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Synthetic method of key intermediate Tuv of natural anti-cancer drug Tubulysins

A synthesis method and technology of anticancer drugs, applied in organic chemistry and other fields, can solve the problems of low practicability, difficult scale-up synthesis, cumbersome operation, etc., and achieve the effect of low cost, simple post-treatment process, and good stereoselectivity

Active Publication Date: 2020-07-28
SHENZHEN ELDERLY MEDICAL RES INST +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0031] This synthetic route is novel in idea, high in yield, and good in stereoselectivity; but it has many steps, tedious operation, and the use of highly toxic sodium cyanide, which is very unsafe, difficult to scale up and synthesized, and not very practical

Method used

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  • Synthetic method of key intermediate Tuv of natural anti-cancer drug Tubulysins
  • Synthetic method of key intermediate Tuv of natural anti-cancer drug Tubulysins
  • Synthetic method of key intermediate Tuv of natural anti-cancer drug Tubulysins

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preparation example Construction

[0063] The present invention provides a method for synthesizing Tuv, a key intermediate of natural anticancer drug Tubulysins, and the route of the synthesis method is as follows:

[0064]

[0065] Including the following steps:

[0066] Step 1. Dissolve the starting material L-valinol 1 in a tetrahydrofuran / water mixed solvent, add solid sodium bicarbonate and benzyl chloroformate CbzCl, and react at room temperature overnight to obtain compound 2;

[0067] Step 2. Dissolve compound 2 obtained in step 1 in acetonitrile, add 2-iodoyl benzoic acid, and react with heating under reflux to obtain intermediate aldehyde 3;

[0068] Dissolve the intermediate aldehyde 3 in dichloromethane, add Wittig reagent 4 and tetramethylguanidine, and react under reflux with heating to obtain compound 5;

[0069] Step 3. Dissolving the compound 5 in a mixed solvent of tetrahydrofuran / water, adding solid sodium hydroxide, and heating and refluxing to react to obtain compound 6;

[0070] Using compound 6 as t...

Embodiment approach

[0080] As an embodiment, in the step 3, the molar ratio of compound 5: sodium hydroxide: compound 7: FDPP: triethylamine: triphenylphosphine: DBU: chlorobromomethane is 1:10-20:0.5- 0.55:1-1.2:2-3:5-6:3-4:2-3, preferably 1:15:0.5:1:2:5:3:2.

[0081] As an embodiment, the compound 5 is reacted with sodium hydroxide for 4-6 hours, preferably for 4 hours. After the reaction, it is concentrated under reduced pressure, acidified with dilute hydrochloric acid, extracted with ethyl acetate three times, and the combined organic phase is washed with saturated brine , Liquid separation, the organic phase was dried with anhydrous sodium sulfate, filtered and concentrated to obtain compound 6;

[0082] Then dissolve compound 6 in dichloromethane, add FDPP (that is, pentafluorophenyl diphenyl phosphate) and triethylamine, react at room temperature for 0.5 to 1 h, preferably 0.5 h, then add compound 7 and triphenyl Phosphine, heat reflux for reaction for 7-12h, preferably 10h, then cool to room...

Embodiment 1

[0088] Example 1: Synthesis of Compound 2

[0089]

[0090] Dissolve L-valinol 1 (20g, 193.9mmol) in a mixed solvent of tetrahydrofuran / water (1:1, 800mL), add sodium bicarbonate (50.4g, 600mmol), stir well, and cool to 0°C in an ice-water bath Benzyl chloroformate, CbzCl (27.3mL, 193.9mmol) was slowly added dropwise. After 30 minutes, the temperature was raised to room temperature and the reaction was stirred for 12h, concentrated under reduced pressure, diluted with water (200mL), and extracted three times with ethyl acetate (300mL). Combine the organic phases. , Dried over anhydrous sodium sulfate, concentrated under reduced pressure to obtain compound 2, 43.7 g of white solid, with a yield of 95%. Used directly in the next reaction.

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Abstract

The invention belongs to the technical field of chemical synthesis, and particularly relates to a synthesis method of a key intermediate Tuv of a natural anti-cancer drug Tubulysins. With L-valinol (1) which is cheap and easy to obtain as a raw material, the synthesis method includes steps of: firstly, protecting amino groups with CbzCl; then carrying out an oxidation reaction and a Wittig reaction; hydrolyzing methyl ester to obtain carboxylic acid, and carrying out a reaction with carboxylic acid serving as a substrate with beta-azido disulfide under mild reaction conditions under the combined action of a coupling reagent and an organic phosphine reagent to prepare a thiazoline intermediate product;, then reacting the and further efficiently synthesizing the 2,4-disubstituted thiazole compound by adding an oxidizing reagent through a one-pot method. The preparation method comprises the following steps: by taking (S)-2-methyl-CBS-oxazolyl borane as a raw material, hydrolyzing under anacidic condition, converting methyl enol ether into a ketone compound, and finally performing asymmetric reduction reaction by taking (S)-2-methyl-CBS-oxazolyl borane as a catalyst, thereby obtainingthe target compound.

Description

Technical field [0001] The invention belongs to the technical field of chemical synthesis, and specifically relates to a method for synthesizing Tuv, a key intermediate of the natural anticancer drug Tubulysins. Background technique [0002] Tuv is a key intermediate of Tubulysins family compounds of natural anticancer drugs. The structural formula of Tubulysins family compounds is as follows, where the structure shown in the dashed circle is derived from the key intermediate Tuv. [0003] [0004] The structural formulas of existing Tubulysins family molecules are shown in Table 1. [0005] Table 1 [0006] [0007] In 2000, Et al. reported for the first time a small linear tetrapeptide molecule isolated from myxobacteria. Because they mainly act on the tubulin cytoskeleto of cells, this class of compounds is named Tubulysins. [0008] Studies have found that Tubulysins not only have high anti-cancer activity, for example, N 14 -IC of DesacetoxytubulysinH 50 It is about 100-5000 tim...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D277/56
CPCC07D277/56
Inventor 吴正治龙伯华李映红姜倩倩刘洁人刘展艳
Owner SHENZHEN ELDERLY MEDICAL RES INST
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