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Synthesizing method of omarigliptin intermediate

A synthesis method and intermediate technology are applied in the synthesis field of alogliptin intermediates, which can solve the problems of low product yield, high cost, complexity and the like, and achieve a simple and easy synthesis method, good product quality and high yield. Effect

Inactive Publication Date: 2017-10-10
SUZHOU XINEN PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] In the prior art, the synthesis process of alogliptin 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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  • Synthesizing method of omarigliptin intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0023] Preparation of compound (4)

[0024] Add 2.18 kg (12 mol) of compound (3) and 710 g (10 mol) of compound (2) in 20L of anhydrous tetrahydrofuran to a 50L reactor at room temperature, and slowly add 27 g (0.05 mol) of catalyst. After stirring for half an hour, 1.94 kg (15 mol) of diisopropylethylamine was slowly added. After the reaction was monitored by TLC, 20L of water was slowly added, stirred and crystallized, filtered, the filter cake was washed with 10L of water, and dried to obtain compound (4) The crude product was recrystallized twice from isopropyl acetate to obtain 2.07 kg (8.87 mol) of the refined product of compound (4), with a yield of 88.7%. HPLC detection purity: 98.1%.

[0025] 1 H NMR (400 MHz, DMSO- d 6 ) δ 7.85 (s, 1H), 4.66 (s, 2H), 2.78-2.71 (m, 2H), 2.59-2.52 (m, 4H), 2.07-2.00 (m, 1H), 1.91-1.82 (m, 1H ).

[0026] ESI+ [M+H] + =234.

[0027] Preparation of compound (6)

[0028] Under nitrogen protection, 1.93 kg (8.3 mol) of compound (4)...

Embodiment 2

[0036] Preparation of compound (4)

[0037] According to the method of Example 1, the reaction solvent was replaced by anhydrous toluene; the reaction temperature was 110°C, and the molar ratio of compound (2) and compound (3) was 1:1; the base used in the reaction was replaced by NaHMDS. The molar ratio of compound (2) to catalyst was 200:1, and finally the refined product of compound (4) was obtained with a yield of 87.4%. HPLC detection purity: 97.8%.

[0038] Preparation of compound (6)

[0039] According to the method in Example 1, the solvent is replaced by anhydrous 2-methyltetrahydrofuran, the reaction temperature is 20-80°C, the preferred temperature is 65-75°C, and the molar ratio of compound (4) to catalyst is 100:1, and finally The refined product of compound (6) has a yield of 92.6%. Purity by HPLC: 97.2%.

[0040] Preparation of compound (1)

[0041] According to the method in Example 1, the reaction solvent was replaced by anhydrous acetone; the reaction te...

Embodiment 3

[0043] Preparation of compound (4)

[0044] According to the method of Example 1, the reaction solvent was replaced by anhydrous dichloromethane; the reaction temperature was 40°C, the molar ratio of compound (2) to compound (3) was 1:2.0; the molar ratio of compound (2) to catalyst was 200 : 1~20, the refined product of compound (4) was finally obtained, and the yield was 89.3%. HPLC detection purity: 98.8%.

[0045] Preparation of compound (6)

[0046] According to the method of Example 1, the solvent was replaced by anhydrous ether, the reaction temperature was 0°C, the molar ratio of compound (4) to catalyst was 100:10, and finally the refined product of compound (6) was obtained with a yield of 93.6%. HPLC detection purity: 97.9%.

[0047] Preparation of compound (1)

[0048] According to the method of Example 1, the reaction solvent was replaced by methanol; the reaction temperature was 0°C, and finally the refined product of compound (1) was obtained with a yield of 9...

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Abstract

The present invention provides a method for synthesizing the intermediate of compound alogliptin of formula (1), using compounds of formula (2) and formula (3) as starting materials, and finally preparing the compound of formula (1) through the following series of reactions Compound, that is, the alogliptin intermediate: Compared with the prior art, the alogliptin intermediate has many synthesis steps and complex synthesis process. The synthesis method of the present invention is simple and easy, with low cost and high yield. The product Good quality, suitable for large-scale industrial production.

Description

technical field [0001] The invention relates to a method for synthesizing an alogliptin intermediate, belonging to the technical field of pharmaceutical synthesis. Background technique [0002] Ologliptin (common name: Omarigliptin, trade name Marizev), chemical name ((2R,3S,5R)-2-(2,5-difluorophenyl)-5-(2-(methylsulfonyl) )pyrrolo[3,4-c]pyrazolyl-5(2H,4H,6H)-yl)tetrahydro-2H-pyran-3-amine). The molecular weight of alogliptin: 398.43; CAS registration number: 1226781-44-7; the structural formula is shown in formula 1: [0003] [0004] Formula 1 [0005] Alogliptin was developed by Merck & Co. Omarigliptin, a drug for the treatment of type 2 diabetes approved in Japan on September 30, 2015, is a type of DPP-4 inhibitor, which can be achieved by taking it only once a week. [0006] prior art literature [0007] Non-patent literature: 1: Org. Lett., 2014, vol.16, pp5422-5425; Non-patent literature 2: J. Med.Chem., 2014, vol.57, pp3205-3212 [0008] Patent documents: W...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D309/30
CPCC07D309/30
Inventor 佘阳
Owner SUZHOU XINEN PHARMA
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