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8, 8-difluoro-swainsonine [(-)-Swainsonine] derivative and preparation method thereof

A technology of swainsonine and its derivatives, applied in the direction of organic chemistry, can solve the problems of (-)-Swainsonine structure-activity relationship that has not been reported, and achieve excellent inhibitory selectivity effect

Active Publication Date: 2017-01-25
ABA CHEM CORP
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] So far, no research on the structure-activity relationship of (-)-Swainsonine has been reported

Method used

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  • 8, 8-difluoro-swainsonine [(-)-Swainsonine] derivative and preparation method thereof
  • 8, 8-difluoro-swainsonine [(-)-Swainsonine] derivative and preparation method thereof
  • 8, 8-difluoro-swainsonine [(-)-Swainsonine] derivative and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0054] Preparation of a 8,8-difluoro-swainsonine [(-)-Swainsonine] derivative

[0055] Step 1: Prepare S-tert-butylsulfinimide 7 by reacting S-tert-butylsulfinamide 5 with acrolein 6. The specific reaction conditions are: adding tetrabutyl titanate (Ti(OEt) 4 ), the solvent was dichloromethane (DCM), room temperature, overnight. The yield of S-tert-butylsulfinimide 7 was 77%.

[0056] Step 2: Add the activated zinc powder to dry tetrahydrofuran (THF), heat to full reflux, and mix S-tert-butylsulfinimide 7 with ethyl difluorobromoacetate (BrCF 2 CO 2 The THF solution of Et) was added thereto, and S-tert-butylsulfinimide 7 reacted with ethyl difluorobromoacetate zinc reagent generated on site by Reformatskii addition reaction to generate ester 4. The specific reaction conditions are: reflux for 1h. After quenching the reaction, the system was detected by fluorine spectroscopy, and the diastereoisomer dr ratio of ester 4 was about 6.5:1, and the two could not be separated by...

Embodiment 2

[0070] Preparation of a 8,8-difluoro-swainsonine [(-)-Swainsonine] derivative

[0071] Step 1: Prepare S-tert-butylsulfinimide 7 by reacting S-tert-butylsulfinamide 5 with acrolein 6. The specific reaction conditions are: adding tetrabutyl titanate (Ti(OEt) 4 ), the solvent was dichloromethane (DCM), room temperature, overnight. The yield of S-tert-butylsulfinimide 7 was 77%.

[0072] Step 2: Add the activated zinc powder to dry tetrahydrofuran (THF), heat to full reflux, and mix S-tert-butylsulfinimide 7 with ethyl difluorobromoacetate (BrCF 2 CO 2 The THF solution of Et) was added thereto, and S-tert-butylsulfinimide 7 reacted with ethyl difluorobromoacetate zinc reagent generated on site by Reformatskii addition reaction to generate ester 4. The specific reaction conditions are: reflux for 1h. After quenching the reaction, the system was detected by fluorine spectroscopy, and the diastereoisomer dr ratio of ester 4 was about 6.5:1, and the two could not be separated by...

Embodiment 3

[0086] Preparation of a 8,8-difluoro-swainsonine [(-)-Swainsonine] derivative

[0087] Step 1: Prepare S-tert-butylsulfinimide 7 by reacting S-tert-butylsulfinamide 5 with acrolein 6. The specific reaction conditions are: adding tetrabutyl titanate (Ti(OEt) 4 ), the solvent was dichloromethane (DCM), room temperature, overnight. The yield of S-tert-butylsulfinimide 7 was 77%.

[0088] Step 2: Add the activated zinc powder to dry tetrahydrofuran (THF), heat to full reflux, and mix S-tert-butylsulfinimide 7 with ethyl difluorobromoacetate (BrCF 2 CO 2 The THF solution of Et) was added thereto, and S-tert-butylsulfinimide 7 reacted with ethyl difluorobromoacetate zinc reagent generated on site by Reformatskii addition reaction to generate ester 4. The specific reaction conditions are: reflux for 1h. After quenching the reaction, the system was detected by fluorine spectroscopy, and the diastereoisomer dr ratio of ester 4 was about 6.5:1, and the two could not be separated by...

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Abstract

The invention provides a 8, 8-difluoro-swainsonine [(-)-Swainsonine] derivative and a preparation method thereof. The preparation method includes following steps: reacting S-tert-butyl sulfonamide with acrolein to prepare S-sulfoximine; reacting S-sulfoximine, zinc powder and difluro ethyl bromoacetate (BrCF2CO2Et) to generate a compound shown as a formula 4; reducing the compound shown as the formula 4 to obtain aldehyde; subjecting aldehyde directly to Wittig reaction to obtain alpha, beta-unsaturated ester; reducing the alpha, beta-unsaturated ester to obtain primary alcohol; adding mesyl on primary hydroxyl of the primary alcohol; enablig an obtained compound to be in intramolecular nucleophilic substitution reaction to obtain a compound shown as a formula 11; removing sulfinyl from the compound shown as the formula 11 to obtain a hydrochloride; adding allyl on the hydrochloride to obtain a compound shown as a formula 3; using the compound shown as the formula 11 as a raw material to prepare a target product. The compound prepared serves as both a glycosidase inhibitor and monosaccharide having inhibition selectivity.

Description

technical field [0001] The invention relates to 8,8-difluoro-swainsonine [(-)-Swainsonine] derivatives and a preparation method thereof. Background technique [0002] Azabicyclic nitrogen sugar swainsonine [(-)-Swainsonine], castanospermine [(+)-Castanospermine] and their analogues are efficient α-, β-glucosidase inhibitors, and have good Antiviral and antitumor activity. Therefore, research on their total synthesis and structure-activity relationship has been widely concerned. [0003] In the research on the structure-activity relationship of (+)-Castanospermine, P.C. Taylor's group has done a lot of systematic work. Among them, after the group modified the C-8, C-1 and C-7 hydroxyl groups of (+)-Castanospermine in 1995 and 1997, they found that: the C-1 hydroxyl group in the (+)-Castanospermine molecular structure and Its configuration is the key site that affects its biological activity, and its chirality is the key to the recognition of nitrogen sugar by glycosidase. ...

Claims

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Application Information

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IPC IPC(8): C07D471/04
CPCC07D471/04
Inventor 徐军蒋信义张敏华肖方亮毛建勇
Owner ABA CHEM CORP
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