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Synthesis process of omarigliptin

A compound and solvent technology, which is applied in the field of preparation of the compound alogliptin, can solve the problems of low reaction yield and high synthesis cost, etc.

Active Publication Date: 2020-10-20
四川凯科医药科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Therefore, in fact, neither Lewis acid nor strong acid can solve the problem of low reaction yield and high synthesis cost in Document 1.

Method used

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  • Synthesis process of omarigliptin
  • Synthesis process of omarigliptin
  • Synthesis process of omarigliptin

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0046]

[0047] Take 8.25g of compound 2, 9.8g of compound 3, 120ml of DMA and 40ml of acetic acid, cool to -15°C in an ice-salt bath, then slowly add 6.9g of sodium triacetylborohydride, after the reaction, add 200ml of water After stirring, the precipitated solid was filtered and dried to obtain 11.74 g of compound 4.

[0048] Add 190 ml of dichloromethane and 9.05 g of benzenesulfonic acid to the reaction vessel, add 11.7 g of compound 4 in batches with stirring, after the reaction is completed, add 190 ml of water, discard the organic phase, and add 100 ml of dichloromethane to the water phase Then slowly add 10.3 grams of sodium bicarbonate, separate the dichloromethane phase, extract the aqueous phase with dichloromethane again, combine the dichloromethane, add ethyl acetate to crystallize after concentration, filter and dry to obtain the final augliptin product 7.52 grams, purity greater than 99.0%, high resolution MS: m / z=399.1298 (M+1).

Embodiment 2

[0050] Take 8.25g of compound 2, 9.8g of compound 3, 120ml of DMA and 40ml of propionic acid, cool to -15℃ in an ice-salt bath, then slowly add 6.9g of sodium triacetylborohydride, after the reaction, add 200ml of water After stirring, the precipitated solid was filtered and dried to obtain 11.42 g of compound 4.

[0051] Add 180 ml of dichloromethane and 8.54 g of benzenesulfonic acid to the reaction vessel, add 11.42 g of compound 4 in batches under stirring. After the reaction is completed, add 180 ml of water, discard the organic phase, and add 100 ml of dichloromethane to the water phase. Then slowly add 9.7 grams of sodium bicarbonate, separate the dichloromethane phase, extract the aqueous phase again with dichloromethane, combine the dichloromethane, add ethyl acetate to crystallize after concentration, filter and dry to obtain the final augliptin product 7.17 g, purity greater than 99.0%, high resolution MS: m / z=399.1298 (M+1).

Embodiment 3

[0053] Take 8.25g of compound 2, 9.8g of compound 3, 120ml of DMA and 40ml of acetic acid, cool to -15℃ in an ice-salt bath, then slowly add 1.3g of sodium borohydride, after the reaction is completed, add 200ml of water, stir and filter The precipitated solid was dried to obtain 11.43 g of compound 4.

[0054] Add 190 ml of dichloromethane and 8.8 g of benzenesulfonic acid to the reaction vessel, add 11.43 g of compound 4 in batches with stirring, after the reaction is completed, add 190 ml of water, discard the organic phase, and add 100 ml of dichloromethane to the water phase Then slowly add 10.0 g of sodium bicarbonate, separate the dichloromethane phase, extract the aqueous phase with dichloromethane again, combine the dichloromethane, add ethyl acetate to crystallize after concentration, filter and dry to obtain the final augliptin product 7.24 grams, purity greater than 99.0%, high resolution MS: m / z=399.1298 (M+1).

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Abstract

The invention discloses a method for preparing omarigliptin and a method for preparing an intermediate. In the method for preparing the key intermediate compound 4 of the omarigliptin, a weak acid with the pKa value of 3.5-5 is added, so that the generation of byproducts is effectively inhibited, the yield of the intermediate compound 4 is very high, and finally, the yield of the omarigliptin is greatly improved.

Description

Technical field [0001] The invention belongs to the technical field of organic compound synthesis technology, and specifically relates to a preparation method of the compound augliptin. Background technique [0002] Omarigliptin is an ultra-long-acting DPP-4 inhibitor. It can be taken orally once a week and can produce sustained DPP-4 inhibition. It has a brand-new blood sugar lowering mechanism, and at the same time has the advantages of no weight gain, no hypoglycemia reaction, and no edema. [0003] The structural formula of Augliptin is shown in Formula 1. For the convenience of description below, it is referred to as compound 1: [0004] [0005] The current synthesis process of compound 1, the synthesis route disclosed in Literature 1 (J. Med. Chem., 2014, 57(8)) is as follows: [0006] [0007] The yield of the process disclosed in this document is relatively low. Calculated based on the data recorded in Literature 1, the yield of the synthesis step of compound 4 in the first ...

Claims

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Application Information

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IPC IPC(8): C07D487/04
CPCC07D487/04
Inventor 钟庆林唐小林
Owner 四川凯科医药科技有限公司
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