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【结 构 式】 
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【分子编号】16984 【品名】(3S)-1-azabicyclo[2.2.2]octan-3-amine; 1-aza-Bicyclo[2.2.2]oct-3-ylamine; (3S)-1-azabicyclo[2.2.2]oct-3-ylamine 【CA登记号】120570-05-0 |
【 分 子 式 】C7H14N2 【 分 子 量 】126.20164 【元素组成】C 66.62% H 11.18% N 22.2% |
合成路线1
该中间体在本合成路线中的序号：(III)RS-25259-197 can be obtained by several related ways: 1) The condensation of naphthalene-1,8-dicarboxylic anhydride (I) or the corresponding imide (II) with quinuclidin-3(S)-amine (III) in refluxing isopropanol gives 2-[3(S)-quinuclidinyl]-2,3-dihydro-1H-benz[de]isoquinoline-1,3-dione (IV), which by hydrogenation with H2 over PtO2 in ethanol yields 3-hydroxy-2-[3(S)-quinuclidinyl]-2,3,3a,4,5,6-hexahydro-1H-benz[de]isoquionlin-1-one (V). The dehydration of (V) with HCl in refluxing isopropanol affords the 2,4,5,6-tetrahydro compound (VI) (1), which is finally hydrogenated with H2 over Pd/C in acetic acid to yield a mixture of (S,S)- and (R,S)-diastereomers that is resolved by crystallization and chromatography. 2) The partial hydrogenation of anhydride (I) with H2 over Pd/C in hot acetic acid gives 3-acetoxy-5,6-dihydro-1H,4H-naphtho[1,8-cd]pyran-1-one (VIII), which is deacetylated by hydrogenation with H2 over Pd/C in ethyl acetate, yielding 5,6-dihydro-1H,4H-naphtho[1,8-cd]pyran-1-one (IX). Finally, this compound is condensed with the quinuclidine (III) by heating at 140 C and digestion with methanol to afford the hydroxy compound (V), already obtained. 3) The cyclization of N-[3(S)-quinuclidinyl]-5,6,7,8-tetrahydronaphthalene-2-carboxamide (X) by means of butyllithium and DMF gives the 2,4,5,6-tetrahydro compound (VI), already obtained.
| 【1】 Clark, R.D.; Miller, A.B.; Berger, J.; et al.; 2-(Quinuclidin-3-yl)pyrido[4,3-b]indol-1-ones and isoquinolin-1-ones.Potent conformationally restricted 5-HT3 receptor antagonists. J Med Chem 1993, 36, 18, 2645. |
| 【2】 Graul, A.; Castañer, J.; RS-25259-197. Drugs Fut 1996, 21, 9, 906. |
| 【3】 Berger, J.; Clark, R.D.; Eglen, R.M.; Smith, W.L.; Weinhardt, K.K. (Syntex (USA), Inc.); New tricyclic cpds. AU 9166963; EP 0430190; US 5202333 . |
| 【4】 Dvorak, C.A.; Kowalczyk, B.A. (F. Hoffmann-La Roche AG); Process for the preparation of 2-(1-azabicyclo[2.2.2]oct-3-yl)-2,4,5,6-tetrahydro- -1H-benz[de]isoquinolin-1-one and intermediate product. WO 9601824 . |
| 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) | 16982 | 1H,3H-benzo[de]isochromene-1,3-dione; 1,8-Naphthalic Anhydride | 81-84-5 | C12H6O3 | 详情 | 详情 |
| (II) | 16983 | 1H-benz[de]isoquinoline-1,3(2H)-dione; 1H-benzo[de]isoquinoline-1,3(2H)-dione | 81-83-4 | C12H7NO2 | 详情 | 详情 |
| (III) | 16984 | (3S)-1-azabicyclo[2.2.2]octan-3-amine; 1-aza-Bicyclo[2.2.2]oct-3-ylamine; (3S)-1-azabicyclo[2.2.2]oct-3-ylamine | 120570-05-0 | C7H14N2 | 详情 | 详情 |
| (IV) | 16985 | 2-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-1H-benzo[de]isoquinoline-1,3(2H)-dione | C19H18N2O2 | 详情 | 详情 | |
| (V) | 16986 | 2-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-3-hydroxy-2,3,3a,4,5,6-hexahydro-1H-benzo[de]isoquinolin-1-one | C19H24N2O2 | 详情 | 详情 | |
| (VI) | 16987 | 2-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-2,4,5,6-tetrahydro-1H-benzo[de]isoquinolin-1-one | C19H22N2O | 详情 | 详情 | |
