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【结 构 式】 
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【分子编号】16970 【品名】(1S,2R)-6,7-dimethoxy-1-(5-propyl-3-thienyl)-1,2,3,4-tetrahydro-2-naphthalenylamine; (1S,2R)-6,7-dimethoxy-1-(5-propyl-3-thienyl)-1,2,3,4-tetrahydro-2-naphthalenamine 【CA登记号】 |
【 分 子 式 】C19H25NO2S 【 分 子 量 】331.47904 【元素组成】C 68.85% H 7.6% N 4.23% O 9.65% S 9.67% |
合成路线1
该中间体在本合成路线中的序号：(VII)ABT-431 can be obtained by two related ways: 1) The reduction of 6,7-dimethoxy-1-tetralone (I) with NaBH4 in ethanol followed by dehydration with p-toluenesulfonic acid in refluxing toluene gives 6,7-dimethoxy-1,2-dihydronaphthalene (II), which is nitrated with tetranitromethane and pyridine in acetone yielding 6,7-dimethoxy-3-nitro-1,2-dihydronaphthalene (III). The condensation of (III) with N-tert-butyl-5-propylthiophene-2-carboxamide (IV) by means of butyllithium in THF affords the trans racemic (V), which is reduced with Zn/HCl to the corresponding amine (VI). The reaction of (VI) with 10% H2SO4 in refluxing methanol gives a mixture of the decarboxylated compound (VII) and the cyclization compound (VIII). The enantiomeric separation of (VIII) by chiral chromatography in a Chiracel(TM) OD column affords the (5aR,11bS)-enantiomer, which is demethylated with BBr3 in dichloromethane to the chiral diol (IX), and finally acetylated with acetyl chloride in trifluoroacetic acid and treated with ethereal HCl. 2) The condensation of (III) with 5-allyl-N-tert-butylthiophene-2-carboxamide (X) by means of butyllithium in THF affords the trans racemic (XI), which by successive treatments with Zn/HCl, hydrogenation with H2 over Pd/C, p-toluenesulfonic acid in refluxing toluene and finally with BH3 in THF, is converted into the previously reported tetracyclic racemic compound (VIII). N-tert-Butyl-5-propylthiophene-2-carboxamide (IV) has been obtained by condensation of 2-propylthiophene (XII) with tert-butyl isocyanate (XIII) by means of butyllithium in THF.
| 【1】 Merlos, M.; Graul, A.; Castañer, J.; ABT-431. Drugs Fut 1997, 22, 8, 821. |
| 【2】 Michaelides, M.R.; Hong, Y.; DiDomenico, S. Jr.; Bayburt, E.K.; Asin, K.E.; Britton, D.R.; Lin, C.W.; Shiosaki; Substituted hexahydrobenzo[f]thieno[c]quinolines as dopamine D1-selective agonists: Synthesis and biological evaluation in vitro and in vivo. J Med Chem 1997, 40, 11, 1585-99. |
| 【3】 Michaelides, M.R.; Hong, Y.; DiDomenico, S. Jr.; Asin, K.E.; Britton, D.R.; Lin, C.W.; Williams, M.; Shiosaki, K.; (5aR,11bS)-4,5,5a,6,7,11b-Hexahydro-2-propyl-3-thia-5-azacyclopent-1-ena[c]phenanthrene-9,10-diol(A-86929): A potent and selective dopamine D1 agonist. J Med Chem 1995, 38, 18, 3445-7. |
| 【4】 Michaelides, M.R.; Hong, Y. (Abbott Laboratories Inc.); Tetracyclic cpds. as dopamine agonists. EP 0690863; JP 1996508487; US 5597832; WO 9422858 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| rac-(VIII) | 16971 | (rac)-(5aR*,11bS*)-10-methoxy-2-propyl-4,5,5a,6,7,11b-hexahydrobenzo[f]thieno[2,3-c]quinolin-9-yl methyl ether; (rac)-(5aR*,11bS*)-9,10-dimethoxy-2-propyl-4,5,5a,6,7,11b-hexahydrobenzo[f]thieno[2,3-c]quinoline | C20H25NO2S | 详情 | 详情 | |
| (I) | 16964 | 6,7-dimethoxy-1-tetralone; 6,7-dimethoxy-3,4-dihydro-1(2H)-naphthalenone | 13575-75-2 | C12H14O3 | 详情 | 详情 |
| (II) | 16965 | 3-methoxy-5,6-dihydro-2-naphthalenyl methyl ether; 6,7-dimethoxy-1,2-dihydronaphthalene | C12H14O2 | 详情 | 详情 | |
