydroxylamine-O-sulfonic acid in water yielding the desired bytyronitrile intermediate (XV) already referenced.
| 【1】 Kaku, Y.; et al.; A novel route for chiral synthesis of the triazole antifungal ER-30346. Chem Pharm Bull 1998, 46, 7, 1125. |
| 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) | 17128 | Methyl (2S)-3-hydroxy-2-methylpropanoate | 72657-23-9 | C5H10O3 | 详情 | 详情 |
| (II) | 17129 | Methyl (2S)-2-methyl-3-(trityloxy)propanoate | C24H24O3 | 详情 | 详情 | |
| (III) | 20259 | (2S)-2-methyl-3-(trityloxy)propionic acid | C23H22O3 | 详情 | 详情 | |
| (IV) | 20260 | 2-Mercaptopyiridine; 2-pyridinethiol; 2-pyridinylhydrosulfide | 2637-34-5 | C5H5NS | 详情 | 详情 |
| (V) | 20261 | S-(2-pyridinyl) (2S)-2-methyl-3-(trityloxy)propanethioate | C28H25NO2S | 详情 | 详情 | |
| (VI) | 20262 | bromo(2,4-difluorophenyl)magnesium | C6H3BrF2Mg | 详情 | 详情 | |
| (VII) | 17130 | (2S)-1-(2,4-difluorophenyl)-2-methyl-3-(trityloxy)-1-propanone | C29H24F2O2 | 详情 | 详情 | |
| (VIII) | 17131 | (2R)-3-(2,4-difluorophenyl)-2-methyl-3-butenyl trityl ether; 2,4-difluoro-1-[1-[(1R)-1-methyl-2-(trityloxy)ethyl]vinyl]benzene | C30H26F2O | 详情 | 详情 | |
| (IX) | 17132 | (2R,3S)-2-(2,4-difluorophenyl)-3-methyl-4-(trityloxy)-1,2-butanediol | C30H28F2O3 | 详情 | 详情 | |
| (X) | 20266 | (2R,3S)-2-(2,4-difluorophenyl)-2-hydroxy-3-methyl-4-(trityloxy)butyl methanesulfonate | C31H30F2O5S | 详情 | 详情 | |
| (XI) | 13135 | 1H-1,2,4-Triazole; 1,2,4-Triazole | 288-88-0 | C2H3N3 | 详情 | 详情 |
| (XII) | 17135 | (2R,3S)-2-(2,4-difluorophenyl)-3-methyl-1-(1H-1,2,4-triazol-1-yl)-4-(trityloxy)-2-butanol | C32H29F2N3O2 | 详情 | 详情 | |
| (XIII) | 17136 | (2S,3R)-3-(2,4-difluorophenyl)-2-methyl-4-(1H-1,2,4-triazol-1-yl)-1,3-butanediol | C13H15F2N3O2 | 详情 | 详情 | |
| (XIV) | 17137 | (2R,3R)-3-(2,4-difluorophenyl)-3-hydroxy-2-methyl-4-(1H-1,2,4-triazol-1-yl)butanal | C13H13F2N3O2 | 详情 | 详情 | |
| (XV) | 17123 | (2S,3R)-3-(2,4-difluorophenyl)-3-hydroxy-2-methyl-4-(1H-1,2,4-triazol-1-yl)butanenitrile | C13H12F2N4O | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(II)Addition of trimethylsilyl cyanide to the known epoxide (I) produced the hydroxy nitrile (II). This was converted to the thioamide (III) upon treatment with diethyl dithiophosphate. Condensation between thioamide (III) and thiadiazolyl thiobenzamide (IV) in the presence of iodine furnished the target thiadiazole derivative.
| 【1】 Fujii, T.; Tsukuda, T.; Shimma, N.; Komiyama, S.; Parallel synthesis of azole antifungals and identification of novel thiadiazole-containing antifungals. 223rd ACS Natl Meet (April 7 2002, Orlando) 2002, Abst MEDI 175. |
| 【2】 Shimma, N.; Tsukuda, T.; Komiyama, S. (Basilea Pharmaceutica AG); Azole derivs.. US 6319933; WO 0179196 . |
| 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) | 13114 | 1-[[(2S,3S)-2-(2,4-Difluorophenyl)-3-methyloxiranyl]methyl]-1H-1,2,4-triazole | C12H11F2N3O | 详情 | 详情 | |
| (II) | 17123 | (2S,3R)-3-(2,4-difluorophenyl)-3-hydroxy-2-methyl-4-(1H-1,2,4-triazol-1-yl)butanenitrile | C13H12F2N4O | 详情 | 详情 | |
| (III) | 17121 | (2R,3R)-3-(2,4-difluorophenyl)-3-hydroxy-2-methyl-4-(1H-1,2,4-triazol-1-yl)butanethioamide | C13H14F2N4OS | 详情 | 详情 | |
| (IV) | 58588 | 4-(1,2,3-Thiadiazol-4-yl)thiobenzamide | C9H7N3S2 | 详情 | 详情 |