A kind of preparation method of Apremilast impurity

A technology of impurities and products, applied in the field of preparation of Apremilast impurities, to achieve the effect of good environmental protection, high product purity and simple operation method

Active Publication Date: 2022-03-15
TLC NANJING PHARMA RANDD CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

The synthesis method of the Apremilast impurity provided by the application has not been reported yet

Method used

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  • A kind of preparation method of Apremilast impurity
  • A kind of preparation method of Apremilast impurity
  • A kind of preparation method of Apremilast impurity

Examples

Experimental program
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Effect test

Embodiment 1

[0031] Preparation of Compound II: Dissolve 25g of Compound I in 200mL of N,N-dimethylformamide, add 21.4g of 2-mercaptoethanol, then add 15g of sodium hydroxide, and react at 100°C for 12 hours. After the reaction is complete, the reaction solution is filtered. The filtrate was spin-dried, and the crude product was purified through a column with dichloromethane and methanol to obtain 21.5 g of yellow solid II with a yield of 87%.

[0032]

[0033] Preparation of compound III: Dissolve 21 g of compound II in 200 mL of tetrahydrofuran, add 12 g of ammonium formate and 4 g of sodium triacetoxyborohydride at room temperature, react at room temperature for 8 hours, monitor the end of the reaction by TLC, spin the reaction solution to dryness, and add 200 mL of water , add 1mol / L sodium hydroxide under ice bath to adjust pH=12, extract three times with dichloromethane, 50mL each time, combine the organic layers and dry with anhydrous sodium sulfate, filter, spin the filtrate to o...

Embodiment 2

[0040] Preparation of compound II: Dissolve 23g of intermediate I in 200mL N,N-dimethylformamide, add 20g of 2-mercaptoethanol, then add 18g of potassium hydroxide, react at 100°C for 12 hours, the reaction is completed, the reaction solution is filtered, and the filtrate The crude product was spin-dried to obtain a crude product, which was purified through a column with dichloromethane and methanol to obtain 18.6 g of yellow solid II with a yield of 81.7%.

[0041]

[0042] Preparation of Compound III: Dissolve 17g of Compound II in 150mL of tetrahydrofuran, add 19g of ammonium formate at room temperature, react for a period of time at room temperature, then add sodium borohydride for reduction, TLC monitors the end of the reaction, spin the reaction solution to dryness, add 200mL of water, Add 1mol / L sodium hydroxide under ice bath to adjust the pH=12, extract three times with dichloromethane, combine the organic layers and dry with anhydrous sodium sulfate, filter, spin t...

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Abstract

The invention discloses a preparation method of apremilast impurity, which belongs to the field of medicine synthesis. The application screens out the optimal preparation steps and reaction conditions through experiments, and obtains the apremilast impurity through four-step reaction synthesis. The process design is reasonable, the operability is strong, and the purification is convenient. The prepared apremilast impurity has a purity of more than 98%, provides test samples for the research of apremilast, and has important research value in clinical pharmacokinetic research.

Description

technical field [0001] The invention belongs to compound synthesis technology, in particular to a preparation method of apremilast impurity. [0002] technical background [0003] Apremilast is an oral, selective phosphodiesterase 4 (PDE4) inhibitor developed by Celgene of the United States, with a trade name of Otezla, which is the first and only FDA-approved drug for plaque psoriasis PDE4 inhibitor for the treatment of adult patients with moderate to severe plaque psoriasis who are candidates for phototherapy and systemic therapy. Compared with similar drugs, apremilast has the following advantages. It can inhibit the production of various pro-inflammatory mediators and play an anti-inflammatory effect; clinical trials have shown that apremilast can reduce the symptoms of severe plaque psoriasis in patients with moderate to severe plaque psoriasis. Erythema, thickening, and desquamation; apremilast was well tolerated with minimal adverse effects. [0004] With the progres...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D209/48
CPCC07D209/48
Inventor 丁铜锁薛金辉胡永铸张池刘春徐一鸣
Owner TLC NANJING PHARMA RANDD CO LTD
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