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Method for preparing glufosfamide and its analogue by enzyme

A technology for glufosfamide and its analogues, which is applied in the field of compound biosynthesis, can solve problems such as the preparation methods of glufosfamide and its analogues that have not been seen, and achieve improved configuration selectivity, reduced generation of impurities, and increased reaction yield Effect

Active Publication Date: 2015-10-28
JIANGSU JIUXU PHARMA +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] But do not see the preparation method of utilizing enzymatic method to prepare glufosfamide and its analogs at present

Method used

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  • Method for preparing glufosfamide and its analogue by enzyme
  • Method for preparing glufosfamide and its analogue by enzyme
  • Method for preparing glufosfamide and its analogue by enzyme

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0039] This example relates to a method for preparing β-D-glufosfamide using enzymes.

[0040] Specific steps are as follows:

[0041](1) take by weighing the IPM of 10g and the β-D-glucose of 25g, adding concentration is that 0.3% sodium dihydrogen phosphate-disodium hydrogen phosphate buffer solution (pH6.0) makes the mass volume concentration of IPM be 20% (with g / ml meter);

[0042] (2) Add β-D-glucosidase equivalent to 0.05 times the amount of IPM to the solution obtained in step (1), and place it in a water bath at 20 to 30°C to start the reaction, and then take a sample every 4 hours, when β- When the D-glucose content is below 5%, stop the reaction, ultrafilter the enzyme component, concentrate the filtrate, and purify the product. After verification, the obtained product is indeed β-D-glufosfamide.

[0043] In this example, the yield of β-D-glufosfamide was 85%, and the purity was 99.2%.

Embodiment 2

[0045] This embodiment provides a synthetic method of β-D-mannose-IPM, specifically as follows:

[0046] (1) take by weighing the IPM of 10g and the β-D-mannose of 30g, adding concentration is that 0.4% sodium dihydrogen phosphate-disodium hydrogen phosphate buffer solution (pH6.5) makes the mass volume concentration of IPM be 25% ( in g / ml);

[0047] (2) Add β-D-mannosidase equivalent to 0.1 times the amount of IPM to the solution obtained in step (1), and place it in a water bath at 20-30°C to start the reaction, and then take samples every 4 hours, when the IPM content When it is less than 5%, the reaction is stopped, the enzyme component is ultrafiltered by an ultrafilter, the filtrate is concentrated, and the product is purified. After verification, the product obtained is indeed β-D-mannose-IPM.

[0048] In this example, the yield of β-D-mannose-IPM was 76%, and the purity was 99.4%.

Embodiment 3

[0050] This embodiment provides a synthetic method of β-D-galactose-IPM, specifically as follows:

[0051] (1) take by weighing the IPM of 10g and the β-D-galactose of 30g, adding concentration is that 0.4% sodium dihydrogen phosphate-disodium hydrogen phosphate buffer solution (pH7.5) makes the mass volume concentration of IPM be 40% ( in g / ml);

[0052] (2) Add β-D-galactosidase equivalent to 0.05 times the amount of IPM to the solution obtained in step (1), and place it in a water bath at 20-30°C to start the reaction, and then take samples every 4 hours, when β When the content of -D-galactose is less than 5%, the reaction is stopped, the enzyme component is ultrafiltered by an ultrafiltration machine, the filtrate is concentrated, and the product is purified. After verification, the obtained product is indeed β-D-galactose-IPM.

[0053] In this example, the yield of β-D-galactose-IPM was 80.3%, and the purity was 99.3%.

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Abstract

The invention relates to a method for preparing glufosfamide and its analogue by enzyme. The method comprises that carbohydrate and an IPM analogue as raw materials and specific enzymes such as beta-D-glucosidase, beta-D-galactosidase, beta-D-mannosidase and beta-L-arabinosidase undergo a glycosylation reaction. The carbohydrate raw material comprises oligosaccharide such as galactooligosaccharide, or monosaccharides such as beta-D-glucose, beta-D-galactose, beta-D-mannose and beta-L-arabinose. The finished product is obtained by purification crystallization. The method can improve reaction configuration selectivity, is free of a conventional multi-step chemical reaction, only needs one-step enzyme digestion, has high specificity and improves a reaction yield.

Description

technical field [0001] The invention relates to the field of compound biosynthesis, in particular to a method for preparing glufosfamide and its analogues by using enzymes. Background technique [0002] Cancer is a serious threat to human health. In cancer treatment, it is necessary to use more chemical drugs with less toxic side effects and good curative effect. Nitrogen mustard, podophyllotoxin and phosphodiamide are all mammalian cytotoxins, but there are Some are too toxic, and some are difficult to enter cancer cells, thereby affecting the curative effect. Isophosphormide mustard (Isophosphormide mustard, IPM parivamil, N,N'-bis-(2-chloroethyl) phosphodiamide) is a metabolite of cyclophosphamide and ifosfamide, which has antitumor activity , but tried to use IPM directly as an anticancer drug, without success, because IPM is unstable, and the monomer cannot be used for human treatment. The structural formula of IPM is as follows: [0003] [0004] Patent US5622936...

Claims

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Application Information

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IPC IPC(8): C12P19/44
Inventor 潘自国李宏岳昌林于自勋刘新红
Owner JIANGSU JIUXU PHARMA
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