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A kind of synthetic method of the key intermediate tuv of natural anticancer drug tubulysins

A synthesis method and technology for anticancer drugs, applied in the direction of organic chemistry and the like, can solve the problems of low practicability, difficult amplification and synthesis, complicated operation, etc., and achieve the effects of low cost, simple post-processing process and good stereoselectivity.

Active Publication Date: 2021-12-14
SHENZHEN ELDERLY MEDICAL RES INST +1
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  • Abstract
  • Description
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  • Application Information

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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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  • A kind of synthetic method of the key intermediate tuv of natural anticancer drug tubulysins
  • A kind of synthetic method of the key intermediate tuv of natural anticancer drug tubulysins
  • A kind of synthetic method of the key intermediate tuv of natural anticancer drug tubulysins

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preparation example Construction

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

[0064]

[0065] Including the following steps:

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

[0067] Step 2, dissolving the compound 2 obtained in step 1 in acetonitrile, adding 2-iodobenzoic acid, and heating to reflux to obtain the intermediate aldehyde 3;

[0068] Dissolving the intermediate aldehyde 3 in dichloromethane, adding Wittig reagent 4 and tetramethylguanidine, and heating under reflux to obtain compound 5;

[0069] Step 3, dissolving the compound 5 in a tetrahydrofuran / water mixed solvent, adding solid sodium hydroxide, and heating to reflux to obtain the compound 6;

[0070] Using co...

Embodiment approach

[0080] As an embodiment, in the step 3, the molar ratio of compound 5: sodium hydroxide: compound 7: FDPP: triethylamine: triphenylphosphine: DBU: trichlorobromomethane 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 three times with ethyl acetate, and the combined organic phases are washed with saturated brine. , liquid separation, the organic phase was dried with anhydrous sodium sulfate, filtered and concentrated to obtain compound 6;

[0082] Then compound 6 was dissolved in dichloromethane, FDPP (pentafluorophenyl diphenyl phosphate) and triethylamine were added, reacted at room temperature for 0.5-1h, preferably 0.5h, and then compound 7 and triphenyl Phosphine, heated to reflux for 7-12 hours, preferably 10 hours, th...

Embodiment 1

[0088] Embodiment 1: the synthesis of compound 2

[0089]

[0090] Dissolve L-valinol 1 (20g, 193.9mmol) in tetrahydrofuran / water (1:1, 800mL) mixed solvent, add sodium bicarbonate (50.4g, 600mmol), stir well and cool to 0 degree with ice-water bath , slowly added benzyl chloroformate CbzCl (27.3mL, 193.9mmol) dropwise, raised to room temperature after 30 minutes and stirred for 12h, concentrated under reduced pressure, diluted with water (200mL), extracted three times with ethyl acetate (300mL), and combined the organic phases , dried over anhydrous sodium sulfate, and 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 in particular relates to a method for synthesizing Tuv, a key intermediate of natural anticancer drug Tubulysins. Using cheap and easy-to-obtain L-valinol 1 as raw material, first protect the amino group with CbzCl, then carry out oxidation reaction and Wittig reaction, then hydrolyze the methyl ester to obtain carboxylic acid, and then use carboxylic acid as substrate, in the coupling reagent and organic Under the combined action of phosphine reagents, thiazoline intermediates are prepared by reacting with β-azidodisulfide under mild reaction conditions, and then 2,4-disubstituted thiazoles are efficiently synthesized in one pot by adding oxidizing reagents compound. Then hydrolyze under acidic conditions to convert methyl enol ether into ketone compound, and finally use (S)-2-methyl-CBS-oxazoboridine as a catalyst to obtain the target compound through asymmetric reduction reaction.

Description

technical field [0001] The invention belongs to the technical field of chemical synthesis, and in particular relates to a method for synthesizing Tuv, a key intermediate of natural anticancer drug Tubulysins. Background technique [0002] Tuv is a key intermediate of the natural anticancer drug Tubulysins family compound, the structural formula of the Tubulysins family compound is as follows, wherein the structure shown in the dotted circle area is derived from the key intermediate Tuv. [0003] [0004] The structural formulas of existing Tubulysins family molecules are specifically 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 anticancer activity, for example, N 14 - IC of Desaceto...

Claims

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Application Information

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Patent Type & Authority Patents(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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