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Method for preparing testolactone and derivative of testolactone

A derivative, testolactone technology, applied in the direction of microorganism-based methods, biochemical equipment and methods, microorganisms, etc., can solve the problems of low feed concentration, complicated process, and large environmental pollution, and achieve high feed amount and conversion rate , The process route is simple and the raw and auxiliary materials are easy to obtain

Inactive Publication Date: 2018-05-01
ZHEJIANG XIANJU PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] At present, the document J.Braz.Chem.Soc., Vol.14, 970-974, 2003 reports the preparation of testolactone by chemical synthesis, the oxidant used is poisonous, explosive, and pollutes the environment greatly, which does not meet the environmental protection requirements of industrial production. Requirements, while the preparation of testolactone by microbial transformation has the characteristics of mild reaction conditions and environmental friendliness, so it is more in line with modern production concepts
U.S. Patents US 2823171 and US 2744120 respectively report that progesterone and its derivatives are used as starting substrates, and testolactone is prepared by transforming Cylindrosporium and Fusarium as strains, but the starting substrate feeding concentration is only 0.5g / L; literature Research Journal of Bio Technology. 2013, 8(7), 56-61) reported the study of progesterone as the starting substrate, which was converted into testolide by Fusarium solani, but the conversion time 240h, the conversion period is too long; Chinese patent CN 103484375 A discloses using androst-1,4-diene-3,17-dione (ADD) as a substrate, using a strain of Fusarium oxysporum Fusarium oxysporum SC1301 was transformed into testolide, the initial feeding concentration was only 1 g / L, and the yield rate was 82.9%; Chinese patent CN102703560 A reported that dehydroepiandrosterone was used as a substrate to pass Fusarium oxysporum and Gordonia The combination of the two bacteria is used to prepare testolactone, but the process adopts a static culture method, and phosphate is used in the process, which causes great environmental pollution, and the synergistic transformation process of the two strains is complicated, which is not conducive to industrial production
[0006] Although the above-mentioned microbial transformation process has achieved certain research results, there are still problems such as low conversion rate, many by-products, low feeding concentration, complicated process, long cycle and high cost in the preparation of testolactone by microbial transformation.

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0022] Example 1: Using pregna-4,16-diene-3,20-dione as the substrate, that is, compound I;

[0023] Fusarium solani culture process: inoculate Fusarium solani on solid slant medium (20% potato, 2% glucose, 2% agar, pH5.1), culture at 30°C for 6 days, and grow from Fusarium solani Cut off about 1cm on the slope 2 Bacteria of the same size were inserted into the seed medium (2% glucose, 2% corn steep liquor, 1% peptone, 0.25% soybean powder, 0.1% K2PO4, pH 4.8), cultured at 220rpm, 28°C for 2 days, and then transplanted with 5% The amount of seed was transferred to the fermentation transformation medium (2% glucose, 2% corn steep liquor, 1% peptone, 0.25% soybean flour, 0.1% K2PO4, pH 4.8), 220rpm, 28°C for 2 days before feeding.

[0024] Weigh 2 g of the starting substrate pregna-4,16-diene-3,20-dione, put it into 100 mL of cultured Fusarium solani, add Tween-80 with a mass concentration of 0.03%, Transform at 30°C and 220rpm for 60 hours. After the transformation is complet...

Embodiment 2

[0025] Example 2: Using pregna-4,9,16-triene-3,20-dione as the substrate, that is, compound I;

[0026] Fusarium solani culture process: inoculate Fusarium solani on solid slant medium (20% potato, 2% glucose, 2% agar, pH5.1), culture at 28°C for 7 days, and grow from Fusarium solani Cut off about 0.5CM on the slope 2 Bacteria of the same size were inserted into the seed medium (1.5% glucose, 2% corn steep liquor, 1% peptone, 0.25% soybean powder, 0.1% K2PO4, pH 5.1), cultured at 220rpm for 2 days at 28°C, and then transplanted with 5% The amount of seed was transferred to the fermentation conversion medium (2% glucose, 2% corn steep liquor, 1% peptone, 0.25% soybean flour, 0.1% K2PO4, pH 5.1), 220rpm, 28°C for 2 days before feeding.

[0027] Weigh 1 g of the starting substrate pregna-4,9,16-triene-3,20-dione, put it into 100 mL of cultured Fusarium solani, add DMF with a mass concentration of 0.1% and shake well Transform at 28°C to 30°C, 220rpm for 48 hours. After the tran...

Embodiment 3

[0028] Example 3: Using 9,11-epoxy-pregna-4,16-diene-3,20-dione as the substrate, namely compound I;

[0029] Fusarium solani culture process: inoculate Fusarium solani on solid slant medium (20% potato, 2% glucose, 2% agar, pH5.1), culture at 28°C for 7 days, and grow from Fusarium solani Cut off about 1cm on the slope 2 Bacteria blocks of different sizes were inserted into the seed medium (2% glucose, 2% corn steep liquor, 1% peptone, 0.5% soybean powder, 0.1% K2PO4, pH 4.8), 200rpm, 28~30℃ for 2 days and then 5% Transfer the inoculum amount to the fermentation transformation medium (2% glucose, 2% corn steep liquor, 1% peptone, 0.25% soybean flour, 0.1% K2PO4, pH 5.1), 200rpm, 30℃ for 2 days before feeding.

[0030] Weigh 0.5g of the starting substrate 9,11-epoxy-pregna-4,16-diene-3,20-dione, add it to Tween-80 with a mass concentration of 0.03%, and add it to 100mL for incubation In Fusarium solani, transform at 28°C to 30°C, 200rpm for 60h. After the transformation is c...

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Abstract

The invention discloses testolactone and derivative of testolactone obtained by fusarium solani. The conversion process is shown in the following formula which is shown in the description. The methodfor preparing the testolactone and the derivative of testolactone disclosed by the invention has the advantages that the technology is simple, the feeding amount and conversion rate are high, the content of impurities is low, the raw materials and auxiliary materials are simple and easy to obtain, the production cost is low, and the like; the defects in the original conversion technology are overcome, and the industrialized production is realized.

Description

technical field [0001] The invention belongs to the field of steroid biotechnology, and in particular relates to a method for preparing testolactone and its derivatives through microbial transformation. Background technique [0002] Testolactone (Testolactone, 17α-oxo-D-expanded-androst-1,4-diene-3,17-dione, CAS: 968-93-4), its chemical structure is as follows: [0003] [0004] Testolactone, also known as dehydrotestolactone, is a derivative of testosterone, white or off-white crystalline powder, and is an endogenous steroidal aromatase inhibitor, which inhibits androgen by binding aromatase non-competitively Converted into estrogen, therefore, testolide is mainly used clinically as an antineoplastic drug for the treatment of breast cancer in postmenopausal women, in addition, it can also be used for the treatment of girls' precocious puberty and male idiopathic oligospermia . [0005] At present, the document J.Braz.Chem.Soc., Vol.14, 970-974, 2003 reports the prepara...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C12P33/20C12R1/77
CPCC12P33/20
Inventor 曹桂阳钱先来张小强刘建李金涛桂珍
Owner ZHEJIANG XIANJU PHARMA