Biological preparation method of (S)-3-methylamino-(2-thienyl)-1-propyl alcohol

A biological preparation and thiophene-based technology, which is applied in the field of biopharmaceuticals and green chemistry, can solve the problems of difficult industrialization, high catalyst addition, and low substrate concentration, so as to increase substrate concentration, reduce enzyme dosage, and reduce production costs Effect

Inactive Publication Date: 2013-04-03
ENZYMEWORKS
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0003] In the biological reduction method, there is an example of using Candida magnoliae recombinant reductase to catalyze the reduction reaction, but this method has a high amount of catalyst added and a low substrate concentration, which is obviously difficult for industrialization (US patent2008 / 0220484A1)

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  • Biological preparation method of (S)-3-methylamino-(2-thienyl)-1-propyl alcohol

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Embodiment 1

[0021] Add 1.0 g of substrate MMAK and 1.2 g of glucose into a 50 mL three-necked reaction flask, and then add 8 mL of prepared 0.1 M triethanolamine buffer solution with a pH of 7.0 to the reaction flask. Stir in a 900r / min magnetic stirring water bath at 30°C, and adjust the pH to 7.0 with 2M NaOH solution. When the temperature is stable, add 0.95 mL of triethanolamine buffer in which 20 mg of ketoreductase and 31 mg of GDH are dissolved in the reaction flask. Adjust the pH to 7.0 with NaOH and rinse with 0.95 mL of triethanolamine buffer and add to the reaction flask. Add 100 μL of triethanolamine buffer dissolved in 0.5 mg NADP to the reaction flask, and the reaction starts. The reaction temperature was maintained at 30°C. The pH of the reaction solution was adjusted by dropping 2M NaOH solution with a pH titrator. The pH is controlled at 7.0, the initial control point is 6.5, and the final control point is 6.99. Regular sampling for HPLC detection central control. Af...

Embodiment 2

[0023] Add 100.0 g of substrate MMAK and 120.0 g of glucose into the reactor, and then add 800 mL of prepared pH 7.0, 0.1 M triethanolamine buffer into the reaction flask. Place at 30°C, stir in a mechanically stirred water bath, and adjust the pH to 7.0 with 2M NaOH solution. When the temperature is stable, add 95 mL of triethanolamine buffer dissolved in 2 g of ketoreductase and 3.1 g of GDH into the reaction flask. Adjust the pH to 7.0 with NaOH and rinse with 95 mL of triethanolamine buffer and add to the reaction flask. Add 10 mL of triethanolamine buffer solution that is dissolved with 50 mg NADP in the reaction bottle again, and the reaction starts. The reaction temperature was maintained at 30°C. The pH of the reaction solution was adjusted by dropping 2M NaOH solution with a pH titrator. The pH is controlled at 7.0, the initial control point is 6.5, and the final control point is 6.99. Regular sampling for HPLC detection central control. After 23 hours of reactio...

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Abstract

The invention relates to a biological preparation method of (S)-3-methylamino-(2-thienyl)-1-propyl alcohol. According to the biological preparation method, 3-methylamino-1-(2-thienyl)-1-acetone is used as a substrate; under the condition that a biocatalyst, a cofactor and a cofactor regeneration system exist, the substrate performs the asymmetric reduction to generate (S)-3-methylamino-(2-thienyl)-1-propyl alcohol; the biocatalyst is ketoreductase; the cofactor regeneration system comprises glucose and glucose dehydrogenase; the asymmetric reduction is carried out in water-phase buffer solution with the pH of 6 to 8; and in a reaction system in an initial state, the concentration of the substrate is 100 to 150 mg / mL and the mass ratio of the ketoreductase to the substrate is 1 to 2 percent. According to the invention, by optimizing the process condition, the concentration of the substrate is improved and the enzyme dosage is reduced, so that production cost is reduced, the high-efficiency biological conversion process is realized and the biological preparation method is suitable for industrial production.

Description

Technical field: [0001] The invention belongs to the fields of biopharmaceuticals and green chemistry, and in particular relates to a biological preparation method of (S)-3-methylamino-1-(2-thienyl)-1-propanol. Background technique: [0002] Duloxetine (Duloxetine) is a kind of low side effect, can effectively treat the medicine (USpatent5,023,269) of mental disorder and metabolic disorder, the key of synthetic duloxetine is to obtain the intermediate (S)- 3-Methylamino-1-(2-thienyl)-1-propanol (MMAA), thus asymmetric reduction of 3-methylamino-1-(2-thienyl)-1-propanone (MMAK) gives the Intermediates are currently one of the most effective and well-studied methods. In the chemical reduction method that realizes this approach, owing to need ruthenium metal catalyst to catalyze, add the hydrogen reaction of 4.5MPa, its economy, safety and environmental friendliness can not satisfy the needs of production (Tetrahedron Lett.1990,31:7101 –7104). The chemical resolution method ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C12P17/00
CPCC12P17/00
Inventor 乐庸堂鞠鑫
Owner ENZYMEWORKS
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