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【结 构 式】 
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【分子编号】13002 【品名】4-Phenyl-1,2,3,6-tetrahydropyridine; 1,2,3,6-Tetrahydro-4-phenyl-pyridine 【CA登记号】10338-69-9 |
【 分 子 式 】C11H13N 【 分 子 量 】159.23096 【元素组成】C 82.97% H 8.23% N 8.8% |
合成路线1
该中间体在本合成路线中的序号：(II)The reaction of 4-(3-indolyl)butyric acid (I) with 4-phenyl-3,4-dehydropiperidine (II) by means of carbonyldiimidazole (A) in THF gives 3-[4-oxo-4-(4-phenyl-3,4-dehydro-1-piperidyl)butyl]indole (III), which is reduced with LiAlH4 in THF.
| 【1】 Hausberg, H.H.; Koppe, V.; Poetsch, E.; Saiko, O.; Seyfried, C.; US 4251538 . |
| 【2】 Blancafort, P.; Hillier, K.; Serradell, M.N.; Castaner, J.; EMD-23,448. Drugs Fut 1983, 8, 5, 400. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (A) | 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 |
| (I) | 26532 | Indole-3-butyric acid; 4-(3-Indolyl)butyric acid; 4-(1H-Indol-3-yl)butyric acid | 133-32-4 | C12H13NO2 | 详情 | 详情 |
| (II) | 13002 | 4-Phenyl-1,2,3,6-tetrahydropyridine; 1,2,3,6-Tetrahydro-4-phenyl-pyridine | 10338-69-9 | C11H13N | 详情 | 详情 |
| (III) | 36089 | 4-(1H-indol-3-yl)-1-[4-phenyl-3,6-dihydro-1(2H)-pyridinyl]-1-butanone | C23H24N2O | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(II)By condensation of (II) with 3-(4chlorobutyl)indole (IV) in acetonitrile. Other compounds with Br, I or tosyloxy substituents instead of Cl can also be used in the above mentioned synthesis.
| 【1】 Hausberg, H.H.; Koppe, V.; Poetsch, E.; Saiko, O.; Seyfried, C.; US 4251538 . |
| 【2】 Blancafort, P.; Hillier, K.; Serradell, M.N.; Castaner, J.; EMD-23,448. Drugs Fut 1983, 8, 5, 400. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (IVa) | 36090 | 4-(1H-indol-3-yl)butyl 4-methylbenzenesulfonate | C19H21NO3S | 详情 | 详情 | |
| (IVb) | 36091 | 3-(4-chlorobutyl)-1H-indole | C12H14ClN | 详情 | 详情 | |
| (IVc) | 36092 | 3-(4-bromobutyl)-1H-indole | C12H14BrN | 详情 | 详情 | |
| (IVd) | 36093 | 3-(4-iodobutyl)-1H-indole | C12H14IN | 详情 | 详情 | |
| (II) | 13002 | 4-Phenyl-1,2,3,6-tetrahydropyridine; 1,2,3,6-Tetrahydro-4-phenyl-pyridine | 10338-69-9 | C11H13N | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(IV)By demethylation of 5-methoxy-3-[4-(4-phenyl-1,2,3,6-tetrahydropyridin-1-yl)butyl]-1H-indole (I) with diisobutylaluminum hydride (DBH) in hot toluene. The methylated compound (I) can be obtained by two similar ways: a) By condensation of 3-(4-chlorobutyl)-5-methoxy-1H-indole (II), or 3-(4-bromobutyl)-5-methoxy-1H-indole (III) with 4-phenyl-1,2,3,6-tetrahydropyridine (IV) in acetonitrile at room temperature. b) By condensation of 4-(3-indolyl)butyric acid (V) with 4-phenyl-1,2,3,6-tetrahydropyridine (IV) by means of carbonyldiimdazole (CDI) in THF yielding 1-[4-(3-indolyl)butyryl]-4-phenyl-1,2,3,6-tetrahydropyridine (VI), followed by reduction of the carbonyl group of (VI) with LiAlH4 in THF.