| (III) | 16966 | 3-methoxy-6-nitro-7,8-dihydro-2-naphthalenyl methyl ether; 6,7-dimethoxy-3-nitro-1,2-dihydronaphthalene | C12H13NO4 | 详情 | 详情 | |
| (IV) | 16967 | N-(tert-butyl)-5-propyl-2-thiophenecarboxamide | C12H19NOS | 详情 | 详情 | |
| (V) | 16968 | N-(tert-butyl)-3-[(1S,2R)-6,7-dimethoxy-2-nitro-1,2,3,4-tetrahydro-1-naphthalenyl]-5-propyl-2-thiophenecarboxamide | C24H32N2O5S | 详情 | 详情 | |
| (VI) | 16969 | 3-[(1S,2R)-2-amino-6,7-dimethoxy-1,2,3,4-tetrahydro-1-naphthalenyl]-N-(tert-butyl)-5-propyl-2-thiophenecarboxamide | C24H34N2O3S | 详情 | 详情 | |
| (VII) | 16970 | (1S,2R)-6,7-dimethoxy-1-(5-propyl-3-thienyl)-1,2,3,4-tetrahydro-2-naphthalenylamine; (1S,2R)-6,7-dimethoxy-1-(5-propyl-3-thienyl)-1,2,3,4-tetrahydro-2-naphthalenamine | C19H25NO2S | 详情 | 详情 | |
| (VIII) | 65064 | (5aR,11bS)-9,10-dimethoxy-2-propyl-4,5,5a,6,7,11b-hexahydrobenzo[f]thieno[2,3-c]quinoline; (5aR,11bS)-10-methoxy-2-propyl-4,5,5a,6,7,11b-hexahydrobenzo[f]thieno[2,3-c]quinolin-9-yl methyl ether | C20H25NO2S | 详情 | 详情 | |
| (IX) | 16972 | (5aR,11bS)-2-propyl-4,5,5a,6,7,11b-hexahydrobenzo[f]thieno[2,3-c]quinoline-9,10-diol | C18H21NO2S | 详情 | 详情 | |
| (X) | 16973 | 5-allyl-N-(tert-butyl)-2-thiophenecarboxamide | C12H17NOS | 详情 | 详情 | |
| (XI) | 16974 | 5-allyl-N-(tert-butyl)-3-[(1S,2R)-6,7-dimethoxy-2-nitro-1,2,3,4-tetrahydro-1-naphthalenyl]-2-thiophenecarboxamide | C24H30N2O5S | 详情 | 详情 | |
| (XII) | 16975 | 2-propylthiophene; Thiophene, 2-propyl- | 1551-27-5 | C7H10S | 详情 | 详情 |
| (XIII) | 16976 | tert-butylisocyanate; tert-butyl isocyanate; 2-isocyanato-2-methylpropane | 1609-86-5 | C5H9NO | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(VI)A new enantioselective synthesis of A-86929, the active form of the diacetyl prodrug ABT-431 has been published: The condensation of 4-bromo-2-propylthiophene (I) with 4-(3,4-dimethoxyphenyl)-N-methoxy-N-methyl-2(R)-(trifluoroacetamido)butyramide (II) by means of butyllithium in ethyl ether gives 4-(3,4-dimethoxyphenyl)-1-(5-propyl-3-thienyl)-2(R)-(trifluoroacetamido)-1-butanone (III), which is reduced with NaBH4 in ethanol yielding 4-(3,4-dimethoxyphenyl)-1-(5-propyl-3-thienyl)-2(R)-(trifluoroacetamido-1(S)-butanol (IV) in a 4:1 ratio with its diastereomeric alcohol. The cyclization of (IV) with SnCl4 in dichloromethane affords the substituted tetraline (V), which is treated with K2CO3 in methanol/water to give (1S,2R)-6,7-dimethoxy-1-(5-propyl-3-thienyl)-1,2,3,4-tetrahydro-2-naphthylamine (VI). The cyclization of (VI) with formaldehyde and HCl in refluxing ethanol yields the tetracyclic intermediate (VII), which is finally demethylated with BBr3 in dichloromethane. The two starting compounds (I) and (II) have been obtained as follows: 1) The bromination of 1-(2-thienyl)-1-propanone (VIII) with Br2/AlCl3 in chloroform gives 1-(4-bromo-2-thienyl)-1-propanone (IX), which is then reduced to (I) with hydrazine and KOH in ethylene glycol at 160 C. 2) The Friedel Craft's condensation of 1,2-dimethoxybenzene (X) with 2(R)-(trifluoroacetamido)succinic anhydride (XI) by means of AlCl3 gives 4-(3,4-dimethoxyphenyl)-4-oxo-2(R)-(trifluoroacetamido)butyric acid (XII), which is reduced with H2 over Pd/C in HCl/isopropanol yielding 4-(3,4-dimethoxyphenyl)-2(R)-(trifluoroacetamido)butyric acid (XIII). Finally, this compound is condensed with N,O-dimethylhydroxylamine by means of isobutyl chloroformate and N-methylmorpholine (NMM) in THF affording amide (II).
