CN114644586A

CN114644586A - Preparation method of lenalidomide related substance

Info

Publication number: CN114644586A
Application number: CN202210381382.1A
Authority: CN
Inventors: 王佩; 韩春雷; 陈飞亚; 潘必高; 石秋敏
Original assignee: Jiangsu Hansoh Pharmaceutical Group Co Ltd
Current assignee: Jiangsu Hansoh Pharmaceutical Group Co Ltd
Priority date: 2022-04-12
Filing date: 2022-04-12
Publication date: 2022-06-21

Abstract

The invention relates to a preparation method of lenalidomide related substances. The invention discloses a method for synthesizing lenalidomide impurities, which comprises the following steps: taking lenalidomide as a raw material, and reacting to obtain the impurity compound shown in the formula III. The preparation method has simple operation and high yield, is suitable for large-scale production, and can quickly obtain the product.

Description

Preparation method of lenalidomide related substance

Technical Field

The invention belongs to the field of drug synthesis, and particularly relates to a preparation method of lenalidomide impurities.

Background

Lenalidomide is a safe and efficient novel anti-tumor drug. In 2005, 12 months, the united states Food and Drug Administration (FDA) approved the application of the united states cell gene (celgene) on the market under the trade name Revlimid, and was approved for import registration in china in 2013 under the trade name remume. In 2018, the sale of lenalidomide is $ 96.85 billion, and the third place around the world.

Lenalidomide is an immunoregulation type medicine, and has multiple action mechanisms, and in vitro research, lenalidomide has three main effects of 1) direct anti-tumor effect, 2) angiogenesis inhibition, and 3) immunoregulation. In vivo, lenalidomide induces apoptosis of tumor cells directly or indirectly by inhibiting the support of bone marrow stromal cells, anti-angiogenic and anti-osteoclastic effects, and immunomodulatory activity. At the molecular level, lenalidomide has been shown to interact with ubiquitin E3 ligase and target the enzyme to degrade ikros transcription factors IKZF1 and IKZF3, which suggests that the primary role of lenalidomide is to relocate the activity of the enzyme, rather than to block the activity of the enzyme or signaling pathway, and thus represents a new mode of drug action. A more specific meaning of this mechanism is that the teratogenic and antitumor properties of lenalidomide can be isolated. The late-stage lenalidomide is thus gradually expanding from hematological tumor applications to solid tumor therapy.

In 11 months in 2017, the lenalidomide in the Shuanglu pharmaceutical industry breaks through the first imitation of the original patent to go to the market, then the imitation drugs of sunny, Qilu and Howson go to the market successively in the day, and the competition of the domestic lenalidomide market is formally pulled.

In the research process of lenalidomide, the effective medicine content and the impurity content of lenalidomide are often required to be detected, the impurity is one of important impurities in lenalidomide medicines and plays an important role in controlling the medicine quality of the lenalidomide, so that the impurity of the lenalidomide is required to be prepared, a proper amount of the impurity is taken and dissolved by methanol, and the mass spectrometry (national pharmacopoeia 2015 edition four-part rules of the world 0431) test is carried out, and the mass-to-charge ratio 277 +/-1 of the impurity is [ M-H ] in a negative ion mode]^-Peak(s).

The research has important significance for monitoring and researching the clinic, pharmacology, pharmacokinetics, toxicology and impurity residue of the lenalidomide.

The prior patent CN105440014 has long synthesis route for the impurity of formula III of lenalidomide, and the hydrogenation method is dangerous. Therefore, a method for preparing the impurity of formula III of lenalidomide, which has the advantages of readily available raw materials and convenient operation, is urgently needed in the field.

Disclosure of Invention

The invention provides a preparation method of lenalidomide impurities, which has the advantages of easily obtained raw materials and convenience in operation.

In order to achieve the purpose of the invention, the invention mainly adopts the following technical scheme:

a. the compounds of formula I and formula II are prepared by lenalidomide,

b. further, the compound of formula III is prepared by the compound of formula I and the compound of formula II,

wherein the lenalidomide in the step a is prepared into the compounds shown in the formula I and the formula II under the action of a reaction solvent and water, the organic solvent is one or more selected from triethylamine, hydrazine hydrate, a sodium hydroxide aqueous solution, a potassium hydroxide aqueous solution and a lithium hydroxide aqueous solution, and triethylamine is more preferable.

Further, lenalidomide in step a: reaction solvent: the concentration range of the water is 1.00g of lenalidomide and 0.30-5.00 mL of water and 5.00-50.00 mL, preferably 1.00g of lenalidomide and 1.00g of triethylamine and water and 0.50 mL-2.00: 7.00-15.00 mL, most preferably the concentration range of the lenalidomide and the triethylamine: 1.00g of water to 1.00mL:10mL, most preferably in a ratio that achieves the best reaction results.

Further, in the step a, the reaction temperature is selected from 60 ℃ to 120 ℃, and the reaction time is selected from 1 hour to 5 hours; more preferably, the reaction temperature is 100 ℃ and the reaction time is selected from 2 hours.

Further, the compound of formula I and the compound of formula II in step b are prepared into the compound of formula III under the action of a reaction reagent, wherein the reaction reagent is selected from one or more of hydrochloric acid, sulfuric acid, acetic acid and sodium hydroxide aqueous solution, hydrochloric acid is more preferable, and the best reaction effect can be realized by hydrochloric acid.

Further, in the step b, the reaction temperature is 60-120 ℃, and the reaction time is selected from 1-10 hours; more preferably, the reaction temperature is 100 ℃ and the reaction time is selected from 8 hours.

