Synthesis method of tirbanibulin

A synthetic method, Teban's technology, applied in the synthesis field of terbanbulin, can solve the problems of long route, increased production cost of terbanbulin, cost of raw materials, high cost, etc.

Active Publication Date: 2021-09-07
HENAN VOCATIONAL COLLEGE OF APPLIED TECH
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  • Abstract
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  • Claims
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Problems solved by technology

However, the current synthetic method has the following problems: use more expensive raw materials; or use very strong base; or need to be synthesized under harsh reaction conditions such as very low temperature
For example, the following is an existing synthetic route, the route is long, the process is complicated, and the cost is very high
Specifically, the raw material of the raw material 2-fluoro-5-bromopyridine is relatively expensive. In addition, the step of reacting with acetonitrile requires the use of a strong base HMDSLi, and requires a low temperature of -78°C. very difficult to achieve
Therefore, the production cost and raw material drug cost of tirbanibulin (tirbanibulin) have also been greatly increased.

Method used

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  • Synthesis method of tirbanibulin
  • Synthesis method of tirbanibulin
  • Synthesis method of tirbanibulin

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Embodiment 1

[0025] The present embodiment provides a kind of method of synthesizing terbanbuline, and the reaction equation is:

[0026]

[0027] The synthesis process is as follows:

[0028] The first step: at room temperature (about 25°C), add 253.8g of ethyl bromoacetate to 3L of anhydrous 1,4-dioxane solution, then cool down to 0°C, add 10g of newly activated zinc powder , then add 0.2g of trimethylchlorosilane (TMSCl) under stirring, stir for 30 minutes, then add 88.8g of zinc powder in batches, slowly heat up under stirring, and control the heating rate at about 1°C per minute until heated to 100 ℃, the zinc powder disappeared completely; the reaction system was cooled to 0 ℃, 300g of 2,5-dibromopyridine and 11.2g of 1,1'-bisdiphenylphosphinoferrocene palladium (PdCl2) were added in batches (dppf)Cl 2 ), then slowly warmed to room temperature, reacted for 3 hours, and then slowly warmed to 100 °C and reacted overnight. Cool the reaction solution to 0°C, then add 500 ml of ammo...

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Abstract

The invention belongs to the technical field of synthesis of medical compounds, which particularly discloses a synthesis method of tirbanibulin. The preparation method comprises the following steps of taking 2, 5-dibromopyridine as a raw material, and reacting with ethyl bromoacetate to obtain a compound 2, then carrying out ammonolysis reaction on the compound 2 and benzylamine to obtain a compound 3, and enabling the compound 3 and the compound 4 to be mixed and react to obtain the final product tirbanibulin. The method has the advantages of cheap and easily available raw materials, convenience in production and easiness in purification, and can be developed into an industrial production method.

Description

technical field [0001] The invention relates to the technical field of synthesis of medicinal compounds, in particular to a method for synthesizing tirbanibulin. Background technique [0002] The US FDA approved the launch of the new drug Klisyri (tirbanibulin, terbanibulin) in December 2020. This medicine is mainly used to treat actinic keratosis (AK) of the face or scalp. Actinic keratosis is a precancerous lesion of the skin caused by exposure of the skin to ultraviolet light. If left untreated, about one in 10 AK lesions will develop into skin cancer. Nearly 50% of squamous cell carcinoma cases are caused by untreated or poorly managed actinic keratosis. AK has been reported to have a high incidence (approximately 25.3%) in the general population, ranging from 6.5% in individuals aged 30-40 years and as high as 69.4% in individuals aged 90-100 years. [0003] Klisyri (tirbanibulin) is a microtubule inhibitor. It can promote the apoptosis of proliferative cells by inh...

Claims

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Application Information

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IPC IPC(8): C07D213/56
CPCC07D213/56
Inventor 刘加艳任宇鹏
Owner HENAN VOCATIONAL COLLEGE OF APPLIED TECH
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