| 【1】 Robinson, C.; Castaner, J.; Roxindole Mesylate. Drugs Fut 1995, 20, 12, 1228. |
| 【2】 Hausberg, H.-H.; Bottcher, H.; Seyfried, C.; Bergmann, R. (Merck Patent GmbH); Use of hydroxyindole derivs. for the preparation of an antihypertensive agent. DE 3419935; EP 0166183; JP 1985258117; US 4711893 . |
| 【3】 Hausberg, H.-H.; Koppe, V.; Poetsch, E.; Saiko, O.; Seyfried, C. (Merck Patent GmbH); Indolalkylamines, pharmaceutical compsns. containing them and process for their preparation. EP 0007399 . |
| 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) | 12999 | 5-Methoxy-3-[4-[4-phenyl-3,6-dihydro-1(2H)-pyridinyl]butyl]-1H-indole; Methyl 3-[4-[4-phenyl-3,6-dihydro-1(2H)-pyridinyl]butyl]-1H-indol-5-yl ether | C24H28N2O | 详情 | 详情 | |
| (II) | 13000 | 3-(4-Chlorobutyl)-1H-indol-5-yl methyl ether; 3-(4-Chlorobutyl)-5-methoxy-1H-indole | C13H16ClNO | 详情 | 详情 | |
| (III) | 13001 | 3-(4-Bromobutyl)-1H-indol-5-yl methyl ether; 3-(4-Bromobutyl)-5-methoxy-1H-indole | C13H16BrNO | 详情 | 详情 | |
| (IV) | 13002 | 4-Phenyl-1,2,3,6-tetrahydropyridine; 1,2,3,6-Tetrahydro-4-phenyl-pyridine | 10338-69-9 | C11H13N | 详情 | 详情 |
| (V) | 13003 | 4-(5-Methoxy-1H-indol-3-yl)butyric acid | C13H15NO3 | 详情 | 详情 | |
| (VI) | 13004 | 4-(5-Methoxy-1H-indol-3-yl)-1-[4-phenyl-3,6-dihydro-1(2H)-pyridinyl]-1-butanone | C24H26N2O2 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(IV)A new synthesis of roxindole has been described: The condensation of 5-methoxyindole (I) with succinic anhydride (II) by means of methylmagnesium bromide in hot anisole gives the 4-oxobutyric acid derivative (III), which is condensed with the 4-phenyltetrahydropyridine (IV) by means of EDC and DIPEA in DMF yielding the butanedione (V). The reduction of (V) with LiAlH4 in refluxing THF affords intermediate (VI), which is finally demethylated with DIBAH in refluxing toluene.
| 【1】 Lange, J.H.M.; et al.; A straightforward synthetic approach for roxindole. Bioorg Med Chem Lett 1999, 9, 7, 1055. |
| 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) | 25902 | 1H-Indol-5-yl methyl ether; 5-Methoxy-1H-indole; 5-Methoxyindole | 1006-94-6 | C9H9NO | 详情 | 详情 |
| (II) | 11291 | Dihydro-2,5-furandione; Succinic anhydride | 108-30-5 | C4H4O3 | 详情 | 详情 |
| (III) | 30614 | 4-(5-methoxy-1H-indol-3-yl)-4-oxobutyric acid | C13H13NO4 | 详情 | 详情 | |
| (IV) | 13002 | 4-Phenyl-1,2,3,6-tetrahydropyridine; 1,2,3,6-Tetrahydro-4-phenyl-pyridine | 10338-69-9 | C11H13N | 详情 | 详情 |
| (V) | 30615 | 1-(5-methoxy-1H-indol-3-yl)-4-[4-phenyl-3,6-dihydro-1(2H)-pyridinyl]-1,4-butanedione | C24H24N2O3 | 详情 | 详情 | |
| (VI) | 12999 | 5-Methoxy-3-[4-[4-phenyl-3,6-dihydro-1(2H)-pyridinyl]butyl]-1H-indole; Methyl 3-[4-[4-phenyl-3,6-dihydro-1(2H)-pyridinyl]butyl]-1H-indol-5-yl ether | C24H28N2O | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(V)Ethyl 3-oxocyclohexanecarboxylate (I) was protected as the ethylene ketal (II) and its ethyl ester group was subsequently hydrolyzed to carboxylic acid (III). After activation of acid (III) as the mixed anhydride (IV) with isobutyl chloroformate, coupling with 4-phenyl-1,2,3,6-tetrahydropyridine (V) gave amide (VI). Reduction of amide (VI) to the corresponding amine (VII) was accomplished by treatment with LiAlH4 in the presence of AlCl3. Addition of phenylmagnesium bromide to the ketone (VIII), obtained by acidic hydrolysis of ketal (VII), provided the tertiary alcohol (IX). Dehydration of alcohol (IX) by means of trifluoroacetic acid gave rise to a mixture of isomeric cyclohexene derivatives (X) and (XI), which were separated by column chromatography. The racemic 3-cyclohexenyl isomer (XI) was then resolved via formation of the salts with (R)-1,1'-binaphthyl-2,2'-diyl hydrogen phosphate to furnish the title (R)-(+)-enantiomer.
