AZD-0947, ZD-0947, -Drug Synthesis Database

【结构式】

【药物名称】AZD-0947, ZD-0947

【化学名称】(-)-3-[5-Oxo-2-(trifluoromethyl)-1,4,5,6,7,8-hexahydroquinolin-4(S)-yl]benzonitrile

【CA登记号】172649-40-0, 159208-31-8 (undefined stereoch.)

【分子式】C₁₇H₁₃F₃N₂O

【分子量】318.30116

【开发单位】AstraZeneca (Originator)

【药理作用】RENAL-UROLOGIC DRUGS, Urinary Incontinence Therapy, K(ATP) Channel Activators

合成路线1 合成路线2 合成路线3

合成路线1

The reaction of trifluoroacetoacetic acid ethyl ester (I) with (?)-isoborneol (II) at 130 C gives the corresponding isobornyl ester (III), which is condensed with cyclohexane-1,3-dione (IV) and 3-cyanobenzaldehyde (V) by means of ammonium acetate in refluxing ethanol to yield the octahydroquinolone (VI). The hydrolysis of the ester group of (VI), with simultaneous dehydration by means of TsOH in refluxing toluene affords 4-(3-cyanophenyl)-5-oxo-2-(trifluoromethyl)-1,4,5,6,7,8-hexahydroquinoline-3-carboxylic acid (VII) as a racemic mixture. Optical resolution of (VII) through the diastereomeric salt with 1(S)-phenylethylamine (VIII) in toluene/butanol provides the desired isomer (IX), which is finally decarboxylated in N-methyl-2-pyrrolidone at 210 C to furnish the target hexahydroquinolone.

参考文献中间体

【1】 Ashworth, I.; Hopes, P.; Levin, D.; Patel, I.; Salloo, R.; An asymmetric synthesis of a 4-substituted-1,4-dihydropyridine. Tetrahedron Lett 2002, 43, 28, 4931.
【2】 Warawa, J.E.; Ohnmacht, C.J. Jr.; Trainor, D.A.; Hulsizer, J.M. (AstraZeneca plc); Quinolone deriv. for treatment of urinary incontinence. EP 0755382; JP 1997512254; WO 9528388 .

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)	62025	propyl 4,4,4-trifluoro-3-oxobutanoate		C₇H₉F₃O₃	详情	详情
(II)	62026	(1R)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-ol		C₁₀H₁₈O	详情	详情
(III)	62027	(1R)-1,7,7-trimethylbicyclo[2.2.1]hept-2-yl 4,4,4-trifluoro-3-oxobutanoate		C₁₄H₁₉F₃O₃	详情	详情
(IV)	11244	1,3-Cyclohexanedione	504-02-9	C₆H₈O₂	详情	详情
(V)	13245	3-Formylbenzonitrile; 3-Cyanobenzaldehyde	24964-64-5	C₈H₅NO	详情	详情
(VI)	62028	(1R)-1,7,7-trimethylbicyclo[2.2.1]hept-2-yl 4-(3-cyanophenyl)-2-hydroxy-5-oxo-2-(trifluoromethyl)-1,2,3,4,5,6,7,8-octahydro-3-quinolinecarboxylate		C₂₈H₃₁F₃N₂O₄	详情	详情
(VII)	62029	4-(3-cyanophenyl)-5-oxo-2-(trifluoromethyl)-1,4,5,6,7,8-hexahydro-3-quinolinecarboxylic acid		C₁₈H₁₃F₃N₂O₃	详情	详情
(VIII)	10039	(1R)-1-Phenylethylamine; (1R)-1-Phenyl-1-ethanamine.; L-alpha-Phenylethylamine	3886-69-9	C₈H₁₁N	详情	详情
(IX)	62030	(4S)-4-(3-cyanophenyl)-5-oxo-2-(trifluoromethyl)-1,4,5,6,7,8-hexahydro-3-quinolinecarboxylic acid		C₁₈H₁₃F₃N₂O₃	详情	详情

合成路线2

The condensation of 3-cyanobenzaldehyde (I) with trifluoroacetone (II) in piperidine gives 3-(4,4,4-trifluoro-3-oxo-2-butenyl)benzonitrile (III). The condensation of cyclohexane-1,3-dione (IV) with 1(R)-phenylethylamine (V) in refluxing toluene or THF yields the secondary enamine (VI), which is condensed with benzonitrile (III) by means of Tms-Cl in hot acetonitrile to afford the chiral adduct (VII). The cyclization of (VII) by means of NH3 in hot acetonitrile provides the chiral octahydroquinolone (VIII), which is finally dehydrated by means of TFA, MsOH, TsOH or HCl in refluxing acetonitrile to give the target hexahydroquinolone.

