4-oxocyclohexyl benzoate -Drug Synthesis Database

【结构式】

【分子编号】16767

【品名】4-oxocyclohexyl benzoate

【CA登记号】

【分子式】C₁₃H₁₄O₃

【分子量】218.25236

【元素组成】C 71.54% H 6.47% O 21.99%

与该中间体有关的原料药合成路线共 2 条

合成路线1 合成路线2

合成路线1

该中间体在本合成路线中的序号：(I)

The cyclization of 4-benzoyloxycyclohexanone (I) with ethyl 2-bromomethylacrylate (II) and propylamine (III) in refluxing toluene gives ethyl 1-propyl-6-benzoyloxy-1,2,3,4,5,6,7,8-octahydroquinoline-3-carboxylate (IV), which is reduced with sodium cyanoborohydride in methanol yielding the corresponding decahydro derivative (V). Debenzoylation of (V) with NaOH in methanol affords the hydroxyquinoline (VI), which is oxidized with CrO3-pyr giving ethyl 1-propyl-6-oxodecahydroquinoline-3-carboxylate (VII). The reaction of (VII) with dimethylformamide dimethylacetal (VIII) in refluxing toluene yields ethyl 1-propyl-6-oxo-7-(dimethylaminomethylene)decahydroquinoline-3-carboxylate (IX), which is cyclized with hydrazine in ethanol affording ethyl 5-propyl-4,4a,5,6,7,8,8a,9-octahydro-2H-pyrazolo[3,4-g]quinoline-7-carboxylic acid (X). The reduction of (X) with LiAlH4 in THF gives the corresponding hydroxymethyl derivative (XI), which is esterified with methanesulfonyl chloride to the mesyl ester (XII). Finally, this compound is treated with methyl mercaptane and NaH in DMF.

参考文献中间体

合成目标

【1】 Bach, N.; Kornfeld, E.C. (Eli Lilly and Company); Prolactin inhibiting octahydropyrazolo[3,4-g]quinolines. DD 148517; EP 0013787; ES 482087; FR 2446820; FR 2446821; FR 2446822; GB 2040915; GB 2092579; US 4198415 .
【2】 Nohria, Y.; Castaner, J.; Serradell, M.N.; Blancafort, P.; LY-141,865. Drugs Fut 1983, 8, 10, 858.

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)	16767	4-oxocyclohexyl benzoate		C₁₃H₁₄O₃	详情	详情
(II)	11328	ethyl 2-(bromomethyl)acrylate	17435-72-2	C₆H₉BrO₂	详情	详情
(III)	23923	1-propanamine	107-10-8	C₃H₉N	详情	详情
(IV)	36234	ethyl 6-(benzoyloxy)-1-propyl-1,2,3,4,5,6,7,8-octahydro-3-quinolinecarboxylate		C₂₂H₂₉NO₄	详情	详情
(V)	36235	ethyl (4aR,8aR)-6-(benzoyloxy)-1-propyldecahydro-3-quinolinecarboxylate		C₂₂H₃₁NO₄	详情	详情
(VI)	36236	ethyl (4aR,8aR)-6-hydroxy-1-propyldecahydro-3-quinolinecarboxylate		C₁₅H₂₇NO₃	详情	详情
(VII)	36237	ethyl (4aR,8aR)-6-oxo-1-propyldecahydro-3-quinolinecarboxylate		C₁₅H₂₅NO₃	详情	详情
(VIII)	11984	N-(Dimethoxymethyl)-N,N-dimethylamine;dimethylformamide dimethylacetal;1,1-dimethoxy-N,N-dimethylmethanamine； Dimethoxy-N,N-dimethylmethanamine; N,N-Dimethylformamide dimethyl acetal	4637-24-5	C₅H₁₃NO₂	详情	详情
(IX)	36238	ethyl (4aR,8aR)-7-[(Z)-(dimethylamino)methylidene]-6-oxo-1-propyloctahydro-3(1H)-quinolinecarboxylate		C₁₈H₃₀N₂O₃	详情	详情
(X)	36239	ethyl (4aR,8aR)-5-propyl-4,4a,5,6,7,8,8a,9-octahydro-2H-pyrazolo[3,4-g]quinoline-7-carboxylate		C₁₆H₂₅N₃O₂	详情	详情
(XI)	36240	[(4aR,8aR)-5-propyl-4,4a,5,6,7,8,8a,9-octahydro-2H-pyrazolo[3,4-g]quinolin-7-yl]methanol		C₁₄H₂₃N₃O	详情	详情
(XII)	36241	[(4aR,8aR)-5-propyl-4,4a,5,6,7,8,8a,9-octahydro-2H-pyrazolo[3,4-g]quinolin-7-yl]methyl methyl sulfone; (4aR,8aR)-7-[(methylsulfonyl)methyl]-5-propyl-4,4a,5,6,7,8,8a,9-octahydro-2H-pyrazolo[3,4-g]quinoline		C₁₅H₂₅N₃O₂S	详情	详情

合成路线2

该中间体在本合成路线中的序号：(II)

