CN115073546A - Preparation method of novel androgen receptor inhibitor - Google Patents
Preparation method of novel androgen receptor inhibitor Download PDFInfo
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- CN115073546A CN115073546A CN202210623403.6A CN202210623403A CN115073546A CN 115073546 A CN115073546 A CN 115073546A CN 202210623403 A CN202210623403 A CN 202210623403A CN 115073546 A CN115073546 A CN 115073546A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J5/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond
- C07J5/0046—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond substituted in position 17 alfa
- C07J5/0053—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond substituted in position 17 alfa not substituted in position 16
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J21/00—Normal steroids containing carbon, hydrogen, halogen or oxygen having an oxygen-containing hetero ring spiro-condensed with the cyclopenta(a)hydrophenanthrene skeleton
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- General Health & Medical Sciences (AREA)
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Abstract
The invention discloses a preparation method of a novel androgen receptor inhibitor, belonging to the technical field of preparation and processing of steroid hormone medicaments. The method takes a compound I, namely 17 alpha, 21-dihydroxypregn-4-ene-3, 20-diketone as a raw material, and prepares a compound III, namely 17 alpha, 21-dihydroxypregn-4-ene-3, 20-diketone-17-propionate through a cyclic etherification reaction and a cyclic ether hydrolysis reaction. The raw material compound I in the method is a steroid drug intermediate which is cheap and easy to obtain, the process flow is simple, the controllability is good, the synthesis cost is low, and the prepared product has high yield and purity and stable quality and is suitable for industrial production.
Description
Technical Field
The invention relates to the technical field of preparation and processing of steroid hormone medicaments, in particular to a preparation method of a novel androgen receptor inhibitor, namely 17 alpha, 21-dyhydroxyl pregn-4-alkene-3, 20-diketone-17-propionate.
Background
17 alpha, 21-dihydroxypregn-4-ene-3, 20-dione-17-propionate, also known as Clascoterone (code: CB-03-01), is a topical Androgen Receptor (AR) inhibitor, and is mainly used for acne, hirsutism or androgenic alopecia, etc.
The existing Clascoterone preparation process takes 17 alpha, 21-diester as a raw material and is prepared by utilizing bio-enzyme catalytic hydrolysis, and the synthetic route is as follows:
the raw material 17 alpha, 21-diester in the method needs to be prepared from 21-site monoester through high-temperature esterification reaction, and the reaction has more impurities and low yield. In addition, the stability control difficulty of the biological enzymatic hydrolysis process is large, and the market competitiveness is lacked in the equipment investment and production cost.
Disclosure of Invention
In order to solve the problems in the prior art, the invention provides a preparation method of a novel androgen receptor inhibitor 17 alpha, 21-dyhydroxy pregn-4-ene-3, 20-diketone-17-propionate which has low impurity content, high yield and stable quality.
The purpose of the invention is realized by the following steps:
the synthetic route of the method is as follows:
wherein R is methyl or ethyl;
the method specifically comprises the following steps:
1) cyclic etherification reaction: dissolving a compound I, namely 17 alpha, 21-dihydroxypregn-4-ene-3, 20-dione in an organic solvent A, sequentially adding an etherification reagent and a catalyst, stirring at 0-60 ℃ to react completely, performing water precipitation or water precipitation after concentration, filtering and drying to obtain a compound II;
2) etherification and hydrolysis reaction: dissolving the compound II in an organic solvent B, adding a hydrolysis reagent, reacting completely under stirring at-10-40 ℃, then adding alkali to adjust the pH value to be neutral, concentrating, precipitating with water, filtering, drying, and refining with ethyl acetate to obtain a compound III, namely 17 alpha, 21-dihydroxypregn-4-ene-3, 20-diketone-17-propionate.
Further, the method specifically comprises the steps of dissolving a compound I, namely 17 alpha, 21-dihydroxypregn-4-ene-3, 20-dione in an organic solvent A, sequentially adding an etherification reagent and a catalyst, completely reacting under stirring at 0-60 ℃, then adding a hydrolysis reagent, completely reacting under stirring at-10-40 ℃, adding an alkali to adjust the pH value to be neutral, carrying out elutriation or concentration, carrying out elutriation, filtering, drying, and refining ethyl acetate to obtain a compound III, namely 17 alpha, 21-dihydroxypregn-4-ene-3, 20-dione-17-propionate.
Further, the organic solvent A is one of dimethylformamide, dimethylacetamide, tetrahydrofuran or dioxane, and the volume consumption of the organic solvent A is 1-10 times of the weight of the substrate compound I.
