GFT505 and preparation method for intermediate thereof

An intermediate and time technology, applied in the field of preparation of GFT505 and its intermediates, can solve the problems of difficult purification, high impurity content, unsuitable for industrial production, etc., and achieve the effects of short reaction time, high purity and few by-products

Active Publication Date: 2017-05-17
上海云晟研新生物科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] The technical problem to be solved by the present invention is to provide a kind of GFT505 and its intermediates in order to overcome the defects of Z-type by-products, high impurity content, difficult purification, and unsuitable for industrial production in the preparation process of GFT505 in the prior art. preparation method

Method used

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  • GFT505 and preparation method for intermediate thereof
  • GFT505 and preparation method for intermediate thereof
  • GFT505 and preparation method for intermediate thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0036] Example 1: Preparation method of GFT505 intermediate IV (refer to patent WO2011 / 144579)

[0037]

[0038] Add 4-methylmercaptoacetophenone (50g, 0.301mol) and 3,5-dimethyl-4-hydroxybenzaldehyde (45g, 0.301mol) into 200ml hydrogen chloride methanol solution (4mol / L), 20~30℃ Stir for 3 hours, lower the temperature to 0-10° C., stir for 1 hour, filter, and dry to obtain 83 g of GFT505 intermediate (IV) as a yellow solid, with a yield of 93%.

Embodiment 2

[0039] Example 2: Preparation method of GFT505 intermediate IV (refer to patent WO2011 / 144579)

[0040] Add 4-methylmercaptoacetophenone (19Kg, 114mol) and 3,5-dimethyl-4-hydroxybenzaldehyde (17.1Kg, 114mol) into 76L hydrogen chloride methanol solution (4mol / L), and stir at 20-30°C After 3 hours, the temperature was lowered to 0-10°C, stirred for 1 hour, centrifuged, and vacuum-dried at 40°C for 12 hours to obtain 31.6Kg of GFT505 intermediate (IV) as a yellow solid, with a yield of 93%. LCMS: m / z=299 (M+H) + .

Embodiment 3

[0041] Embodiment 3: the preparation method of GFT505 intermediate II (reference document US2006 / 142611)

[0042]

[0043] GFT505 intermediate IV (78.8g, 0.263mol) was added to the reaction flask, acetonitrile (480ml) was added, potassium carbonate (54.5g, 0.395mol), tert-butyl 2-bromoisobutyrate (39.3g, 0.176 mol), heated to 75~85°C for 10 hours, added potassium carbonate (54.5g, 0.395mol), and tert-butyl 2-bromoisobutyrate (39.3g, 0.176mol) for 10 hours, then added carbonic acid Potassium (54.5g, 0.395mol), tert-butyl 2-bromoisobutyrate (39.3g, 0.176mol) were reacted for 10 hours until the compound was completely reacted, concentrated under reduced pressure to dryness, added 800g water and 400g dichloromethane, and divided layer, washed with water, the organic phase was dried over anhydrous sodium sulfate, filtered, the organic phase was concentrated to dryness, and recrystallized with ethyl acetate and petroleum ether to obtain 81.1 g of solid compound II with a yield of...

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PUM

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Abstract

The invention discloses GFT505 and a preparation method for an intermediate thereof. The invention provides the preparation method for an intermediate I of GFT505, comprising the following steps: in an organic solvent, carrying out isomerization reaction on a compound II and tert-butanol alkali metal salt to obtain the intermediate I of GFT505. According to the preparation method disclosed by the invention, the operation is simple and safe, a special purifying device is not required, the reaction time is short, by-products are few, the yield is high, the tedious operation due to using column chromatography isolation in the aftertreatment process is avoided, and the purity of prepared products is greater than 99.0%; the content of the Z-type isomer falls to be below 0.1%, and the contents of other impurities are all less than 0.5%, so that the preparation method is suitable for industrial production. For GFT505III prepared from the intermediate I of the GFT505, which is obtained through adopting the preparation method of the invention, the purity is greater than 99.50%, and the content of all the impurities is less than 0.1%, thereby reaching the raw material medicine standard.

Description

technical field [0001] The present invention relates to the preparation method of GFT505 and its intermediate. Background technique [0002] The liver is one of the most important organs in the human body, and it is also one of the organs with the highest risk of disease. Many factors can lead to liver disease. For example, drinking too much alcohol can lead to cirrhosis of the liver, taking too many drugs can lead to liver damage, and even obesity can lead to fatty liver. Therefore, drugs for the treatment of fatty liver diseases have also become a hot spot in the development of biomedicine. [0003] France's Genfit biopharmaceutical company recently stated that the US Food and Drug Administration has agreed to continue the development of the peroxisome proliferator-activated receptor α / δ dual agonist GFT505, and began Phase IIb studies in the United States. GFT505 is expected to treat fatty liver, early diagnosis, prevention and treatment of heart disease and its compli...

Claims

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Application Information

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IPC IPC(8): C07C319/20C07C323/22
CPCC07C319/20C07C319/28C07C323/22
Inventor 应述欢皮红军陈健邹宝勤何淼
Owner 上海云晟研新生物科技有限公司
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