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Preparation method for linagliptin

A technology of methyl and purine, which is applied in the field of preparation of raw materials, can solve the problems of restricting industrialized large-scale production, increasing production costs, and difficulty in feeding and proportioning, and achieves the effects of shortening reaction time, improving purity, and reducing reaction temperature

Active Publication Date: 2016-06-01
SHANGHAI WANXIANG PHARMA
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  • Abstract
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Problems solved by technology

[0026] The final purification of this route uses column chromatography purification, which is not conducive to large-scale industrial production
[0027] In summary, the current industrial synthesis process of linagliptin is mainly through compound A (8-bromo-7-(2-butynyl)-3-methylxanthine) and compound B (2-chloroform base-4-methylquinazoline) reacts to generate intermediate D(8-bromo-7-(2-butynyl)-3,7-dihydro-3-methyl-1-[(4-methyl -2-quinazolinyl)methyl]-1H-purine-2,6-dione), and then react with (R)-3-aminopiperidine compounds (compound C, C') to obtain the corresponding intermediate E-type compounds, and the intermediate E-type compounds are usually paste compounds. First, it is difficult to purify, and second, it brings difficulties to the proportioning of subsequent reactions, which is not conducive to large-scale industrial production.
In addition, phase transfer catalyst tetrabutylammonium bromide and iodine-containing inorganic salt catalysts are also used in most processes, which also increase production costs and limit industrialized large-scale production

Method used

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  • Preparation method for linagliptin
  • Preparation method for linagliptin
  • Preparation method for linagliptin

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0050] Compound A (8-bromo-7-(2-butynyl)-3,7-dihydro-3-methyl-1H-purine-2,6-dione) (10 g, 33.7 mmol) was added to compound N-methyl- 2-Pyrrolidone 30ml solution, reacted at 55~60°C for 4 hours, then added 50 μm sodium carbonate (5.4g, 50.55mmol), and added compound C ((R)-3-tert-butoxycarbonylaminopiperidine) ( 8.1g, 40.4mol), reacted at 55-60°C for 6h, added 60ml of pure water after the reaction, precipitated solid, filtered, dissolved the wet filter cake with 80ml of dichloromethane, washed with water, dried with anhydrous sodium sulfate, filtered, Concentrate under reduced pressure to 20ml, add 80ml of n-hexane, precipitate a solid, filter, and dry to obtain the linagliptin intermediate E (1-[(4-methyl-quinazolin-2-yl)methyl]-3- Methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert-butoxycarbonylamino)-piperidin-1-yl]-2,6-dione-2, 3,6,7-tetrahydro--1H-purine) 17.7g, the yield was 91.8%, and the purity was 99.6%.

[0051] Dissolve intermediate E (15g, 26.2mmol) in 150ml of dichlorometha...

Embodiment 2

[0053] Add compound A (10g, 33.7mmol) to compound B (7.8g, 40.4mmol) and 100μm sodium carbonate (5.4g, 50.55mmol) in N-methyl-2-pyrrolidone 30ml solution, at 55~60°C React for 4 hours, then add 100 μm sodium carbonate (5.4g, 50.55mmol), and add compound C (8.1g, 40.4mol) at the same time, react at 55-60°C for 6h, add 60ml of pure water after the reaction, precipitate solid, filter , the wet filter cake was dissolved in 80ml of dichloromethane, washed with water, dried with anhydrous sodium sulfate, filtered, concentrated to 20ml under reduced pressure, added 80ml of n-hexane, precipitated solid, filtered, and dried to obtain Linagliptin intermediate E17.6g , the yield was 91.3%, and the purity was 99.5%.

[0054] Dissolve intermediate E (15g, 26.2mmol) in 150ml of dichloromethane, cool to below 10°C, add 37.5ml of trifluoroacetic acid dropwise, after the dropwise completion, react at room temperature for 5 hours, add dropwise an aqueous potassium carbonate solution with a mass...

Embodiment 3

[0056] Add compound A (10g, 33.7mmol) to compound B (7.8g, 40.4mmol) and 200μm sodium carbonate (5.4g, 50.55mmol) in N-methyl-2-pyrrolidone 30ml solution, at 55~60°C React for 4 hours, then add 200μm sodium carbonate (5.4g, 50.55mmol), and add compound C (8.1g, 40.4mol) at the same time, react at 55-60°C for 6h, add 60ml of pure water after the reaction, precipitate solid, filter , the wet filter cake was dissolved in 80ml of dichloromethane, washed with water, dried with anhydrous sodium sulfate, filtered, concentrated to 20ml under reduced pressure, added with 80ml of n-hexane, precipitated solid, filtered, and dried to obtain Linagliptin intermediate E17.5g , the yield was 90.8%, and the purity was 99.5%.

[0057] Dissolve intermediate E (15g, 26.2mmol) in 150ml of dichloromethane, cool to below 10°C, add 37.5ml of trifluoroacetic acid dropwise, after the dropwise completion, react at room temperature for 5 hours, add dropwise an aqueous potassium carbonate solution with a ...

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Abstract

The invention belongs to the technical field of bulk drug preparation and particularly relates to an improvement in a preparation method for linagliptin. According to the preparation method for linagliptin, the particle diameter of an acid-binding agent anhydrous sodium carbonate used in a linagliptin two-step condensation reaction is controlled on a micron order, an iodide catalyst is not needed during the reaction, similarly, the reaction temperature is decreased, reaction time is shortened, the two-step reaction is changed into a one-pot reaction, and a key intermediate E compound with high purity and yield is prepared. The preparation method is suitable for industrial mass production of linagliptin, and finally linagliptin with high purity and yield is obtained.

Description

technical field [0001] The invention belongs to the technical field of preparation of crude drugs, and in particular relates to the improvement of the preparation method of linagliptin. Background technique [0002] Linagliptin, 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, CAS: 668270-12-0, the chemical structure is as follows: [0003] [0004] Linagliptin was developed by the Boehringer Ingelheim-Eli Lilly Diabetes Alliance. It is a type 2 diabetes (T2DM) treatment drug with a new mechanism of action. It was approved by the US FDA in May 2011. Approved for listing in Europe. In January 2012, the US FDA approved linagliptin / metformin hydrochloride for the treatment of adult patients with T2DM. In October 2010, Linagliptin was approved in Europe as a combination therapy drug for insulin in patients with T2DM. In April 2013, Linagliptin obtained the import drug registration certificate issue...

Claims

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Application Information

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IPC IPC(8): C07D473/04
CPCC07D473/04
Inventor 袁相富赵铭张崇东
Owner SHANGHAI WANXIANG PHARMA
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