Application of asymmetric hydrogenation in synthesis of Trelagliptin intermediate

An intermediate and asymmetric technology, applied in the field of drug synthesis, can solve problems such as low product yield, high cost, and complexity, and achieve the effect of simple synthesis method, good product quality, and high yield

Inactive Publication Date: 2017-12-08
SUZHOU XINEN PHARMA
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0010] In the prior art, the synthesis process of trexagliptin intermediates is often more complicated, the cost is higher, and there are also defects of low product yield and poor quality, which cannot be suitable for industrialized large-scale production

Method used

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  • Application of asymmetric hydrogenation in synthesis of Trelagliptin intermediate

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Embodiment

[0028] Preparation of compound (3)

[0029] Add 20 L of absolute ethanol and 2 kg (10 mol) of compound (2) as the reaction solvent into a 50 L reactor at room temperature, then add 848 g (11 mol) of ammonium acetate, and heat the reaction solution to reflux after the addition. The reaction was tracked by TLC. After 7 hours, the reaction was completed. The temperature was lowered to about 25°C, 20L of water was added, stirred and crystallized for 2 hours, filtered, the filter cake was washed with 10L of water, and dried to obtain 1.86 kg (9.37 mol) of compound (3). The rate is 93.7%. HPLC detection purity: 97.7%.

[0030] 1 H NMR (400 MHz, DMSO- d 6 ) δ 6.92 (s, 2H), 5.97 – 5.70 (m, 1H), 3.10 –2.83 (m, 2H), 2.05 – 1.80 (m, 4H), 1.43 (s, 9H).

[0031] ESI+ [M-Boc] + =97.

[0032] Preparation of compound (4)

[0033] Add 1.78 kg (9 mol) of compound (3) in 25L of anhydrous dichloromethane to a 50L autoclave at room temperature, add [Rh(cod) 2 ] BF 4 36 g (0.09 mol) and ...

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Abstract

The present invention provides a method for synthesizing an intermediate of compound trexagliptin of formula (1). The compound of formula (2) is used as the starting material, and the compound of formula (1) is finally obtained through the following series of reactions, that is, the Trexagliptin intermediate: Compared with the prior art, there are many synthesis steps and complicated synthesis process for the trexagliptin intermediate. The synthesis method of the present invention is simple and easy, with low cost, high yield and good product quality, suitable for large-scale industrial production.

Description

technical field [0001] The invention relates to a synthesis method of a trexagliptin intermediate, which belongs to the technical field of medicine synthesis. Background technique [0002] Trelagliptin (common name: Trelagliptin succinate, trade name Zafatek), chemical name: (R)-2-((6-(3-aminopyridin-1-yl)-3-methyl-2,4 -Dioxy-3,4-dihydropyrimidin-1(2H)-yl)methyl)-4-fluorobenzonitrile succinate. The molecular weight of trelagliptin succinate: 475.47; CAS registration number: 1029877-94-8 (Trelagliptin Succinate), 865759-25-7 (Trelagliptin); the structural formula is shown in formula 1: [0003] [0004] Formula 1 [0005] Trexagliptin was developed by Takeda Pharmaceutical Company of Japan. On March 26, 2015, it was approved by PMDA in Japan for the treatment of type 2 diabetes. Trexagliptin is a DPP-4 inhibitor drug. It is a long-acting selective dipeptidyl peptidase-4 (DPP- 4) Inhibitor, which can effectively inhibit the activity of DPP-4, prevent the glucagon-like p...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D211/56C07B53/00
CPCC07D211/56C07B53/00C07B2200/07
Inventor 王爱玉
Owner SUZHOU XINEN PHARMA
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