Ravuconazole, BMS-207147, ER-30346, -Drug Synthesis Database

【结构式】

【药物名称】Ravuconazole, BMS-207147, ER-30346

【化学名称】4-[2-[2(R)-(2,4-Difluorophenyl)-2-hydroxy-1(R)-methyl-3-(1,2,4-triazol-1-yl)propyl]thiazol-4-yl]benzonitrile
　　　　　　(2R,3R)-3-[4-(4-Cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl]-2-butanol

【CA登记号】182760-06-1

【分子式】C₂₂H₁₇F₂N₅OS

【分子量】437.47449

【开发单位】Eisai (Originator), Bristol-Myers Squibb (Licensee)

【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4

合成路线1

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.

参考文献中间体

【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

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.

参考文献中间体

【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	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

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.

参考文献中间体

【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

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.

参考文献中间体

【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

Extended Information