CN112574203A

CN112574203A - Method for preparing high-purity linagliptin

Info

Publication number: CN112574203A
Application number: CN202011514154.4A
Authority: CN
Inventors: 陈�胜
Original assignee: Shandong Yongcheng Pharmaceutical Co ltd
Current assignee: Shandong Yongcheng Pharmaceutical Co ltd
Priority date: 2020-12-21
Filing date: 2020-12-21
Publication date: 2021-03-30

Abstract

The invention discloses a method for preparing high-purity linagliptin, which takes a linagliptin crude product (with the purity of 98.76%) as a starting raw material, the purity can not reach the quality standard of raw material medicines, and the high-purity linagliptin is obtained by the following process scheme: and (3) adding an organic solvent to dissolve the crude linagliptin, dropwise adding an acid solution to extract, and separating liquid. Adding organic solvent into the water phase, dripping alkali solution for extraction, separating liquid, and evaporating the organic phase to dryness under reduced pressure. And dissolving the reduced-pressure evaporated solid in an organic solvent, and cooling and crystallizing to obtain a high-purity target product linagliptin solid. According to the method for preparing high-purity linagliptin, the purity can reach 99.99% to the maximum, compared with the prior art, the method uses methyl acetate, acetonitrile and other solvents, is low in toxicity, and the mother solution solvent can be recycled, so that the environmental pollution is low; and the operation is simple and easy, and the industrial scale production is convenient.

Description

Method for preparing high-purity linagliptin

Technical Field

The invention relates to a novel method for preparing high-purity linagliptin, belonging to the technical field of medicines and chemical industry.

Background

Linagliptin, a white solid with the chemical name 8- [ (3R) -3-amino-1-piperidinyl ] -7- (2-butynyl) -3, 7-dihydro-3-methyl-1- [ (4-methyl-2-quinazolinyl) methyl ] -1H-purine-2, 6-dione. The chemical structure is as follows:

linagliptin is a serine protease dipeptidyl peptidase IV (DPP-IV) inhibitor, can maintain the level of glucagon-like peptide 1(GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) in vivo, promotes the secretion of insulin, thereby exerting the effect of reducing blood sugar, and has good treatment effect on type 2 diabetes, thereby having great development prospect in the future market.

At present, a plurality of patents for preparing linagliptin are published at home and abroad, such as CN104672238, CN105906628 and the like, but all patents relate to the preparation of linagliptin. The purity of linagliptin purchased from the market is generally 98 percent and can not reach the quality standard of linagliptin bulk drug.

Disclosure of Invention

Aiming at the defects of the prior art, the invention provides a method for preparing high-purity linagliptin, and finally linagliptin with the purity of 99.99% can be obtained.

The method for preparing high-purity linagliptin takes a linagliptin crude product (with the purity of 98.76%) as an initial raw material.

And (3) adding an organic solvent to dissolve the crude linagliptin, dropwise adding an acid solution to extract, and separating liquid. Adding organic solvent into the water phase, dripping alkali solution for extraction, separating liquid, and evaporating the organic phase to dryness under reduced pressure.

And dissolving the reduced-pressure evaporated solid in an organic solvent, cooling and crystallizing to obtain a high-purity target product linagliptin solid, wherein the purity can reach 99.99% through HPLC (high performance liquid chromatography) detection.

According to the method for preparing high-purity linagliptin, methyl acetate is used as a solvent for dissolving and extracting the linagliptin crude product.

In the method for preparing high-purity linagliptin, the alkali solution is ammonia water, and the preferable concentration is 1 mol/L.

According to the method for preparing high-purity linagliptin, the crystallization temperature is-5-20 ℃, and preferably 0-10 ℃.

In the method for preparing high-purity linagliptin, the refined solvents acetonitrile, acetonitrile-ethanol (1:1) and acetonitrile-acetone (1:1) are preferably acetonitrile.

According to the method for preparing high-purity linagliptin, the purity can reach 99.99% to the maximum, compared with the prior art, the method uses methyl acetate, acetonitrile and other solvents, is low in toxicity, and the mother solution solvent can be recycled, so that the environmental pollution is low; and the operation is simple and easy, and the industrial scale production is convenient.

Detailed Description

Example 1:

1kg of 8-bromo-7- (2-butyn-1-yl) -3, 7-dihydro-3-methyl-1- [ (4-methyl-2-quinazolinyl) methyl ] -1H-purine-2, 6-dione, 401g of (R) -3-aminopiperidine dihydrochloride (1.05eq), 6L N, N-Dimethylformamide (DMF), 342g N, N-Diisopropylethylamine (DIPEA) were added to a reaction flask, and stirring was continued at 60-70 ℃ for TLC detection until the reaction was complete within 7 hours. The solvent was evaporated under reduced pressure to give 1222g crude linagliptin as a white solid in 96.7% yield and 98.76% purity by HPLC.

Example 2:

adding 122.2g of crude linagliptin into 300ml of water and 300ml of methyl acetate, dropwise adding 2mol/L of acetic acid with the pH value of 2-3, and separating. The organic phase was extracted with 100ml of 2 ml of water and separated. And (3) combining the water phases, adding 300ml of methyl acetate, dropwise adding 1mol/L ammonia water solution with the pH value of 8-9, and separating the solution. The aqueous phase was added with 100ml of methyl 2 acetate, separated, the organic phases combined, dried over anhydrous sodium sulfate and filtered. The filtrate is decompressed and evaporated to dryness at 40 ℃ to obtain 118.8g of white solid linagliptin, the yield is 97.2 percent, and the HPLC purity is 99.82 percent.

