CEM-101;OP-1068;Solithromycin, -Drug Synthesis Database

【结构式】

【药物名称】CEM-101;OP-1068;Solithromycin

【化学名称】11-[4-[4-(3-Aminophenyl)-1H-1,2,3-triazol-1-yl]butylamino]-11-deoxy-3-des(hexopyranosyloxy) 2-fluoro-6-O-methyl-3-oxoerythromycin A 11-N,12-O-cyclic carbamate;(3aS,4R,7S,9R,10R,11R,13R,15R,15aR)-1-[4-[4-(3-Aminophenyl)-1H-1,2,3-triazol-1-yl]butyl]-4-ethyl-7-fluorooctahydro-11-methoxy-3a,7,9,11,13,15-hexamethyl-10-[[3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosyl]oxy]-2H-oxacyclotetradecino[4,3-d]oxazole-2,6,8,14(1H,7H,9H)-tetrone

【CA登记号】760981-83-7

【分子式】C₄₃H₆₅FN₆O₁₀

【分子量】845.0088

【开发单位】Cempra Pharmaceuticals, Inc. (US)

【药理作用】Macrolide Antibiotic

合成路线1 合成路线2

合成路线1

6-O-Methylerythromycin A (I) is protected with benzoic anhydride in the presence of triethylamine and DMAP in ethyl acetate to afford 2’,4”-di-O-benzoyl-6-O-methylerythromycin A (II). Treatment of the protected intermediate (II) with 1,8 diazabicyclo[5.4.0]undec-7-ene (DBU) followed by 1,1-carbonyldiimidazole (CDI) (III) in DMF yields 10,11-anhydro-2’,4”-di-O-benzoyl-12-O-imidazolylcarbonyl-6-Omethylerythromycin A (IV), which is converted to the 2’,4”-di-O-benzoyl-11-N-(4-azidobutyl)-6-O-methylerythromycin A 11,12-cyclic carbamate (V) by treatment with 4-azidobutylamine (XIII) and DBU in DMF. The cladinose sugar is cleaved from carbamate (V) by hydrolysis with 1 N HCl in acetone to provide 11-N-(4-azidobutyl)-5-(2’-benzoyldesosaminyl)-3-hydroxy-6-O-methylerythronolide A 11,12-cyclic carbamate (VI). 1-N-(4-Azidobutyl)-5-(2’-benzoyldesosaminyl)-3-oxo-6-O-methylerythronolide A 11,12-cyclic carbamate (VII) is prepared by oxidation of the secondary alcohol of intermediate (VI) with Dess-Martin periodinane (DMP).

参考文献中间体

【1】 Hwang, C., Duffield, J., Chiu, Y. et al. SAR of 11,12-carbamate macrolides/ketolides linked with 1,4-substituted-[1,2,3]-triazoles. 48th Intersci Conf Antimicrob Agents Chemother/Infect Dis Soc Am 46th Annu Meet (Oct 25-28, Washington, DC) 2008, Abst F1-3973.

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)	68888	(3S,4R,5R,6S,7S,9S,11S,12S,13R,14S)-6- (((2R,3S,4R,6S)-4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-14-ethyl-12,13-dihydroxy-4-(((2S,4S,5R,6R)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-7-methoxy-3,5,7,9,11,13-hexamethyloxacyclotetradecane-2,10-dione		C₃₈H₆₉NO₁₃	详情	详情
(II)	68889	(2R,3R,4S,6S)-6-(((3S,4R,5R,6S,7S,9S,11S,12S,13R,14S)-6-(((2R,3S,4R,6S)-3-(benzoyloxy)-4-(dimethylamino)-6-methyltetrahydro-2H-pyran-2-yl)oxy)-14-ethyl-12,13-dihydroxy-7-methoxy-3,5,7,9,11,13-hexamethyl-2,10-dioxooxacyclotetradecan-4-yl)oxy)-4-methoxy-2,4-dimethyltetrahydro-2H-pyran-3-yl benzoate		C₅₂H₇₇NO₁₅	详情	详情
(III)	11353	1,1'-Carbonyldiimidazole; Di(1H-imidazol-1-yl)methanone; N,N-Carbonyldiimidazole; 1,1'-Carbonylbis(1H-imidazole)	530-62-1	C₇H₆N₄O	详情	详情
(IV)	68890	(2S,3R,7S,9S,10S,11R,12R,13S)-10-(((2R,3S,4R,6S)-3-(benzoyloxy)-4-(dimethylamino)-6-methyltetrahydro-2H-pyran-2-yl)oxy)-12-(((2S,4S,5R,6R)-5-(benzoyloxy)-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-2-ethyl-9-methoxy-3,5,7,9,11,13-hexamethyl-6,14-dioxooxacyclotetradec-4-en-3-yl 1H-imidazole-1-carboxylate		C₅₆H₇₇N₃O₁₅	详情	详情
(V)	68891	(2R,3R,4S,6S)-6-(((3aR,4S,7S,8R,9R,10S,11S,13S,15S,15aS)-1-(4-azidobutyl)-10-(((2R,3S,4R,6S)-3-(benzoyloxy)-4-(dimethylamino)-6-methyltetrahydro-2H-pyran-2-yl)oxy)-4-ethyl-11-methoxy-3a,7,9,11,13,15-hexamethyl-2,6,14-trioxotetradecahydro-1H-[1]oxacyclotetradecino[4,3-d]oxazol-8-yl)oxy)-4-methoxy-2,4-dimethyltetrahydro-2H-pyran-3-yl benzoate		C₅₇H₈₃N₅O₁₅	详情	详情
(VI)	68892	(2R,3S,4R,6S)-2-(((3aR,4S,7S,8R,9R,10S,11S,13S,15S,15aS)-1-(4-azidobutyl)-4-ethyl-8-hydroxy-11-methoxy-3a,7,9,11,13,15-hexamethyl-2,6,14-trioxotetradecahydro-1H-[1]oxacyclotetradecino[4,3-d]oxazol-10-yl)oxy)-4-(dimethylamino)-6-methyltetrahydro-2H-pyran-3-yl benzoate		C₄₂H₆₅N₅O₁₁	详情	详情
(VII)	68893	(2R,3S,4R,6S)-2-(((3aR,4S,7S,9S,10S,11S,13S,15S,15aS)-1-(4-azidobutyl)-4-ethyl-11-methoxy-3a,7,9,11,13,15-hexamethyl-2,6,8,14-tetraoxotetradecahydro-1H-[1]oxacyclotetradecino[4,3-d]oxazol-10-yl)oxy)-4-(dimethylamino)-6-methyltetrahydro-2H-pyran-3-yl benzoate		C₄₂H₆₃N₅O₁₁	详情	详情
(XI)	11883	1,4-Dibromobutane; 1,4-Butylene bromide	110-52-1	C₄H₈Br₂	详情	详情
(XII)	68896	1,4-diazidobutane		C₄H₈N₆	详情	详情
(XIII)	68887	azidobutylamine;4-azidobutan-1-amine		C₄H₁₀N₄	详情	详情

