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Preparation method of antitumor drug molecule (+)-Preussin intermediate

A technology for anti-tumor drugs and intermediates, which is applied in the field of preparation of anti-tumor drug molecules-Preussin intermediates, can solve the problems of limited reaction volume, easy configuration reversal, and difficult purification, and achieve good economy, simple steps, Solve the effect of many impurities

Pending Publication Date: 2020-03-10
JINHUA VOCATIONAL TECH COLLEGE
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

For example, in 2003, the Raghavan group started from the sulfoxide compound and converted the raw material into oxazolidinone through four steps, then underwent Pummer rearrangement, hydrolyzed to form the compound, and then added, deprotected the carbonyl group, protected the hydroxyl group, reduced, and finally Carry out catalytic hydrogenation and deprotection to generate preussin synthesis, the route is 12 steps long, the total yield is only 8%, and the intermediate needs to be purified by column chromatography. There are many impurities in the direct catalytic hydrogenation process, and the configuration is easy to reverse. Difficult to purify, the amount of one reaction is very limited, staying at the milligram level

Method used

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  • Preparation method of antitumor drug molecule (+)-Preussin intermediate
  • Preparation method of antitumor drug molecule (+)-Preussin intermediate
  • Preparation method of antitumor drug molecule (+)-Preussin intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0035] The preparation of intermediate compound described in formula (I)

[0036]

[0037] Dissolve the compound aziridine-unsaturated aldehyde (201mg) shown in formula (A) in ethanol (3.3mL), stir well, add catalyst (0.03mL, 0.01mol) and percentage concentration be 35% Hydrogen peroxide (0.2mL, 1.2mmol), after 5-7 hours of reaction, quenched with distilled water, then extracted three times with 10mL of dichloromethane, dried the collected organic phase with anhydrous sodium sulfate, vacuumed and removed the solvent The crude product was obtained, and 180 mg of the intermediate compound of formula (I) was obtained after separation by flash column chromatography, and the yield was 75%;

[0038] Wherein said catalyst chemical formula is:

[0039]

[0040] The coupling constant of the compound described in the formula (I) obtained wherein is: [α] D20=+57.1 (c1.00, CHCl 3 ); Rf = 0.35 (EtOAc / hexanes = 1:1); 1 H NMR (400MHz, CDCl 3 )δ8.92(d,J=6.2Hz,1H),7.38–7.21(m,5H),3.1...

Embodiment 2

[0043] The preparation of intermediate compound described in formula (II)

[0044]

[0045]Dissolve the compound (200mg, 0.92mmol) of the formula (I) prepared in Example 1 in dichloromethane (3ml), mix well, stir well at room temperature, then add NHC catalyst (0.023mL, 0.092mmol ), the above mixture was quenched with 5 mL of saturated ammonium chloride solution after 24 hours of reaction, and then extracted twice with 10 mL of ethyl acetate.

[0046] Then the collected organic phase was dried with anhydrous sodium sulfate, and the solvent was removed after vacuuming to obtain the crude product, which was separated by flash column chromatography to obtain 175mg of the intermediate compound described in formula (II), with a yield of 76%;

[0047] The coupling constant of the compound described in the formula (II) obtained wherein is: [α] D20=+35.6 (c1.00, CHCl3); Rf=0.28 (EtOAc / hexanes=1:1); 1H NMR (400MHz, CDCl3) δ7.42–7.26(m,5H),3.79(dt,J=7.7,4.8Hz,1H),3.63(s,3H),3.16(s,1...

Embodiment 3

[0050] The preparation of intermediate compound described in formula (III)

[0051]

[0052] Under the reaction condition of -5~5 ℃, in the reactor of nitrogen protection, add the intermediate compound (200mg, 0.92mmol) described in formula (II) prepared by the preparation method of Example 2 and dichloromethane (3mL), mix After uniformity, 200mg TBSCl (1.382mmol0 and DMAP (337mg, 2.763mmol) were added under magnetic stirring, and the above mixture was kept at -5-5°C. After stirring for 5-10 minutes, the temperature was slowly raised to room temperature. After reacting at room temperature for 6-8 hours, quench with saturated sodium bicarbonate solution (5mL), collect the organic phase, then extract the aqueous phase twice with dichloromethane solution (25mL), after the organic phases of collection are combined, use Wash with 10 mL of saturated brine, then dry with anhydrous sodium sulfate, filter, remove the solvent after vacuuming to obtain a crude product, and obtain 341 ...

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Abstract

The invention discloses a preparation method of an antitumor drug molecule (+)-Preussin intermediate, and the method comprises the following steps: carrying out epoxidation reaction on chiral aziridine-unsaturated aldehyde to generate chiral epoxide-aziridine, reacting the chiral epoxide-aziridine with methanol to reserve an aziridine ring by regioselectivity, and opening the epoxide ring to generate aziridine-beta-hydroxy ester; reactingthe aziridine-beta-hydroxy ester with a protective reagent TBSC1 to protect the beta position of the aziridine-beta-hydroxy ester, reacting with a Grignard reagent PhMgBr to generate an aziridine ring opening product, and finally carrying out reduction and cyclization reactions to generate the Preussin intermediate. According to the invention, the antitumor drug molecule (+)-Preussin medical intermediate is efficiently prepared only through a conventional organic reaction; according to the present invention, the problems of more impurities, easy configuration overturning, low yield, difficult purification and the like in the Preussin intermediate synthesis reaction are effectively solved, the total yield of the Preussin intermediate is substantially improved, the post-purification treatment is convenient, and the method has good economy, and is suitable for industrial production.

Description

technical field [0001] The invention belongs to the technical field of drug synthesis, and in particular relates to a preparation method of an antineoplastic drug molecule (+)-Preussin intermediate. Background technique [0002] The alkaloid Preussin has antifungal activity and antitumor activity, and more and more Chinese and foreign researchers are exploring its synthesis method. At present, there are two main methods for synthesizing Preussin: one is to use achiral compound as the starting material to construct the target compound through asymmetric reaction using chiral prosthetic group, chiral reagent control and chiral catalyst; the other is to construct the target compound through chiral Natural products or synthetic substrates are used as starting materials to construct target products. For example, in 2003, the Raghavan group started from the sulfoxide compound and converted the raw material into oxazolidinone through four steps, then underwent Pummer rearrangement...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07F7/18
CPCC07F7/1892Y02P20/55
Inventor 毛辉刘振香
Owner JINHUA VOCATIONAL TECH COLLEGE
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