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3α,20,20-trihydroxy-5α-pregnant-18-carboxylic acid-γ-lactone and preparation method thereof

A trihydroxy, progesterone technology, applied in the directions of lactone steroids, chemical instruments and methods, steroids, etc., can solve the problems of difficult compound preparation, difficult to use compound preparation in large quantities, long routes, etc., and achieves easy control of reaction conditions, The effect of promoting the synthesis method and shortening the technical route

Active Publication Date: 2022-07-01
TAIZHOU POLYTECHNIC COLLEGE
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This synthetic method route is too long, synthetic steps is many, needs to use special reagent nitrosyl chloride, and reaction condition is extremely difficult to control, and overall yield is also on the low side, is difficult to be used in the large-scale preparation of this class compound [D.H.R, Barton , J.M.Beaton, L.E.Geller and.M.Pechet, A New Photochemical Reaction, J.Am.Chem.Soc., 1961, 83, 4076-4082.]
[0012] As can be seen from the literature reports on the synthetic methods of pregna-18-carboxylic acid-γ-lactone derivatives, these methods have relatively long routes, many synthetic steps, need to use expensive chemical reagents, and the reaction conditions are not easy control, the total yield is also low, and it is difficult to be used in the large-scale preparation of such compounds

Method used

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  • 3α,20,20-trihydroxy-5α-pregnant-18-carboxylic acid-γ-lactone and preparation method thereof
  • 3α,20,20-trihydroxy-5α-pregnant-18-carboxylic acid-γ-lactone and preparation method thereof
  • 3α,20,20-trihydroxy-5α-pregnant-18-carboxylic acid-γ-lactone and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1-1

[0108] Example 1-1: Synthesis of 5α-pregnantine--3α,20β-diol (2)

[0109]

[0110] The synthesis method is as follows: 0.62 g of 3α-hydroxy-5α-pregna-20-one (1) (2 mmol) was dissolved in 15 mL of methanol at room temperature, then the solution was cooled to -5 °C, and 0.25 mg of boron was slowly added in four portions. Sodium hydride (6.0 mmol) was added, and the resulting mixture was stirred at -5 °C for 2 h. Subsequently, 1.5 mL of 4M HCl was slowly added dropwise to the reaction system to terminate the reaction, and then extracted with ethyl acetate (2×10 mL). The organic phase of ethyl acetate was washed with 10 mL of saturated brine, dried with 5 g of anhydrous sodium sulfate, and distilled under reduced pressure. The crude product was obtained after removing the solvent, which was purified by column chromatography (silica gel, eluent: 35% ethyl acetate-petroleum ether (60-90°C)) to give the product 0.45g 5α-pregna-3α,20β-diol (2), the yield was 69%. 1 H NMR (CDCl 3...

Embodiment 2-1

[0111] Example 2-1: Synthesis of 18-iodo-5α-pregnant-3α,20β-diol (3)

[0112]

[0113] At room temperature, 0.65g of 5α-pregnant-3α, 20β-diol (2) (2mmol) was dissolved in 180mL of anhydrous petroleum ether, and then 1.02g of iodophenyl acetate (3mmol) was slowly added to the solution, resulting in The suspension was deaired with nitrogen for 15 minutes. Subsequently, 626 mg of iodine (2.5 mmol) was slowly added dropwise to the reaction system, and the reaction system was irradiated with a 300W tungsten lamp for 1 hour at a reaction temperature of 25°C, and then irradiated with a 300W tungsten lamp at 70°C for 30 minutes. After the reaction, it was cooled to room temperature, transferred to a separatory funnel, washed with 6 ml of 10% sodium thiosulfate, washed with 10 ml of saturated brine, dried with 5 g of anhydrous sodium sulfate, and distilled under reduced pressure to remove the solvent to obtain a crude product , purified using column chromatography (silica gel, elue...

Embodiment 3-1

[0114] Example 3-1: Synthesis of 5α-pregnant-18,20β-oxo-3α-ol (4)

[0115]

[0116] 0.89 g of 18-iodo-5α-pregna-3α,20β-diol (3) (2 mmol) was dissolved in 10 mL of anhydrous tetrahydrofuran, and 0.22 g of potassium tert-butoxide (2 mmol) was slowly added. It was then heated (oil bath temperature 76°C) and stirred for 12 hours. After the reaction, the solvent was evaporated, 10 mL of distilled water was added to the residue, and then ethyl acetate (2×10 mL) was used for extraction. The ethyl acetate organic phase was washed with 10 mL of saturated brine, dried with 6 g of anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure. The crude product was then obtained and purified using column chromatography (silica gel, eluent: 35% ethyl acetate-petroleum ether (60-90°C)) to give the product 0.45g 5α-pregnant-18,20β-oxo-3α- Alcohol (4) in 71% yield. 1 H NMR (CDCl 3 ,400MHz)δ: 4.04(d,1H,J=2.5Hz,C 3β -H),3.74(d,1H,J=3Hz,C 20 -H),3.71(d,2H J...

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Abstract

The invention provides a pregnanoid compound named 3α, 20,20-trihydroxy-5α-pregnant-18-carboxylic acid-γ-lactone, and a preparation method thereof. The present invention has the following technical effects: 1) The inventors of the present invention have unexpectedly discovered a new progesterone compound capable of inhibiting tumor performance, especially for lung cancer cells, ovarian cancer cells, gastric cancer cells and breast cancer high metastatic cells. The good inhibitory effect enriches the types of tumor drugs. 2) The present invention provides a new method for synthesizing pregnanoid compounds. Compared with the existing synthesis methods for pregnanoid compounds, the technical route is relatively shortened, the synthesis method is simple and can be generalized, the reaction conditions are easy to control, and the total yield is improved, which can be improved. for the large-scale preparation of such compounds.

Description

technical field [0001] The invention relates to a progesterone compound, a preparation method and application thereof, and belongs to the technical field of medicinal chemistry. Background technique [0002] Natural steroids have important physiological activities, and steroids with unique biological activities can often be obtained through the transformation and structural modification of natural steroids. One of the important ways of structural modification and transformation of natural steroids, more and more studies have shown that pentacyclic steroids and their derivatives have potential anticancer activities. The drug structure-activity relationship indicated that the lactone backbone plays an important role in the biological activity of the steroid nucleus. For example, the currently clinically used Oxandrolone (Oxandrolone): as a male hormone, its main role is protein assimilation. For the treatment of high cholesterol and triglycerides. Also used to promote weigh...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07J21/00
CPCC07J21/001
Inventor 王立中刘竺云张茂风马永刚卞小琴
Owner TAIZHOU POLYTECHNIC COLLEGE
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