合成路线2

Fluorination of the keto intermediate (VII) is accomplished with potassium tert-butoxide and N-fluo-robenzenesulfonamide (NFSI) in THF/CH2Cl2 at –20 °C to –15 °C to afford the fluoro-azide intermediate (VIII). The triazole intermediate (X) is prepared by a copper-catalyzed azide-alkyne cycloaddition reaction between the fluoro-azide intermediate (VIII) and 3-ethynylaniline (IX) in the presence of copper(I) iodide and DIEA in acetonitrile. Deprotection of the triazole intermediate (X) is accomplished by refluxing in methanol to yield solithromycin . 4-Azidobutylamine (XIII) is prepared by substitution of 1,4-dibromobutane (XI) with sodium azide in DMF/H2O at 80 °C to produce 1,4-diazidobutane (XII), which, without isolation, is subjected to partial reduction with triphenylphosphine in MTBE to afford 4-azidobutylamine (XIII) .

参考文献中间体

【1】 Hwang, C., Duffield, J., Chiu, Y. et al. SAR of 11,12-carbamate macrolides/ketolides linked with 1,4-substituted-[1,2,3]-triazoles. 48th Intersci Conf Antimicrob Agents Chemother/Infect Dis Soc Am 46th Annu Meet (Oct 25-28, Washington, DC) 2008, Abst F1-3973.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(VII)	68893	(2R,3S,4R,6S)-2-(((3aR,4S,7S,9S,10S,11S,13S,15S,15aS)-1-(4-azidobutyl)-4-ethyl-11-methoxy-3a,7,9,11,13,15-hexamethyl-2,6,8,14-tetraoxotetradecahydro-1H-[1]oxacyclotetradecino[4,3-d]oxazol-10-yl)oxy)-4-(dimethylamino)-6-methyltetrahydro-2H-pyran-3-yl benzoate		C₄₂H₆₃N₅O₁₁	详情	详情
(VIII)	68894	(2R,3S,4R,6S)-2-(((3aR,4S,7R,9S,10S,11S,13S,15S,15aS)-1-(4-azidobutyl)-4-ethyl-7-fluoro-11-methoxy-3a,7,9,11,13,15-hexamethyl-2,6,8,14-tetraoxotetradecahydro-1H-[1]oxacyclotetradecino[4,3-d]oxazol-10-yl)oxy)-4-(dimethylamino)-6-methyltetrahydro-2H-pyran-3-yl benzoate		C₄₂H₆₂FN₅O₁₁	详情	详情
(IX)	56445	3-Aminophenylacetylene; 3-Ethynylaniline; m-Aminophenylacetylene	54060-30-9	C₈H₇N	详情	详情
(X)	68895	(2R,3S,4R,6S)-2-(((3aR,4S,7R,9S,10S,11S,13S,15S,15aS)-1-(4-(4-(3-aminophenyl)-1H-1,2,3-triazol-1-yl)butyl)-4-ethyl-7-fluoro-11-methoxy-3a,7,9,11,13,15-hexamethyl-2,6,8,14-tetraoxotetradecahydro-1H-[1]oxacyclotetradecino[4,3-d]oxazol-10-yl)oxy)-4-(dimethylamino)-6-methyltetrahydro-2H-pyran-3-yl benzoate		C₅₀H₆₉FN₆O₁₁	详情	详情

Extended Information

Drug NewChemical Entity Original Patent(1)