And adding 300ml of acetonitrile into the linagliptin solid, heating and dissolving at 60-70 ℃, stirring for half an hour, stirring at room temperature for 1 hour, crystallizing at 0-10 ℃ for 1 hour, performing suction filtration, leaching with a small amount of cold acetonitrile, and performing vacuum drying at 50-60 ℃ to obtain 109.9g of white high-purity linagliptin, wherein the yield is 92.5%, and the HPLC purity is 99.99%.

Example 3:

And adding 300ml of acetonitrile into the linagliptin solid, heating and dissolving at 60-70 ℃, stirring for half an hour, stirring at room temperature for 1 hour, crystallizing at-5 ℃ for 1 hour, performing suction filtration, leaching with a small amount of cold acetonitrile, and performing vacuum drying at 50-60 ℃ to obtain 111.3g of white high-purity linagliptin, wherein the yield is 93.7%, and the HPLC purity is 99.92%.

Example 4:

Adding 300ml of acetonitrile into the linagliptin solid, heating and dissolving at 60-70 ℃, stirring for half an hour, stirring at room temperature for 1 hour, crystallizing at 10-20 ℃ for 1 hour, performing suction filtration, leaching with a small amount of cold acetonitrile, and vacuum drying at 50-60 ℃ to obtain 107.9g of white high-purity linagliptin, wherein the yield is 90.8%, and the HPLC purity is 99.99%.

Example 5:

adding 122.2g of crude linagliptin into 300ml of water and 300ml of methyl acetate, dropwise adding 2mol/L of acetic acid with the pH value of 2-3, and separating. The organic phase was extracted with 100ml of 2 ml of water and separated. And (3) combining the water phases, adding 300ml of methyl acetate, dropwise adding 2mol/L ammonia water solution with the pH of 8-9, and separating the solution. The aqueous phase was added with 100ml of methyl 2 acetate, separated, the organic phases combined, dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated to dryness under reduced pressure at 40 ℃ to obtain 119.3g of white solid linagliptin with a yield of 97.6% and a HPLC purity of 99.76%.

And adding 300ml of acetonitrile into the linagliptin solid, heating and dissolving at 60-70 ℃, stirring for half an hour, stirring at room temperature for 1 hour, crystallizing at 0-10 ℃ for 1 hour, performing suction filtration, leaching with a small amount of cold acetonitrile, and performing vacuum drying at 50-60 ℃ to obtain 110.1g of white high-purity linagliptin, wherein the yield is 92.3%, and the HPLC purity is 99.96%.

Example 6:

adding 122.2g of crude linagliptin into 300ml of water and 300ml of methyl acetate, dropwise adding 2mol/L of acetic acid with the pH value of 2-3, and separating. The organic phase was extracted with 100ml of 2 ml of water and separated. And (3) combining the water phases, adding 300ml of methyl acetate, dropwise adding 1mol/L of sodium hydroxide solution with the pH value of 8-9, and separating the solution. The aqueous phase was added with 100ml of methyl 2 acetate, separated, the organic phases combined, dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated to dryness under reduced pressure at 40 ℃ to obtain 119.4g of white solid linagliptin with a yield of 97.7% and an HPLC purity of 99.73%.

And adding 300ml of acetonitrile into the linagliptin solid, heating and dissolving at 60-70 ℃, stirring for half an hour, stirring at room temperature for 1 hour, crystallizing at 0-10 ℃ for 1 hour, performing suction filtration, leaching with a small amount of cold acetonitrile, and performing vacuum drying at 50-60 ℃ to obtain 110g of white high-purity linagliptin, wherein the yield is 92.1%, and the HPLC purity is 99.89%.

Example 7:

And adding 150ml of acetonitrile and 150ml of ethanol into the linagliptin solid, heating and dissolving at 60-70 ℃, stirring for half an hour, stirring for 1 hour at room temperature, crystallizing for 1 hour at 0-10 ℃, performing suction filtration, leaching with a small amount of cold acetonitrile, and performing vacuum drying at 50-60 ℃ to obtain 106.7g of white high-purity linagliptin, wherein the yield is 89.8%, and the HPLC purity is 99.96%.

Example 8:

And adding 150ml of acetonitrile and 150ml of acetone into the linagliptin solid, heating and dissolving at 60-70 ℃, stirring for half an hour, stirring for 1 hour at room temperature, crystallizing for 1 hour at 0-10 ℃, performing suction filtration, leaching with a small amount of cold acetonitrile, and performing vacuum drying at 50-60 ℃ to obtain 110.5g of white high-purity linagliptin, wherein the yield is 92.1%, and the HPLC purity is 99.95%.

Summary table of influence of different solvents, alkali solutions and crystallization temperatures on yield and purity

Claims

1. The method for preparing high-purity linagliptin is characterized by comprising the following steps of: taking a linagliptin crude product (with the purity of 98.76%) as a starting material, adding an organic solvent to dissolve the linagliptin crude product, dropwise adding an acid solution to extract, and separating liquid. Adding organic solvent into the water phase, dripping alkali solution for extraction, separating liquid, and evaporating the organic phase to dryness under reduced pressure. And dissolving the reduced-pressure evaporated solid in an organic solvent, cooling and crystallizing to obtain a high-purity target product linagliptin solid, wherein the purity can reach 99.99% through HPLC (high performance liquid chromatography) detection.

2. The process for preparing high purity linagliptin according to claim 1, characterized in that: the solvents for dissolving and extracting the crude linagliptin are methyl acetate.

3. The process for preparing high purity linagliptin according to claim 1, characterized in that: the alkali solution is ammonia water, and the preferable concentration is 1 mol/L.

4. According to the method for preparing high-purity linagliptin, the crystallization temperature is-5-20 ℃, and preferably 0-10 ℃.

5. In the method for preparing high-purity linagliptin, the refined solvents acetonitrile, acetonitrile-ethanol (1:1) and acetonitrile-acetone (1:1) are preferably acetonitrile.