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Preparation method of tetraene intermediates

A technology for intermediates and tetraenes, applied in the field of preparation of tetraenes intermediates, can solve the problems of many by-products, low yield of target products and the like

Active Publication Date: 2018-06-15
HUNAN NORCHEM PHARMACEUTICAL CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] In the synthesis route of tetraene intermediates, the appropriate upstream intermediates are usually selected and carried out by biotransformation methods, but the general biotransformation method converts the target product with low yield and many by-products

Method used

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preparation example Construction

[0023] A method for preparing a tetraene intermediate according to an embodiment of the present invention includes the following steps: using Nocardia simplex to perform microbial transformation on the first compound to obtain a tetraene intermediate, the first compound is shown in general formula I, four The alkene intermediate is shown in general formula II,

[0024]

[0025] In the general formula I and the general formula II, R is H, a halogen atom, an alkyl group, an alkoxy group, a hydroxyl group or a phenyl group.

[0026] In this embodiment, the first compound represented by the above general formula I is selected as the substrate, and only Nocardioides simplex is used for biotransformation, and the substrate is simultaneously dehydrogenated at positions 1 and 2 and acetate at position 21 hydrolysis to obtain a tetraene intermediate, and the hydrolysis of the 21-position acetate can effectively promote the dehydrogenation of the 1 and 2 positions, so that most of th...

Embodiment 1

[0049] Put 6 liters of fermentation medium into 10 liters of fermenters, inoculate 100 mL of Nocardia simplex seed liquid (thalline concentration: 2.4 × 10 9 cells / ml), culture was started, and the culture conditions were temperature 31°C, rotation speed 180 rpm, and culture time 16 hours.

[0050] Samples were diluted 30 times and detected at 580 nm with a spectrophotometer, and the OD value was 0.58. 120g of 2TR, 4.8g of PPE and 1.2g of Tween 80 were added to the fermenter to start the fermentative conversion. The culture conditions during fermentation transformation were temperature 31±1°C, rotation speed 200rpm, air flow rate 0.2-0.3vvm, tank pressure 0.05Mpa, after 72 hours of transformation, samples were taken and sent for HPLC analysis. The results are shown in Table 1:

[0051] Table 1

[0052] name

substrate

tetraenyl acetate

2TR Deesterified

target product

purity

0.56％

6.81％

0.15％

93.25％

[0053] After the conversio...

Embodiment 2

[0067] Put 6 liters of fermentation medium into a 10 liter fermenter, inoculate 100 mL of Nocardia simplex seed liquid (thalline concentration: 3.2×10 9 cells / ml), culture was started, and the culture conditions were temperature 31°C, rotation speed 180 rpm, and culture time 16 hours.

[0068] Samples were diluted 30 times and detected at 580 nm with a spectrophotometer, and the OD value was 0.45. 180g of 2TR, 4.8g of PPE and 1.2g of Tween 80 were added to the fermenter to start the fermentative conversion. The culture conditions during fermentation transformation were temperature 31±1°C, rotation speed 200rpm, air flow rate 0.2vvm, tank pressure 0.05Mpa, after 72 hours of transformation, samples were taken and sent for HPLC analysis. The results are shown in Table 5:

[0069] table 5

[0070] name

substrate

tetraenyl acetate

2TR Deesterified

target product

purity

0.66％

4.62％

0.45％

94.15％

[0071] After the conversion is comp...

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Abstract

The invention relates to a preparation method of tetraene intermediates. According to the preparation method, a first compound is converted by Nocardioides simplex to obtain tetraene intermediates; wherein the first compound is represented by a formula I, tetraene intermediates are represented by a formula II, and R in the formula I and the formula II represents H, a halogen atom, an alkyl group,an alkoxyl group, a hydroxyl group, or a phenyl group. According to the preparation method, the first compound is taken as the substrate, only Nocardioides simplex is used to carry out biological conversion; the substrate is subjected to 1,2-dehydrogenation and 21-acetate hydrolysis at the same time; most of the conversion products is target products, the byproduct ratio is low; after purification, the product is white or white-like crystals; relative to the weight of the substrate, the yield is 80-90%; the target product yield is high; through HPLC analysis, the purify of the product is not less than 95%; and the total content of target products and secondary products is not less than 99%.

Description

technical field [0001] The invention relates to the field of preparation of pharmaceutical intermediates, in particular to a preparation method of a tetraene intermediate. Background technique [0002] Steroids have a variety of biological activities, and their applications are very extensive, some of which are used to treat diseases or develop production, such as hydrocortisone for the treatment of allergic diseases, progesterone for contraceptives, spironolactone for diuretics, synthetic steroids Hormone diosgenin, cardiotonic Digoxin, bufotoxin, etc. are all steroidal compounds. The tetraene intermediates can be further synthesized to obtain a series of drugs such as 3TR, fluocinolone, and triamcinolone acetonide, which are widely used in clinical practice. [0003] In the synthesis route of tetraene intermediates, the appropriate upstream intermediates are usually selected and carried out by biotransformation methods, but the general biotransformation method converts th...

Claims

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Application Information

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IPC IPC(8): C12P33/02C12P33/00C12R1/365
CPCC12P33/005C12P33/02
Inventor 孟浩刘喜荣杨芳赵小娟
Owner HUNAN NORCHEM PHARMACEUTICAL CO LTD
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