Synthesis method of linagliptin intermediate

A synthesis method and intermediate technology are applied in the synthesis field of linagliptin intermediates, can solve the problems of low purity, low yield, and difficult removal of iodine-containing inorganic salts of intermediates, achieve high purity, and avoid debromination of impurities , the effect of slow filtering

Active Publication Date: 2016-08-31
赤峰赛林泰药业有限公司
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

But because the second reaction has iodine-containing inorganic salts, other impurities can be produced, and iodine-containing inorganic salts are difficult to remove, so even if complicated post-treatment purification methods are used, the intermediate (g) obtained has low purity and low yield. Moreover, the product obtained by one-step reaction will also contain corresponding impurities, causing the final product to be directly used as a medicine

Method used

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  • Synthesis method of linagliptin intermediate
  • Synthesis method of linagliptin intermediate
  • Synthesis method of linagliptin intermediate

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0043] The method for preparing formula g compound linagliptin, it may further comprise the steps:

[0044] (1) Synthesis of intermediate (c)

[0045] Reaction of 8-bromo-3-methylxanthine (a) with 1-bromo-2-butyne (b) affords intermediate (c).

[0046]

[0047] Operation steps: Add 908g (3.7mol) 8-bromo-3-methylxanthine (a), 574.1g (4.442mol) N,N-diisopropylethylamine (DIEA) into a 2L three-necked flask, 591.1 g (4.445 mol) of 1-bromo-2-butyne (b), 12 L of acetone. Start stirring, heat to reflux reaction, and the reaction ends after 4-6 hours. The reaction solution was cooled to room temperature, filtered with suction, and the filter cake was washed with 4L of methanol to obtain a pale yellow solid, which was dried to obtain 1013.7g of the product with a purity of 95.7% and a yield of 105.9%.

[0048] (2) Synthesis of intermediate (e)

[0049] Intermediate (c) is reacted with 2-chloromethyl-4-methylquinazoline (d) to give intermediate (e).

[0050]

[0051] Operatio...

Embodiment 2

[0064] The method for preparing formula g compound linagliptin, it may further comprise the steps:

[0065] (1) Synthesis of intermediate (c)

[0066] Reaction of 8-bromo-3-methylxanthine (a) with 1-bromo-2-butyne (b) affords intermediate (c).

[0067]

[0068] Operation steps: Add 36.75g (0.15mol) 8-bromo-3-methylxanthine (a), 23.26g (0.18mol) N,N-diisopropylethylamine (DIEA) into a 500mL three-necked flask , 21.94g (0.165mol) 1-bromo-2-butyne (b), acetone 350mL. Start stirring, heat to reflux reaction, and the reaction ends after 7h. The reaction solution was cooled to room temperature, filtered with suction, and the filter cake was washed with 100 mL of methanol to obtain a pale yellow solid, which was dried to obtain 52.96 g of the product with a purity of 92.0% and a yield of 118.8%.

[0069] (2) Synthesis of intermediate (e)

[0070] Intermediate (c) is reacted with 2-chloromethyl-4-methylquinazoline (d) to give intermediate (e).

[0071]

[0072] Operation st...

Embodiment 3

[0082] The method for preparing formula g compound linagliptin, it may further comprise the steps:

[0083] (1) Synthesis of intermediate (c)

[0084] Reaction of 8-bromo-3-methylxanthine (a) with 1-bromo-2-butyne (b) affords intermediate (c).

[0085]

[0086] Operation steps: In a 500mL three-necked flask, add 10g (0.04mol) 8-bromo-3-methylxanthine (a), 6.2g (0.048mol) N,N-diisopropylethylamine (DIEA), 6.9g (0.052mol) of 1-bromo-2-butyne (b), 120mL of acetone. Start stirring, heat to reflux reaction, and the reaction ends after 5.5h. The reaction solution was cooled to room temperature, filtered with suction, and the filter cake was washed with 50 mL of methanol to obtain a pale yellow solid, which was dried to obtain 12.9 g of the product with a purity of 93.6 and a yield of 106.3%.

[0087] (2) Synthesis of intermediate (e)

[0088] Intermediate (c) is reacted with 2-chloromethyl-4-methylquinazoline (d) to give intermediate (e).

[0089]

[0090] Operation steps...

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Abstract

The invention discloses a synthesis method of a linagliptin intermediate. The synthesis method comprises adding 1-[(4-methylquinazolin-2-yl)methyl]-3-methyl-7-(2-butyne-1-yl)-8-bromoxanthine (e), (R)-3-Boc-aminopiperidine (f), potassium carbonate and acetonitrile into a reactor, carrying out uniform mixing and carrying out a reaction process under the conditions of heating reflux, a reaction temperature of 80-85 DEG C and reaction time of 24-48h, wherein a mole ratio of 1-[(4-methylquinazolin-2-yl)methyl]-3-methyl-7-(2-butyne-1-yl)-8-bromoxanthine (e), (R)-3-Boc-aminopiperidine (f) to potassium carbonate is 1: (1.2-1.6): (3-7) and a ratio of 1-[(4-methylquinazolin-2-yl)methyl]-3-methyl-7-(2-butyne-1-yl)-8-bromoxanthine (e) to acetonitrile is 100: (400-1000)g / ml. The synthesis method of the linagliptin intermediate (g) prevents generation of debromination impurities (i), is simple and easy in a post-treatment step and solves the problem that the intermediate is not easily separated from a solvent and is difficultly purified and separated.

Description

technical field [0001] The invention relates to a synthesis method of a linagliptin intermediate. Background technique [0002] Currently, several DPP-4 inhibitors have been approved for the treatment of T2DM patients. Linagliptin (linagliptin) is one of the new members. Linagliptin is an 8-(3-aminopiperidine)-xanthine derivative designed and synthesized by Boehringer Ingelheim (WO 2004018468 / CN 1675212), which is a DPP-4 inhibitor with strong activity (IC50= 1nmol / L), has the characteristics of high selectivity, long-acting and oral effectiveness, and has good safety and tolerance. [0003] In May 2011, it was approved for marketing by the US FDA, and in June 2011, it was approved for marketing in Europe. 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 issued by China Food and Drug Administration (CFDA), and was approved to be...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D473/04
CPCC07D473/04
Inventor 张丽华崔玉杰赵宏伟王艳峰季丽萍盛丽王洁婷马征
Owner 赤峰赛林泰药业有限公司
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