Preparation method of vimodegil

A technology of compound and molar ratio, applied in the field of preparation of vemodaji, can solve the problems of high price of 2-haloacrolein, low product stability, low total yield, etc., and achieve high reaction selectivity, purity and total yield. The effect of high yield, product purity and high yield

Active Publication Date: 2020-04-24
XINFA PHARMA
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Problems solved by technology

[0029] The raw material 2-haloacrolein used in the above synthetic route 6 has a high price and high cost, and produces bromine-containing wastewater, which is not conducive to environmental protection; the Michael addition of the compound 2-chloro-5-nitrobenzophenone and 2-bromoacrolein The reaction product has low stability and is prone to side reactions of ammonia and bromine substitution, resulting in a slightly lower yield in this step and a relatively low overall yield

Method used

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  • Preparation method of vimodegil
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  • Preparation method of vimodegil

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0073] Embodiment 1: Preparation of 2-(2-chloro-5-nitrophenyl)pyridine (IV)

[0074] Add 200 grams of 1,2-dichloroethane, 20.0 grams (0.1 moles) of 2-chloro-5-nitroacetophenone, 0.5 grams of piperidine, and 6.2 grams (0.11 moles) of acrolein into a 500 mL four-neck flask, React at 30-35°C for 4 hours, lower the reaction solution to 25°C, transfer it to a constant pressure dropping funnel, and drop it into another 500mL four-necked flask containing 85 grams of 10% ammonia water at 20-25°C. The addition was completed in 1 hour, and then the reaction was stirred at 25-30°C for 3 hours. Then add 17.0 grams (0.15 moles) of 30wt% hydrogen peroxide, stir and react at 40-45°C for 3 hours, cool to 20-25°C, separate layers, and extract the water layer twice with 1,2-dichloroethane, 30 grams each time , the combined organic phases were washed once with 20 gram of 5% sodium sulfite aqueous solution, the organic phase was distilled to reclaim the solvent, and dried to obtain 21.5 gram of ...

Embodiment 2

[0075] Embodiment 2: Preparation of 2-(2-chloro-5-nitrophenyl)pyridine (IV)

[0076] Add 200 grams of tetrahydrofuran, 20.0 grams (0.1 moles) of 2-chloro-5-nitroacetophenone, 0.5 grams of DBU, 6.2 grams (0.11 moles) of acrolein into a 500 mL four-neck flask, and react at 25-30 ° C for 4 hours. Transfer the reaction solution to a constant pressure dropping funnel, and drop it into another 500mL four-neck flask containing 85 grams of 10% ammonia water at 20-25°C, and add it in 1 hour, then stir the reaction at 25-30°C 3 Hour. Then add 29.3 grams (0.13 moles) of 40% tert-butanol peroxide, 30-35 DEG C stirred and reacted for 4 hours, cooled to 20-25 DEG C, separated layers, and the aqueous layer was extracted 3 times with dichloromethane, each 50 grams, Combine the organic phases, wash once with 20 grams of 5% sodium sulfite aqueous solution, distill the organic phase to reclaim the solvent, dry to obtain 22.3 grams of 2-(2-chloro-5-nitrophenyl)pyridine, the liquid phase purity i...

Embodiment 3

[0077] Embodiment 3: Preparation of 2-(2-chloro-5-aminophenyl)pyridine (Ⅴ)

[0078] 23.5 grams (0.1 moles) of 2-(2-chloro-5-nitrophenyl) pyridine prepared by the method in Example 2, 150 grams of isopropanol, and 0.25 grams of 5% palladium carbon were put into a 500 mL autoclave. After nitrogen replacement 3 times, fill the hydrogen pressure to 0.2-0.3MPa, heat up to 40-50°C, keep the temperature for 3 hours, after the hydrogenation reaction, cool down to room temperature, filter and separate palladium carbon, and recover isopropanol to dryness , to obtain 19.8 g of 2-(2-chloro-5-aminophenyl)pyridine with a liquid phase purity of 99.6% and a yield of 96.8%.

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Abstract

The invention provides a preparation method of vimodegil. 2-chloro-5-nitroacetophenone is used as a raw material; 5-oxo-5-(2-chloro-5-nitrophenyl) n-valeraldehyde is prepared through an addition reaction between 2-chloro-5-nitroacetophenone and acrolein, then 5-oxo-5-(2-chloro-5-nitrophenyl) n-valeraldehyde reacts with ammonia and an oxidizing agent in sequence to prepare 2-(2-chloro-5-nitrophenyl) pyridine, 2-(2-chloro-5-nitrophenyl) pyridine is reduced to obtain 2-(2-chloro-5-aminophenyl) pyridine, and 2-(2-chloro-5-aminophenyl) pyridine reacts with 2-chloro-4-methylsulfonylbenzoyl chlorideto obtain vimodegil. The preparation method has the advantages of cheap and easily available raw materials, low cost, short technical process, safe, simple and convenient operation, easily controllable and easily realized reaction conditions, little amount of generated waste liquid, green, environmental friendliness, stable intermediate compounds, high reaction selectivity, high product purity, and high yield, and is suitable for industrial production.

Description

technical field [0001] The invention relates to a preparation method of Vimodergib, which belongs to the field of pharmaceutical biochemical industry. Background technique [0002] Vimodegib, the trade name is Erivedge, and the English name is Vismodegib. Vimodegib is developed by Roche for adults with symptomatic metastatic basal cell carcinoma (BCC) or locally advanced BCC who are not suitable for surgery or radiotherapy. The patient's medication. On January 30, 2012, the FDA approved Vimodeji through the priority review process, which is the first drug approved in the United States for the treatment of advanced BCC. Vimodegil is an oral tablet that works by inhibiting the Hedgehog pathway, which is highly active in most basal cell carcinomas. Vimodeji was approved by the European Union on July 15, 2013 due to its safety and efficacy, and has now been approved by Australia, Israel, South Korea, Mexico, Ecuador and other countries. [0003] The CAS number of Vimodeji is ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D213/40
CPCC07D213/40
Inventor 王德银屈虎戚聿新胡金山
Owner XINFA PHARMA
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