CS-758, R-120758, -Drug Synthesis Database

【结构式】

【药物名称】CS-758, R-120758

【化学名称】trans-4-[4-[5-[2(R)-(2,4-Difluorophenyl)-2-hydroxy-1(R)-methyl-3-(1H-1,2,4-triazol-1-yl)propylsulfanyl]-1,3-dioxan-2-yl]-1(E),3(E)-butadienyl]-3-fluorobenzonitrile

【CA登记号】329744-44-7

【分子式】C₂₇H₂₅F₃N₄O₃S

【分子量】542.5845

【开发单位】Sankyo (Originator), Fujisawa (Licensee)

【药理作用】Antifungal Agents, ANTIINFECTIVE THERAPY, Lanosterol 14alpha-demethylase Inhibitors

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

Benzylic bromination of 3-fluoro-4-methylbenzaldehyde (I) using N-bromosuccinimide afforded bromide (II), which was converted to phosphonate (III) by reaction with triethyl phosphite. Horner-Emmons condensation of phosphonate (III) with monoprotected fumaraldehyde (IV) produced the diene acetal (V), which was then hydrolyzed to aldehyde (VI) with aqueous HCl.

参考文献中间体

【1】 Sorbera, L.A.; del Fresno, M.; Rabasseda, X.; CS-758. Drugs Fut 2003, 28, 3, 217.
【2】 Nakamura, Y.; Konosu, T.; Oida, S.; et al.; Synthesis and in vitro antifungal activities of novel triazole antifungal agent CS-758. Chem Pharm Bull 2001, 49, 12, 1647.
【4】 Mori, M.; Oida, S.; Uchida, T.; Nakagawa, A.; Kounosu, T.; Ohya, T. (Sankyo Co., Ltd.); Triazole antifungal agents. JP 2002161035 .
【5】 Mori, M.; Oida, S.; Konosu, T.; Uchida, T.; Ohya, S.; Nakagawa, A. (Sankyo Co., Ltd.); Triazole derivs. having antifungal activity. EP 1083175; JP 2001348384; JP 2002114782; US 6337403; US 6391903 .
【3】 Oida, S.; Mori, M.; nakamura, Y.; Habuki, S.; Kuwahara, S.; Somada, A.; Harada, Y.; Uchida, T.; Konosu, T.; R-120758, a novel triazole antifungal agent: Synthesis and structure-activity relationship. 40th Intersci Conf Antimicrob Agents Chemother (Sept 17 2000, Toronto) 2000, Abst F-1087.

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)	45510	3-fluoro-4-methylbenzonitrile	170572-49-3	C₈H₆FN	详情	详情
(II)	45511	4-(bromomethyl)-3-fluorobenzonitrile		C₈H₅BrFN	详情	详情
(III)	45512	diethyl 4-cyano-2-fluorobenzylphosphonate		C₁₂H₁₅FNO₃P	详情	详情
(IV)	45513	(E)-4,4-dimethoxy-2-butenal	4093-49-6	C₆H₁₀O₃	详情	详情
(V)	45514	4-[(1E,3E)-5,5-dimethoxy-1,3-pentadienyl]-3-fluorobenzonitrile		C₁₄H₁₄FNO₂	详情	详情
(VI)	45515	3-fluoro-4-[(1E,3E)-5-oxo-1,3-pentadienyl]benzonitrile		C₁₂H₈FNO	详情	详情

合成路线2

Addition of the thiol liberated from thioester (VII) in the presence of NaOMe to the chiral epoxide (VIII) afforded thioether (IX). Acid hydrolysis of the acetal function of (IX) yielded diol (X). Then, acetalization of diol (IX) with aldehyde (XI) furnished the title compound.

