A kind of preparation method of 9-position dehalogenation of 9-halogenated steroid hormone compound

A technology of steroid hormones and compounds, which is applied in the field of medicine and chemical industry, can solve the problems of difficult treatment, large pollution of three wastes, and odor of mercapto fatty acid, etc., and achieve the effects of reducing pollution of three wastes, less reaction impurities, and simple operation

Active Publication Date: 2021-10-08
AURISCO PHARMACEUTICAL CO LTD
View PDF10 Cites 0 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This is the most widely used steroid hormone debromination method in industry at present. It is mainly used in the industrial production of hydrocortisone, methylprednisolone, prednisolone and other products. However, chromium-containing wastewater is very harmful to human health. Post-treatment Difficult, the three wastes are under great pressure
[0004] 2) In 1950, Kapp et al. (US250647) reported the use of acetic acid or propionic acid to reduce steroidal bromides with zinc powder, but the yield was only about 30%
Joel et al. (WO8901482) improved the zinc powder reduction method, using mercapto fatty acid as a hydrogen donor, and adding a small amount of chromium trichloride as a catalyst to successfully remove 9a-halogen with a yield of more than 90%. The use of chromium has been reduced, but the mercapto fatty acid used has a serious stench, and there are still disadvantages of difficult disposal of the three wastes
[0005] 3) In 1990, Pearlman et al. (WO9009394) reported the use of tin powder (lead powder) or divalent inorganic tin (lead) salt as a reducing agent for the removal of 9a in the synthesis of prednisolone acetate and hydrocortisone acetate - Halogen, but the catalyst AIBN and thioglycolic acid must be used in the reaction, the cost is high, and the post-processing of malodorous thioglycolic acid is difficult
[0006] 4) In 1957, Josef et al. (Journal of the American Chemical Society, 1957, 79, 1130-1141) reported the 9-position halogen removal reaction of cortisone and hydrocortisone derivatives, and tried Raney nickel hydride reduction The effect of using zinc powder, sodium iodide or chromium ion reduction after failure is not ideal, and the best effect is zinc powder / ethanol, but the yield is only 15%
[0007] Analyzing the existing literature, we found that basically all 11-position steroidal halide dehalogenation processes have used metal dehalogenation reagents, and also used malodorous mercapto fatty acids as hydrogen donor reagents, which is not conducive to improving product quality. The cost of waste treatment is also high
Therefore, it is urgent to develop a clean and efficient steroid hormone 9-position dehalogenation method to replace the existing metal-catalyzed debromination method with high cost and three-waste pollution, so as to better realize the industrial production of steroid hormones

Method used

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
View more

Image

Smart Image Click on the blue labels to locate them in the text.
Viewing Examples
Smart Image
  • A kind of preparation method of 9-position dehalogenation of 9-halogenated steroid hormone compound
  • A kind of preparation method of 9-position dehalogenation of 9-halogenated steroid hormone compound
  • A kind of preparation method of 9-position dehalogenation of 9-halogenated steroid hormone compound

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0024]

[0025] Add 48.2 g (0.10 mol, 1.0 equiv) of 9-bromo-acetic acid hydrocortisone in the reaction kettle under nitrogen protection conditions, 250 ml of tetrahydrofuran is heated and refluxed, and di-tert-butyl peroxide is slowly added dropwise (TBP) 7.3g (0.05mol, 0.5equiv), TLC detection to control the reaction end point, after the reaction is over, reduce the temperature of the reaction kettle, and distill under reduced pressure (distillation temperature does not exceed 40°C, vacuum degree is about -0.08MPa) to remove tetrahydrofuran About 150ml, the reaction system was charged into 1000ml of ice water, filtered, and dried to obtain 36.6g of white solid cortisone acetate, with a molar yield of 90.0% and an HPLC purity of >97.0%.