| 【1】 Caprathe, B.W.; Downing, D.M.; Jaen, J.C.; Johnson, S.J.; Smith, W.J. III; Wise, L.D.; Wright, J.; Wustrow, D.J. (Pfizer Inc.); 1,3-Substd. cycloalkenes and cycloalkanes as central nervous system agents. EP 0545095; EP 0613465; JP 1995501075; US 5314896; WO 9310092 . |
| 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) | 54933 | ethyl 3-oxocyclohexanecarboxylate | C9H14O3 | 详情 | 详情 | |
| (II) | 54934 | ethyl 1,4-dioxaspiro[4.5]decane-7-carboxylate | C11H18O4 | 详情 | 详情 | |
| (III) | 54935 | 1,4-dioxaspiro[4.5]decane-7-carboxylic acid | C9H14O4 | 详情 | 详情 | |
| (IV) | 54936 | C14H22O6 | 详情 | 详情 | ||
| (V) | 13002 | 4-Phenyl-1,2,3,6-tetrahydropyridine; 1,2,3,6-Tetrahydro-4-phenyl-pyridine | 10338-69-9 | C11H13N | 详情 | 详情 |
| (VI) | 54937 | 1,4-dioxaspiro[4.5]dec-7-yl[4-phenyl-3,6-dihydro-1(2H)-pyridinyl]methanone | n/a | C20H25NO3 | 详情 | 详情 |
| (VII) | 54938 | 1-(1,4-dioxaspiro[4.5]dec-7-ylmethyl)-4-phenyl-1,2,3,6-tetrahydropyridine | C20H27NO2 | 详情 | 详情 | |
| (VIII) | 54939 | 3-{[4-phenyl-3,6-dihydro-1(2H)-pyridinyl]methyl}cyclohexanone | C18H23NO | 详情 | 详情 | |
| (IX) | 54940 | 1-phenyl-3-{[4-phenyl-3,6-dihydro-1(2H)-pyridinyl]methyl}cyclohexanol | C24H29NO | 详情 | 详情 | |
| (X) | 54941 | 4-phenyl-1-[(3-phenyl-2-cyclohexen-1-yl)methyl]-1,2,3,6-tetrahydropyridine | C24H27N | 详情 | 详情 | |
| (XI) | 54942 | 4-phenyl-1-[(3-phenyl-3-cyclohexen-1-yl)methyl]-1,2,3,6-tetrahydropyridine | C24H27N | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(II)Racemic amide (VI) was also prepared by a closely related procedure. Coupling of keto acid (XII) with tetrahydropyridine (V) using DCC gave keto amide (XIII), which was then protected as the ethylene ketal (VI) upon treatment with 2-methoxy-1,3-dioxolane (XIV) in the presence of methanesulfonic acid.
| 【1】 Wright, J.L.; et al.; The discovery and structure-activity relationships of 1,2,3, 6-tetrahydro-4-phenyl-1-[(arylcyclohexenyl)alkyl]pyridines. Dopamine autoreceptor agonists and potential antipsychotic agents. J Med Chem 1994, 37, 21, 3523. |
| 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) | 54943 | 3-oxocyclohexanecarboxylic acid | C7H10O3 | 详情 | 详情 | |
| (II) | 13002 | 4-Phenyl-1,2,3,6-tetrahydropyridine; 1,2,3,6-Tetrahydro-4-phenyl-pyridine | 10338-69-9 | C11H13N | 详情 | 详情 |
| (III) | 54944 | 3-{[4-phenyl-3,6-dihydro-1(2H)-pyridinyl]carbonyl}cyclohexanone | C18H21NO2 | 详情 | 详情 | |
| (IV) | 54945 | 2-Methoxy-1,3-dioxolane | 19693-75-5 | C4H8O3 | 详情 | 详情 |
| (V) | 54957 | 3-(4-morpholinyl)-1-propanol | C7H15NO2 | 详情 | 详情 |
合成路线7
该中间体在本合成路线中的序号：(V)The analogous asymmetric synthesis starting from the (R)-enantiomer of 3-oxocyclohexanecarboxylic acid (XV) was also reported. The chiral (R)-keto acid (XV), prepared by resolution of the racemic acid (XII) with brucine, was coupled with tetrahydropyridine (V) to give keto amide (XVI). Protection as the ethylene ketal (XVII), followed by amide reduction and acidic ketal hydrolysis, furnished the (R)-amino ketone (XVIII). This was converted into the title compound by addition of phenylmagnesium bromide, followed by acidic dehydration and separation of isomers as in Scheme 19758501a.