参考文献中间体

【1】 Sorbera, L.A.; del Fresno, M.; Rabasseda, X.; CS-758. Drugs Fut 2003, 28, 3, 217.
【2】 Nakamura, Y.; Konosu, T.; Oida, S.; et al.; Synthesis and in vitro antifungal activities of novel triazole antifungal agent CS-758. Chem Pharm Bull 2001, 49, 12, 1647.
【4】 Tajima, Y.; Oida, S.; Konosu, T.; et al.; Synthesis and antifungal activities of R-102557 and related dioxane-triazole derivatives. Chem Pharm Bull 2000, 48, 5, 694.
【5】 Oida, S.; Tanaka, T.; Tajima, Y.; Konosu, T.; Somada, A.; Miyaoka, T.; Yasuda, H. (Sankyo Co., Ltd.); Triazole antifungal agent. EP 0841327; JP 1996333350; US 5977152; WO 9631491 .
【6】 Mori, M.; Oida, S.; Uchida, T.; Nakagawa, A.; Kounosu, T.; Ohya, T. (Sankyo Co., Ltd.); Triazole antifungal agents. JP 2002161035 .
【3】 Oida, S.; Mori, M.; nakamura, Y.; Habuki, S.; Kuwahara, S.; Somada, A.; Harada, Y.; Uchida, T.; Konosu, T.; R-120758, a novel triazole antifungal agent: Synthesis and structure-activity relationship. 40th Intersci Conf Antimicrob Agents Chemother (Sept 17 2000, Toronto) 2000, Abst F-1087.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(VI)	45515	3-fluoro-4-[(1E,3E)-5-oxo-1,3-pentadienyl]benzonitrile	C₁₂H₈FNO	详情	详情
(VII)	41336	S-(2-phenyl-1,3-dioxan-5-yl) ethanethioate	C₁₂H₁₄O₃S	详情	详情
(VIII)	13114	1-[[(2S,3S)-2-(2,4-Difluorophenyl)-3-methyloxiranyl]methyl]-1H-1,2,4-triazole	C₁₂H₁₁F₂N₃O	详情	详情
(IX)	41337	(2R,3R)-2-(2,4-difluorophenyl)-3-[(2-phenyl-1,3-dioxan-5-yl)sulfanyl]-1-(1H-1,2,4-triazol-1-yl)-2-butanol	C₂₂H₂₃F₂N₃O₃S	详情	详情
(X)	41338	2-[[(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]sulfanyl]-1,3-propanediol	C₁₅H₁₉F₂N₃O₃S	详情	详情

合成路线3

The known chiral epoxide (IX) can be synthesized by several different ways shown in the following: 1) 2(S)-Acetoxypropionic acid (XII) is treated first with oxalyl chloride in DMF/CH2Cl2, and then the resultant acyl chloride is submitted to a Friedel-Crafts reaction with 1,3-difluorobenzene (XIII) by means of AlCl3 to provide a 1:1 mixture of a(S)-acetoxypropiophenone (XIV) and a(S)-hydroxy-propiophenone (XV). This mixture is treated with H2SO4 in MeOH to give the pure alcohol (XV). Tosylation of alcohol (XV) with p-toluenesulfonyl chloride in pyridine furnishes tosylate (XVI), which is converted into a(R)-hydroxypropiophenone (XVII) by an SN2 displacement reaction with LiOH in DMF/H2O. Reaction of the hydroxy group of (XVII) with 2,3-dihydropyran (XVIII) and pyridi-nium p-toluenesulfonate (PPTS) in CH2Cl2 gives the protected compound (XIX), which is converted into the silyl alcohol (XXI) by a Grignard reaction with (chloro-methyl)dimethylisopropoxysilane (XX) in the presence of Mg and a small amount of MeI. Oxidative desilylation of (XXI) by means of NaHCO3 and H2O2 in THF/MeOH, followed by hydrolysis with TsOH in MeOH, affords the triol (XXII), which is then mesylated with methanesulfonyl chloride in pyridine to provide the dimesylate (XXIII). Finally, nucleofilic substitution of one mesylate group of (XXIII) with 1H-1,2,4-triazole (XXIV) by means of NaH in DMF with concomitant epoxide formation affords the desired intermediate (IX).

参考文献中间体

【1】 Sorbera, L.A.; del Fresno, M.; Rabasseda, X.; CS-758. Drugs Fut 2003, 28, 3, 217.
【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.

