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Method for preparing dextral biotin intermediate lactone

An intermediate, biotin technology, applied in the field of preparation of dextro-biotin intermediate lactone, can solve the problems of high condition control requirements, low yield, high price and the like

Active Publication Date: 2008-05-28
ZHEJIANG UNIV OF TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] 1. Chemical resolution, such as using photoactive alcohol menthol, or chiral amine ephedrine to split precursor substances, and then transforming to obtain D-biotin intermediate lactone. The disadvantage of chemical resolution is that the resolution agent is expensive , the separation is not complete, and there are environmental pollution and toxicity problems;
[0010] 2. Physical separation, such as the separation of precursor monomethyl ester by induced crystallization, and then reduction to obtain D-biotin intermediate lactone, requires high condition control, poor optical purity, and low yield
[0014] Some progress has been made in the production of biotin by biological fermentation. Compared with the production of biotin by chemical synthesis, its advantages are becoming more and more prominent. However, the price of genetically engineered bacteria obtained by biotechnology is still expensive, and it is still in the stage of small-scale research. To achieve Industrialization, the output still needs to be improved, and many technical problems still need to be solved

Method used

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  • Method for preparing dextral biotin intermediate lactone
  • Method for preparing dextral biotin intermediate lactone
  • Method for preparing dextral biotin intermediate lactone

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0050] Slant medium: NaNO 3 0.2%, K 2 HPO 4 0.1%, KCl 0.5%, FeSO 4 0.001%, MgSO 4 0.05%, 3% sucrose, 1.5% agar, natural pH, sterilized at 121°C for 20 minutes, inoculated with Aspergillus oryzae CCTCC No.M 206105 (Aspergillusoryzae WZ007) after sterilization, and cultivated at 30°C for 3 days as slant activated seeds.

[0051] The liquid fermentation medium is glucose 20g, peptone 20g, sucrose 10g, urea 3g, NaCl 5g, k 2 HPO 4 2g, MgSO 4 1g,, (NH 4 ) 2 SO 4 5g, constant volume to 1L, natural pH, 500ml triangular bottle, 80ml liquid, sterilized at 121°C for 20 minutes, cooled and inoculated with slant seeds after sterilization, cultivated at 30°C for 48 hours, filtered to obtain mycelium, and dried to obtain 4 grams as enzyme powder 1.

[0052] Enzyme activity determination method: Take 0.1g of dry mycelium, add 10ml of toluene solution with 1% mixed organic acid 2 concentration to the bacteria, at 40°C, stir in a water bath at a speed of 200rpm, react for 60min,...

Embodiment 2

[0055] 0.1 g of Aspergillus oryzaeWZ007 enzyme powder 1 was added to 20 mL of toluene containing 2% racemic organic acid 2, and reacted for 12 hours at 40° C., the reaction conversion rate was 32.6%. After the reaction was completed and filtered, the organic solvent was distilled under reduced pressure at a pressure of 0.1 MPa to obtain the product lactone. The optical purity of the product lactone was determined by an automatic polarimeter, and the enantiomeric excess value was about 96.2%.

Embodiment 3

[0057] Add 0.1g of Aspergillus oryzaeWZ007 enzyme powder 1 to 20mL of toluene containing 2% racemic organic acid 2, and react for 12 hours at 40°C to convert the converted reaction solution, remove the bacteria by filtration, and add a new reaction substrate Continue to react, repeat like this, and reuse 5 times. The enzymatic hydrolysis results are shown in Table 1. After lactonization, the product d-biotin intermediate lactone was concentrated to 5mL under reduced pressure at 0.1Mp, and crystallized at room temperature to obtain D-biotin intermediate lactone, with an enantiomeric excess of over 96% and a yield of 93%. , with a purity of over 98%. After using the enzyme powder 1 for 5 times, the enzyme conversion rate still did not drop significantly.

[0058] Table 1: Results of repeated batch enzyme conversion

[0059]

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Abstract

The invention provides a process for preparing the lactone of the intermediate of dextral biotin. The invention employs racemic acid 2 (1, 3-dibenzyl-5(hydroxymethyl)-2-oxo-4-Imidazolidinecarboxylic aid) which is achieved by the hydrolyzing the lactone 1 of the intermediate of racemization biotin 1 (tetrahydro-1, 3-bis (phenylylmethyl)-1 H-Furo (3, 4-d) imidazole-2, 4-dione) is utilized as reaction substrate, and the lactone of the intermediate of dextral biotin 9 is selectively synthesized in the function of lactone synthase. Further, the lactone synthase is one of the following materials, including (1) pig liver esterase, (2) pancreatin, (3) aspergillus oryzae lipase, (4) aspergillus niger lipase, (5) aspergillus flavus lipase, (6) blue mold lipase, (7) rhizopus chinensis lipase, and (8) yeast lipase. The beneficial effects of the process for preparing the lactone of the intermediate of dextral biotin include that resolution specificity is high, the resolution efficiency is high, the manufacture cost is greatly reduced, the operation is simple, the environmental pollution is low, and the invention is adaptable for industrial production.

Description

(1) Technical field [0001] The present invention relates to a preparation method of D-biotin intermediate lactone, especially a kind of racemic biotin intermediate lactone (tetrahydro-1,3-bis(phenylmethyl)-1H-Furo[3,4-d] The racemic organic acid (1,3-dibenzyl-5-(hydroxymethyl)-2-oxo-4-Imidazolidinecarboxylic acid) obtained after hydrolysis of imidazole-2,4-dione) is used as the reaction substrate, and the lactone synthase acts on A method for selectively synthesizing D-biotin intermediate lactone. (2) Background technology [0002] Biotin (Biotin) [CAS: 5828525] also known as vitamin H (Vitamin H) or vitamin B 7 And coenzyme R (Coenzyme R), is an important water-soluble B vitamins. Biotin is widely used in medical treatment, multidimensional preparations and feed additives, especially one of the key components of formulated feed. Biotin is the coenzyme of fatty acid synthesis and sugar metabolism carboxylase, which is necessary for the whole biological world, and is also ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C12P17/18C12N9/16C12R1/69
Inventor 汪钊郑建永章银军鄢洪德朱勍沈雪亮沈寅初
Owner ZHEJIANG UNIV OF TECH
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