Embodiment 2

[0027]

[0028] Add 9-bromo-11-formic acid ester-21-acetate hydrocortisone 51.0g (0.10mol, 1.0equiv) in the reaction flask under nitrogen protection conditions, 2-methyltetrahydrofuran 2500ml, Heat up to reflux, slowly add 18.0 g (0.20 mol, 2.0 equiv) of tert-butyl hydroperoxide (TBHP) dropwise, be careful not to let the water in tert-butyl hydroperoxide enter the reaction bottle, TLC detection controls the reaction end point, and wait for the reaction to end , reduce the temperature of the reaction kettle, and distill under reduced pressure (distillation temperature does not exceed 50°C, vacuum degree is about -0.08MPa) to remove about 2300ml of 2-methyltetrahydrofuran, cool the reaction system to 0°C, stir and crystallize for two hours, filter , and dried to obtain 39.8 g of white solid 11-formate-21-acetate hydrocortisone, the molar yield was 92.0%, and the HPLC purity was >98.5%.

Embodiment 3

[0030]

[0031] Add 48.0 g (0.10 mol, 1.0 equiv) of 9-bromo-prednisolone acetate in the formula (III) and 1000 ml of 3-methyltetrahydrofuran to the reaction flask under the condition of nitrogen protection, heat up and reflux, and slowly add peroxide Tert-butyl benzoate (TBPB) 38.8g (0.20mol, 2.0equiv), TLC detection to control the reaction end point, after the reaction is finished, reduce the temperature of the reactor, and distill under reduced pressure (distillation temperature does not exceed 50°C, vacuum degree is about -0.08 MPa) about 800ml of 3-methyltetrahydrofuran was removed, the reaction system was cooled to 0°C, stirred and crystallized for two hours, filtered, and dried to obtain 32.4g of prednisone acetate as a white solid, with a molar yield of 81.0%, HPLC purity>98.5 %.

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to view more

PUM

No PUM Login to view more

Abstract

The invention discloses a method for dehalogenating the 9-position of a steroid hormone compound. The method comprises: dissolving a 9-halogenated-11-hydroxy steroid compound or a 9-halogenated-11-hydroxy ester steroid compound in an organic In the solvent, after heating up to a certain temperature, slowly add an appropriate amount of dehalogenation reagent, and detect after a period of reaction. After the reaction is complete, concentrate under reduced pressure to remove part of the solvent, cool down to crystallize or add water to crystallize, precipitate a solid, and filter to obtain the target product 11 ‑carbonyl steroids or 11‑hydroxyester steroids. The invention has simple operation, less reaction impurities, high yield, avoids the use of metal dehalogenating agent and mercapto fatty acid, reduces pollution of three wastes, and is suitable for industrial production.

Description

technical field [0001] The invention belongs to the technical field of medicine and chemical industry, and in particular relates to a method for dehalogenating the 9-position of a 9-halogenated steroid hormone compound. Background technique [0002] Steroid hormone drugs (steroid hormone drugs) refer to hormone drugs containing steroidal structure in their molecular structure, which are widely used clinically and mainly include adrenocortical hormones and sex hormones. Among them, corticosteroids have various pharmacological effects such as anti-inflammation, anti-allergy, immune suppression, enhancement of stress response, anti-endotoxin and anti-shock. They can be used to treat many diseases clinically and are an indispensable class of important drugs in clinical practice. In the synthesis process of many corticosteroid drugs, in order to obtain 11β-hydroxy steroid compounds, some intermediates need to undergo reductive dehalogenation reaction. Divalent chromium metal redu...

Claims

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to view more

Application Information

Patent Timeline
no application Login to view more
Patent Type & Authority Patents(China)
IPC IPC(8): C07J5/00
CPCC07J5/0053C07J5/0076C07J5/0092Y02P20/55
Inventor 许挺俊谢晓强徐雅峰尉海锋金明亮汤顺杰张德法
Owner AURISCO PHARMACEUTICAL CO LTD
Who we serve
  • R&D Engineer
  • R&D Manager
  • IP Professional
Why Eureka
  • Industry Leading Data Capabilities
  • Powerful AI technology
  • Patent DNA Extraction
Social media
Try Eureka
PatSnap group products

Browse by: Latest US Patents, China's latest patents, Technical Efficacy Thesaurus, Application Domain, Technology Topic.

© 2024 PatSnap. All rights reserved.Legal|Privacy policy|Modern Slavery Act Transparency Statement|Sitemap