1) The cyclization of 4-hydrazinobenzonitrile (I) with 4-(benzoyloxy)cyclohexanone (II) in refluxing acetic acid gives 3-(benzoyloxy)-1,2,3,4-tetrahydro-9H-carbazole-6-carbonitrile (III), which is hydrolyzed with aqueous KOH to the corresponding alcohol (IV). The tosylation of (IV) with tosyl chloride in pyridine yields the tosylate (V), which by treatment with methylamine in hot ethanol is converted into 3-(methylamino)-1,2,3,4-tetrahydro-9H-carbazole-6-carbonitrile (VI). The partial hydrolysis of the nitrile group with NaOH/H2O2, with previous protection of the amino group with di-tert-butyl dicarbonate, affords 3-(methylamino)-1,2,3,4-tetrahydro-9H-carbazole-6-carboxamide (VII) as a racemic mixture. The reaction of (VII) with di-tert-butyl dicarbonate gives the carbamate (VIII), which is submitted to chiral HPLC in hexane/ethanol giving the (R)-isomer (IX). Finally, this carbamate is hydrolyzed with aqueous HCl/methanol. 2) The optical resolution can also be performed with the benzoyloxycarbonyl derivative of (VII) in a similar way. 3) The optical resolution of (VII) can also be performed directly with (1S)-(+)-camphorsulfonic acid in methanol. 4) The reaction of cyclohexane-1,4-dione mono 2,2-dimethyltrimethylene ketal (X) with methylamine in toluene gives the corresponding methylimine (XI), which is reduced with H2 over Pd/C in ethanol to the expected methylamine (XII). Finally, this compound is cyclized with 4-aminobenzamide (XIII) by treatment first with NaNO2/HCl and then with sodium dithionite affording the racemic mixture (VII) already described.

参考文献中间体

合成目标

【1】 Graul, A.; Leeson, P.; Castañer, J.; SB-209509/VML-251. Drugs Fut 1997, 22, 7, 725.
【2】 King, F.D.; Gaster, L.M.; Kaumann, A.J.; Young, R.C. (SmithKline Beecham plc); Use of tetrahydrocarbazole derivs. as 5HT1 receptor agonists. EP 0591280; JP 1994508827; US 5464864; US 5827871; WO 9300086 .
【3】 Borrett, G.T.; Kitteringham, J.; Porter, R.A.; Shipton, M.R.; Vimal, M.; Young, R.C. (SmithKline Beecham plc); Enantiomers of carbazole derivs. as 5-HT1-like agonists. EP 0674621; JP 1996504790; US 5650426; US 5962501; WO 9414772 .
【4】 King, F.D.; Gaster, L.M.; Kuamann, A.J.; Young, R.C. (SmithKline Beecham plc); Tetrahydrocarbazole derivs. for the manufacture of a medicament for the treatment of a disease where a 5-HT1-like agonist is indicated. EP 0603432 .

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)	16766	4-hydrazinobenzonitrile		C₇H₇N₃	详情	详情
(II)	16767	4-oxocyclohexyl benzoate		C₁₃H₁₄O₃	详情	详情
(III)	16768	6-cyano-2,3,4,9-tetrahydro-1H-carbazol-3-yl benzoate		C₂₀H₁₆N₂O₂	详情	详情
(IV)	16769	3-hydroxy-2,3,4,9-tetrahydro-1H-carbazole-6-carbonitrile		C₁₃H₁₂N₂O	详情	详情
(V)	16770	6-cyano-2,3,4,9-tetrahydro-1H-carbazol-3-yl 4-methylbenzenesulfonate		C₂₀H₁₈N₂O₃S	详情	详情
(VI)	16771	3-(methylamino)-2,3,4,9-tetrahydro-1H-carbazole-6-carbonitrile		C₁₄H₁₅N₃	详情	详情
(VII)	16772	3-(methylamino)-2,3,4,9-tetrahydro-1H-carbazole-6-carboxamide		C₁₄H₁₇N₃O	详情	详情
(VIII)	16773	tert-butyl N-[6-(aminocarbonyl)-2,3,4,9-tetrahydro-1H-carbazol-3-yl]-N-methylcarbamate		C₁₉H₂₅N₃O₃	详情	详情
(IX)	16774	tert-butyl N-[(3R)-6-(aminocarbonyl)-2,3,4,9-tetrahydro-1H-carbazol-3-yl]-N-methylcarbamate		C₁₉H₂₅N₃O₃	详情	详情
(X)	16775	3,3-Dimethyl-1,5-dioxaspiro[5.5]undecan-9-one; 1,4-Cyclohexanedione mono-2,2-dimethyltrimethylene ketal	69225-59-8	C₁₁H₁₈O₃	详情	详情
(XI)	16776	N-(3,3-dimethyl-1,5-dioxaspiro[5.5]undec-9-ylidene)-N-methylamine; N-(3,3-dimethyl-1,5-dioxaspiro[5.5]undec-9-ylidene)methanamine		C₁₂H₂₁NO₂	详情	详情
(XII)	16777	N,3,3-trimethyl-1,5-dioxaspiro[5.5]undecan-9-amine; N-(3,3-dimethyl-1,5-dioxaspiro[5.5]undec-9-yl)-N-methylamine		C₁₂H₂₃NO₂	详情	详情
(XIII)	16778	4-aminobenzamide; p-aminobenzamide	2835-68-9	C₇H₈N₂O	详情	详情

Extended Information