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Sitagliptin derivative or pharmaceutically acceptable salt, as well as preparation method and application thereof

A derivative and pharmaceutical technology, applied in the field of synthesis of pharmaceutical intermediates, can solve problems such as low-energy molecular conformation, reduced drug selectivity, unfavorable safe drug use, etc., to reduce the formation of low-energy isomerism, improve selectivity, and improve drug safety sexual effect

Active Publication Date: 2018-01-05
ZHEJIANG LEPU PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] However, in the currently reported structure of sitagliptin or its salt-forming drug, both the amino group and the carbonyl group are flexible chain structures, which can easily cause the production of low-energy molecular conformations, reduce the selectivity of the drug, and be unfavorable for safe drug use.

Method used

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  • Sitagliptin derivative or pharmaceutically acceptable salt, as well as preparation method and application thereof
  • Sitagliptin derivative or pharmaceutically acceptable salt, as well as preparation method and application thereof
  • Sitagliptin derivative or pharmaceutically acceptable salt, as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0053] Preparation of enamine key intermediate formula II compound:

[0054]

[0055] Add dichloromethane (20mL) in the reaction flask equipped with stirring, condenser, thermometer, formula VI compound (0.01mol), namely wherein R 3 For hydrogen, tert-butyl carbamate (1.76g, 0.015mol), p-toluenesulfonic acid (0.1g) and MS type molecular sieves (3.0g), stirred overnight at room temperature, after the reaction was completed, the reaction solution was filtered, The filtrate was concentrated to dryness under reduced pressure, then purified by silica gel column chromatography, and the purified eluate was collected and then concentrated to dryness under reduced pressure to obtain an off-white solid compound enamine key intermediate formula II compound with a yield of more than 60%. .

[0056] For the synthesis of the target compound in the specific synthesis process, the substituent R in the molecular structure of the corresponding compound 1 Selective replacement is enough to ...

Embodiment 2

[0060] Preparation of intermediate formula IV compound

[0061]

[0062] Select the corresponding enamine key intermediate formula II compound (3.4mmol) obtained in the above-mentioned embodiment 1 and add in the reaction flask, then, add the dichloromethane (50mL) solution of the corresponding formula III compound (3.4mmol) again, control the temperature at Add HOBT (545mg, 4.2mmol) at about 0°C, stir for 10 minutes, then add EDC (1.9g, 10.0mmol), then remove the ice bath, and slowly raise the temperature to room temperature under stirring to carry out the coupling reaction 14 Hours, after the reaction was over, the compound was concentrated, subjected to silica gel column chromatography, and the pure components were combined and then concentrated to dryness under reduced pressure to obtain an off-white solid intermediate compound of formula IV.

[0063] For the difference in the target compound intermediate formula IV compound in the specific synthetic process, the substi...

Embodiment 3

[0069] Preparation of intermediate formula IV-1 compound

[0070]

[0071] Select the corresponding enamine key intermediate compound (3.4mmol) obtained in the above-mentioned embodiment 1 and add it to the reaction flask, and then add the corresponding compound 3-(trifluoromethyl)-5,6,7,8 -Tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine (3.4mmol) in dichloromethane (50mL) solution, add HOBT (545mg, 4.2mmol), stirred for 10 minutes, then added EDC (1.9g, 10.0mmol), then removed the ice bath, slowly warmed up to room temperature under stirring conditions, and stirred for 14 hours for coupling reaction. After the reaction was over, concentrated the reaction solution to remove Solvent, the corresponding residue was obtained, after silica gel column chromatography, the pure components were combined and then concentrated to dryness under reduced pressure to obtain 1.3 g of an off-white solid intermediate compound of formula IV-1.

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Abstract

The invention relates to a sitagliptin derivative or pharmaceutically acceptable salt, as well as a preparation method and application thereof, and belongs to the technical field of synthesis of a medicine intermediate. In order to solve the problem that the conventional chain easily generates low-energy conformation, the invention provides the sitagliptin derivative or pharmaceutically acceptablesalt, and the preparation method thereof. The method comprises the following steps: under the existence of a coupling agent, performing coupling reaction on an enamine intermediate and a triazol[4,3-a]pyrazine compound to obtain an intermediate; performing deprotection reaction on the intermediate to remove a Boc group, and performing cyclization reaction on the hydroxylamine hydrochloride to obtain the corresponding sitagliptin derivative or pharmaceutically acceptable salt. Amino and carbonyl in flexible chain alkyl in the molecular structure are cyclized to form a five-membered ring structure, so that low-energy isomerism phenomena are effectively reduced, medicine stability is improved, and selectivity and medicine use safety are improved. The synthesis method is simple, and use of anexpensive chiral reagent can be avoided.

Description

technical field [0001] The invention relates to a sitagliptin derivative or a pharmaceutically acceptable salt thereof, a preparation method and application thereof, and belongs to the technical field of pharmaceutical intermediate synthesis. Background technique [0002] Dipeptidyl peptidase-IV (DPP-IV) inhibitor drugs reduce the degradation of glucagon-like peptide-I (GLP-I) by inhibiting DPP-IV, increasing the plasma concentration of GLP-I, thereby To improve postprandial blood sugar control, taking DPP-Ⅳ inhibitor drugs is a new way to treat type 2 diabetes. [0003] Sitagliptin was developed and marketed by Merck, which was launched in the United States in October 2006, and then in Europe and other countries. In October 2007, the drug was approved by the US FDA for combination therapy with metformin. Wherein, the structural formula of sitagliptin is as follows: [0004] [0005] The chemical name of the sitagliptin compound above is (2R)-4-oxo-4-[3-(trifluoromethy...

Claims

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Application Information

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IPC IPC(8): C07D487/04A61P3/10
Inventor 成碟林义颜剑波洪华斌
Owner ZHEJIANG LEPU PHARMA CO LTD
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