| (VII) | 16988 | 2-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-3a,4,5,6-tetrahydro-1H-benzo[de]isoquinoline-1,3(2H)-dione | C19H22N2O2 | 详情 | 详情 | |
| (VIII) | 16989 | 1-oxo-5,6-dihydro-1H,4H-benzo[de]isochromen-3-yl acetate | C14H12O4 | 详情 | 详情 | |
| (IX) | 16990 | 5,6-dihydro-1H,4H-benzo[de]isochromen-1-one | C12H10O2 | 详情 | 详情 | |
| (X) | 16991 | N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-5,6,7,8-tetrahydro-1-naphthalenecarboxamide | 135729-78-1 | C18H24N2O | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(III)Tritium-labeled RS-25259-197 can be obtained by the reaction of methyl 4-bromophenylacetate (XI) with methyl chloroformate (XII) by means of lithium diisopropylamide (LDA) in THF, giving the malonic ester (XIII), which is condensed with methyl acrylate (XIV) by means of Na in methanol to yield the tricarboxylic ester (XV). The decarboxylative hydrolysis of (XV) first with NaOH and finally in acidic medium (HCl) affords 2-(4-bromophenyl)glutaric acid (XVI), which is cyclized with hot polyphosphoric acid (PPA) to give 6-bromo-4-oxo-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (XVII). The reduction of (XVII) with NaBH4 in isopropanol yields the corresponding hydroxy acid (XVIII), which is dehydrated with p-toluenesulfonic acid to the lactone (XIX). Isomerization of (XIX) with H3PO4 in THF affords 6-bromo-1,2-dihydronaphthalene-1-carboxylic acid (XX), which is condensed with quinuclidin-3(S)-ylamine (III) by means of dicyclohexylcarbodiimide (DCC) and hydroxybenzotriazole (HOBT) in acetonitrile to give the corresponding amide as a mixture of diastereomers that is resolved by chromatography and crystallization in order to obtain the (S,S)-isomer (XXI). The hydrogenation of (XXI) with tritium (3H2) and Pd/C in ethyl acetate affords (S,S)-N-(3-quinuclidinyl)-3,4,7-tri-3H-1,2,3,4-tetrahydronaphthalene-1-carboxamide (XXII), which is reduced with the complex borane.dimethylsulfide to the corresponding amine (XXIII). Finally, this compound is cyclized with trichloromethyl chloroformate (diphosgene) in refluxing toluene.
| 【1】 Graul, A.; Castañer, J.; RS-25259-197. Drugs Fut 1996, 21, 9, 906. |
| 【2】 Gong, L.; Parnes, H.; Synthesis of the 3H-labelled 5-HT3 antagonist (RS-25259-197) at high specific activity. J Label Compd Radiopharm 1996, 38, 5, 425. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (III) | 16984 | (3S)-1-azabicyclo[2.2.2]octan-3-amine; 1-aza-Bicyclo[2.2.2]oct-3-ylamine; (3S)-1-azabicyclo[2.2.2]oct-3-ylamine | 120570-05-0 | C7H14N2 | 详情 | 详情 |
| (XI) | 16992 | methyl 2-(4-bromophenyl)acetate | 41841-16-1 | C9H9BrO2 | 详情 | 详情 |
| (XII) | 16993 | methyl chlorocarbonate;Carbonochloridic acid methyl ester；[(chlorocarbonyl)oxy]methane；methyl chloroformate | 79-22-1 | C2H3ClO2 | 详情 | 详情 |
| (XIII) | 16994 | dimethyl 2-(4-bromophenyl)malonate | C11H11BrO4 | 详情 | 详情 | |
| (XIV) | 14156 | methyl acrylate | 96-33-3 | C4H6O2 | 详情 | 详情 |
| (XV) | 16996 | trimethyl 1-(4-bromophenyl)-1,1,3-propanetricarboxylate | C15H17BrO6 | 详情 | 详情 | |
| (XVI) | 16997 | 2-(4-bromophenyl)pentanedioic acid | C11H11BrO4 | 详情 | 详情 | |
| (XVII) | 16998 | 6-bromo-4-oxo-1,2,3,4-tetrahydro-1-naphthalenecarboxylic acid | C11H9BrO3 | 详情 | 详情 | |
| (XVIII) | 16999 | 6-bromo-4-hydroxy-1,2,3,4-tetrahydro-1-naphthalenecarboxylic acid | C11H11BrO3 | 详情 | 详情 | |
