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Preparation method of baricitinib key raw material

A technology based on sulfonyl and azetidine, which is applied in the field of preparation of key raw materials of baricitinib, can solve problems such as time-consuming, difficult batch production, and low yield, and achieve shortened preparation routes and broad industrialization prospects , Improve the effect of the preparation effect

Inactive Publication Date: 2020-02-28
刘立敏
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] As a product with a relatively complex molecular structure, the synthesis steps of baricitinib are very long. According to statistics, although there are different synthetic steps to synthesize baricitinib, at least more than 15 steps of synthesis are required to obtain the final product Therefore, long time-consuming, low yield, low efficiency, and difficulty in batch production have become the production bottleneck of baricitinib
As one of the key raw materials of baricitinib, 1-(ethylsulfonyl)azetidin-3-one is not readily available on the market, and the synthesis reported in the prior art requires multiple steps reaction, which greatly increases the length and difficulty of baricitinib synthesis steps

Method used

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  • Preparation method of baricitinib key raw material
  • Preparation method of baricitinib key raw material
  • Preparation method of baricitinib key raw material

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0034] Preparation of 1-(ethylsulfonyl)azetidin-3-one (1D)

[0035]

[0036] Under nitrogen protection, dissolve ethylamine (10mmol) and hydroxyacetyl chloride (10mmol) in anhydrous tetrahydrofuran and stir, add palladium acetate (0.1wt% ethylamine), heat to 60°C for 4h, and then filter off the precipitate , take the filtrate and slowly inject chloro(ethylthio)methanone (10mmol) into the filtrate with a syringe, and the speed is controlled at 1 drop / s. After the addition is completed, add potassium permanganate solids in batches to In the reaction system, the amount of potassium permanganate added each time is 1 / 5 of the amount of the substance of chloro(ethylthio) ketone, and the time interval between two adjacent batches of potassium permanganate adding is 15min, and each addition After potassium permanganate, control the temperature of the system below 20°C. After the addition, raise the temperature of the system to 80°C and react for 4 hours; then stop the reaction and ...

Embodiment 2

[0040] Preparation of 1-(ethylsulfonyl)-2-chloro-azetidin-3-one derivative (2D)

[0041]

[0042] Under nitrogen protection, dissolve 2-chloro-ethylamine (10mmol) and hydroxyacetyl chloride (10mmol) in anhydrous tetrahydrofuran and stir, add triphenylphosphopalladium chloride (0.2wt% ethylamine), and heat to React at 70°C for 4 hours, then filter out the precipitate, take the filtrate and slowly inject chloro(ethylthio)methanone (10mmol) into the filtrate dropwise with a syringe, the speed is controlled at 2 drops / s, after the addition is completed, at -5°C , add potassium permanganate solids in batches to the reaction system, the amount of potassium permanganate added each time is 1 / 6 of the amount of chloro(ethylthio)methanone, and two adjacent batches of potassium permanganate are added The time interval is 10min, and after each addition of potassium permanganate, the temperature of the system is controlled below 17°C. After the addition is completed, the temperature of ...

Embodiment 3

[0046] Preparation of 1-(ethylsulfonyl)-2-chloro-azetidin-3-one derivative (3D)

[0047]

[0048]Under nitrogen protection, dissolve 2-ethyl-ethylamine (10mmol) and hydroxyacetyl chloride (10mmol) in anhydrous tetrahydrofuran and stir, add palladium dichloride (0.2wt% ethylamine), and heat to 80°C React for 4 hours, then filter out the precipitate, take the filtrate and slowly inject chloro(ethylthio)methanone (10mmol) into the filtrate with a syringe, the speed is controlled at 3 drops / s. Add potassium permanganate solids to the reaction system in batches, the amount of potassium permanganate added each time is 1 / 7 of the amount of chloro(ethylthio)methanone, and the time for adding two adjacent batches of potassium permanganate The interval is 12 minutes, and after each addition of potassium permanganate, the temperature of the system is controlled below 15°C. After the addition is completed, the temperature of the system is raised to 100°C and reacted for 4 hours; then s...

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Abstract

The invention discloses a key raw material of baricitinib, and more specifically discloses a preparation method of 1-(ethylsulfonyl) azetidine-3-one. According to the preparation method, adopted reaction substrates are 2-bromo-benzoyl chloride, aniline, triethylamine ethylamine, hydroxyacetyl chloride and chlorine (ethylthio) ketone, and 1-(ethylsulfonyl) azetidine-3-one is prepared in divalent palladium and potassium permanganate two catalytic systems respectively. The reaction can avoid the defects of long and complex preparation process, high cost, long consumed time and low yield in a traditional method; the intermediate 1-(ethylsulfonyl) azetidine-3-one and derivatives of 1-(ethylsulfonyl) azetidine-3-one are obtained through one-step reaction, the yield of the target product reachesup to 55-65%, the preparation route of 1-(ethylsulfonyl) azetidine-3-one is greatly shortened, the preparation effect of 1-(ethylsulfonyl) azetidine-3-one is improved, and the preparation method has awide industrial prospect.

Description

technical field [0001] The invention belongs to the field of organic synthesis, and in particular relates to a preparation method of a key raw material of baricitinib. Background technique [0002] Baricitinib, also known as Baricitinib, has a molecular formula of C16H17N7O2S, a relative molecular mass of 371.417, and a chemical name of 1-(ethylsulfonyl)-3-[4-(7H-pyrrolo[2 ,3-d]pyrimidin 4-yl)-1H-pyrazol-1-yl]-3-azetidine acetonitrile is an oral anti-inflammatory drug developed by Eli Lilly and Incyte. In February 2017, baricitinib was approved for marketing by the European Union. This is the first JAK inhibitor drug approved by the European Union for the treatment of rheumatoid arthritis. Its role is to fight against rheumatism and relieve symptoms of moderate or severe RA. At present, companies with baricitinib as the subject are also planning to go public in China and the United States. Therefore, it can be predicted that baricitinib, as an important class of anti-rheum...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D205/06C07D205/08
CPCC07D205/06C07D205/08
Inventor 不公告发明人
Owner 刘立敏