【结 构 式】 |
【分子编号】17536 【品名】(2R)-4-(3,4-dimethoxyphenyl)-N-methoxy-N-methyl-2-[(2,2,2-trifluoroacetyl)amino]butanamide 【CA登记号】 |
【 分 子 式 】C16H21F3N2O5 【 分 子 量 】378.3484296 【元素组成】C 50.79% H 5.59% F 15.06% N 7.4% O 21.14% |
合成路线1
该中间体在本合成路线中的序号:(II)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 |