Unlock instant, AI-driven research and patent intelligence for your innovation.

Preparation of medicine and derivative thereof

A technology of difluocoron derivatives and compounds, which is applied in the field of preparation of difluocoron derivatives, can solve the problems of cumbersome routes, too backward, and low yield of biological fermentation, and achieve the effect of optimizing the product route

Inactive Publication Date: 2011-05-04
TIANJIN PHARMA GROUP CORP
View PDF2 Cites 0 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] The synthesis method of difluorocorone derivatives of German Schering Company is more and more backward with the advancement of steroid chemical synthesis methods, and has quite deficiencies
First of all, the basis of this route is the biological fermentation of 16α-methyl-4-pregnene-11β, 21-dihydroxy-3,20-ketone (16α-methylcorticosterone). The fermentation technology is relatively complicated, and it is difficult to master the best method.
Secondly, the yield of biological fermentation is low, the separation is difficult, the pollution is large, and the cost of industrialization is high
[0008] In addition to the relevant reports of German Schering Company, there is also a Spanish patent Span.ES 473544 16 May 1979 mentioning the synthesis of difluorocorrone valerate. Although the process adopts full synthesis, the process route is relatively complicated (the following route diagram)
The starting material is 16α-methyl-6α, 9α-difluoro-1,4-pregnane-11β,17α,21-trihydroxy-3,20-one, the cost of the starting material itself is relatively high, and after A six-step reaction is required to obtain the final product. The route is cumbersome and the yield is low. If it is industrialized, the cost will be particularly high

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
  • Preparation of medicine and derivative thereof
  • Preparation of medicine and derivative thereof
  • Preparation of medicine and derivative thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0054] Synthesis of 6α,9α-difluoro-1,4,16-pregnatriene-11β-hydroxy-3,20-one (VIII):

[0055] 1) 6α-fluoro-1,4,9(11),16-pregnene-3,20-one

[0056] Add 10g of 6α-fluoro-1,4,16-pregnatriene-11β-hydroxy-3,20-one (DE2264001), 10ml of pyridine and 50ml of DMF into a 250ml three-necked reaction flask, blow nitrogen, stir, heat up to 70°C, add 5ml of chloromethane was kept at 80-85°C for half an hour and diluted into 1000ml of water to obtain 9.21g of 6α-fluoro-1,4,9(11),16-pregnant-3,20-one. Mp: 150-165°C.

[0057] 2) 6α-fluoro-9β, 11β-epoxy-1,4,16-pregnatriene-3,20-one

[0058] Add 9.21g of 6α-fluoro-1,4,9(11), 16-pregnant-3,20-one and 45ml of dioxane and 10ml into a 100ml reaction flask, stir, add 6g of dibromohydantoin (DBDMH ), add 0.75ml70% perchloric acid, keep it at 8~10℃ for 3 hours, dilute it in 600ml10%Na 2 S 2 o 3 solution, and filtered to obtain the wet product 6α-fluoro-9α-bromo-11β-hydroxy-1,4,16-gestrin-3,20-one. Add the wet product 6α-fluoro-9α-bromo-11β-hydrox...

Embodiment 2

[0062] 1) Synthesis of Difluorocorone Hydroxide (V)

[0063] Add 90ml of THF, 0.1g of ketone chloride and 10.0g of 6α, 9α-difluoro-1,4,16-pregnatriene-11β-hydroxyl-3,20-one (VIII) into a 250ml three-necked reaction flask, and blow nitrogen , stir, cool down to 0-5°C, add the prepared Grignard reagent, keep warm at -5°C for 1.5 hours, take samples and spot the plate, after the TLC plate is qualified, add 0.5ml of acetic acid, dilute the reaction solution in the prepared 450ml of 10% ammonium chloride water was stirred at 0-5°C for 1 hour, allowed to stand for 1 hour, filtered, discharged, and dried to obtain 9.01g of difluorocorone dehydroxylate (V).

[0064] 2) Synthesis of Difluorocorone Acetate (II)

[0065] Add 100ml of THF, 0.1g of ketone chloride and 10.0g of 6α, 9α-difluoro-1,4,16-pregnatriene-11β-hydroxyl-3,20-keto-21-acetate (US3210341) into 250ml three ports The reaction bottle was blown with nitrogen, stirred, cooled to below -15°C, added the prepared Grignard reag...

Embodiment 3

[0070] 1): Hydrolysis reaction:

[0071]Put 8.67g difluorocorrone acetate (II) and 50ml methanol / dichloromethane (volume ratio 1:1) into a 100ml three-neck reaction flask, blow nitrogen gas, stir to dissolve, keep the temperature at 0-5°C, add 2ml 2% NaOH / ethanol solution, react for 1.5 hours, take samples and point the plate, after the TLC plate is qualified, use acetic acid to adjust the pH value to 6.5-7.5, concentrate under reduced pressure, and concentrate until there is no dichloromethane smell, then pour into methanol three times, leave Appropriate volume, that is, concentrated to a thick state, cooled to below 5°C, kept at 0-5°C for 1 hour, filtered, washed with a small amount of methanol, discharged, and dried to obtain 4.51g of the product Difluorocorone (III) .

[0072] 2): Esterification reaction:

[0073] Put 4.51g of the product Difluorocorone (III) and 15ml of pyridine into a 50ml three-necked reaction flask, stir to dissolve, add 4.5ml of valeric anhydride, h...

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 relates to a preparation method for pharmaceutical, and the derivative thereof, in particular to a method for preparing the pharmaceutical and the derivative (VI) by utilizing compound (I) as the starting material. The compound (I) is a very useful intermediate, the required pharmaceutical and the derivative can be gained through a shorter route, and the reaction procedures are common procedures used for synthesizing steroid compound, the relative reactions mainly comprise Grinard reaction, 21-potential hydrolysis, 21-potential esterification, and 21-potential adding-iodine displacement. Compared with the prior method, the route is simple and easy, the industrialization is easy, and the cost is low. Especially, the compound with the structural formula (VIII) in the compound (1) is the compound with new structure.

Description

technical field [0001] The invention relates to a preparation method of difluorocorrone derivatives. In particular, it relates to the preparation of difluorocorrone derivatives (VI) using compound (I) as a starting material. Background technique [0002] Difluorocorone derivatives currently mainly include difluorocorone, difluorocorone acetate and difluorocorone valerate, all three of which are steroidal drugs, the most important of which is difluorocorone valerate . Diflucortolone valerate was first developed by Schering. This series of products, like traditional corticosteroids, have anti-inflammatory and antipruritic effects. Its characteristic is that it belongs to high-end corticosteroids, and it is mainly used for dermatitis and eczema at present, and its characteristic is that it can be used on the skin all over the body. The product is currently not produced by relevant domestic manufacturers, and there is no relevant imported product on the market. At present, t...

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): C07J5/00C07J7/00C07J75/00
Inventor 卢彦昌李金禄李静吴雅琳
Owner TIANJIN PHARMA GROUP CORP