| 【1】 Wright, J.L.; et al.; The discovery and structure-activity relationships of 1,2,3, 6-tetrahydro-4-phenyl-1-[(arylcyclohexenyl)alkyl]pyridines. Dopamine autoreceptor agonists and potential antipsychotic agents. J Med Chem 1994, 37, 21, 3523. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (V) | 13002 | 4-Phenyl-1,2,3,6-tetrahydropyridine; 1,2,3,6-Tetrahydro-4-phenyl-pyridine | 10338-69-9 | C11H13N | 详情 | 详情 |
| (XII) | 54943 | 3-oxocyclohexanecarboxylic acid | C7H10O3 | 详情 | 详情 | |
| (XIV) | 54948 | (7R)-1,4-dioxaspiro[4.5]dec-7-yl[4-phenyl-3,6-dihydro-1(2H)-pyridinyl]methanone | C20H25NO3 | 详情 | 详情 | |
| (XV) | 54946 | (1R)-3-oxocyclohexanecarboxylic acid | C7H10O3 | 详情 | 详情 | |
| (XVI) | 54947 | (3R)-3-{[4-phenyl-3,6-dihydro-1(2H)-pyridinyl]carbonyl}cyclohexanone | C18H21NO2 | 详情 | 详情 | |
| (XVII) | 54948 | (7R)-1,4-dioxaspiro[4.5]dec-7-yl[4-phenyl-3,6-dihydro-1(2H)-pyridinyl]methanone | C20H25NO3 | 详情 | 详情 | |
| (XVIII) | 54949 | (3R)-3-{[4-phenyl-3,6-dihydro-1(2H)-pyridinyl]methyl}cyclohexanone | C18H23NO | 详情 | 详情 |
合成路线8
该中间体在本合成路线中的序号：(V)A further procedure employed the chiral keto acid (XXII) as the key intermediate. The cyclohexenone carboxylic acid (XXI) was synthesized via aldol condensation between 3-benzoylacrylic acid (XIX) and ethyl acetoacetate (XX), followed by cyclization and decarboxylation under Robinson annulation reaction conditions. Resolution of (XXI) to furnish the desired (S)-enantiomer (XXII) was accomplished either via formation of the diastereomeric salts with cinchonidine or, alternatively, by esterification of (XXI) with n-butanol --yielding the isomeric mixture (XXIII)--, followed by enantioselective hydrolysis of the (S)-butyl ester from in the presence of alpha-chymotrypsin. Coupling of keto acid (XXII) with tetrahydropyridine (V) provided keto amide (XXIV). The keto group of (XXIV) was then reduced with NaBH4 to form a diastereomeric mixture of allylic alcohols (XXV), which were further reduced employing NaBH3CN in the presence of ZnCl2 to furnish the target (R)-cyclohexenecarboxamide (XXVI). The amide function of (XXVI) was finally reduced to the title amine by means of LiAlH4 in methyl tert-butyl ether.
