BAL-8557, RO-0098557, -Drug Synthesis Database

【结构式】

【药物名称】BAL-8557, RO-0098557

【化学名称】1-[3(R)-[4-(4-Cyanophenyl)thiazol-2-yl]-2(R)-(2,5-difluorophenyl)-2-hydroxybutyl]-4-[1-[N-methyl-N-[3-[2-(methylammonio)acetoxymethyl]pyridin-2-yl]carbamoyloxy]ethyl]-1H-1,2,4-triazol-4-ium dichloride

【CA登记号】338990-84-4

【分子式】C₃₅H₃₆Cl₂F₂N₈O₅S

【分子量】789.69457

【开发单位】Basilea Pharmaceutica (Proprietary), Chugai (Originator)

【药理作用】Antifungal Agents, ANTIINFECTIVE THERAPY, Chemical Delivery Systems, DRUG DELIVERY, Drug Delivery Systems, Azoles

合成路线1 合成路线2

合成路线1

Addition of 2,5-difluorophenylmagnesium bromide (I) to the O-tetrahydropyranyl lactic acid amide (II) afforded the propiophenone derivative (III). Oxirane (IV) was then obtained by reaction of ketone (III) with the sulfur ylide generated from trimethylsulfoxonium iodide and either NaH or BuLi. Epoxide ring opening with the sodium salt of 1,2,4-triazole (V) led to the triazolyl alcohol (VI) as a mixture of diastereoisomers. After acid hydrolysis of the tetrahydropyranyl protecting group of (VI), the resultant mixture of diols was separated by column chromatography. The desired (R,R) diastereoisomer (VII) was converted to epoxide (IX) via formation of mesylate (VIII), which was subsequently cyclized in the presence of NaOMe. Nitrile (X) was then obtained by reaction of oxirane (IX) with either trimethylsilyl cyanide, followed by desilylation with Bu4NF, or with acetone cyanohydrin and LiH. Conversion of nitrile (X) into thioamide (XI) was accomplished by treatment with diethyl dithiophosphate. Cyclization of thioamide (XI) with 4-cyanophenacyl bromide (XII) gave rise to the thiazole derivative (XIII).

参考文献中间体

【1】 Yamazaki, T.; Sakai, T.; Shimma, N.; Umeda, I.; Ichihara, S.; Ohwada, J.; Hayase, T.; Isshiki, Y.; Liu, P.; Tsukazaki, M. (F. Hoffmann-La Roche AG); 3-[4-(4-Cyanophenyl)thiazol-2-yl)]-1-(1H-1,2,4-triazol-1-yl)-butan-2-ol derivs. having antifungal activity. US 6300353; WO 9945008 .

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)	55920	bromo(2,5-difluorophenyl)magnesium		C₆H₃BrF₂Mg	详情	详情
(II)	45574	(2R)-1-(4-morpholinyl)-2-(tetrahydro-2H-pyran-2-yloxy)-1-propanone		C₁₂H₂₁NO₄	详情	详情
(III)	55921	(2R)-1-(2,5-difluorophenyl)-2-(tetrahydro-2H-pyran-2-yloxy)-1-propanone		C₁₄H₁₆F₂O₃	详情	详情
(IV)	55922	(1R)-1-[2-(2,5-difluorophenyl)-2-oxiranyl]ethyl tetrahydro-2H-pyran-2-yl ether; 2-({(1R)-1-[2-(2,5-difluorophenyl)-2-oxiranyl]ethyl}oxy)tetrahydro-2H-pyran		C₁₅H₁₈F₂O₃	详情	详情
(V)	13135	1H-1,2,4-Triazole; 1,2,4-Triazole	288-88-0	C₂H₃N₃	详情	详情
(VI)	55923	(3R)-2-(2,5-difluorophenyl)-3-(tetrahydro-2H-pyran-2-yloxy)-1-(1H-1,2,4-triazol-1-yl)-2-butanol		C₁₇H₂₁F₂N₃O₃	详情	详情
(VII)	55924	(2R,3R)-2-(2,5-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2,3-butanediol		C₁₂H₁₃F₂N₃O₂	详情	详情
(VIII)	55925	(1R,2R)-2-(2,5-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl methanesulfonate		C₁₃H₁₅F₂N₃O₄S	详情	详情
(IX)	55926	1-{[(2S,3R)-2-(2,5-difluorophenyl)-3-methyloxiranyl]methyl}-1H-1,2,4-triazole		C₁₂H₁₁F₂N₃O	详情	详情
(X)	55927	(2S,3R)-3-(2,5-difluorophenyl)-3-hydroxy-2-methyl-4-(1H-1,2,4-triazol-1-yl)butanenitrile		C₁₃H₁₂F₂N₄O	详情	详情
(XI)	55928	(2R,3R)-3-(2,5-difluorophenyl)-3-hydroxy-2-methyl-4-(1H-1,2,4-triazol-1-yl)butanethioamide		C₁₃H₁₄F₂N₄OS	详情	详情
(XII)	17122	4-(2-bromoacetyl)benzonitrile; 4-Cyanophenacyl bromide	20099-89-2	C₉H₆BrNO	详情	详情
(XIII)	55929	4-{2-[(1R,2R)-2-(2,5-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-1,3-thiazol-4-yl}benzonitrile		C₂₂H₁₇F₂N₅OS	详情	详情

