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【结 构 式】

【分子编号】55929

【品名】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

【CA登记号】

【 分 子 式 】C22H17F2N5OS

【 分 子 量 】437.4728864

【元素组成】C 60.4% H 3.92% F 8.69% N 16.01% O 3.66% S 7.33%

与该中间体有关的原料药合成路线共 2 条

合成路线1

该中间体在本合成路线中的序号:(XIII)

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).

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

该中间体在本合成路线中的序号:(XIII)

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.

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