| 【1】 Ehrlich, P.P.; Ralston, J.W.; Michaelides, M.R.; An efficient enantioselective synthesis of the D1 agonist (5aR,11bS)-4,5,5a,6,7,11b-hexahydro-2-propyl-3-thia-5-azacyclo-penta[c]phenanthrene-9,10-diol (A-86929). J Org Chem 1997, 62, 9, 2782. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 65063 | N-{(1R)-3-(3,4-dimethoxyphenyl)-1-[(R)-hydroxy(5-propyl-3-thienyl)methyl]propyl}-2,2,2-trifluoroacetamide | C21H26F3NO4S | 详情 | 详情 | ||
| (I) | 17535 | 4-bromo-2-propylthiophene | 36155-79-0 | C7H9BrS | 详情 | 详情 |
| (II) | 17536 | (2R)-4-(3,4-dimethoxyphenyl)-N-methoxy-N-methyl-2-[(2,2,2-trifluoroacetyl)amino]butanamide | C16H21F3N2O5 | 详情 | 详情 | |
| (III) | 17537 | N-[(1R)-3-(3,4-dimethoxyphenyl)-1-[(5-propyl-3-thienyl)carbonyl]propyl]-2,2,2-trifluoroacetamide | C21H24F3NO4S | 详情 | 详情 | |
| (IV) | 17538 | N-[(1R)-3-(3,4-dimethoxyphenyl)-1-[(S)-hydroxy(5-propyl-3-thienyl)methyl]propyl]-2,2,2-trifluoroacetamide | C21H26F3NO4S | 详情 | 详情 | |
| (V) | 17539 | N-[(1S,2R)-6,7-dimethoxy-1-(5-propyl-3-thienyl)-1,2,3,4-tetrahydro-2-naphthalenyl]-2,2,2-trifluoroacetamide | C21H24F3NO3S | 详情 | 详情 | |
| (VI) | 16970 | (1S,2R)-6,7-dimethoxy-1-(5-propyl-3-thienyl)-1,2,3,4-tetrahydro-2-naphthalenylamine; (1S,2R)-6,7-dimethoxy-1-(5-propyl-3-thienyl)-1,2,3,4-tetrahydro-2-naphthalenamine | C19H25NO2S | 详情 | 详情 | |
| (VII) | 16971 | (rac)-(5aR*,11bS*)-10-methoxy-2-propyl-4,5,5a,6,7,11b-hexahydrobenzo[f]thieno[2,3-c]quinolin-9-yl methyl ether; (rac)-(5aR*,11bS*)-9,10-dimethoxy-2-propyl-4,5,5a,6,7,11b-hexahydrobenzo[f]thieno[2,3-c]quinoline | C20H25NO2S | 详情 | 详情 | |
| (VIII) | 17542 | 1-(2-thienyl)-1-propanone | 13679-75-9 | C7H8OS | 详情 | 详情 |
| (IX) | 17543 | 1-(4-bromo-2-thienyl)-1-propanone | C7H7BrOS | 详情 | 详情 | |
| (X) | 17398 | 2-methoxyphenyl methyl ether; Veratrole; 1,2-dimethoxybenzene | 91-16-7 | C8H10O2 | 详情 | 详情 |
| (XI) | 17545 | N-[(3R)-2,5-dioxotetrahydro-3-furanyl]-2,2,2-trifluoroacetamide | C6H4F3NO4 | 详情 | 详情 | |
| (XII) | 17546 | (2R)-4-(3,4-dimethoxyphenyl)-4-oxo-2-[(2,2,2-trifluoroacetyl)amino]butyric acid | C14H14F3NO6 | 详情 | 详情 | |
| (XIII) | 17547 | (2R)-4-(3,4-dimethoxyphenyl)-2-[(2,2,2-trifluoroacetyl)amino]butyric acid | C14H16F3NO5 | 详情 | 详情 |