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Method for preparing miglitol midbody N-substituted-1-deoxidization nojirimycin derivative

A technology for miglitol and intermediates, which is applied in the field of preparation of N-substituted-1-deoxynojirimycin derivatives of miglitol intermediates, and can solve the problem of large differences between bacterial batches and high cost of biotransformation , unable to adapt to industrialized large-scale production and other problems, to achieve the effects of small bacterial loss, short processing time, and excellent slow-release performance

Inactive Publication Date: 2013-05-01
ZHEJIANG MEDICINE CO LTD XINCHANG PHAMACEUTICAL FACTORY
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0018] The purpose of the present invention is to overcome the high cost of thalline culture and biotransformation cost in the prior art, the large difference between thalline batches, and the inability to adapt to large-scale industrial production. Or immobilized oxidative gluconic acid bacteria to prepare the method of N-substituted-1-deoxynojirimycin derivatives, the key intermediate of miglitol, to reduce the cost of biotransformation production, reduce the difference between batches of bacteria, and be suitable for industrial scale Production

Method used

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  • Method for preparing miglitol midbody N-substituted-1-deoxidization nojirimycin derivative
  • Method for preparing miglitol midbody N-substituted-1-deoxidization nojirimycin derivative
  • Method for preparing miglitol midbody N-substituted-1-deoxidization nojirimycin derivative

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Effect test

Embodiment 1

[0042] A. Bacterial liquid preparation: Take 10000L of the fermentation liquid of Glucose oxidase bacteria cultured to the end of logarithmic growth, remove the fermentation liquid by microfiltration with a ceramic membrane with a pore size of 0.2 μm, and use 0.3% MgSO 4 The solution was top-washed until the total sugar was 0.065%, the amino nitrogen was 2.8mg / 100ml, the temperature was controlled at 25±1°C, the pressure was 0.03MPa, and the pH was 5.0 to obtain 100L of bacterial solution.

[0043] B, conversion production: drop into conversion substrate N-(2-hydroxyethyl)-glucosamine 100kg and dissolve with purified water in 5000L fermenter, make conversion substrate final concentration be 10%, adjust pH value to be 6.0, add 0.32% MgSO 4 , adding the bacterial solution, so that the weight ratio of the transformed substrate to the bacterial body is 1:1, the automatic control transformation temperature is 24±1°C, the automatic control transformation pH value is 6.0, and the dis...

Embodiment 2

[0048] A. Bacterial solution preparation: take 10000L of gluconoxidase fermentation broth cultivated to the end of logarithmic growth, remove the fermentation broth by microfiltration with a ceramic membrane with a pore size of 0.05 μm, and use 0.6% MgSO 4 The solution was top-washed until the total sugar was 0.134%, the amino nitrogen was 5.6mg / 100ml, the temperature was controlled at 20°C, the pressure was 0.04MPa, and the pH was 7.0 to obtain 100L of bacterial solution.

[0049] B, conversion production: put into 5000L fermentor and put into conversion substrate N-(2-hydroxyethyl)-glucosamine 100kg and dissolve with purified water, make conversion substrate final concentration be 10%, adjust pH value to be 6.5, add 0.6% MgSO 4 , add the bacterial solution, the weight ratio of the transformation substrate to the bacteria is 1:3, the transformation temperature is manually controlled to be 6±1°C, the pH value of the transformation is manually controlled to be 6.5, and the diss...

Embodiment 3

[0054] A. Bacterial solution preparation: Take 10000L of glucose oxidative bacteria fermentation broth cultivated to the end of logarithmic growth, filter and remove the fermentation broth with a polytetrafluoroethylene membrane with a pore size of 1.0 μm, and wash with deionized water until the total sugar is 0.98%. The amino nitrogen content was 47.6mg / 100ml, the temperature was controlled at 15°C, the pressure was 0.03Mpa, the pH was 6.0, and 100L of bacterial liquid was obtained.

[0055] B, transformation production: put into 5000L fermentor and put into transformation substrate N-(2-hydroxyethyl)-glucosamine 100kg and dissolve with purified water, make transformation substrate final concentration be 10%, adjust pH value to be 4.0, add 0.32% MgSO 4 , add the bacterial solution, the weight ratio of the transformation substrate to the bacteria is 1:2, the automatic control transformation temperature is 10±1°C, the automatic control transformation pH value is 4.0, and the di...

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Abstract

The invention relates to a preparation method of miglitol intermediate, in particular to a preparation method of a derivative of N-substitution-1-deoxynojirimycin which is the key intermediate of miglitol. Gluoconobacter oxydans or the Gluoconobacter oxydans treated by immobilized cell technology are used repeatedly for transforming the substrate to the derivative of N-substitution-1-deoxynojirimycin which is the miglitol intermediate, the transfer temperature is controlled at 5 to 25 DEG C, pH value is controlled at 4.0 to 6.5 and dissolved oxygen is controlled at 5 to 80 percent (in volume). Adopting the invention can decrease the biotransformation cost, reduce the inter-assay of cell, and be suitable for the large scale industrial production, increase the mechanical strength of the wall of the strain prepared, make the strain not to dissolve during the cultivation in long-term liquid environment, lengthen the service life and have outstanding slow release performance.

Description

technical field [0001] The present invention relates to a kind of preparation method of Miglitol intermediate, especially, relate to the preparation method of N-substituted-1-deoxynojirimycin derivative of Miglitol key intermediate, specifically, adopt multiple mechanical oxidation A method for preparing miglitol intermediate 6-(2-hydroxyethyl)-amino-6-deoxy-α-L-sorbofuranose by gluconic acid bacteria or immobilized oxidative gluconic acid bacteria. Background technique [0002] Miglitol, as a new type of α-glucosidase inhibitor, can effectively treat type II diabetes. Its main function is to reduce the postprandial blood sugar level of patients and reduce the occurrence of diabetic complications. It has quickly become the drug of choice. [0003] The preparation method of the important intermediate N-substituted-1-deoxynojirimycin derivative as Miglitol synthesis mainly contains following several kinds at present: (1) Kinast etc. (KinastG, Schedel M.USP4 246 345.(1981 )) I...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C12P17/12C12N11/08C12N11/10C12R1/01
Inventor 王跃勇陶正利
Owner ZHEJIANG MEDICINE CO LTD XINCHANG PHAMACEUTICAL FACTORY
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