Method for preparing saxagliptin chiral intermediate by enzyme-catalyzed asymmetric transamination reaction

A chiral intermediate and asymmetric technology, which is applied in the field of preparation of saxagliptin intermediate by enzyme-catalyzed asymmetric transamination reaction, can solve the problems of high price and difficult industrialization

Active Publication Date: 2018-07-27
福州基石医药科技有限公司
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  • Abstract
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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

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  • Method for preparing saxagliptin chiral intermediate by enzyme-catalyzed asymmetric transamination reaction

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Effect test

Embodiment 1

[0021] With 0.1 μmol / L NADH as the starting coenzyme, saxagliptin intermediate 1 at a concentration of 10 mmol / L and glycerol at 50 mmol / L were used for coupling reaction; the reaction conditions were: pH 8.5, 1.0 mol / L NH 4 Cl−NH 4 The OH buffer system, the dosage of GDH and phenylalanine dehydrogenase are 1U / mL and 1U / mL respectively, the total reaction volume is 1.5 mL, the temperature is 30°C, and the rotation speed is 140 r / min. After the reaction reaches equilibrium for 5 minutes, Take a sample of 200 μL, and detect the concentration of the product DHA and the chiral intermediate of saxagliptin respectively; 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, again Take a sample of 200 μL, detect the product concentration and supplement 44 μL of NAD + Make the total concentration of coenzyme reach 0.3 μmol / L; add coenzyme repeatedly in this way for a total of 4 times, th...

Embodiment 2

[0023] With 0.1 μmol / L NADH as the starting coenzyme, saxagliptin intermediate 1 at a concentration of 20mmol / L and glycerol at 200mmol / L were used for coupling reaction; the reaction conditions were: pH 8.5, 1.0mol / L NH 4 Cl−NH 4 The OH buffer system, the dosage 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 140 r / min. After the reaction reaches equilibrium for 5 minutes, Take out 200 μL, and 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; after the reaction is balanced, sample 200 μL again, Check product concentration and supplement with 22 μL of NAD + Make the total concentration of coenzyme reach 0.3 μmol / L; add coenzyme repeatedly in this way for a total of 4 times, and the final total co...

Embodiment 3

[0025] With 0.1 μmol / L NADH as the starting coenzyme, saxagliptin intermediate 1 at a concentration of 20mmol / L and glycerol at 200mmol / L were used for coupling reaction; the reaction conditions were: pH 8.5, 1.0mol / L NH 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 140 r / min. After the reaction reaches equilibrium for 5 minutes, Take out 200 μL, and detect the concentration of the product DHA and the chiral intermediate of saxagliptin respectively; then add 28 μL of 10 μmol / L NADH 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 24 μL NAD + Make the total concentration of coenzyme reach 0.3 μmol / L; add coenzyme repeatedly in this way for a total of 4 times, the final total conc...

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Abstract

The invention discloses a method for preparing a saxagliptin chiral intermediate through an enzyme-catalyzed asymmetric transamination reaction. The present invention couples phenylalanine dehydrogenase (phenylalanine dehydrogenase, PDH) and glycerol dehydrogenase (Glycerol dehydrogenase, GDH) in an aqueous solution containing amino groups, using saxagliptin intermediate and glycerol as substrates, and at the same time Generate 1,3-dihydroxyacetone (DHA) and saxagliptin chiral intermediates, and realize the cyclic regeneration of coenzyme NAD+, realizing the efficient synthesis of saxagliptin chiral intermediates.

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 dipeptidyl peptidase Ⅳ (Dipeptidyl Peptidase 4, DPP-4) inhibitor, by selectively inhibiting DPP-4, it can increase endogenous glucagon-like peptide-1 (GLP -1) and gluc...

Claims

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Application Information

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Patent Type & Authority Patents(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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