Furthermore, in the step b, the reaction solution is subjected to reduced pressure concentration after pH adjustment.

Further, the pH regulator in step b is selected from saturated aqueous sodium bicarbonate solution, saturated aqueous sodium carbonate solution, saturated aqueous sodium hydroxide solution, preferably saturated aqueous sodium bicarbonate solution.

Further, the pH is adjusted in the range of 5 to 9, preferably 5 to 6 in step b.

Detailed Description

In order to embody the technical solutions and the effects obtained by the technical solutions of the present invention, the present invention will be further described with reference to specific embodiments, but the scope of the present invention is not limited to the specific embodiments.

Example 1

Synthesis of Compounds of formula III

Lenalidomide (10.0g), triethylamine (10.0mL) and water (100mL) were added to a 250mL reaction flask and allowed to warm to 100 ℃ for 2 hours, and the reaction mixture was concentrated under reduced pressure to give a mixture of formula I and formula II (8.90 g). Concentrated hydrochloric acid (44.5mL) was added to a mixture of formula i and formula ii (8.90g) in a 250mL reaction flask, the mixture was heated to 100 ℃ for 8 hours, the reaction mixture was concentrated under reduced pressure, the pH was adjusted to 5-6 with saturated aqueous sodium bicarbonate, the reaction mixture was concentrated under reduced pressure, and column chromatography purification was performed to obtain formula iii (7.70g) with a purity of 96.77%.

Example 2

Synthesis of Compounds of formula III

Lenalidomide (10.0g), sodium hydroxide (5.00g) and water (100mL) were charged into a 250mL reaction flask and allowed to warm to 100 ℃ to react for 2 hours, the reaction mixture was adjusted to pH 7-8 with hydrochloric acid, concentrated under reduced pressure and purified by column chromatography to give a mixture of formula i and formula ii (1.20 g). A50.0 mL reaction flask was charged with the mixture of formula I and formula II (1.20g), concentrated hydrochloric acid (6.00mL) was added, the reaction was warmed to 100 ℃ for 8 hours, the reaction was concentrated under reduced pressure, the pH was adjusted to 5-6 with saturated aqueous sodium bicarbonate, the reaction was concentrated under reduced pressure, and column chromatography purification was performed to give formula III (1.03g) with a purity of 96.08%.

Example 3

Synthesis of Compounds of formula III

Lenalidomide (10.0g), potassium hydroxide (7.00g) and water (100mL) were charged into a 250mL reaction flask and allowed to warm to 100 ℃ to react for 2 hours, the reaction mixture was adjusted to pH 7-8 with hydrochloric acid, concentrated under reduced pressure and purified by column chromatography to give a mixture of formula i and formula ii (1.40 g). A50.0 mL reaction flask was charged with the mixture of formula I and formula II (1.40g), concentrated hydrochloric acid (7.00mL) was added, the temperature was raised to 100 ℃ and the reaction was allowed to react for 8 hours, the reaction was concentrated under reduced pressure, the pH was adjusted to 5-6 with saturated aqueous sodium bicarbonate, the reaction was concentrated under reduced pressure and purified by column chromatography to give formula III (1.10g) with a purity of 95.81%.

Claims

1. A preparation method of lenalidomide impurities is characterized in that compounds shown in formula I and formula II are prepared by lenalidomide,

2. the method for preparing lenalidomide impurity according to claim 1, wherein the compound of formula I and the compound of formula II are prepared to obtain the compound of formula III,

3. the method for preparing lenalidomide impurity according to claim 1, wherein the lenalidomide is prepared into the compound shown in formula I and the compound shown in formula II under the action of reaction solvent and water, wherein the reaction solvent is selected from one or more of triethylamine, hydrazine hydrate, sodium hydroxide aqueous solution, potassium hydroxide aqueous solution and lithium hydroxide aqueous solution, and is preferably triethylamine.

4. The method of claim 1, wherein the ratio of lenalidomide: reaction solvent: the amount of water used is 1.00 g/0.30-5.00 mL/1.00 g/0.50-2.00 mL/7.00-15.00 mL/7.00-15.00 mL/triethylamine: 1.00g of water to 1.00mL of 10 mL.

5. The method of claim 1, wherein the reaction temperature is selected from 60 ℃ to 120 ℃ and the reaction time is selected from 1 to 5 hours; the preferred reaction temperature is 100 ℃ and the reaction time is 2 hours.

6. The method for preparing lenalidomide impurity according to claim 2, wherein the compound of formula I and the compound of formula II are prepared to obtain the compound of formula III under the action of a reaction reagent, wherein the reaction reagent is selected from one or more of hydrochloric acid, sulfuric acid, acetic acid and sodium hydroxide aqueous solution, and hydrochloric acid is preferred.

7. The method of claim 2, wherein the reaction temperature is 60 ℃ to 120 ℃ and the reaction time is selected from 1 to 10 hours; the preferred reaction temperature is 100 ℃ and the reaction time is 8 hours.

8. The method of claim 2, wherein the reaction mixture is concentrated under reduced pressure after adjusting the pH.

9. A process according to claim 8, wherein the pH adjusting agent is selected from saturated aqueous sodium bicarbonate, saturated aqueous sodium carbonate or saturated aqueous sodium hydroxide, preferably saturated aqueous sodium bicarbonate.

10. The process for the preparation of lenalidomide impurity according to claim 8, wherein the pH adjustment range is 5-9, preferably 5-6.