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Preparation method for linagliptin and intermediate thereof

An intermediate and solid technology, applied in the field of preparation of linagliptin and its intermediates, can solve the problems of difficulty in filtration or centrifugal drying, genotoxic impurities, bromide residues, etc., and achieves reduction of time and labor costs, and purity. Improve and reduce the effect of impurities

Active Publication Date: 2020-04-07
GAN&LEE PHARMA +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Among them, in the synthetic route disclosed in WO2004018468A, the raw material intermediates are cheap and easy to obtain, the route steps are shorter, the reaction conditions are mild, and the quality control of chiral carbon is easier, but there are many problems in the preparation process of intermediate D, such as reaction time Longer, and intermediate D is usually a paste compound, which is difficult to filter or centrifugally dry, and purification is difficult. In addition, there are a large number of by-product bromide residues in the intermediate, and the residue of bromide will produce a large amount of bromide in the last step of deprotection reaction. Genotoxic impurities, which are difficult to remove; and in the last step of removing tert-butoxycarbonyl protection, improper post-processing will produce linagliptin dimer impurities

Method used

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  • Preparation method for linagliptin and intermediate thereof
  • Preparation method for linagliptin and intermediate thereof
  • Preparation method for linagliptin and intermediate thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0034] 1) Preparation of linagliptin intermediate

[0035] a) At room temperature, add the compound 8-bromo-7-(2-butynyl)-3,7-dihydro-3-methyl-1-[(4-methyl-2-quinazole) into the reaction flask Phenyl)methyl]-1H-purine-2,6-dione (100.00g, 220.6mmol), (R)-3-tert-butoxycarbonylaminopiperidine (57.50g, 287.0mmol), potassium carbonate (122.00g , 883.0mmol), acetonitrile 475ml, dimethyl sulfoxide 25ml, stirred and heated up to 84-86°C, kept stirring for about 20 hours.

[0036] b) After the reaction, add 750ml of purified water dropwise to the reaction bottle. After the dropwise addition, stir to dissolve, control the temperature at 65-67°C, keep stirring, and wait for white solid to precipitate, then keep stirring at 65-67°C for 2 hour, cooled to about 25°C, stirred for 1 hour, filtered, and after the filter cake was drained, rinsed and drained with 500ml of purified water to obtain a white crystalline powder solid product D (120.40g, 210.2mmol), yield 95.30% , 99.935% purity. T...

Embodiment 2

[0045] Steps 1)-2) of Example 1 were used to prepare linagliptin, the difference being that the heat preservation and crystallization temperature of step b) in step 1) was 56-58°C. After step 1), a white crystalline powder solid product D (120.31 g, 210.1 mmol) was obtained with a yield of 95.23% and a purity of 99.877%. After step 2), a white solid E (35.93 g, 76.0 mmol) was obtained with a yield of 87.09% and a purity of 99.905%.

[0046] Example 2(b)

[0047] Steps 1)-2) of Example 1 were used to prepare linagliptin, the difference being that the heat preservation and crystallization temperature of step b) in step 1) was 72-74°C. After step 1), a white crystalline powder solid product D (120.29 g, 210.1 mmol) was obtained with a yield of 95.22% and a purity of 99.930%. After step 2), a white solid E (35.91 g, 76.00 mmol) was obtained with a yield of 87.04% and a purity of 99.923%.

Embodiment 3

[0049] Steps 1)-2) of Example 1 were used to prepare linagliptin, the difference being that the solvent used in step a) in step 1) was 475ml of acetonitrile, 25ml of N,N-dimethylformamide, Reaction time 18 hours. After step 1), a white crystalline powder solid product D (120.16 g, 209.8 mmol) was obtained with a yield of 95.11% and a purity of 99.896%. After step 2), a white solid E (36.02 g, 76.2 mmol) was obtained with a yield of 87.30% and a purity of 99.911%.

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Abstract

The invention discloses a preparation method for linagliptin and an intermediate thereof. In the process of preparation of a linagliptin intermediate D from a compound 8-bromine-7-(2-butynyl)-3, 7-dihydro-3-methyl-1-[(4-methyl-2-quinazoline)methyl]-1H-purine-2, 6-dione, on one hand, a mixed solvent of acetonitrile and an aprotic polar solvent is adopted, so that the reaction time is shortened, andon the other hand, by increasing the water adding amount in the post-treatment process, crystals are separated out through heat preservation at 56-74 DEG C and then cooled, the content of impuritiescontained in the crystals is reduced, and the purity of a product is improved; in the step of removing tert-butyloxycarboryl protection, reaction liquid is directly added into alkali liquor in a reverse dripping mode in post-treatment, impurities generated due to improper post-treatment are reduced, and the reaction yield is increased. According to the preparation method, linagliptin with high purity and high yield can be obtained, and the preparation method is suitable for industrial production.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and in particular relates to a preparation method of linagliptin and an intermediate thereof. Background technique [0002] The chemical name of linagliptin is (8-[(3R)-3-amino-1-piperidinyl]-7-(2-butynyl-1)-3,7-dihydro-3- Methyl-1-[(4-methyl-2-quinazolinyl)methyl]-1H-purine-2,6-dione), the chemical structure is shown in formula E, developed by Boehringer Ingelheim , which inhibits dipeptidyl peptidase-4 [0003] (DPP-4) is an active type 2 diabetes (T2DM) drug, which has the characteristics of high selectivity, long-acting, oral effectiveness, and good safety and tolerance. It was approved for marketing by the US FDA in May 2011, and was approved for marketing in Europe in August 2011. In April 2013, it was approved to be marketed in China by the Imported Drug Registration Certificate issued by the State Food and Drug Administration of China. The approval of the drug is The majority of diab...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D473/04
CPCC07D473/04C07B2200/13Y02P20/55
Inventor 张一宁韩福庆廖明明
Owner GAN&LEE PHARMA
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