|
【结 构 式】 
|
【分子编号】40513 【品名】(1S)-3-chloro-1-(2-thienyl)propyl 1-naphthyl ether; 2-[(1S)-3-chloro-1-(1-naphthyloxy)propyl]thiophene 【CA登记号】 |
【 分 子 式 】C17H15ClOS 【 分 子 量 】302.8242 【元素组成】C 67.43% H 4.99% Cl 11.71% O 5.28% S 10.59% |
合成路线1
该中间体在本合成路线中的序号：(VIII)The reaction of thiophene-2-carboxylic acid (I) with oxalyl chloride and PPh3 gives the corresponding acyl chloride (II), which is condensed with vinyltributylstannane to yield 1-(2-thienyl)-2-propen-1-one (III). The addition of HCl to the double bond of (III) affords 3-chloro-1-(2-thienyl)-1-propanone (IV), which is reduced with BH3 and the chiral (S)-oxazaborolidine catalyst (V) in THF to give the (R)-3-chloro-1-(2-thienyl)-1-propanol (VI). The condensation of (VI) with [1-14C]-1-naphthol (VII) by means of DEAD and PPh3 in THF affords the labeled naphthyl ether derivative (VIII), which is treated with NaI in acetone to give the labeled iodo derivative (IX). Finally, this compound is treated with methylamine in hot THF.
| 【1】 Wheeler, W.J.; Kuo, F.; Approaches to an asymmetric synthesis of duloxetine, a mixed uptake inhibitor of serotonin and norepinephrine, and its C-14 labeled analogs. Synthesis and Applications of Isotopically Labelled Compounds 1994, 597-603. |
| 【2】 Sorbera, L.A.; Castaner, R.M.; Castaner, J.; Duloxetine oxalate. Drugs Fut 2000, 25, 9, 907. |
| 【3】 Wheeler, W.J.; Kuo, F.; An asymmetric synthesis of duloxetine hydrochloride, a mixed uptake inhibitor of serotonin and norepinephrine, and its C-14 labeled isotopomers. J Label Compd Radiopharm 1995, 36, 3, 213. |
| 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) | 40505 | 2-thiophenecarboxylic acid | 527-72-0 | C5H4O2S | 详情 | 详情 |
| (II) | 14103 | 2-Thiophenecarbonyl chloride | 5271-67-0 | C5H3ClOS | 详情 | 详情 |
| (III) | 40506 | 1-(2-thienyl)-2-propen-1-one | C7H6OS | 详情 | 详情 | |
| (IV) | 40507 | 3-chloro-1-(2-thienyl)-1-propanone | C7H7ClOS | 详情 | 详情 | |
| (V) | 28292 | (S)-Methyl oxazaborolidine; (3aS)-1-methyl-3,3-diphenyltetrahydro-3H-pyrrolo[1,2-c][1,3,2]oxazaborole | 112022-81-8 | C18H20BNO | 详情 | 详情 |
| (VI) | 40512 | (1R)-3-chloro-1-(2-thienyl)-1-propanol | C7H9ClOS | 详情 | 详情 | |
| (VII) | 22935 | alpha-naphthol; 1-naphthol | 90-15-3 | C10H8O | 详情 | 详情 |
| (VII) | 45152 | 1-naphthol | C10H8O | 详情 | 详情 | |
| (VIII) | 40513 | (1S)-3-chloro-1-(2-thienyl)propyl 1-naphthyl ether; 2-[(1S)-3-chloro-1-(1-naphthyloxy)propyl]thiophene | C17H15ClOS | 详情 | 详情 | |
| (VIII) | 45153 | (1S)-3-chloro-1-(2-thienyl)propyl 1-naphthyl ether; 2-[(1S)-3-chloro-1-(1-naphthyloxy)propyl]thiophene | C17H15ClOS | 详情 | 详情 | |
| (IX) | 40514 | (1S)-3-iodo-1-(2-thienyl)propyl 1-naphthyl ether; 2-[(1S)-3-iodo-1-(1-naphthyloxy)propyl]thiophene | C17H15IOS | 详情 | 详情 | |
| (IX) | 45154 | 2-[(1S)-3-iodo-1-(1-naphthyloxy)propyl]thiophene; (1S)-3-iodo-1-(2-thienyl)propyl 1-naphthyl ether | C17H15IOS | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(IX)The enantioselective reduction of 3-chloro-1-(2-thienyl)-1-propanone (I) by means of BH3 catalyzed by (R)-1-methyl-3,3-diphenyltetrahydropyrrolo[1,2-c][1,3,2]oxazaborole (II) in THF gives 3-chloro-1-(2-thienyl)propan-1(S)-ol (III), which is treated with methylamine and NaI in acetone/THF to yield (S)-N-methyl-N-[3-(2-thienyl)propyl]amine (IV). Finally, this compound is condensed with 1-fluoronaphthalene (V) by means of NaH in DMA to provide duloxetine. Alternatively, the enantioselective reduction of 3-chloro-1-(2-thienyl)-1-propanone (I) by means of BH3 catalyzed by (S)-1-methyl-3,3-diphenyltetrahydropyrrolo[1,2-c][1,3,2]oxazaborole (VI) in THF gives 3-chloro-1-(2-thienyl)propan-1(R)-ol (VII), which is condensed with 1-naphthol (VIII) by means of DEAD and PPh3 to yield the expected aryl ether (IX), with inversion of the configuration. Finally, this compound is treated with methylamine and NaI in acetone/THF to provide duloxetine.
| 【1】 Bymaster, F.P.; Beedle, E.E.; Findlay, J.; Gallagher, P.T.; Krushinski J.H.; Mitchell, S.; Robertson, D.W.; Thompson, D.C.; Wallace, L.; Wong, D.T.; Duloxetine (Cymbalta(TM)), a dual inhibitor of serotonin and norepinephrine reuptake. Bioorg Med Chem Lett 2003, 13, 24, 4477. |
| 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) | 40507 | 3-chloro-1-(2-thienyl)-1-propanone | C7H7ClOS | 详情 | 详情 | |
| (II) | 20631 | (R)-Methyl oxazaborolidine; (3aR)-1-methyl-3,3-diphenyltetrahydro-3H-pyrrolo[1,2-c][1,3,2]oxazaborole | 112022-83-0 | C18H20BNO | 详情 | 详情 |
| (III) | 40509 | (1S)-3-chloro-1-(2-thienyl)-1-propanol | C7H9ClOS | 详情 | 详情 | |
| (IV) | 40511 | (1S)-3-(methylamino)-1-(2-thienyl)-1-propanol | 116539-55-0 | C8H13NOS | 详情 | 详情 |
| (V) | 40503 | 1-fluoronaphthalene | 321-38-0 | C10H7F | 详情 | 详情 |
| (VI) | 28292 | (S)-Methyl oxazaborolidine; (3aS)-1-methyl-3,3-diphenyltetrahydro-3H-pyrrolo[1,2-c][1,3,2]oxazaborole | 112022-81-8 | C18H20BNO | 详情 | 详情 |
| (VII) | 40512 | (1R)-3-chloro-1-(2-thienyl)-1-propanol | C7H9ClOS | 详情 | 详情 | |
| (VIII) | 22935 | alpha-naphthol; 1-naphthol | 90-15-3 | C10H8O | 详情 | 详情 |
| (IX) | 40513 | (1S)-3-chloro-1-(2-thienyl)propyl 1-naphthyl ether; 2-[(1S)-3-chloro-1-(1-naphthyloxy)propyl]thiophene | C17H15ClOS | 详情 | 详情 |