Biological preparation method of (S)-3-(dimethylamino)-1-(thiophene-2-radical)-1-propyl alcohol

A dimethylamine-based, biological preparation technology, applied in the direction of fermentation, can solve the problems of complicated operation, difficult to repeat, and flammability, and achieve the effect of strong process stability

Inactive Publication Date: 2013-12-04
ENZYMEWORKS
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Problems solved by technology

[0003] In the bioreduction method, U.S. Patent US2010 / 0151534A1 discloses a production of (S)-3-(dimethylamino)-1-(thiophen-2-yl)-1-propanol using ketoreductase (KRED) method, the process requires strict temperature control and reaction control, and isopropanol is added, and a negative pressure needs to be introduced during the reaction to remove the by-product acetone of the reaction. The operation is complicated and difficult to repeat, and acetone is dangerous and volatile. flammable

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  • Biological preparation method of (S)-3-(dimethylamino)-1-(thiophene-2-radical)-1-propyl alcohol
  • Biological preparation method of (S)-3-(dimethylamino)-1-(thiophene-2-radical)-1-propyl alcohol

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preparation example Construction

[0021] The invention provides a method for the biological preparation of (S)-3-(dimethylamino)-1-(thiophen-2-yl)-1-propanol by using a combination of ketoreductase and glucose reductase, and the reaction equation as follows:

[0022]

Embodiment 1

[0025] Add 1.0 g of substrate and 1.5 g of glucose to a 50 mL three-necked reaction flask, and then add 10 mL of triethanolamine buffer solution with a pH of 7.0 prepared in advance to the reaction flask. Stir in a magnetic stirring water bath at 30°C, and adjust the pH to 7.0 with 10wt% sodium carbonate solution. After the temperature stabilized, 20 mg of ketoreductase, 40 mg of glucose dehydrogenase and 10 mg of NADP were added to the reaction bottle to start the reaction, and the reaction temperature was maintained at 30°C. The pH of the reaction solution was adjusted by adding sodium carbonate solution dropwise with a pH titrator. Control the pH at 7.0. Regular sampling for HPLC detection central control. React for 22-24 hours, conversion rate > 98%, adjust the reaction solution to alkaline with concentrated sodium hydroxide solution, filter with diatomaceous earth, add toluene for extraction, combine the organic phase, dry the organic phase with anhydrous sodium sulfate...

Embodiment 2

[0027] Add 10 g of substrate and 15 g of glucose into a 500 mL three-necked reaction flask, and then add 100 mL of a pre-prepared triethanolamine buffer solution with a pH of 7.0 into the reaction flask. Stir in a magnetic stirring water bath at 30°C, and adjust the pH to 7.0 with 10wt% sodium carbonate solution. When the temperature is stable, add 200 mg ketoreductase, 400 mg glucose dehydrogenase and 100 mg NADP into the reaction flask, and the reaction starts. The reaction temperature was maintained at 30°C. The pH of the reaction solution was adjusted by adding sodium carbonate solution dropwise with a pH titrator, and the pH was controlled at 7.0. Regular sampling for HPLC detection central control. React for 22-24 hours, conversion rate > 98%, adjust the reaction solution to alkaline with concentrated sodium hydroxide solution, filter with diatomaceous earth, add toluene for extraction, combine the organic phase, dry the organic phase with anhydrous sodium sulfate, con...

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Abstract

The invention relates to a biological preparation method of (S)-3-(dimethylamino)-1-(thiophene-2-radical)-1-propyl alcohol. According to the method, (S)-3-(dimethylamino)-1-(thiophene-2-radical)-1-acetone or salt thereof is taken as a substrate, and the substrate is subjected to asymmetric reduction reaction in the presence of biocatalyst, cofactor and hydrogen donor to produce (S)-3-(dimethylamino)-1-(thiophene-2-radical)-1-propyl alcohol, wherein the biocatalyst is a combination of ketoreductase (KRED) and glucose dehydrogenase, the ydrogen donor is glucose, and the asymmetric reduction reaction is conducted at pH 6.8-7.0 and 25 DEG C-35 DEG C. Compared with the biological method in the prior art, the biological preparation method has higher processing stability, and is simpler, more efficient and safer. During the reaction, the generation of highly toxic organic solvents such as acetone can be avoided, the application principle of green chemistry is met, and the industrialized application is facilitated.

Description

technical field [0001] The invention belongs to the technical fields of biopharmaceuticals and biochemical engineering, and in particular relates to a biological preparation method of a duloxetine intermediate. Background technique [0002] Duloxetine (Duloxetine) is a drug with low side effects and can effectively treat mental disorders and metabolic disorders (US5,023,269). The key to the synthesis of duloxetine is to obtain the intermediate (S)-3-(dimethylamino)-1-(thiophen-2-yl)-1-propanol (DMAA) containing a chiral center. Therefore, asymmetric reduction of 3-(dimethylamino)-1-(thiophen-2-yl)-1-propanone (DMAK) to obtain this intermediate is one of the most effective and most studied methods. In the chemical reduction method that realizes this approach, because it needs hydrogen reaction under the catalysis of ruthenium metal catalyst, its economy, safety and environmental friendliness cannot meet the needs of production. The chemical resolution method using a chiral ...

Claims

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Application Information

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IPC IPC(8): C12P17/00
CPCC12P17/00
Inventor 陶军华李斌乐庸堂
Owner ENZYMEWORKS
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