Asymmetric synthesis method of triptolide intermediate

A technology for triptolide alcohol and a synthesis method, which is applied to the production of steroids, bulk chemicals, organic chemistry, etc., can solve the problems of low yield, harsh reaction conditions, insufficient yield, etc., and achieves non-corresponding selectivity Good, mild reaction conditions, the effect of improving the reaction yield

Active Publication Date: 2016-08-17
甘肃皓天医药科技有限责任公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, the free radical cyclization reaction conditions catalyzed by triacetic acid are relatively harsh, and the yield is still not high, and the stereoselectivity is not high enough to cause the yield to be not high enough. Can only be used for small batch synthesis in the laboratory
[0005] In view of the inefficiency and low selectivity of the existing method for synthesizing triptolide intermediate 4, triptolide and triptolide, and the good biological activity and potential application value of triptolide natural products, the development of compound 4 And the new efficient asymmetric synthesis method of triptolide and triptolide is of great significance

Method used

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  • Asymmetric synthesis method of triptolide intermediate
  • Asymmetric synthesis method of triptolide intermediate
  • Asymmetric synthesis method of triptolide intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0023] Example 1: In the synthetic route shown in formula 2 and formula 3, R is phenyl, R 1 is ethyl, R 2 It is trifluoromethyl, and compound 7 is converted into compound 8 under the action of 60% sodium hydride and trifluoromethanesulfonic anhydride. The catalyst is palladium acetate, and the catalyst used for catalytic hydrogenation reduction of compound 3 to compound 4 is Raney Ni.

[0024] Formula 6

[0025] Preparation of compound 7

[0026] In a 250mL three-neck round bottom flask, add 9.5g 1-methyl-5-methoxyl-2-tetralone 5, 6.7g (R)-α-phenylethylamine, 0.95g p-toluenesulfonic acid, and use Dissolve it in 100mL toluene, reflux and separate water under stirring until no water is separated, then cool down to 0 o C, what is obtained is compound 5-1, and 10.0g Nazanov reagent 3-oxo-4-ene-pentanoic acid ethyl ester 6 is slowly added dropwise to the above reaction solution with a constant pressure dropping funnel, after the dropwise addition is completed, the temper...

Embodiment 2

[0041] Embodiment two: in the synthetic route shown in formula 2, R is naphthyl, R 1 is methyl, R 2 For methyl, the chiral amine used is (R)-α-naphthyl ethylamine, compound 7 is converted into compound 8 under the action of potassium hexamethyldisilazide and methanesulfonic anhydride, the reduction of compound 8 The reagent is sodium borohydride-iodine, the catalyst for the carbonyl insertion reaction of compound 9 is palladium chloride, and the catalyst used for catalytic hydrogenation reduction of compound 3 to compound 4 is 5% Pd-C.

[0042] Formula 7

[0043] Preparation of compound 7

[0044] In a 250mL three-neck round bottom flask, add 9.5g 1-methyl-5-methoxy-2-tetralone 5, 8 g (R)-α-naphthylethylamine, 0.95g p-toluenesulfonic acid, and use Dissolve it in 100mL of benzene, reflux and separate water under stirring until no water is separated, and then cool down to 0 oC, to obtain 5-1, slowly drop 10.0g Nazarov reagent 3-oxo-4-ene-pentanoic acid methyl ester 6 ...

Embodiment 3

[0060] In the synthetic route shown in formula 2 and formula 4, R is phenyl, R 1 is isopropyl, R 2 For p-tolyl, the chiral amine used is (R)-α-naphthylethylamine, and the conversion of compound 7 into compound 8 is carried out under the action of potassium hexamethyldisilazide and p-toluenesulfonyl chloride, and the reduction of compound 8 The reducing agent is DiBAl-H, the catalyst for the carbonyl insertion reaction of compound 9 is palladium chloride, and the catalyst used for catalytic hydrogenation reduction of compound 3 to compound 4 is Raney Ni.

[0061]

[0062] Formula 8

[0063] Preparation of compound 7

[0064] In a 250mL three-neck round bottom flask, add 9.5g 1-methyl-5-methoxy-2-tetralone 5, 8g (R)-α-phenylethylamine, 0.95g benzenesulfonic acid, and use 100mL Dissolve it in toluene, reflux and separate water under stirring until no water comes out, and then cool down to 0 o C, to obtain 5-1, slowly drop 10.0g Nazarov reagent 3-oxo-4-ene-valeric acid...

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Abstract

The invention relates to a preparation method of an organic compound, and particularly relates to an asymmetric synthesis method of triptolide intermediate namely a compound 4 shown in formula in the specification. The synthesis method comprises the steps of: reacting a compound 5 shown in a formula 2 with a chiral amine reagent; reacting the product with a Nazarov reagent; acidifying to obtain a compound 7; reacting the compound 7 with a sulfonyl esterification reagent to obtain enol sulphonate 8; reducing ester group of the compound 8 to obtain alcohol 9; and finally, obtaining a key intermediate compound 4 for synthesizing triptolide.

Description

technical field [0001] The present invention relates to a kind of preparation method of organic compound, specifically the present invention relates to the triptolide intermediate synthesis method of compound 4 shown in following formula 1. [0002] Formula 1 Background technique [0003] Tripterygium wilfordii is a plant of the Euonymus family. As a traditional Chinese medicine, it has been used in the treatment of many diseases for a long time. Compounds 1 and 2 shown in the above formula, ie, triptolide and triptolide, are diterpene lactone compounds isolated from Tripterygium wilfordii plant. Studies in the past two decades have shown that they have a variety of significant biological activities such as anti-inflammatory, immunosuppressive, anti-tumor, and antibacterial. They are used by many research groups as lead compounds for new immunosuppressive and anti-cancer drugs. In addition, triptolide is also the main active ingredient in preparations such as Tripterygiu...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07J73/00
CPCY02P20/55
Inventor 薛吉军李海峰张虹锐王仕祥李瀛
Owner 甘肃皓天医药科技有限责任公司
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