Preparation method of halcinonide and derivative thereof

A technology of derivatives and products, which is applied in the field of preparation of halcinide and its derivatives, can solve the problems of difficult control of catalytic reactions, poor yields, side reactions, etc., so as to inhibit the generation of side reaction products and improve the effect of catalysis , the effect of reducing production costs

Active Publication Date: 2018-01-12
SHANDONG TAIHUA BIO & TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] However, in the method of the prior art CN1361112A, the concentration of hydrogen fluoride in the HF / DMF solution used is too high, the reaction is violent, and side reactions are likely to occur, which will lead to great difficulty in purification and poor yield of the upper fluorine reaction product intermediate, thereby affecting Product Quality and Yield of Halcinonide
However, boron trifluoride is used as the ketal catalyst in the prior art WO201313170761A. Since boron trifluoride is highly toxic and the catalytic reaction is difficult to control, it will also increase the difficulty of the purification reaction and affect the yield of halcinonide.

Method used

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  • Preparation method of halcinonide and derivative thereof
  • Preparation method of halcinonide and derivative thereof
  • Preparation method of halcinonide and derivative thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0112] Prepare Halcinonide as follows:

[0113] (a) After dissolving hydrocortisone acetate in N,N-dimethylformamide, controlling the temperature of the solution at about -20°C, and then adding concentrated sulfuric acid for dehydration to obtain the dehydration intermediate (1);

[0114] (b) dissolving the dehydration intermediate (1) in tetrahydrofuran, controlling the temperature of the solution at about 0°C, and then adding dibromocyanoacetamide and perchloric acid to obtain the halide intermediate;

[0115] Then, the temperature of the solution is raised and controlled at about 30° C., and sodium hydroxide solution is added to obtain the epoxy intermediate (2);

[0116] (c) adding the epoxy intermediate (2) into the dimethylformamide solution, then adjusting the temperature of the solution to about -10°C, adding a HF / DMF solution with a concentration of 35%, and performing ring-opening and fluorination reactions, The ring-opening intermediate (3) is obtained;

[0117] (...

Embodiment 2

[0123] Prepare Halcinonide as follows:

[0124] (a) After dissolving hydrocortisone acetate in N,N-dimethylacetamide, the temperature of the solution is controlled at about 0°C, and then phosphorus pentachloride is added for dehydration to obtain the dehydration intermediate (1);

[0125] (b) dissolving the dehydration intermediate (1) in acetone, controlling the temperature of the solution at about 10°C, and then adding N-bromosuccinimide and nitric acid to obtain the halide intermediate;

[0126] Then, after the halide intermediate is separated, it is dissolved in the acetone solution again, and the temperature of the solution is controlled at about 50° C., and potassium hydroxide solution is added to obtain the epoxy intermediate (2);

[0127] (c) Add the epoxy intermediate (2) into the tetrahydrofuran solution, then adjust the temperature of the solution to about -40°C, add a HF / DMF solution with a concentration of 45%, and perform ring-opening and fluorination reactions t...

Embodiment 3

[0134] Prepare hydrotriamcinolone acetonide according to the following steps:

[0135] (a) After dissolving hydrocortisone acetate in N,N-dimethylformamide, controlling the temperature of the solution at about -20°C, and then adding concentrated sulfuric acid for dehydration to obtain the dehydration intermediate (1);

[0136] (b) dissolving the dehydration intermediate (1) in tetrahydrofuran, controlling the temperature of the solution at about 0°C, and then adding dibromocyanoacetamide and perchloric acid to obtain the halide intermediate;

[0137] Then, the temperature of the solution is raised and controlled at about 30° C., and sodium hydroxide solution is added to obtain the epoxy intermediate (2);

[0138] (c) adding the epoxy intermediate (2) into the dimethylformamide solution, then adjusting the temperature of the solution to about -10°C, adding a HF / DMF solution with a concentration of 35%, and performing ring-opening and fluorination reactions, The ring-opening in...

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Abstract

The invention provides a preparation method of halcinonide and a derivative thereof. The method comprises the following steps: taking hydrocortisone acetate as a raw material, performing dehydration and then epoxidation on the raw material, performing ring opening, performing hydrolysis and chlorination, and then performing oxidation and ketalization, so as to obtain halcinonide; or performing dehydration and then epoxidation on the raw material, performing ring opening, performing hydrolysis, and then performing oxidation and ketalization, so as to obtain 9-fluoro-16a,17-(isopropylidenedioxy)corticosterone. In ring opening fluorination unit reaction, safe and mild reaction environment is selected, a fluorizating agent with low concentration is used as a reaction reagent, the reaction rate is effectively controlled, the production of side reaction products is restrained, and the product quality and yield are greatly improved. Moreover, in 16, 17-ketalization unit reaction, an acid catalyst which is low in toxicity and easy to control is adopted to replace boron trifluoride with high toxicity to perform catalysis, and the catalytic effect is effectively improved.

Description

technical field [0001] The invention relates to the field of drug synthesis, in particular to a preparation method of halcinonide and its derivatives. Background technique [0002] Halcinonide, also known as chlorofluocinolone, is an adrenocorticosteroid drug. External use can shrink dermal capillaries, inhibit epidermal cell proliferation or regeneration, inhibit fibroblast regeneration in connective tissue, and stabilize intracellular lysosomal membranes. Prevents tissue damage caused by the release of lysosomal enzymes, and has strong anti-inflammatory and anti-allergic effects. For allergic dermatitis, atopic dermatitis, contact dermatitis, seborrheic dermatitis, eczema, pruritus, psoriasis, neurodermatitis, etc. [0003] Regarding the preparation method of halcinonide, many studies have also been done in the prior art. For example, the prior art CN1361112A discloses a preparation method of halcinonide, and discloses the use of 54-62% HF / DMF for the above-mentioned Flu...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07J71/00
Inventor 陈芳张青孔维涛
Owner SHANDONG TAIHUA BIO & TECH
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