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【结 构 式】 
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【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% |
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.
| 【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.
| 【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 |