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Crystal form of linagliptin intermediate and preparation method thereof

An intermediate and crystal form technology, applied in the field of medicinal chemistry, can solve problems such as difficult removal, difficult filtration or centrifugal drying, and difficult purification, and achieve the advantages of simplifying separation and purification steps, reducing production and operating costs, and reducing waste liquid discharge. Effect

Pending 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

[0005] There are many synthetic routes of linagliptin in the prior art, for example, the synthetic routes described in patents WO2004018468A, WO2004018468A, WO2006048427A1, US20120165525A1, etc. Among them, in the synthetic route disclosed in WO2004018468A, the raw material intermediates are cheap and easy to obtain, and the route steps Shorter, mild reaction conditions, the quality control of chiral carbon is easier, but described route and prior art still have the following problems to the improvement of this route: by tert-butoxycarbonyl linagliptin (D) under acidic condition Protecting and preparing linagliptin is one of the most commonly used methods, that is, intermediate D is the key intermediate of linagliptin, but intermediate D is usually a paste compound, which is difficult to filter or centrifugally dry, and it is difficult to purify, especially The content of bromide is relatively high, and the presence of bromide further leads to the production of a large amount of genotoxic impurities in the process of preparing the final product linagliptin, which is difficult to remove, and ultimately affects the quality and purity of the final product linagliptin

Method used

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  • Crystal form of linagliptin intermediate and preparation method thereof
  • Crystal form of linagliptin intermediate and preparation method thereof
  • Crystal form of linagliptin intermediate and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0044] At room temperature, add 8-bromo-7-(2-butynyl)-3,7-dihydro-3-methyl-1-[(4-methyl-2-quinazoline)methanol to the reaction flask base]-1H-purine-2,6-dione (100.00g, 220.6mmol), (R)-3-Boc-aminopiperidine (57.50g, 287mmol), potassium carbonate (122.00g, 883.0mol), acetonitrile 475ml, 25ml dimethyl sulfoxide (DMSO), stirred and heated to 84-86°C, kept stirring for about 20 hours, and the reaction was completed.

[0045] b) Add 750ml of purified water dropwise to the reaction solution in step a). After the dropwise addition, stir to dissolve, control the temperature at 65-67°C, keep stirring, and wait for white solid to precipitate, continue to keep warm for about 2 hours, slowly Cool down to about 25°C, stir for 1 hour, filter, and after the filter cake is drained, rinse and drain with 500ml of purified water to obtain a white crystalline powder solid product 1-[(4-methyl-quinazoline-2- Base) methyl] -3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert-butoxycarbonylamino)-piperidin-1-...

Embodiment 2

[0052] The preparation of tert-butoxycarbonyl linagliptin was carried out by adopting the steps of Example 1, the difference is that, in step b), the reaction liquid after adding water has a heat preservation crystallization temperature of 56-58°C. After steps a) to b), a white crystalline powder solid product D (120.31 g, 210.1 mmol) was obtained. The obtained white solid was in the form of crystal form A, with a yield of 95.23% and a purity of 99.877%.

[0053] Example 2(b)

[0054] The steps of Example 1 were used to prepare tert-butoxycarbonyl linagliptin, the difference being that, in step b), the reaction liquid after adding water had a heat preservation and crystallization temperature of 72-74°C. After steps a) to b), a white crystalline powder solid product D (120.29 g, 210.1 mmol) was obtained. The obtained white solid was in the form of crystal form A, with a yield of 95.22% and a purity of 99.930%.

Embodiment 3

[0056] The steps of Example 1 were used to prepare tert-butoxycarbonyl linagliptin, except that the solvent used in the reaction in step a) was 475ml of acetonitrile, 25ml of N,N-dimethylformamide, and the reaction time was 18 hours . After steps a) to b), a white crystalline powder solid product D (120.16 g, 209.8 mmol) was obtained. The obtained white solid was in the form of crystal form A, with a yield of 95.11% and a purity of 99.896%.

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Abstract

The invention relates to a crystal form A of a linagliptin intermediate 1-[(4-methyl-quinazoline-2-yl) methyl]-3-methyl-7-(2-butyne-1-yl)-8-[(R)-3-(tert-butyloxycarbonylamino)-piperidine-1-yl]-2, 6-diketone-2, 3, 6, 7-tetrahydro-1H-purine (D) and a preparation method thereof.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and relates to a crystal form A of a linagliptin intermediate and a preparation method thereof. Specifically, the invention relates to 1-[(4-methyl-quinazolin-2-yl)methanol Base] -3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert-butoxycarbonylamino)-piperidin-1-yl]-2,6- Crystal form A of diketone-2,3,6,7-tetrahydro-1H-purine and a preparation method 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 I, 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 w...

Claims

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Application Information

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IPC IPC(8): C07D473/04
CPCC07D473/04C07B2200/13
Inventor 张一宁韩福庆廖明明
Owner GAN&LEE PHARMA
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