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Preparation method of key chiral intermediate of febrifugine and halofuginone

A technology of chiral intermediates and hemosanone, which is applied in organic chemical methods, bulk chemical production, organic chemistry, etc., can solve the problems of cumbersome routes, expensive prices, and difficult operations, and achieve simple routes, simple operations, and reduced costs Effect

Active Publication Date: 2018-04-24
FUDAN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

As a chemically synthesized product, fushenone is currently only produced and sold by a French company (trade name Sudan), and the price is very expensive. Most of the domestic research is limited to the preparation process of quinazolones, but there are few reports on the key chirality. fragment preparation method
Although the preparation methods of key chiral fragments have been reported in the literature, the reactions involved are relatively difficult, or the routes are cumbersome, or difficult to operate. Practice has proved that it is difficult to achieve a large number of preparations.

Method used

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  • Preparation method of key chiral intermediate of febrifugine and halofuginone
  • Preparation method of key chiral intermediate of febrifugine and halofuginone
  • Preparation method of key chiral intermediate of febrifugine and halofuginone

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0021] Step 1: Synthesis of (5S,6R)-6-allyl-5-(tert-butyldimethylsilyloxy)piperidin-2-one 2(P 1 =TBS)

[0022] Dissolve compound 1 (2.0g, 5.51mmol) in 50mL of water, add indium powder (1.27g, 11.02mmol), add allyl bromide (1.33g, 11.02mmol) dropwise after stirring, stir at room temperature for 12 hours, then use ethyl acetate The ester was extracted three times, and the organic phases were combined, washed once with saturated brine, dried, concentrated, dissolved in tetrahydrofuran (20 mL), added potassium tert-butoxide (1.24 g, 11.02 mmol) and stirred at room temperature for 3 hours, then added saturated aqueous ammonium chloride, ethyl acetate The ester was extracted three times, and the combined organic phases were washed with saturated brine, dried, concentrated, and purified on a silica gel column to obtain Compound 2 with a yield of 41%;

[0023] 1 H NMR (400MHz, CDCl 3)δ: 5.63-5.72 (m, 2H), 5.13-5.22 (m, 2H), 3.60-3.67 (ddd, J=10.0, 6.4, 3.2Hz, 1H), 3.18-3.25 (m, 1H)...

Embodiment 2

[0038] Step 1: Synthesis of (5S,6R)-6-allyl-5-(tert-butyldimethylsilyloxy)piperidin-2-one 2(P 1 =TBS)

[0039] Compound 1 (2.0 g, 5.51 mmol) was dissolved in tetrahydrofuran (50 mL), indium powder (1.27 g, 11.02 mmol) was added, allyl bromide (1.33 g, 11.02 mmol) was added dropwise after stirring. Stir at room temperature for 12 hours, concentrate, dilute with water, extract three times with ethyl acetate, combine the organic phases, wash once with saturated brine, dry, concentrate, dissolve in tetrahydrofuran (50 mL), and add lithium diisopropylamide after cooling down to -78 degrees (1.24g, 11.02mmol) After stirring for 3 hours at -78 degrees, add saturated aqueous ammonium chloride solution, extract three times with ethyl acetate, combine the organic phases with saturated brine, wash and dry, concentrate, and purify on a silica gel column to obtain compound 2. The yield is 46%;

[0040] 1 H NMR (400MHz, CDCl 3 )δ: 5.63-5.72 (m, 2H), 5.13-5.22 (m, 2H), 3.60-3.67 (ddd, J=...

Embodiment 3

[0044] Step 1: Synthesis of (5S,6R)-6-allyl-5-(tert-butyldimethylsilyloxy)piperidin-2-one 2(P 1 =TBS)

[0045] Compound 1 (2.0g, 5.51mmol) was dissolved in saturated sodium bromide aqueous solution (50mL), indium powder (1.27g, 11.02mmol) was added, allyl bromide (1.33g, 11.02mmol) was added dropwise after stirring, and room temperature After stirring for 12 hours, it was extracted three times with ethyl acetate, the organic phases were combined, washed once with saturated brine, dried and concentrated, dissolved in tetrahydrofuran (50mL), and added lithium diisopropylamide (1.24g, 11.02mmol ) after stirring at -78°C for 3 hours, adding saturated aqueous ammonium chloride solution, extracting with ethyl acetate three times, combining the organic phases, washing with saturated brine, drying, concentrating, and purifying on a silica gel column to obtain Compound 2 with a yield of 48%;

[0046] 1 H NMR (400MHz, CDCl 3 )δ: 5.63-5.72 (m, 2H), 5.13-5.22 (m, 2H), 3.60-3.67 (ddd, J...

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Abstract

The invention belongs to the field of chemical synthesis, and relates to a preparation method of a key chiral intermediate trans-3-hydroxy-2-allyl piperidine of febrifugine and halofuginone and analogues of the chiral intermediate. The technical route of preparing the trans-3-hydroxy-2-allyl piperidine and the analogues of the trans-3-hydroxy-2-allyl piperidine provided by the invention has simpleoperation, concise route and high yield, and the used reagents are all common reagents. The costs of the trans-3-hydroxy-2-allyl piperidine and the analogues of the trans-3-hydroxy-2-allyl piperidineprepared by the method are obviously reduced; the preparation of a 100-gram grade can be conveniently realized in a laboratory; the preparation method can be suitable for large-scale preparation; andthe febrifugine and halofuginone can be obtained through simple transformation of the obtained target compound.

Description

technical field [0001] The present invention belongs to the field of chemical synthesis, and relates to the preparation method of the key chiral intermediates of hemosine and hiradhenone, especially the preparation method of trans-3-hydroxyl-2-allylpiperidine, the key chiral intermediate of halosine and hiradhenone. Preparation. Background technique [0002] According to reports, malaria is still one of the most serious tropical parasitic diseases in the world, and it is the most deadly case of infectious diseases after tuberculosis. It infects about 200 million people in some developing and poor countries every year, and Half a million people died. It still threatens the lives of millions of people in the Americas, Asia and the Pacific. Among the many antimalarial drugs, quinine, chloroquine and artemisinin products account for a considerable proportion. It is worth mentioning that the artemisinin discovered in traditional Chinese medicine by the older generation of Chin...

Claims

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Application Information

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IPC IPC(8): C07D211/42
CPCC07B2200/07C07D211/42Y02P20/55
Inventor 魏邦国刘艺雯毛卓亚司长梅林国强
Owner FUDAN UNIV
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