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Method for synthetizing orixine and RU-19110 intermediate

A technology of RU-19110 and intermediates, applied in the direction of organic chemistry, etc., can solve the problems of low total yield and unsatisfactory selectivity of key steps, and achieve the effect of high yield and simple operation and separation

Inactive Publication Date: 2005-02-23
XIAMEN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0021] Though above-mentioned synthesis method says that route is shorter, the selectivity of key step is not ideal, and total yield is lower (3.6%)

Method used

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  • Method for synthetizing orixine and RU-19110 intermediate
  • Method for synthetizing orixine and RU-19110 intermediate
  • Method for synthetizing orixine and RU-19110 intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0036] Step 1 Synthesis of (S)-3-tert-butyldimethylsilyloxy-1-(4-methoxybenzyl)-2,6-piperidinedione 5

[0037] Under the protection of nitrogen, to the solution of compound 4 (17.61 mmol) and imidazole (35.21 mmol) in dichloromethane was added a solution of tert-butyldimethylsilyl chloride (17.61 mmol) in dichloromethane (20 mL). Stir at room temperature for 6 h, add water, separate the layers, extract the aqueous phase with dichloromethane three times, wash the organic layer with saturated brine (10 mL×3) three times, dry over anhydrous sodium sulfate, and concentrate. The crude product was purified by silica gel column to obtain 5 (83%) as a colorless solid.

[0038] Step 2 Synthesis of (S)-1-(4-methoxybenzyl)-5-(tert-butyldimethylsilyloxy)-6-allyl-6-hydroxyl-2-piperidone 6

[0039]Under the protection of nitrogen, to dissolve compound 5 (2.8 mmol) in dichloromethane, slowly add a solution of AllyMgBr (8.4 mmol) in diethyl ether at -78°C, and stir for 3 h. Add 10mL NH 4 Q...

Embodiment 2

[0049] Step 1 Synthesis of (S)-3-tert-butyldimethylsilyloxy-1-(4-methoxybenzyl)-2,6-piperidinedione 5

[0050] The operation of compound 5 was the same as that in Example 1, the reaction solvent was changed to tetrahydrofuran, stirred at room temperature for 12 h, and the yield was 89%.

[0051] Step 2 Synthesis of (S)-1-(4-methoxybenzyl)-5-(tert-butyldimethylsilyloxy)-6-allyl-6-hydroxy-2-piperidone 6

[0052] Under the protection of nitrogen, a diethyl ether solution of allylmagnesium bromide was slowly added into THF dissolving compound 5 (300mg) at -78°C, and stirred for 5h. with saturated NH 4 Cl quenched. Extracted 3 times with anhydrous ether. Na 2 SO 4 After drying and concentration, the crude product was purified by silica gel (EtOAc / PE) column to obtain 6 in 76% yield and 20 / 80 regioselectivity.

[0053] Step 3 Synthesis of (S)-1-(4-methoxybenzyl)-5-(tert-butyldimethylsilyloxy)-6-allyl-2-piperidone 7

[0054] Under nitrogen protection, compound 6 was dissolved ...

Embodiment 3

[0062] Step 1 Synthesis of (S)-3-tert-butyldimethylsilyloxy-1-(4-methoxybenzyl)-2,6-piperidinedione 5

[0063] The operation of compound 5 was the same as that in Example 1, the solvent of the reaction was changed to N'N-dimethylformamide, the base used was triethylamine, stirred at room temperature for 15 h, and the yield was 55%.

[0064] Step 2 Synthesis of (S)-1-(4-methoxybenzyl)-5-(tert-butyldimethylsilyloxy)-6-allyl-6-hydroxy-2-piperidone 6

[0065] Compound 6 was prepared according to step 2 of Example 1.

[0066] Step 3 Synthesis of (S)-1-(4-methoxybenzyl)-5-(tert-butyldimethylsilyloxy)-6-allyl-2-piperidone 7

[0067] Under nitrogen protection, compound 6 was dissolved in dichloromethane, cooled to -78°C, and triethylsilane and tin tetrachloride were added. Natural stirring rose to room temperature for 16h. with saturated NaHCO 3 Quench the reaction, separate the layers, and use CH for the aqueous phase 2 Cl 2 Extracted 3 times, the organic phase was washed 3 tim...

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Abstract

A process for preparing dichroine and (2R, 3S)-1-benzyloxy-2-allyl-3-alkoxy piperidine as the intermediate of RU-19110 includes such steps as the reaction of imide on protecting agent to obtain compound E, reacting on allyl magnesium to obtain compound F, reacting on lewis acid and silane to obtain compound G, reacting on cerium ammonium nitrate to obtain compound H, reacting on litium aluminium hybrid to obtain protected (2R, 3S)-9, and reacting on meta-chloroperoxy benzoic acid to obtain compound J.

Description

technical field [0001] The present invention relates to a kind of heterocyclic compound, especially containing six-membered ring, not fused with other rings, with a nitrogen atom as the only heterocyclic atom, especially a kind of synthetic rhodosine and RU-19110 intermediate (2R, 3S)-1-benzyloxycarboxy-2-allyl-3-alkoxypyridine method. Background technique [0002] Malaria is one of the most serious typical parasitic diseases, and besides tuberculosis, it is the most deadly case of infectious diseases. Many drugs, such as Changshan, chloroquine, and quinoline are effective against malaria. Changshan (Dichroa febrifugelour) is a commonly used traditional Chinese medicine, which is mainly used to treat malaria. The active ingredients of antimalarial are Dichroa febrifugelour and Dichroa febrifugelour. The anti-malarial activity of halosine is more than 100 times that of quinine resistance, and the anti-malarial activity of halosine is equivalent to that of quinine. Although ...

Claims

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Application Information

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IPC IPC(8): C07D211/40C07D239/36C07D405/06
Inventor 黄培强魏邦国
Owner XIAMEN UNIV
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