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A kind of preparation method of anticancer drug intermediate

A technology for intermediates and compounds, applied in the direction of organic chemistry, etc., can solve the problems of difficult post-processing purification, affecting yield, and many reaction impurities.

Active Publication Date: 2021-02-26
重庆南松凯博生物制药有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

There are many reaction sites in the last step, and self-condensation is very easy to occur. There are many impurities in the reaction, and the post-treatment purification is difficult, which greatly affects the yield of the reaction and increases the difficulty of separation.
Although the literature reports a yield of 77%, the post-treatment is still achieved through a column, which is greatly limited in industry

Method used

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  • A kind of preparation method of anticancer drug intermediate
  • A kind of preparation method of anticancer drug intermediate
  • A kind of preparation method of anticancer drug intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0028] Synthesis of Compound II (R=Et)

[0029] 1.1 Dissolve 10g (0.054mol) of L-cysteine ​​ethyl ester hydrochloride in 100ml of water, and add 4.5g of sodium bicarbonate. Stir to dissolve and drop into a solution of 10.5g (0.081mol) of D-glyceraldehyde acetone in ethanol (65ml). After dropping, the temperature was raised to 25~35°C for 1 hour reaction. After the reaction was completed, it was extracted twice with 100ml of dichloromethane. The organic layers were combined and washed with 50 ml of water. Dry over anhydrous magnesium sulfate and concentrate to obtain 12.1 g.

[0030] 1.2 Dissolve 10g (0.054mol) of L-cysteine ​​ethyl ester hydrochloride in 100ml of water, and add 4.5g of sodium bicarbonate. Stir to dissolve and drop into a solution of 10.5g (0.081mol) of D-glyceraldehyde acetone in ethanol (65ml). After dripping, raise the temperature to 40~50°C for 0.5h reaction. After the reaction was completed, it was extracted twice with 100ml of dichloromethane. The ...

Embodiment 2

[0032] Synthesis of Compound III (R=Et)

[0033] 2.1 Dissolve 10g of compound II (R=Et, 0.038mol) in 100ml of acetonitrile, add 80g of manganese dioxide, stir and heat up to 60~65℃ for 2 hours, filter with suction, add 17ml of concentrated hydrochloric acid to the filtrate and stir at 30~40℃ 1h. After concentrating under reduced pressure at 30~40°C, add 50ml of dichloromethane and 20ml of water to dissolve, and adjust the alkali to neutral with saturated sodium bicarbonate solution. Separate the layers, extract the aqueous layer with 25ml of dichloromethane, combine the organic layers, wash with 50ml of water, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. 7.4 g of solid were obtained.

[0034] 2.2 Dissolve 10g of compound II (R=Et, 0.038mol) into 100ml of acetonitrile, add 80g of manganese dioxide, stir and raise the temperature to 50~55°C for 3h. Suction. Add 17ml of concentrated hydrochloric acid to the filtrate and stir at 30~40°C for 1h. A...

Embodiment 3

[0036] Synthesis of Compound IV (R=Et)

[0037] 3.1 Dissolve 10g of compound III (R=Et, 0.046mol) into 100ml of acetonitrile, add 40g of manganese dioxide, stir and raise the temperature to 60~65°C for 2h. Suction. Concentrate under reduced pressure. 8.9 g of solid were obtained.

[0038] 3.2 Dissolve 10g of compound III (R=Et, 0.046mol) in 100ml of chloroform, add 40g of manganese dioxide, stir and raise the temperature to 60~65°C for reflux reaction for 4h. Suction. Concentration under reduced pressure gave 8.2 g of solid.

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Abstract

The invention discloses a preparation method of an anticancer drug intermediate, which uses glyceraldehyde acetone and L-cysteine ​​hydrochloride as raw materials, and undergoes the steps of ring closing, oxidation, depropylidene, reoxidation, halogenation, etc. The compound of formula VI is obtained, and the compound of formula VI is further reacted with isobutyraldehyde by Wittig to obtain the compound of formula I.

Description

technical field [0001] The invention belongs to the field of medicine and chemical industry. Background technique [0002] Tubulysins is a drug that has an important curative effect on prostate cancer, and the research on its key intermediates and process is particularly important. At present, L-cysteine ​​ethyl ester hydrochloride is commonly used as a raw material to obtain enone intermediate 2-acetyl-4-carboxylate thiazole through ring closure and oxidation. Enone intermediates are prepared through a series of reactions to obtain Tubulysins. [0003] The preparation of the enone intermediate is as follows: [0004] [0005] This route involves ring closure of L-cysteine ​​ester hydrochloride and methylglyoxal followed by oxidation by manganese dioxide. According to literature reports, the yield of these two steps is only 52%. Then the condensation reaction in the next step is catalyzed by titanium tetrachloride to generate enone and then dehydrated to generate the ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D277/56
CPCC07D277/56
Inventor 刘登贵杨坤于周伟陈浩曾庆东
Owner 重庆南松凯博生物制药有限公司