| (XIX) | 17000 | 5-bromo-9-oxatricyclo[6.2.2.0(2,7)]dodeca-2,4,6-trien-10-one | C11H9BrO2 | 详情 | 详情 | |
| (XX) | 17001 | 6-bromo-1,2-dihydro-1-naphthalenecarboxylic acid | C11H9BrO2 | 详情 | 详情 | |
| (XXI) | 17002 | (1S)-N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-6-bromo-1,2-dihydro-1-naphthalenecarboxamide | C18H21BrN2O | 详情 | 详情 | |
| (XXII) | 17003 | (1S)-N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-1,2,3,4-tetrahydro-1-naphthalenecarboxamide | C18H24N2O | 详情 | 详情 | |
| (XXII) | 45319 | (1S)-N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-1,2,3,4-tetrahydro-1-naphthalenecarboxamide | C18H24N2O | 详情 | 详情 | |
| (XXIII) | 17004 | (3S)-N-[(1S)-1,2,3,4-tetrahydro-1-naphthalenylmethyl]-1-azabicyclo[2.2.2]octan-3-amine; N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-N-[(1S)-1,2,3,4-tetrahydro-1-naphthalenylmethyl]amine | C18H26N2 | 详情 | 详情 | |
| (XXIII) | 45320 | N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-N-[(1S)-1,2,3,4-tetrahydro-1-naphthalenylmethyl]amine; (3S)-N-[(1S)-1,2,3,4-tetrahydro-1-naphthalenylmethyl]-1-azabicyclo[2.2.2]octan-3-amine | C18H26N2 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(VIII)5-Chlorosalicylic acid (I) was esterified to ester (II) by refluxing in MeOH in the presence of H2SO4. Iodination of methyl ester (II) was performed by treatment with chloramine-T (III) and NaI in DMF to afford methyl 5-chloro-3-iodosalicylate (IV). Subsequent methylation of (IV) with dimethyl sulfate and K2CO3 in refluxing acetone gave methyl ether (V), which was then saponified with NaOH in aqueous EtOH. The resulting carboxylic acid (VI), after conversion to the corresponding acid chloride (VII) by treatment with SOCl2, was coupled with (S)-3-aminoquinuclidine (VIII) in acetonitrile to furnish unlabeled compound (IX). Treatment with bis(tri-n-butyltin) in the presence of Pd(PPh3)4 in refluxing Et3N afforded the tributylstannyl derivative (X), which was then iodinated with chloramine-T (III) in the presence of 125INa to yield the labeled product.
| 【1】 Mason, N.S.; et al.; Labeling of (S)-des-4-amino-3-[125I]iodozacopride (DAIZAC), a high-affinity radioligand for the 5-HT-3 receptor. J Label Compd Radiopharm 1996, 38, 11, 955. |
| 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) | 13895 | 5-Chloro-2-hydroxybenzoic acid; 5-Chlorosalicylic acid | 321-14-2 | C7H5ClO3 | 详情 | 详情 |
| (II) | 13714 | Methyl 5-chloro-2-hydroxybenzoate; Methyl 5-chlorosalicylate | 4068-78-4 | C8H7ClO3 | 详情 | 详情 |
| (III) | 19670 | Chloramine T | 127-65-1 | C7H7ClNNaO2S | 详情 | 详情 |
| (IV) | 19671 | methyl 5-chloro-2-hydroxy-3-iodobenzoate | C8H6ClIO3 | 详情 | 详情 | |
| (V) | 19672 | methyl 5-chloro-3-iodo-2-methoxybenzoate | C9H8ClIO3 | 详情 | 详情 | |
| (VI) | 19673 | 5-chloro-3-iodo-2-methoxybenzoic acid | C8H6ClIO3 | 详情 | 详情 | |
| (VII) | 19674 | 5-chloro-3-iodo-2-methoxybenzoyl chloride | C8H5Cl2IO2 | 详情 | 详情 | |
| (VIII) | 16984 | (3S)-1-azabicyclo[2.2.2]octan-3-amine; 1-aza-Bicyclo[2.2.2]oct-3-ylamine; (3S)-1-azabicyclo[2.2.2]oct-3-ylamine | 120570-05-0 | C7H14N2 | 详情 | 详情 |
| (IX) | 19676 | N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-5-chloro-3-iodo-2-methoxybenzamide | C15H18ClIN2O2 | 详情 | 详情 | |
| (X) | 19677 | N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-5-chloro-2-methoxy-3-(tributylstannyl)benzamide | C27H45ClN2O2Sn | 详情 | 详情 |