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【结 构 式】 
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【分子编号】40510 【品名】(1S)-3-iodo-1-(2-thienyl)-1-propanol 【CA登记号】 |
【 分 子 式 】C7H9IOS 【 分 子 量 】268.11833 【元素组成】C 31.36% H 3.38% I 47.33% O 5.97% S 11.96% |
合成路线1
该中间体在本合成路线中的序号：(XIV)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：(XIII)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 |