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【结 构 式】 
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【分子编号】40509 【品名】(1S)-3-chloro-1-(2-thienyl)-1-propanol 【CA登记号】 |
【 分 子 式 】C7H9ClOS 【 分 子 量 】176.66656 【元素组成】C 47.59% H 5.13% Cl 20.07% O 9.06% S 18.15% |
合成路线1
该中间体在本合成路线中的序号：(XIII)Reaction of thiophene-2-carboxylic acid (VIII) with oxalyl chloride and PPh3 gives the corresponding acyl chloride (IX), which is condensed with vinyltributylstannane, yielding 1-(2-thienyl)-2-propen-1-one (X). The addition of HCl to the double bond of (X) affords 3-chloro-1-(2-thienyl)-1-propanone (XI), which is reduced with BH3 and the chiral (R)-oxazaborolidine catalyst (XII) in THF to give (S)-3-chloro-1-(2-thienyl)-1-propanol (XIII) (4). Treatment of (XIII) with NaI in acetone affords the (S)-3-iodopropanol derivative (XIV), which is condensed with methylamine in THF to provide (S)-3-(methylamino)-1-(2-thienyl)-1-propanol (XV). Finally, this compound is condensed with 1-fluoronaphthalene (V) by means of NaH in DMA. The Friedel-Crafts condensation of thiophene (XVI) with 3-chloropropionyl chloride (XVII) by means of SnCl4 in benzene gives the previously reported 3-chloro-1-(2-thienyl)-1-propanone (XI), which is reduced with NaBH4 in ethanol to yield the racemic alcohol (XVIII). Optical resolution of (XVIII) performed by means of immobilized CALB (Novozyme 435, Novo-Nordisk A/S) affords the previously reported (S)-alcohol (XIII).
| 【1】 Sorbera, L.A.; Castaner, R.M.; Castaner, J.; Duloxetine oxalate. Drugs Fut 2000, 25, 9, 907. |
| 【2】 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. |
| 【3】 Hoff, B.H.; Liu, H.; Anthonsen, T.; Chemo-enzymatic synthesis of the antidepressant duloxetine and its enantiomer. Chirality 2000, 12, 1, 26. |
| 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) | 40503 | 1-fluoronaphthalene | 321-38-0 | C10H7F | 详情 | 详情 |
| (VIII) | 40505 | 2-thiophenecarboxylic acid | 527-72-0 | C5H4O2S | 详情 | 详情 |
| (IX) | 14103 | 2-Thiophenecarbonyl chloride | 5271-67-0 | C5H3ClOS | 详情 | 详情 |
| (X) | 40506 | 1-(2-thienyl)-2-propen-1-one | C7H6OS | 详情 | 详情 | |
| (XI) | 40507 | 3-chloro-1-(2-thienyl)-1-propanone | C7H7ClOS | 详情 | 详情 | |
| (XII) | 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 |
| (XIII) | 40509 | (1S)-3-chloro-1-(2-thienyl)-1-propanol | C7H9ClOS | 详情 | 详情 | |
| (XIV) | 40510 | (1S)-3-iodo-1-(2-thienyl)-1-propanol | C7H9IOS | 详情 | 详情 | |
| (XV) | 40511 | (1S)-3-(methylamino)-1-(2-thienyl)-1-propanol | 116539-55-0 | C8H13NOS | 详情 | 详情 |
| (XVI) | 13297 | Thiophene | 110-02-1 | C4H4S | 详情 | 详情 |
| (XVII) | 18936 | 3-chloropropanoyl chloride | 625-36-5 | C3H4Cl2O | 详情 | 详情 |
| (XVIII) | 40508 | 3-chloro-1-(2-thienyl)-1-propanol | C7H9ClOS | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XII)The reaction of thiophene-2-[14C]carboxylic acid (VII) with oxalyl chloride and PPh3 gives the corresponding labeled acyl chloride (VIII), which is condensed with vinyltributylstannane, yielding 1-(2-thienyl)-[1-14C]prop-2-en-1-one (IX). The addition of HCl to the double bond of (IX) affords 3-chloro-1-(2-thienyl)-[1-14C]propan-1-one (X), which is reduced with BH3 and the chiral (R)-oxazaborolidine catalyst (XI) in THF to give (S)-3-chloro-1-(2-thienyl)-[1-14C]propan-1-ol (XII). Treatment of (XII) with NaI in acetone affords the labeled (S)-3-iodopropanol derivative (XIII), which is condensed with methylamine in THF to provide (S)-3-(methylamino)-1-(2-thienyl)-[1-14C]propan-1-ol (XIV). Finally, this compound is condensed with 1-fluoronaphthalene (V) by means of NaH in DMA.
| 【1】 Sorbera, L.A.; Castaner, R.M.; Castaner, J.; Duloxetine oxalate. Drugs Fut 2000, 25, 9, 907. |
| 【2】 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 |
|---|---|---|---|---|---|---|
| (V) | 40503 | 1-fluoronaphthalene | 321-38-0 | C10H7F | 详情 | 详情 |
| (VII) | 40505 | 2-thiophenecarboxylic acid | 527-72-0 | C5H4O2S | 详情 | 详情 |
| (VII) | 45145 | 2-thiophenecarboxylic acid | C5H4O2S | 详情 | 详情 | |
| (VIII) | 14103 | 2-Thiophenecarbonyl chloride | 5271-67-0 | C5H3ClOS | 详情 | 详情 |
| (VIII) | 45146 | 2-thiophenecarbonyl chloride | C5H3ClOS | 详情 | 详情 | |
| (IX) | 40506 | 1-(2-thienyl)-2-propen-1-one | C7H6OS | 详情 | 详情 | |
| (IX) | 45147 | 1-(2-thienyl)-2-propen-1-one | C7H6OS | 详情 | 详情 | |
| (X) | 40507 | 3-chloro-1-(2-thienyl)-1-propanone | C7H7ClOS | 详情 | 详情 | |
| (X) | 45148 | 3-chloro-1-(2-thienyl)-1-propanone | C7H7ClOS | 详情 | 详情 | |
| (XI) | 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 |
| (XII) | 40509 | (1S)-3-chloro-1-(2-thienyl)-1-propanol | C7H9ClOS | 详情 | 详情 | |
| (XII) | 45149 | (1S)-3-chloro-1-(2-thienyl)-1-propanol | C7H9ClOS | 详情 | 详情 | |
| (XIII) | 40510 | (1S)-3-iodo-1-(2-thienyl)-1-propanol | C7H9IOS | 详情 | 详情 | |
| (XIII) | 45150 | (1S)-3-iodo-1-(2-thienyl)-1-propanol | C7H9IOS | 详情 | 详情 | |
| (XIV) | 40511 | (1S)-3-(methylamino)-1-(2-thienyl)-1-propanol | 116539-55-0 | C8H13NOS | 详情 | 详情 |
| (XIV) | 45151 | (1S)-3-(methylamino)-1-(2-thienyl)-1-propanol | C8H13NOS | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(III)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 |