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Preparation method of 2-chlorine-N-(4-chlorine-3-(2-pyridyl)phenyl)-4-methyl sulfone phenyl benzamide

A technology of methyl sulfone phenyl benzamide and pyridyl, applied in the field of preparation of 2-chloro-N-phenyl)-4-methyl sulfone phenyl benzamide, achieving various types, high yield, Simple operation effect

Inactive Publication Date: 2015-09-23
TIANJIN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The bromine atom can be converted into an amino group through a transition metal-catalyzed coupling reaction, and finally the introduction of the meta-amino group has not been reported.

Method used

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  • Preparation method of 2-chlorine-N-(4-chlorine-3-(2-pyridyl)phenyl)-4-methyl sulfone phenyl benzamide
  • Preparation method of 2-chlorine-N-(4-chlorine-3-(2-pyridyl)phenyl)-4-methyl sulfone phenyl benzamide

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0030] Preparation of 2-(2-chloro-5-bromophenyl)pyridine (II):

[0031] Dissolve 2-phenylpyridine (I, 0.155g, 1.0mmol), N-bromosuccinimide (NBS, 0.356g, 2.0mmol) in N,N-dimethylacetamide (DMA, 5.0mL ), add ruthenium catalyst (4-methyl-cumene) ruthenium dichloride dimer (31mg, 0.05mmol, 10mol%) and add the first ketone catalyst copper acetate (44mg , 0.2mmol, 20mol%) and N-chlorosuccinimide (NCS, 0.266g, 2.0mmol), the temperature was raised to 120°C for 48 hours. After the reaction was completed, it was extracted with ethyl acetate, washed with water, dried, and purified by column chromatography to obtain 0.203 g of 2-(2-chloro-5-bromophenyl)pyridine (II), with a yield of 76%.

[0032] Experiments have proved that N,N-dimethylformamide can also be used as the solvent in this example. The ruthenium catalyst can also use (1,5-cyclooctadiene) ruthenium dichloride, Grubbs catalyst, (1.2.3.4.5-pentamethylcyclopentadiene) ruthenium dichloride polymer or trichloride ruthenium. The...

Embodiment 2

[0034] Preparation of 2-(2-chloro-5-amidophenyl)pyridine(III)

[0035] Dissolve 2-(2-chloro-5-bromophenyl)pyridine (II, 0.134g, 0.5mmol) in 1,4-dioxane, add the second copper catalyst copper iodide (19mg, 0.1 mmol, 20mol%), ligand N,N'-dimethylethylenediamine (29mg, 0.2mmol, 40mol%), reacted with benzamide (0.121g, 1.0mmol) at 100°C for 24 hours under nitrogen protection . After the reaction was completed, it was extracted with ethyl acetate, washed with water, dried, and purified by column chromatography to obtain 0.140 g of 2-(2-chloro-5-amidophenyl)pyridine (III), with a yield of 91%.

[0036] Experiments have proved that toluene, isopropanol, ethylene glycol, N,N-dimethylformamide or N,N-dimethylacetamide can also be used as the solvent in this embodiment. The second copper catalyst can also use cuprous chloride, cuprous bromide or cuprous oxide; or select palladium acetate, three (dibenzylidene acetone) dipalladium, (ferrocene) palladium chloride in the palladium cataly...

Embodiment 3

[0038] Preparation of 2-(2-chloro-5-aminophenyl)pyridine (IV)

[0039] Add 2-(2-chloro-5-amidophenyl)pyridine (III, 0.123g, 0.4mmol) into dilute sulfuric acid aqueous solution (volume concentration 20%, 4.0mL), and react at 100°C for 24 hours. After the reaction was completed, it was neutralized with dilute sodium carbonate aqueous solution, extracted with ethyl acetate, dried and purified by column chromatography to obtain 0.079 g of 2-(2-chloro-5-aminophenyl)pyridine (IV), with a yield of 96% .

[0040] Experiments have proved that: the volumetric concentration of sulfuric acid aqueous solution also can use 10% or 30%; Also can use the hydrochloric acid aqueous solution of 10%, 20% or 30%. The reaction can also be carried out at 90° C. for 20 hours, and dichloromethane can also be used as the extractant.

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Abstract

The invention discloses a preparation method of 2-chlorine-N-(4-chlorine-3-(2-pyridyl)phenyl)-4-methyl sulfone phenyl benzamide. The reaction formula is as shown in the specification. The method disclosed by the invention has the advantages that the operation is simple; the reaction materials and reaction reagents are easy to obtain; the substituent groups of products are varied in types; the yield is high, and the like.

Description

technical field [0001] The present invention relates to a process for the preparation of 2-chloro-N-(4-chloro-3-(2-pyridyl)phenyl)-4-methylsulfonephenylbenzamide (Erivedge). Background technique [0002] Erivedge (Vismodegib) is a novel oral drug with selective Hedgehog signaling pathway. Manufactured by Roche's Genentech company, it has been approved by the FDA for the treatment of basal cell carcinoma, the first drug ever approved for the treatment of basal cell carcinoma. It works by inhibiting the Hedgehog pathway, which is active in most basal cell carcinomas but only in a few normal tissues, such as hair follicles [1] . [0003] Utilizing the traditional method to synthesize the drug requires a long route. Among them, the most critical method of introducing the meta-amino group of phenylpyridine is to use the method of first introducing the nitro group and then reducing it. [2-4] . [0004] [1] B. Leach. Vismodegib, First Hedgehog Inhibitor, Approved for BCC Patie...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D213/40
CPCC07D213/40
Inventor 黄剑辉于庆贞郑莎莎
Owner TIANJIN UNIV
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