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Synthetic method of Taladegib

A synthetic method and compound technology, applied in the field of medicine and chemical industry, can solve the problems of complicated operation, high cost, unsuitable for mass production, etc., and achieve the effect of simple operation and increased yield

Active Publication Date: 2017-01-04
SOUTHEAST UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] In summary, this route has high cost, complex operation, low yield, and is not suitable for mass production

Method used

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  • Synthetic method of Taladegib
  • Synthetic method of Taladegib
  • Synthetic method of Taladegib

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0038] The preparation of embodiment 1 compound 6 (structure such as formula 6)

[0039] The raw material N-benzylpiperidone (Formula 5, 2g, 10.568mmol, 1.0eq.) was dissolved in 30mL of methanol, 4 drops of glacial acetic acid was added dropwise to the solution, and after stirring evenly, 0.785g (11.625mmol, 1.1 eq.) of methylamine hydrochloride, react at room temperature (25°C) for 2h; move the reaction into an ice-water bath, and after the reaction temperature drops to 0°C, add 1.328g (21.136mmol, 2eq.) of cyano group in batches Sodium borohydride, the batch addition time is controlled at about 10min; after stirring evenly, remove the reaction from the ice-water bath, and react at room temperature for 16h; after the reaction, pour the reaction mixture into saturated sodium bicarbonate solution or sodium carbonate solution, and use two Chloromethane was extracted three times, the organic layers were combined, dried by adding anhydrous sodium sulfate, and concentrated under re...

Embodiment 2

[0042] The preparation of embodiment 2 compound 8 (structure such as formula 8)

preparation example 2-1

[0043] Preparation Example 2-1: Dissolve compound 6 (1.5g, 7.342mmol, 1eq.) in 30mL of dichloromethane, add 2mL of triethylamine to the solution, stir well and add 1.663g (1eq.) of 4-fluoro-2-(trifluoromethyl)benzoyl chloride (CAS No. 189807-21-4), reacted at room temperature for 6h; after the reaction, concentrated under reduced pressure to obtain a crude product, purified by column chromatography (eluent (dichloromethane / methanol, the volume ratio is 20:1) to obtain the pure product 8 (compound 8, 2.720 g, yield 94%) as a colorless oil.

[0044] The test data of product 8 are as follows:

[0045] 1 H NMR (300Mz, CDCl 3 )δ7.39(m,1H),7.32-7.22(m,7H),4.60(m,1H),3.40(s,2H),3.10-2.83(m,2H),2.65(s,3H),2.16 (m,2H),1.93-1.58(m,4H)ppm; MS(ESI)m / z:[M+H] + = 395.18077.

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Abstract

The invention discloses a synthetic method of Taladegib. The synthetic method is characterized by comprising the following steps that reductive amination is carried out on N-benzyl-4-piperidone to obtain a compound in formula VI; in the presence of an organic base, an acylation reaction is carried out on the compound in the formula VI and an acylation reagent to obtain a compound in the formula VIII; the acylation reagent is 4-fluoro-2-(trifluoromethyl)benzoyl chloride; in the presence of a hydrogen source and a palladium catalyst, debenzylation is carried out on the compound in formula VIII to obtain a compound in the formula IX; in the presence of an inorganic base, the compound in the formula IX is reacted with 1,4-dichloro phthalazine to obtain a compound in the formula X; in the presence of the inorganic base and the palladium catalyst, an SUZUKI coupling reaction is carried out on the compound in the formula X and 1-methyl-1H-pyrazole-5-boronic acid pinacol ester to obtain Taladegib. According to the invention, the process route is improved, cheap N-benzyl-4-piperidone is taken as a starting material, the processes of Boc protection and deprotection are removed to reduce the synthesis steps and reduce the production cost.

Description

technical field [0001] The invention belongs to the field of medicine and chemical industry, and in particular relates to a synthesis method of Taladegib. Background technique [0002] The Hedgehog signaling pathway is a classic signal transduction pathway controlling embryonic development, which plays an important role in embryonic development and cell growth and differentiation after embryogenesis. A large amount of evidence shows that abnormal activation of the Hedgehog signaling pathway is related to tumorigenesis, such as basal cell carcinomas (BCCs), medulloblastoma and some solid tumors; in addition, studies have also found that Hedgehog signaling has some associations with cancer stem cells. Therefore, the Hedgehog signaling pathway has emerged as a promising target for anticancer drug discovery. [0003] At present, people have developed many small molecule inhibitors targeting the key component protein Smoothened in the Hedgehog signaling pathway, some of which ar...

Claims

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Application Information

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IPC IPC(8): C07D401/14
CPCC07D401/14
Inventor 蔡进郭明亮吉民刘文景陈国庆徐华
Owner SOUTHEAST UNIV
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