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Synthetic method for omarigliptin

A synthesis method and a series of technologies, applied in the field of drug synthesis, can solve the problems of low product yield, high cost and poor quality, and achieve the effects of simple and easy synthesis method, good product quality and low cost

Inactive Publication Date: 2016-03-16
黄燕鸽
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] In the prior art, the synthesis process of alogliptin is often more complicated, the cost is higher, and there are defects of low product yield and poor quality, which cannot be suitable for industrialized large-scale production

Method used

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  • Synthetic method for omarigliptin
  • Synthetic method for omarigliptin
  • Synthetic method for omarigliptin

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0024] Preparation of compound (4)

[0025] Under nitrogen protection, add 1.2kg (12mol) compound (3) and 31g (0.05mol) catalyst 3 in 20L anhydrous tetrahydrofuran in 50L reactor at room temperature, slowly drop 1.42kg (10mol) compound (2 ). Slowly add 1.94kg (15mol) of diisopropylethylamine after stirring for half an hour, after TLC monitors that the reaction is completed, the reaction solution is neutralized to pH 6.8 with acetic acid, filtered, the filter cake is washed with 5L tetrahydrofuran, and the filtrate and washings are combined. The crude product of compound (4) was obtained by concentration, and the crude product was recrystallized twice from ethyl acetate to obtain 2.13 kg (8.83 mol) of the refined product of compound (4), with a yield of 88.3%. Purity by HPLC: 98.2%.

[0026] 1 HNMR (400MHz, DMSO-d 6 )δ7.25-7.15(m,1H),7.13-7.06(m,2H),7.40-5.27(m,2H),2.97-2.87(m,1H),2.93(s,1H),2.72-2.62( m,1H).

[0027] ESI+[M+H] + =242.

[0028] Preparation of compound (...

Embodiment 2

[0045] Preparation of compound (4)

[0046] According to the method of Example 1, the reaction solvent was replaced by anhydrous toluene; the reaction temperature was -78°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 reaction catalyst is catalyst 3; the molar ratio of compound (2) to the catalyst is 200:1, and finally the refined product of compound (4) is obtained with a yield of 87.4%. Purity by HPLC: 97.8%.

[0047] Preparation of compound (5)

[0048] According to the method of Example 1, the solvent is replaced by anhydrous DMA, the reaction temperature is 20-80°C, and the preferred temperature is 65-75°C, the base is replaced by sodium bicarbonate, and the catalyst is replaced by bis(triphenylphosphine) dichloride Palladium, the molar ratio of compound (4) to the catalyst is 100:1; the ligand is replaced by PipPhos, and finally the refined product of compound (5) is obtained with a yield of 92...

Embodiment 3

[0056] Preparation of compound (4)

[0057] According to the method of Example 1, the reaction solvent is replaced by anhydrous dichloromethane; the reaction temperature is 110 ° C, and the molar ratio of compound (2) and compound (3) is 1:2.0; the base used in the reaction is replaced by tert-butyl Potassium alcohol. The reaction catalyst is catalyst 5; the molar ratio of the compound (2) to the catalyst is 200:1-20, and finally the refined product of the compound (4) is obtained with a yield of 89.3%. Purity by HPLC: 98.8%.

[0058] Preparation of compound (5)

[0059] According to the method of Example 1, the solvent is replaced by anhydrous DMF, the reaction temperature is 80 ° C, the base is replaced by triethylamine, and the catalyst is replaced by [(3-F-Ph) 3 P] 3 RhCl, the molar ratio of compound (4) to catalyst was 100:10; the ligand was replaced by BINAP, and finally the refined product of compound (5) was obtained with a yield of 93.6%. Purity by HPLC: 97.9%. ...

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Abstract

The invention provides a synthetic method for a formula (I) compound omarigliptin. A formula (2) compound and a formula (3) compound are taken as initial raw materials and are subjected to a series of reactions shown in the specification, so that the formula (1) compound omarigliptin is finally prepared. Compared with the prior art defects that omarigliptin synthetic steps are more and synthetic technology is complex, the synthetic method is simple and practicable, relatively low in cost, relatively high in yield, relatively good in product quality, and is suitable for large-batch industrialized production.

Description

technical field [0001] The invention relates to a synthesis method of alogliptin, which belongs to the technical field of medicine 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] 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. [0005] prior art literature [0006] Non-patent literature: 1: Org.Lett., 2014, vol.16, pp5422-5425; Non-patent literature 2: J.Med.Chem., 2014, vol.57, pp3205-3212 [0007] Patent documents: WO2013 / 003249 and US2010 / 120863A1. [0008] ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/04
CPCC07D487/04
Inventor 黄燕鸽
Owner 黄燕鸽
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