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Sitagliptin and enzyme-chemical preparation method of intermediate of sitagliptin

A technology for enzymatic preparation and recycling of enzymes, which is applied in the field of medical biochemistry, can solve problems that have not been reported, and achieve the effects of reducing process routes, reducing production costs, and improving product purity and yield

Active Publication Date: 2016-02-17
ZHEJIANG SUPOR PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

At present, the biosynthetic method of this compound, especially the synthetic method utilizing amino acid dehydrogenase, has not been reported yet.

Method used

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  • Sitagliptin and enzyme-chemical preparation method of intermediate of sitagliptin
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  • Sitagliptin and enzyme-chemical preparation method of intermediate of sitagliptin

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0032] The preparation of embodiment 1 (R)-3-amino-4-(2,4,5-trifluorophenyl) butanoic acid (I)

[0033] Add 3-carbonyl-4-(2,4,5-trifluorophenyl)butanoic acid (18.6g) and NAD (0.1g) successively in potassium phosphate buffer (100ml, 0.1mol / l, pH=7.5) , ammonium formate (10g), dimethyl sulfoxide (10ml), formate dehydrogenase (5g), D-amino acid dehydrogenase (5g), stirred and reacted in a water bath at 30°C for 24h, when the conversion rate reached 95% as detected by HPLC , adjust the pH to 2-3 to terminate the reaction, filter to remove the precipitate, add an equal volume of ethyl acetate to the filtrate to extract 3 times, combine the extracts, add anhydrous sodium sulfate to dry, filter and concentrate to obtain (R)-3-amino- 4-(2,4,5-trifluorophenyl)butanoic acid (16.5g), the yield was 88%, and the ee value of the product was >99%.

Embodiment 2

[0034] Example 2 Preparation of (R)-N-tert-butoxycarbonyl-3-amino-4-(2,4,5-trifluorophenyl)butanoic acid (II)

[0035] Add (R)-3-amino-4-(2,4,5-trifluorophenyl) butanoic acid (10g) in the reaction flask, (Boc) 2 O (11.2g), sodium bicarbonate (7.9g), tetrahydrofuran (50ml) and water (50ml), react at room temperature for 24h, adjust the pH to 2-3, add ethyl acetate for extraction (50ml*3), and combine the extracts , added anhydrous sodium sulfate for drying treatment, filtered and concentrated to give (R)-N-tert-butoxycarbonyl-3-amino-4-(2,4,5-trifluorophenyl)butanoic acid (13.6g), yield 95%.

Embodiment 37-

[0036]Example 37-[(R)-3-(tert-butoxycarbonylamino)-1-oxo-4-(2,4,5-trifluorophenyl)butyl]-5,6,7,8- Preparation of tetrahydro-3-(trifluoromethyl)-1,2,4-triazol[4,3-a]pyrazole (V)

[0037] Add (R)-N-tert-butoxycarbonyl-3-amino-4-(2,4,5-trifluorophenyl)butanoic acid (10g) into the reaction flask, 3-(trifluoromethyl)-5 ,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine hydrochloride (12.1g), triethylamine (6.8g), 1-hydroxybenzo Triazole (6g) and 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (7.2g), tetrahydrofuran (80ml), reacted at room temperature for 12h, added water (80ml), The layers were separated, the aqueous layer was extracted with ethyl acetate (50ml*2), the organic layers were combined, dried by adding anhydrous sodium sulfate, concentrated by filtration, and crystallized from a mixed solvent of isopropanol / water (10:1, 50ml) to obtain 7-[ (R)-3-(tert-butoxycarbonylamino)-1-oxo-4-(2,4,5-trifluorophenyl)butyl]-5,6,7,8-tetrahydro-3- (Trifluoromethyl)-1,2,4-tr...

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Abstract

The invention discloses sitagliptin and an enzyme-chemical preparation method of an intermediate of the sitagliptin. The method comprises the steps of mixing 3-carbonyl-4-(2, 4, 5-trifluoro-phenyl)butyrate, D-amino acid dehydrogenase, a cofactor, cofactor-catalyzing cyclophorase, an amino doner, a cosolvent and a buffer solution according to a certain ratio to obtain a product (R)-3-amino-4-(2, 4, 5 trifluoro-phenyl)butyrate; enabling the (R)-3-amino-4-(2, 4, 5 trifluoro-phenyl)butyrate to be subjected to the steps of amino protection, condensation and deprotection to obtain sitagliptin free alkali. Compared with the prior art, the method adopted by the invention is less in process route, shorter in reaction time, improved in product purity and yield and lower in production cost, and is suitable for industrial production.

Description

technical field [0001] The invention belongs to the field of medical biochemistry, and in particular relates to an enzyme-chemical preparation method of sitagliptin and an intermediate thereof. Background technique [0002] Sitagliptin phosphate (Sitagliptinphosphate) is the first dipeptidylase-IV (DPP-4) inhibitor developed by Merck that was approved by the FDA in 2006. Its trade name is Januvia. For the treatment of type II diabetes, it has obvious hypoglycemic effect when used alone or in combination with metformin and pioglitazone, and it is safe to take, well tolerated, and has few adverse reactions. At present, the drug has been approved for use in more than 60 countries around the world, and its sales volume in 2014 has reached 4 billion US dollars. It is a veritable "blockbuster" drug. Therefore, its efficient synthetic method has become an interesting research direction. [0003] [0004] In the synthetic route of sitagliptin, chiral (R)-2,4,5-trifluorophenyl-β...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C12P13/04C12P17/18C07D487/04
CPCC07D487/04C12P13/04C12P17/182
Inventor 竺伟高新星王波
Owner ZHEJIANG SUPOR PHARM CO LTD
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