Ro-09-2550, -Drug Synthesis Database

【结构式】

【药物名称】Ro-09-2550

【化学名称】(1S,2R,3R,6R)-4-[2-[2-Methoxy-1-methyl-3-(1H-1,2,4-triazol-1-ylmethyl)-4-[4-(trifluoromethoxy)phenoxymethyl]cyclohexyl]ethyl]morpholine

【CA登记号】212890-42-1

【分子式】C₂₅H₃₅F₃N₄O₄

【分子量】512.5773

【开发单位】Chugai (Originator)

【药理作用】Antifungal Agents, ANTIINFECTIVE THERAPY

合成路线1 合成路线2

合成路线1

Reduction of (-)-R-carvone (I) with LiAlH4 in Et2O at -78 C gave alcohol (II). Inversion of the hydroxyl group was then achieved by Mitsunobu reaction with 4-nitrobenzoic acid (III), followed by hydrolysis of the resulting 4-nitrobenzoate ester (IV) to give (V). Treatment of alcohol (V) with ethyl vinyl ether (VI) and N-bromosuccinimide produced the bromoacetal (VII). Subsequent intermolecular radical cyclization of (VII) with NaBH4 in the presence of a catalytic amount of Bu3SnCl and AIBN yielded cyclic acetal (VIII). Acidic hydrolysis of (VIII) followed by reduction of the resulting aldehyde (IX) with LiAlH4 provided diol (X). Protection of the primary alcohol group with trityl chloride in the presence of DMAP gave (XI), and subsequent oxidation of the secondary alcohol with pyridinum chlorochromate afforded ketone (XII). Further carbomethoxylation of (XII) by treatment with LDA and methyl cyanoformate yielded ketoester (XIII), which was reduced to alcohol (XIV) with NaBH4 in MeOH at 0 C. Then, alcohol (XIV) was converted to methyl ether (XV) by reaction with methyl iodide and NaH in DMF, and the ester group was reduced to alcohol (XVI) with LiAlH4 in Et2O at 0 C. Alcohol (XVI) was converted to mesylate (XVII) with methanesulfonyl chloride and Et3N.

参考文献中间体

【1】 Tsukuda, T.; Watanabe, M.; Ontsuka, H.; Hattori, K.; Shirai, M.; Shimma, N.; Synthesis of novel antifungal agents (2). Bioorg Med Chem Lett 1998, 8, 14, 1825.

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)	13386	(5R)-5-Isopropenyl-2-methyl-2-cyclohexen-1-one; L-(-)-Carvone	6485-40-1	C₁₀H₁₄O	详情	详情
(II)	18758	(1R,5R)-5-isopropenyl-2-methyl-2-cyclohexen-1-ol		C₁₀H₁₆O	详情	详情
(III)	18119	4-nitrobenzoic acid; p-nitrobenzoic acid	62-23-7	C₇H₅NO₄	详情	详情
(IV)	18760	(1S,5R)-5-isopropenyl-2-methyl-2-cyclohexen-1-yl 4-nitrobenzoate		C₁₇H₁₉NO₄	详情	详情
(V)	18761	(1S,5R)-5-isopropenyl-2-methyl-2-cyclohexen-1-ol		C₁₀H₁₆O	详情	详情
(VI)	18762	1-Ethoxyethylene; Ethyl vinyl ether；Ethoxyethene	109-92-2	C₄H₈O	详情	详情
(VII)	18763	2-bromo-1-ethoxyethyl (1S,5R)-5-isopropenyl-2-methyl-2-cyclohexen-1-yl ether; (4R,6S)-6-(2-bromo-1-ethoxyethoxy)-4-isopropenyl-1-methyl-1-cyclohexene		C₁₄H₂₃BrO₂	详情	详情
(VIII)	18764	(3aS,6R,7aS)-2-ethoxy-6-isopropenyl-3a-methyloctahydro-1-benzofuran; (3aS,6R,7aS)-6-isopropenyl-3a-methyloctahydro-1-benzofuran-2-yl ethyl ether		C₁₄H₂₄O₂	详情	详情
(IX)	18765	2-[(1S,2S,4R)-2-hydroxy-4-isopropenyl-1-methylcyclohexyl]acetaldehyde		C₁₂H₂₀O₂	详情	详情
(X)	18766	(1S,2S,5R)-2-(2-hydroxyethyl)-5-isopropenyl-2-methylcyclohexanol		C₁₂H₂₂O₂	详情	详情
(XI)	18767	(1S,2S,5R)-5-isopropenyl-2-methyl-2-[2-(trityloxy)ethyl]cyclohexanol		C₃₁H₃₆O₂	详情	详情
(XII)	18768	(2S,5R)-5-isopropenyl-2-methyl-2-[2-(trityloxy)ethyl]cyclohexanone		C₃₁H₃₄O₂	详情	详情
(XIII)	18769	methyl (3S,6R)-6-isopropenyl-3-methyl-2-oxo-3-[2-(trityloxy)ethyl]cyclohexanecarboxylate		C₃₃H₃₆O₄	详情	详情
(XIV)	18770	methyl (1S,2R,3S,6R)-2-hydroxy-6-isopropenyl-3-methyl-3-[2-(trityloxy)ethyl]cyclohexanecarboxylate		C₃₃H₃₈O₄	详情	详情
(XV)	18771	methyl (1S,2R,3S,6R)-6-isopropenyl-2-methoxy-3-methyl-3-[2-(trityloxy)ethyl]cyclohexanecarboxylate		C₃₄H₄₀O₄	详情	详情
(XVI)	18772	[(1R,2R,3S,6R)-6-isopropenyl-2-methoxy-3-methyl-3-[2-(trityloxy)ethyl]cyclohexyl]methanol		C₃₃H₄₀O₃	详情	详情
(XVII)	18773	[(1R,2R,3S,6R)-6-isopropenyl-2-methoxy-3-methyl-3-[2-(trityloxy)ethyl]cyclohexyl]methyl methanesulfonate		C₃₄H₄₂O₅S	详情	详情

