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Preparation method of synthetic 2-(3,5-bis(trifluoromethyl)phenyl)-2-methyl propioric acid

A technology of trifluoromethyl and methylpropionic acid, which is applied in the field of preparation of 2-phenyl)-2-methylpropionic acid, which can solve the problems of high reaction risk factor, expensive auxiliary materials, and large production sewage discharge , to achieve the effect of short synthesis process, low raw material cost and high yield

Inactive Publication Date: 2018-02-23
ASTATECH CHENGDU BIOPHARM CORP
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0007] The invention provides a preparation method for synthesizing 2-(3,5-bis(trifluoromethyl)phenyl)-2-methylpropionic acid, which is used to solve the existing problems in the prior art: the reaction risk factor is high, and the production Large amount of sewage, easy to cause environmental pollution, expensive auxiliary materials, low yield and other technical problems

Method used

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  • Preparation method of synthetic 2-(3,5-bis(trifluoromethyl)phenyl)-2-methyl propioric acid
  • Preparation method of synthetic 2-(3,5-bis(trifluoromethyl)phenyl)-2-methyl propioric acid
  • Preparation method of synthetic 2-(3,5-bis(trifluoromethyl)phenyl)-2-methyl propioric acid

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Embodiment 1

[0040] A kind of preparation method of synthetic 2-(3,5-bis(trifluoromethyl)phenyl)-2-methylpropionic acid, as shown in following chemical reaction formula:

[0041]

[0042] Wherein S1 prepares the specific parameters of 2-(3,5-bis(trifluoromethyl)phenyl)-2-methylpropyl-1-one:

[0043]Isopropylmagnesium chloride (42g, 1.3eq) was added to a three-necked flask, and a solution of 3,5-bis(trifluoromethyl)bromobenzene (100g, 1.0eq) in tetrahydrofuran (300g) was added dropwise at 0°C. After the dropwise addition, the reaction system was reacted at 0°C for 1-1.5h, and then a solution of morpholine amide (43g, 0.8eq) in tetrahydrofuran (200 g) was added dropwise to the reaction system. Under reaction 3-4h. After the reaction, the reaction system was slowly added to water, the organic phase was separated, and the aqueous phase was extracted with methyl tert-butyl ether (500g,) again, the organic phase was concentrated to dryness, and column chromatography (PE:MTBE=30:1 ) to obtai...

Embodiment 2

[0054] A kind of preparation method of synthetic 2-(3,5-bis(trifluoromethyl)phenyl)-2-methylpropionic acid, as shown in following chemical reaction formula:

[0055]

[0056] Wherein S1 prepares the specific parameters of 2-(3,5-bis(trifluoromethyl)phenyl)-2-methylpropyl-1-one:

[0057] Isopropylmagnesium chloride (42g, 1.2eq) was added to a three-necked flask, and a solution of 3,5-bis(trifluoromethyl)bromobenzene (100g, 1.0eq) in tetrahydrofuran (300g) was added dropwise at 0°C. After the dropwise addition, the reaction system was reacted at 0°C for 1-1.5h, and then a solution of morpholine amide (43g, 0.8eq) in tetrahydrofuran (200 g) was added dropwise to the reaction system. Under reaction 3-4h. After the reaction, the reaction system was slowly added to water, the organic phase was separated, and the aqueous phase was extracted with methyl tert-butyl ether (500g,) again, the organic phase was concentrated to dryness, and column chromatography (PE:MTBE=30:1 ) to obta...

Embodiment 3

[0068] A kind of preparation method of synthetic 2-(3,5-bis(trifluoromethyl)phenyl)-2-methylpropionic acid, as shown in following chemical reaction formula:

[0069]

[0070] Wherein S1 prepares the specific parameters of 2-(3,5-bis(trifluoromethyl)phenyl)-2-methylpropyl-1-one:

[0071] Isopropylmagnesium chloride (42g, 1.4eq) was added to a three-necked flask, and a solution of 3,5-bis(trifluoromethyl)bromobenzene (100g, 1.0eq) in tetrahydrofuran (300g) was added dropwise at 0°C. After the dropwise addition, the reaction system was reacted at 0°C for 1-1.5h, and then a solution of morpholine amide (43g, 0.8eq) in tetrahydrofuran (200 g) was added dropwise to the reaction system. Under reaction 3-4h. After the reaction, the reaction system was slowly added to water, the organic phase was separated, and the aqueous phase was extracted with methyl tert-butyl ether (500g,) again, the organic phase was concentrated to dryness, and column chromatography (PE:MTBE=30:1 ) to obta...

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Abstract

The invention discloses a preparation method of synthetic 2-(3,5-bis(trifluoromethyl)phenyl)-2-methyl propioric acid. S1: 3,5-bis(trifluoromethyl)bromobenzene is dissolved in an organic solvent, the solution is added dropwisely into isopropylmagnesium chloride, and a Grignard reagent is obtained; mafosfamide is dissolved in an organic solvent, the solution is added dropwisely into the Grignard reagent, in order to obtain 2-(3,5-bis(trifluoromethyl)phenyl)-2-methyl propyl-1-ketone; S2: 2-(3,5-bis(trifluoromethyl)phenyl)-2-methyl propyl-1-ketone obtained in the step S1 is dissolved in an organicsolvent, and 2-(3,5-bis(trifluoromethyl)phenyl)-2-bromo-methyl propyl-1-ketone is obtained; S3: 2-(3,5-bis(trifluoromethyl)phenyl)-2-bromo-2-methyl propyl-1-ketone obtained in the step S2 is dissolved in an organic solvent, zinc bromide is added, in order to obtain 2-(3,5-bis(trifluoromethyl)phenyl)-2-methyl methacrylate; S4: 2-(3,5-bis(trifluoromethyl)phenyl)-2-methyl methacrylate obtained in the step S3 is dissolved in an organic solvent, the solution is added into an aqueous solution of alkali, and 2-(3,5-bis(trifluoromethyl)phenyl)-2-methyl propioric acid is obtained.

Description

technical field [0001] The present invention relates to the technical field of organic chemistry synthesis, specifically, refer to a kind of preparation method of synthesizing 2-(3,5-bis(trifluoromethyl)phenyl)-2-methylpropionic acid. Background technique [0002] On October 10, 2014, the U.S. FDA approved the compound drug of netupitant and palonosetron developed by Helsinn Company to be launched in the U.S., which can effectively prevent the nausea and Vomit. This medicine is composed of netupitant (300 mg) and palonosetron (0.50 mg). It can be seen that the importance of netupitant in the pharmaceutical industry. But so far, the synthesis process of netupitant is still a difficult problem for chemists. Among them, the most important fragment 2-(3,5-bis(trifluoromethyl)phenyl)-2-methyl There are big problems in the synthetic route of propionic acid (raw material cost is expensive, reaction safety factor is low). Therefore, it is particularly important to study the synt...

Claims

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Application Information

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IPC IPC(8): C07C27/02C07C57/58
CPCC07C45/004C07C45/45C07C45/63C07C51/09C07C67/00C07C49/80C07C69/65C07C57/58
Inventor 罗建业李亮郭鹏
Owner ASTATECH CHENGDU BIOPHARM CORP
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