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【结 构 式】 
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【分子编号】32813 【品名】(2R,3S)-3-iodo-2-(2-propynyloxy)tetrahydrofuran; (2R,3S)-3-iodotetrahydro-2-furanyl 2-propynyl ether 【CA登记号】 |
【 分 子 式 】C7H9IO2 【 分 子 量 】252.05173 【元素组成】C 33.36% H 3.6% I 50.35% O 12.7% |
合成路线1
该中间体在本合成路线中的序号：(XIV)The intermediate succinimidinyl carbonate (XI) has been obtained as follows: The reaction of 2,3-dihydrofuran (XII) with N-iodosuccinimide (NIS) and propargyl alcohol (XIII) in dichloromethane gives trans-3-iodo-2-(propargyloxy)tetrahydrofuran (XIV), which is cyclized by means of Bu3SnH and AIBN in hot toluene yielding the methylenic compound (XV). The ozonolysis of (XV) with O3, followed by reduction with NaBH4 in ethanol affords the racemic alcohol (XVI), which is submitted to an enantioselective acylation with Ac2O and lipase 30 to obtain the chiral alcohol (3R,3aS,6aR)-(XVI). Finally, this compound is treated with disuccinimidinyl carbonate and triethylamine in acetonitrile to provide the target intermediate (XI).
| 【1】 Ghosh, A.K.; Kincaid, J.F.; Cho, W.; Walters, D.E.; Krishnan, K.; Hussain, K.A.; Koo, Y.; Cho, H.; Rudall, C.; Holland, L.; Buthod, J.; Potent HIV protease inhibitors incorporating high-affinity P2-ligands and (R)-(hydroxyethylamino)sulfonamide isostere. Bioorg Med Chem Lett 1998, 8, 6, 687. |
| 【2】 Hussain, K.A.; Gulnik, S.V.; Ghosh, A.K.; Erickson, J.W. (University of Illinois; US Department of Health & Human Services); Multi-drug resistant retroviral protease inhibitors and associated methods. WO 9967254 . |
| 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)-(XVI) | 32815 | (3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-ol | C6H10O3 | 详情 | 详情 | |
| 3R,3aS,6aR-XVI) | 32815 | (3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-ol | C6H10O3 | 详情 | 详情 | |
| (XI) | 32812 | 1-([[(3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yloxy]carbonyl]oxy)-2,5-pyrrolidinedione | C11H13NO7 | 详情 | 详情 | |
| (XII) | 22766 | 2,3-dihydrofuran | 1191-99-7 | C4H6O | 详情 | 详情 |
| (XIII) | 16664 | Propargyl Alcohol; 2-propyn-1-ol | 107-19-7 | C3H4O | 详情 | 详情 |
| (XIV) | 32813 | (2R,3S)-3-iodo-2-(2-propynyloxy)tetrahydrofuran; (2R,3S)-3-iodotetrahydro-2-furanyl 2-propynyl ether | C7H9IO2 | 详情 | 详情 | |
| (XV) | 32814 | (3aS,6aR)-3-methylenehexahydrofuro[2,3-b]furan | C7H10O2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(III)The mixed carbonate ester intermediate (X) has been obtained as follows: The reaction of dihydrofuran (I) with propargyl alcohol (II) and N-iodosuccinimide (NIS) gives the propargyl ether (III), which is cyclized by means of tributyltin hydride and AIBN in refluxing toluene to yield the perhydrofuro[2,3-b]furan (IV). The oxidation of the methylene group of (IV) with ozone in methanol/dichloromethane affords the bicyclic ketone (V), which is reduced with NaBH4 in ethanol to provide racemic (VI). The digestion of (rac)-(VI) with immobilized lipase 30 and acetic anhydride in DME provides a mixture of the (3R)-alcohol (VII) and the (3S)-acetoxy derivative (VIII) that is separated by chromatography. Finally, the (3R)-(VII) alcohol is condensed with disuccinimidyl carbonate (IX) and TEA in acetonitrile to give the target mixed carbonate ester intermediate (X).
| 【1】 Hussain, K.A.; Gulnik, S.V.; Ghosh, A.K.; Erickson, J.W. (University of Illinois; US Department of Health & Human Services); Multi-drug resistant retroviral protease inhibitors and associated methods. WO 9967254 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VI),(VII) | 32815 | (3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-ol | C6H10O3 | 详情 | 详情 | |
| (I) | 22766 | 2,3-dihydrofuran | 1191-99-7 | C4H6O | 详情 | 详情 |
| (II) | 16664 | Propargyl Alcohol; 2-propyn-1-ol | 107-19-7 | C3H4O | 详情 | 详情 |
| (III) | 32813 | (2R,3S)-3-iodo-2-(2-propynyloxy)tetrahydrofuran; (2R,3S)-3-iodotetrahydro-2-furanyl 2-propynyl ether | C7H9IO2 | 详情 | 详情 | |
| (IV) | 32814 | (3aS,6aR)-3-methylenehexahydrofuro[2,3-b]furan | C7H10O2 | 详情 | 详情 | |
| (V) | 53547 | (3aR,6aR)tetrahydrofuro[2,3-b]furan-3(2H)-one | n/a | C6H8O3 | 详情 | 详情 |
| (VIII) | 53548 | (3S,3aR,6aS)hexahydrofuro[2,3-b]furan-3-yl acetate | n/a | C8H12O4 | 详情 | 详情 |
| (IX) | 20417 | 1-([[(2,5-dioxo-1-pyrrolidinyl)oxy]carbonyl]oxy)-2,5-pyrrolidinedione | 74124-79-1 | C9H8N2O7 | 详情 | 详情 |
| (X) | 32812 | 1-([[(3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yloxy]carbonyl]oxy)-2,5-pyrrolidinedione | C11H13NO7 | 详情 | 详情 |