合成路线2

Reaction of mesylate (XVII) with triazole sodium salt (XVIII) gave (XIX). Ozonization of olefinic double bond, followed by treatment with Me2S and K2CO3 provided ketone (XX). Then, haloform reaction with NaOBr gave acid (XXI), and reduction with LiAlH4 in cold Et2O afforded primary alcohol (XXII). Alcohol (XXII) was converted to mesylate (XXIII), and this was condensed with 4-(trifluoromethoxy)phenol (XXIV) to give ether (XXV). Deprotection of the trityl group with formic acid in EtOAc and subsequent reaction with methanesulfonyl chloride provided mesylate (XXVI), which was finally condensed with morpholine (XXVII) to furnish the target compound.

参考文献中间体

【1】 Tsukuda, T.; Watanabe, M.; Ontsuka, H.; Hattori, K.; Shirai, M.; Shimma, N.; Synthesis of novel antifungal agents (2). Bioorg Med Chem Lett 1998, 8, 14, 1825.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(XVII)	18762	1-Ethoxyethylene; Ethyl vinyl ether；Ethoxyethene	109-92-2	C₄H₈O	详情	详情
(XVIII)	16341	1H-1,2,4-triazol-1-ylsodium		C₂H₂N₃Na	详情	详情
(XIX)	18775	2-[(1S,2R,3R,4R)-4-isopropenyl-2-methoxy-1-methyl-3-(1H-1,2,4-triazol-1-ylmethyl)cyclohexyl]ethyl trityl ether; 1-([(1R,2R,3S,6R)-6-isopropenyl-2-methoxy-3-methyl-3-[2-(trityloxy)ethyl]cyclohexyl]methyl)-1H-1,2,4-triazole		C₃₅H₄₁N₃O₂	详情	详情
(XX)	18776	1-[(1R,2R,3R,4S)-3-methoxy-4-methyl-2-(1H-1,2,4-triazol-1-ylmethyl)-4-[2-(trityloxy)ethyl]cyclohexyl]-1-ethanone		C₃₄H₃₉N₃O₃	详情	详情
(XXI)	18777	(1R,2R,3R,4S)-3-methoxy-4-methyl-2-(1H-1,2,4-triazol-1-ylmethyl)-4-[2-(trityloxy)ethyl]cyclohexanecarboxylic acid		C₃₃H₃₇N₃O₄	详情	详情
(XXII)	18778	[(1R,2R,3R,4S)-3-methoxy-4-methyl-2-(1H-1,2,4-triazol-1-ylmethyl)-4-[2-(trityloxy)ethyl]cyclohexyl]methanol		C₃₃H₃₉N₃O₃	详情	详情
(XXIII)	18779	[(1R,2R,3R,4S)-3-methoxy-4-methyl-2-(1H-1,2,4-triazol-1-ylmethyl)-4-[2-(trityloxy)ethyl]cyclohexyl]methyl methanesulfonate		C₃₄H₄₁N₃O₅S	详情	详情
(XXIV)	18780	4-(trifluoromethoxy)phenol	828-27-3	C₇H₅F₃O₂	详情	详情
(XXV)	18781	1-([(1R,2R,3S,6R)-2-methoxy-3-methyl-6-[[4-(trifluoromethoxy)phenoxy]methyl]-3-[2-(trityloxy)ethyl]cyclohexyl]methyl)-1H-1,2,4-triazole; 2-((1S,2R,3R,4R)-2-methoxy-1-methyl-3-(1H-1,2,4-triazol-1-ylmethyl)-4-[[4-(trifluoromethoxy)phenoxy]methyl]cyclohexyl)ethyl trityl ether		C₄₀H₄₂F₃N₃O₄	详情	详情
(XXVI)	18782	2-((1S,2R,3R,4R)-2-methoxy-1-methyl-3-(1H-1,2,4-triazol-1-ylmethyl)-4-[[4-(trifluoromethoxy)phenoxy]methyl]cyclohexyl)ethyl methanesulfonate		C₂₂H₃₀F₃N₃O₆S	详情	详情
(XXVII)	10388	Morpholine	110-91-8	C₄H₉NO	详情	详情

Extended Information