| 【1】 Butler, D.E.; Wustrow, D.J.; Smith, W.J. III; Gailey, J. (Pfizer Inc.); Improved process for R (+) 1,2,3,6-tetrahydro-4-phenyl-1-[(3-phenyl-3-cyclohexen-1-yl)methyl]pyridine, a central nervous system agent. WO 9608473 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (V) | 13002 | 4-Phenyl-1,2,3,6-tetrahydropyridine; 1,2,3,6-Tetrahydro-4-phenyl-pyridine | 10338-69-9 | C11H13N | 详情 | 详情 |
| (XIX) | 28661 | (E)-4-oxo-4-phenyl-2-butenoic acid | 583-06-2 | C10H8O3 | 详情 | 详情 |
| (XX) | 11819 | ethyl acetoacetate; ethyl 3-oxobutanoate；Acetoacetic ester;Ethyl beta-ketobutyrate;ethyl 3-oxobutyrate | 141-97-9 | C6H10O3 | 详情 | 详情 |
| (XXI) | 54950 | 5-oxo-3-phenyl-3-cyclohexene-1-carboxylic acid | C13H12O3 | 详情 | 详情 | |
| (XXII) | 54952 | (1S)-5-oxo-3-phenyl-3-cyclohexene-1-carboxylic acid | C13H12O3 | 详情 | 详情 | |
| (XXIII) | 54951 | butyl 5-oxo-3-phenyl-3-cyclohexene-1-carboxylate | C17H20O3 | 详情 | 详情 | |
| (XXIV) | 54953 | (5S)-3-phenyl-5-{[4-phenyl-3,6-dihydro-1(2H)-pyridinyl]carbonyl}-2-cyclohexen-1-one | C24H23NO2 | 详情 | 详情 | |
| (XXV) | 54954 | [(1S)-5-hydroxy-3-phenyl-3-cyclohexen-1-yl][4-phenyl-3,6-dihydro-1(2H)-pyridinyl]methanone | C24H25NO2 | 详情 | 详情 | |
| (XXVI) | 50955 | 2-[7-fluoro-4-(2-hydroxyethyl)-2-oxo-1(2H)-quinolinyl]acetamide | C13H13FN2O3 | 详情 | 详情 |
合成路线9
该中间体在本合成路线中的序号：(V)Swern oxidation of 4-hydroxypiperidine-1-carboxylic acid tert-butyl ester (I) with oxalyl chloride in DMSO/dichloromethane gives the corresponding piperidone (II), which is submitted to a Grignard reaction with [U-14C]phenylmagnesium bromide (III) in THF to yield 4-hydroxy-4-phenylpiperidine-1-carboxylic acid tert-butyl ester (IV). The reaction of (IV) with BF3/Et2O in dichloromethane affords labeled 4-phenyl-1,2,3,6-tetrahydropyridine (V), which is condensed with 3-phenyl-3-cyclohexene-1(R)-carboxylic acid (VI) by means of HOBT, DCC and TEA in ethyl acetate to provide the labeled 1-(3-phenyl-3-cyclohexen-1(R)-yl)-1-(4-phenyl-1,2,3,6-tetrahydropyridin-1-yl)methanone (VII). Finally, this compound is reduced with LiAlH4 and AlCl3 in THF to obtain the target tetrahydropyridine derivative.
| 【1】 Ekhato, I.V.; Huang, C.C.; Synthesis of (R)-(+)-1,2,3,6-tetrahydro-4-[U-14C]phenyl-1[(3-phenyl-3-cyclohexenyl-1-yl)methyl]pyridine, a potential antipsychotic agent. J Label Compd Radiopharm 1995, 36, 1, 57. |
| 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) | 18625 | tert-butyl 4-hydroxy-1-piperidinecarboxylate | C10H19NO3 | 详情 | 详情 | |
| (II) | 18620 | tert-butyl 4-oxo-1-piperidinecarboxylate;BOC-Piperidone;N-(tert-Butoxycarbonyl)-4-piperidone; N-Boc-4-piperidone | 79099-07-3 | C10H17NO3 | 详情 | 详情 |
| (II) | 45167 | C6H5BrMg | 详情 | 详情 | ||
| (III) | 17616 | bromo(phenyl)magnesium; Phenyl Magnesium Bromide | 100-58-3 | C6H5BrMg | 详情 | 详情 |
| (IV) | 57878 | tert-butyl 4-hydroxy-4-phenyl-1-piperidinecarboxylate | C16H23NO3 | 详情 | 详情 | |
| (IV) | 64702 | tert-butyl 4-hydroxy-4-phenyl-1-piperidinecarboxylate | C16H23NO3 | 详情 | 详情 | |
| (V) | 13002 | 4-Phenyl-1,2,3,6-tetrahydropyridine; 1,2,3,6-Tetrahydro-4-phenyl-pyridine | 10338-69-9 | C11H13N | 详情 | 详情 |
| (V) | 64703 | 4-Phenyl-1,2,3,6-tetrahydro-pyridine | 10338-69-9 | C11H13N | 详情 | 详情 |
| (VI) | 57879 | (1R)-3-phenyl-3-cyclohexene-1-carboxylic acid | C13H14O2 | 详情 | 详情 | |
| (VII) | 54955 | [(1R)-3-phenyl-3-cyclohexen-1-yl][4-phenyl-3,6-dihydro-1(2H)-pyridinyl]methanone | C24H25NO | 详情 | 详情 | |
| (VII) | 64704 | [(1R)-3-phenyl-3-cyclohexen-1-yl][4-phenyl-3,6-dihydro-1(2H)-pyridinyl]methanone | C24H25NO | 详情 | 详情 |