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)	31738	1-[[(2R,3S)-2-(2,4-difluorophenyl)-3-methyloxiranyl]methyl]-1H-1,2,4-triazole		C₁₂H₁₁F₂N₃O	详情	详情
(XII)	10142	(2R)-2-(Acetoxy)propionic acid	18668-00-3	C₅H₈O₄	详情	详情
(XIII)	13095	m-Difluorobenzene; 1,3-Difluorobenzene	372-18-9	C₆H₄F₂	详情	详情
(XIV)	59948	(1S)-2-(2,4-difluorophenyl)-1-methyl-2-oxoethyl acetate		C₁₁H₁₀F₂O₃	详情	详情
(XV)	45571	(2S)-1-(2,4-difluorophenyl)-2-hydroxy-1-propanone		C₉H₈F₂O₂	详情	详情
(XVI)	59949	(1S)-2-(2,4-difluorophenyl)-1-methyl-2-oxoethyl 4-methylbenzenesulfonate		C₁₆H₁₄F₂O₄S	详情	详情
(XVII)	13100	(2R)-1-(2,4-Difluorophenyl)-2-hydroxy-1-propanone		C₉H₈F₂O₂	详情	详情
(XVIII)	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
(XIX)	13102	(2R)-1-(2,4-Difluorophenyl)-2-(tetrahydro-2H-pyran-2-yloxy)-1-propanone		C₁₄H₁₆F₂O₃	详情	详情
(XX)	59950	(chloromethyl)(dimethyl)silyl isopropyl ether; (chloromethyl)(isopropoxy)dimethylsilane		C₆H₁₅ClOSi	详情	详情
(XXI)	59951	(2S,3R)-2-(2,4-difluorophenyl)-1-[isopropoxy(dimethyl)silyl]-3-(tetrahydro-2H-pyran-2-yloxy)-2-butanol		C₂₀H₃₂F₂O₄Si	详情	详情
(XXII)	59952	(2R,3R)-2-(2,4-difluorophenyl)-1,2,3-butanetriol		C₁₀H₁₂F₂O₃	详情	详情
(XXIII)	59953	(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-[(methylsulfonyl)oxy]propyl methanesulfonate		C₁₂H₁₆F₂O₇S₂	详情	详情
(XXIV)	13135	1H-1,2,4-Triazole; 1,2,4-Triazole	288-88-0	C₂H₃N₃	详情	详情

合成路线4

2) Propiophenone derivative (XXV) - prepared according to a procedure similar to that described for compound (XIX) - is subjected to a Grignard reaction with (chloromethyl)trimethylsilane (XXVI) and Mg in ether to give the silyl alcohol (XXVII), which by treatment with p-toluenesulfonic acid in MeOH undergoes b-elimination and deprotection to yield the allylic alcohol (XXVIII). Epoxidation of (XXVIII) with tert-butyl hydroperoxide and catalytic oxyvanadium acetylacetonate gives the epoxy-alcohol (XXIX), which is subjected to a Mitsunobu reaction with benzoic acid (XXX) by means of DEAD and PPh3 in THF to provide benzoate (XXXI). Solvolysis of compound (XXXI) in MeOH with catalytic NaOMe yields the epoxyalcohol (XXXII), which is mesylated with methanesulfonyl chloride and triethylamine in CH2Cl2 to afford the protected alcohol (XXXIII). Finally, treatment of compound (XXXIII) with 1H-1,2,4-triazole (XXIV) and NaH in DMF affords the desired intermediate (IX).

参考文献中间体

【1】 Sorbera, L.A.; del Fresno, M.; Rabasseda, X.; CS-758. Drugs Fut 2003, 28, 3, 217.
【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.

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)	31738	1-[[(2R,3S)-2-(2,4-difluorophenyl)-3-methyloxiranyl]methyl]-1H-1,2,4-triazole		C₁₂H₁₁F₂N₃O	详情	详情
(XIV)	13135	1H-1,2,4-Triazole; 1,2,4-Triazole	288-88-0	C₂H₃N₃	详情	详情
(XXV)	43511	(2S)-1-(2,4-difluorophenyl)-2-(tetrahydro-2H-pyran-2-yloxy)-1-propanone		C₁₄H₁₆F₂O₃	详情	详情
(XXVI)	59954	(chloromethyl)(trimethyl)silane		C₄H₁₁ClSi	详情	详情
(XXVII)	59955	(3S)-2-(2,4-difluorophenyl)-3-(tetrahydro-2H-pyran-2-yloxy)-1-(trimethylsilyl)-2-butanol		C₁₈H₂₈F₂O₃Si	详情	详情
(XXVIII)	59956	(2S)-3-(2,4-difluorophenyl)-3-buten-2-ol		C₁₀H₁₀F₂O	详情	详情
(XXIX)	27877	(1S)-1-[(2R)-2-(2,4-difluorophenyl)oxiranyl]-1-ethanol		C₁₀H₁₀F₂O₂	详情	详情
(XXX)	10202	Benzoic acid	65-85-0	C₇H₆O₂	详情	详情
(XXXI)	43518	(1S)-1-[(2S)-2-(2,4-difluorophenyl)oxiranyl]ethyl benzoate		C₁₇H₁₄F₂O₃	详情	详情
(XXXII)	27875	(1R)-1-[(2R)-2-(2,4-difluorophenyl)oxiranyl]-1-ethanol		C₁₀H₁₀F₂O₂	详情	详情
(XXXIII)	59957	(1R)-1-[(2R)-2-(2,4-difluorophenyl)oxiranyl]ethyl methanesulfonate		C₁₁H₁₂F₂O₄S	详情	详情

Extended Information

Drug NewChemical Entity Original Patent(1)