参考文献中间体

【1】 Patel, I.; Hopes, P. (AstraZeneca AB); Process for synthesis of alpha,beta-unsaturated ketones. WO 0210103 .
【2】 Patel, I.; Ashworth, I.; Levin, D. (AstraZeneca AB); Process for asymmetric synthesis of substd. 1,4-dihydropyridines. WO 0210134 .

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)	13245	3-Formylbenzonitrile; 3-Cyanobenzaldehyde	24964-64-5	C₈H₅NO	详情	详情
(II)	35450	3,3-dibromo-1,1,1-trifluoroacetone	431-67-4	C₃HBr₂F₃O	详情	详情
(III)	62031	3-[(E)-4,4,4-trifluoro-3-oxo-1-butenyl]benzonitrile		C₁₁H₆F₃NO	详情	详情
(IV)	11244	1,3-Cyclohexanedione	504-02-9	C₆H₈O₂	详情	详情
(V)	10039	(1R)-1-Phenylethylamine; (1R)-1-Phenyl-1-ethanamine.; L-alpha-Phenylethylamine	3886-69-9	C₈H₁₁N	详情	详情
(VI)	62032	3-{[(1R)-1-phenylethyl]amino}-2-cyclohexen-1-one		C₁₄H₁₇NO	详情	详情
(VII)	62033	3-[(1S)-4,4-dimethyl-3-oxo-1-(6-oxo-2-{[(1R)-1-phenylethyl]amino}-1-cyclohexen-1-yl)pentyl]benzonitrile		C₂₈H₃₂N₂O₂	详情	详情
(VIII)	62034	3-[(4S)-2-hydroxy-5-oxo-2-(trifluoromethyl)-1,2,3,4,5,6,7,8-octahydro-4-quinolinyl]benzonitrile		C₁₇H₁₅F₃N₂O₂	详情	详情

合成路线3

The condensation of trifluoroacetoacetic acid ethyl ester (I) with cyclohexane-1,3-dione (II) and 3-cyanobenzaldehyde (III) by means of ammonium acetate in refluxing ethanol gives the octahydroquinolone (IV), which is hydrolyzed at its ester group by means of LiOH in hot ethanol/water to yield the corresponding carboxylic acid (V). Finally, this compound is dehydrated by means of TsOH in refluxing toluene to afford the target intermediate (rac)-4-(3-cyanophenyl)-5-oxo-2-(trifluoromethyl)-1,4,5,6,7,8-hexahydroquinoline-3-carboxylic acid (VI).

参考文献中间体

【1】 Ohnmacht, C.J.; Trainor, D.A.; Forst, J.M.; Stein, M.M.; Harris, R.J. (AstraZeneca plc); Quinolone and acridinone derivs. for the treatment of urinary incontinence. EP 0665834; JP 1996502282; US 5622964; WO 9408966 .

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)	62025	propyl 4,4,4-trifluoro-3-oxobutanoate		C₇H₉F₃O₃	详情	详情
(II)	11244	1,3-Cyclohexanedione	504-02-9	C₆H₈O₂	详情	详情
(III)	13245	3-Formylbenzonitrile; 3-Cyanobenzaldehyde	24964-64-5	C₈H₅NO	详情	详情
(IV)	62035	propyl 4-(3-cyanophenyl)-2-hydroxy-5-oxo-2-(trifluoromethyl)-1,2,3,4,5,6,7,8-octahydro-3-quinolinecarboxylate		C₂₁H₂₁F₃N₂O₄	详情	详情
(V)	62036	4-(3-cyanophenyl)-2-hydroxy-5-oxo-2-(trifluoromethyl)-1,2,3,4,5,6,7,8-octahydro-3-quinolinecarboxylic acid		C₁₈H₁₅F₃N₂O₄	详情	详情
(VI)	62029	4-(3-cyanophenyl)-5-oxo-2-(trifluoromethyl)-1,4,5,6,7,8-hexahydro-3-quinolinecarboxylic acid		C₁₈H₁₃F₃N₂O₃	详情	详情

Extended Information

Drug NewChemical Entity Original Patent(1)