Method for preparing saxagliptin chiral intermediate through enzymatic-catalysis asymmetric transamination

A chiral intermediate and asymmetric technology, which is applied in the field of enzyme-catalyzed asymmetric transamination reaction to prepare saxagliptin intermediates, can solve the problems of high price and difficulty in realizing industrialization.

Active Publication Date: 2015-12-02
福州基石医药科技有限公司
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  • Abstract
  • Description
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Problems solved by technology

The use of amino acid dehydrogenase to transaminate carbonyl groups is an effective means to synthesize chiral intermediate compounds, but this process requires the continuous addition of continuously consumed nicotinamide adenine dinucleotide (NADH) as a coenzyme, and the coenzyme NADH is expensive. oxidized coenzyme NAD + It is a competitive inhibitor of NADH, so the enzymatic synthesis of saxagliptin chiral intermediates is difficult to achieve industrialization

Method used

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  • Method for preparing saxagliptin chiral intermediate through enzymatic-catalysis asymmetric transamination

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Experimental program
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Effect test

Embodiment 1

[0021] Saxagliptin intermediate with 0.1μmol / L NADH as the starting coenzyme and concentration of 10mmol / L 1 Carry out coupling reaction with glycerin of 50mmol / L; Reaction condition is: pH8.5, 1.0mol / LNH 4 Cl?NH 4 OH buffer system, the dosage of GDH and phenylalanine dehydrogenase are 1U / mL and 1U / mL respectively, the total reaction volume is 1.5mL, the temperature is 30°C, and the rotation speed is 140r / min. After the reaction reaches equilibrium for 5 minutes, take a sample 200 μL, respectively detect the concentration of the product DHA and the chiral intermediate of saxagliptin; then add 8 μL of NADH (10 μmol / L) to the system to make the total coenzyme concentration in the system reach 0.2 μmol / L; after the reaction is balanced, take another sample 200 μL, detect product concentration and supplement with 44 μL NAD + Make the total coenzyme concentration reach 0.3 μmol / L; add the coenzyme repeatedly in this way for a total of 4 times, and finally the total coenzyme conce...

Embodiment 2

[0023] Saxagliptin intermediate with 0.1μmol / L NADH as the starting coenzyme and concentration of 20mmol / L 1 Carry out coupling reaction with glycerol of 200mmol / L; Reaction condition is: pH8.5, 1.0mol / LNH 4 Cl?NH 4 OH buffer system, the dosages of GDH and phenylalanine dehydrogenase are 40U / mL and 40U / mL respectively, the total reaction volume is 1.5mL, the temperature is 30°C, and the rotation speed is 140r / min. After the reaction reaches equilibrium for 5 minutes, take out 200 μL, detect the concentration of the product DHA and the chiral intermediate of saxagliptin respectively; then add 25 μL of 10 μmol / L NADH to the system to make the total coenzyme concentration in the system reach 0.2 μmol / L; Product concentration and supplemented with 22 μL of NAD + Make the total coenzyme concentration reach 0.3 μmol / L; add the coenzyme repeatedly in this way for a total of 4 times, and finally the total coenzyme concentration reaches 0.5 μmol / L; finally detect the product DHA and ...

Embodiment 3

[0025] Saxagliptin intermediate with 0.1μmol / L NADH as the starting coenzyme and concentration of 20mmol / L 1 Carry out coupling reaction with glycerol of 200mmol / L; Reaction condition is: pH8.5, 1.0mol / LNH 4 Cl?NH 4 OH buffer system, the dosages of GDH and phenylalanine dehydrogenase are 50U / mL and 50U / mL respectively, the total reaction volume is 1.5mL, the temperature is 30°C, and the rotation speed is 140r / min. After the reaction reaches equilibrium for 5 minutes, take out 200 μL, respectively detect the concentration of the product DHA and the chiral intermediate of saxagliptin; then add 28 μL of 10 μmol / L NADH to the system, so that the total coenzyme concentration in the system reaches 0.2 μmol / L; after the reaction is balanced, sample 200 μL again , detect product concentration and supplement with 24 μL of NAD + Make the total coenzyme concentration reach 0.3 μmol / L; add the coenzyme repeatedly in this way for a total of 4 times, and finally the total coenzyme concent...

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Abstract

The invention discloses a method for preparing a saxagliptin chiral intermediate through enzymatic-catalysis asymmetric transamination. The method includes that phenylalanine dehydrogenase (PDH) and glycerol dehydrogenase (GDH) are coupled in a water solution containing amino, and a saxagliptin intermediate and glycerol are used as substrates; 1, 3-dihydroxy acetone (DHA) and the saxagliptin chiral intermediate are generated at the same time, recycling of coenzyme NAD+ is realized, and efficient synthesis of the saxagliptin chiral intermediate is realized.

Description

technical field [0001] The invention belongs to the field of preparation of saxagliptin adamantane intermediates, in particular to a method for preparing saxagliptin intermediates through an enzyme-catalyzed asymmetric transamination reaction. technical background [0002] Diabetes (diabetes) is caused by various pathogenic factors such as genetic factors, immune dysfunction, microbial infection and its toxins, free radical toxins, and mental factors acting on the body, leading to hypofunction of pancreatic islets and insulin resistance. Syndrome of a series of metabolic disorders including fat, water and electrolytes. Diabetes has become the fourth leading cause of death in the world today, and China may surpass India to become the world's largest diabetes country. [0003] Saxagliptin is a highly effective inhibitor of dipeptidyl peptidase Ⅳ (Dipeptidyl Peptidase 4, DPP-4). By selectively inhibiting DPP-4, it can increase endogenous glucagon-like peptide-1 (GLP-1 ) and g...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C12P15/00C12P7/26
Inventor 赵学清李劲超孟春黄杨威
Owner 福州基石医药科技有限公司
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