合成路线2

The intermediate amino alcohol (XVIII) was prepared by two ways. 2-Chloronicotinic acid (XIV) was converted to the corresponding acid chloride (XV) by treatment with oxalyl chloride, and then reacted with potassium tert-butoxide to afford the tert-butyl ester (XVI). Displacement of the chloride group of (XVI) with methanolic methylamine gave rise to the 2-(methylamino)nicotinic ester (XVII), which was then reduced to alcohol (XVIII) employing LiAlH4. Alternatively, 2-aminonicotinic acid (XIX) was esterified to (XX) by means of 2-chloro-1,3-dimethylimidazolinium chloride in MeOH. The amino group of (XX) was acylated with formic acetic anhydride to give formamide (XXI). Amino alcohol (XVIII) was then obtained by reduction of amido ester (XXI) in the presence of LiAlH4. Condensation of (XVIII) with 1-chloroethyl chloroformate produced the carbamate alcohol (XXII), which was subsequently esterified with N-Boc-sarcosine (XXIII) by means of EDC yielding (XXIV) (2). Quaternization of the triazole compound (XIII) with the chloroethyl carbamate (XXIV) in the presence of NaI furnished the corresponding triazolium salt, which was finally subjected to acidic Boc group cleavage to produce the title compound.

参考文献中间体

【1】 Ohwada, J.; Tsukazaki, M.; Hayase, T.; et al.; Design, synthesis and antifungal activity of a novel water soluble prodrug of antifungal triazole. Bioorg Med Chem Lett 2003, 13, 2, 191.
【2】 Hayase, T.; Tsukazaki, M.; Ohwada, J.; et al.; Development of novel water antifungal, RO0098557. 21st Symp Med Chem (Nov 28 2001, Kyoto) 2001, Abst 1P-06.
【3】 Ohwada, J.; et al.; RO0098557, a novel water soluble azole prodrug for parenteral and oral administration (I). Design, synthesis, physicochemical properties and bioconversion. 42nd Intersci Conf Antimicrob Agents Chemother (Sept 27 2002, San Diego) 2002, Abst F-820.
【4】 Shimma, N.; Fukuda, H.; Umeda, I.; Ohwada, J.; Sakaitani, M.; Oikawa, N.; Hayase, T.; Tsukazaki, M.; Mizuguchi, E. (F. Hoffmann-La Roche AG); N-Substd. carbamoyloxyalkyl-azolium derivs.. WO 0132652 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(XIII)	55929	4-{2-[(1R,2R)-2-(2,5-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-1,3-thiazol-4-yl}benzonitrile		C₂₂H₁₇F₂N₅OS	详情	详情
(XIV)	28824	2-Chloropyridine-3-carboxylic acid; 2-Chloronicotinic acid	2942-59-8	C₆H₄ClNO₂	详情	详情
(XV)	15224	2-chloronicotinoyl chloride	49609-84-9	C₆H₃Cl₂NO	详情	详情
(XVI)	55930	tert-butyl 2-chloronicotinate		C₁₀H₁₂ClNO₂	详情	详情
(XVII)	55931	tert-butyl 2-(methylamino)nicotinate		C₁₁H₁₆N₂O₂	详情	详情
(XVIII)	55932	[2-(methylamino)-3-pyridinyl]methanol		C₇H₁₀N₂O	详情	详情
(XIX)	55933	2-Aminonicotinic acid; 2-Aminopyridine-3-carboxylic acid	5345-47-1	C₆H₆N₂O₂	详情	详情
(XX)	55934	methyl 2-aminonicotinate	14667-47-1	C₇H₈N₂O₂	详情	详情
(XXI)	55935	methyl 2-(formylamino)nicotinate		C₈H₈N₂O₃	详情	详情
(XXII)	55936	1-chloroethyl 3-(hydroxymethyl)-2-pyridinyl(methyl)carbamate		C₁₀H₁₃ClN₂O₃	详情	详情
(XXIII)	55937	Boc-L-sarcosine; Boc-N-Methylglycine; Boc-sarcosine; N-tert-Butoxycarbonylsarcosine	13734-36-6	C₈H₁₅NO₄	详情	详情
(XXIV)	55938	{2-[[(1-chloroethoxy)carbonyl](methyl)amino]-3-pyridinyl}methyl 2-[(tert-butoxycarbonyl)(methyl)amino]acetate		C₁₈H₂₆ClN₃O₆	详情	详情

Extended Information

Drug NewChemical Entity Original Patent(1)