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Preparation method of linagliptin

A methanol aqueous solution, tert-butoxycarbonyl technology, applied in organic chemistry and other directions, can solve problems such as amide bond cleavage, and achieve the effect of slow filtration rate and high purity

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

AI Technical Summary

Problems solved by technology

However, since hydrochloric acid is a strong acid, it is easy to cause the amide bond in the intermediate (g) and listagliptin to break

Method used

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  • Preparation method of linagliptin
  • Preparation method of linagliptin
  • Preparation method of linagliptin

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0040] The method for preparing formula g compound linagliptin, it may further comprise the steps:

[0041] (1) Synthesis of intermediate (c)

[0042] Reaction of 8-bromo-3-methylxanthine (a) with 1-bromo-2-butyne (b) affords intermediate (c).

[0043]

[0044] 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 4 L of methanol to obtain a pale yellow solid, which was dried to obtain 1013.7 g of the product with a purity of 95.7% and a yield of 105.9%.

[0045] (2) Synthesis of intermediate (e)

[0046] Intermediate (c) is reacted with 2-chloromethyl-4-methylquinazoline (d) to give intermediate (e).

[0047]

[0048]Operati...

Embodiment 2

[0061] The method for preparing formula g compound linagliptin, it may further comprise the steps:

[0062] (1) Synthesis of intermediate (c)

[0063] Reaction of 8-bromo-3-methylxanthine (a) with 1-bromo-2-butyne (b) affords intermediate (c).

[0064]

[0065] 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%.

[0066] (2) Synthesis of intermediate (e)

[0067] Intermediate (c) is reacted with 2-chloromethyl-4-methylquinazoline (d) to give intermediate (e).

[0068]

[0069] Operation st...

Embodiment 3

[0079] The method for preparing formula g compound linagliptin, it may further comprise the steps:

[0080] (1) Synthesis of intermediate (c)

[0081] Reaction of 8-bromo-3-methylxanthine (a) with 1-bromo-2-butyne (b) affords intermediate (c).

[0082]

[0083] 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%.

[0084] (2) Synthesis of intermediate (e)

[0085] Intermediate (c) is reacted with 2-chloromethyl-4-methylquinazoline (d) to give intermediate (e).

[0086]

[0087] Operation steps...

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Abstract

The invention discloses a preparation method of linagliptin. The preparation method comprises putting t-butyloxycarbonyl-linagliptin (g) into a methanol aqueous solution and carrying out stirring so that the solution undergoes a reaction along with heating reflux in an inert atmosphere at a temperature of 25-50 DEG C for 3-12h, wherein a weight ratio of the t-butyloxycarbonyl-linagliptin (g) to the methanol aqueous solution is 100: (400-550). The preparation method carries out Boc protection base removal in a methanol aqueous solution in an inert gas protective atmosphere, is free of expensive trifluoroacetic acid-DCM in a Boc protection base removal reaction, only utilizes a cheap methanol-water system and has simple after-treatment processes. A trifluoroacetic acid-DCM system reaction produces more impurities and needs a very complex post-treatment purifying process. The preparation method prevents strong acid-produced intermediate (g) impurities and linagliptin amide bond fracture impurities.

Description

technical field [0001] The invention relates to a preparation method of linagliptin. 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 marketed in ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D473/04
CPCC07D473/04
Inventor 崔玉杰张丽华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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