Further, the etherification reagent is trimethyl or triethyl orthopropionate, and the volume of the etherification reagent is 0.3-2 times of the weight of the substrate compound I.
Further, the catalyst is one of p-toluenesulfonic acid, benzenesulfonic acid, methanesulfonic acid, trichloroacetic acid or trifluoroacetic acid, and the weight or volume consumption of the catalyst is 0.01-0.1 times of that of the substrate compound I.
Further, the organic solvent B is one of methanol, ethanol, propanol, isopropanol, dichloromethane, chloroform, tetrahydrofuran or dioxane, and the volume consumption of the organic solvent B is 1-30 times of the weight of the substrate compound II.
Further, the hydrolysis reagent is AlCl 3 The hydrolysis reagent is one of aqueous solutions of formic acid, acetic acid, propionic acid, a mixture of formic acid and formate, a mixture of acetic acid and acetate, a mixture of propionic acid and propionate or a mixture of phosphoric acid and dihydrogen phosphate, the pH range of the aqueous solution of the hydrolysis reagent is 2-5, and the volume consumption of the aqueous solution of the hydrolysis reagent is 1-10 times of the weight of the substrate compound II.
Further, the alkali is one or more of aqueous solutions of formate, acetate, bicarbonate, carbonate and hydroxide, and the mass fraction of the aqueous alkali solution is 2-20%.
The invention has the technical characteristics and beneficial effects that:
1) the raw materials and reagents in the synthesis method are low in price and easy to obtain, biological enzyme fermentation is not needed, and the method has extremely high market competitiveness in equipment investment and production cost;
2) the production process is easy to control, the reaction temperature is-10-60 ℃, the condition is mild, and the method is suitable for industrial production;
3) the product prepared by the preparation method has the advantages of yield higher than 91%, purity higher than 99% and stable quality;
Detailed Description
The invention is further illustrated with reference to the following examples, which are not intended to limit the invention.
The specific experimental procedures or conditions are not shown in the examples, and the procedures can be performed according to the conventional experimental methods described in the publications in the field, and the reagents or equipment used are not indicated by manufacturers, and are all conventional products which can be obtained commercially.
Example 117 preparation of α, 21-dihydroxypregn-4-ene-3, 20-dione-17-propionate, comprising the following steps:
1) cyclic etherification reaction: preparation of Compound II
Adding compound I, namely 17 alpha, 21-dihydroxypregn-4-ene-3, 20-dione 20g, dimethylformamide 120mL and trimethyl orthopropionate 20mL into a reaction bottle, then adding p-toluenesulfonic acid 2g, stirring at 40 ℃ to react completely, precipitating with water, filtering and drying to obtain compound II 22.5 g.
2) Etherification and hydrolysis reaction: preparation of Compound III
Adding 22.5g of compound II and 400mL of ethanol into a reaction bottle, then adding 110mL of AlCl3 aqueous solution with pH of 3, stirring at 20 ℃ to completely react, dropwise adding 2 wt% of sodium hydroxide aqueous solution to adjust the pH to be neutral, concentrating, elutriating, filtering, drying, and refining with ethyl acetate to obtain 18.5g of compound III, namely 17 alpha, 21-dihydroxypregn-4-ene-3, 20-diketone-17-propionate, wherein the total mass yield is as follows: 92.5%, HPLC purity: more than 99 percent.
Example 217 preparation of α, 21-dihydroxypregn-4-ene-3, 20-dione-17-propionate, comprising the following steps:
1) cyclic etherification reaction: preparation of Compound II
Adding compound I, namely 20g of 17 alpha, 21-dihydroxypregn-4-ene-3, 20-dione, 120mL of dimethylacetamide and 20mL of triethyl orthopropionate into a reaction bottle, adding 2g of trichloroacetic acid, completely reacting under stirring at 40 ℃, performing elutriation, filtering and drying to obtain 22.7g of compound II.
2) Etherification and hydrolysis reaction: preparation of Compound III
Adding 22.7g of compound II, 200mL of methanol and 200mL of dichloromethane into a reaction bottle, then adding 110mL of acetic acid aqueous solution with pH of 4, stirring at 20 ℃ to completely react, dropwise adding 10 wt% of potassium acetate aqueous solution to adjust the pH to be neutral, concentrating, elutriating with water, filtering, drying and refining with ethyl acetate to obtain 18.7g of compound III, namely 17 alpha, 21-dihydroxypregn-4-ene-3, 20-diketone-17-propionate, wherein the total mass yield is as follows: 93.5%, HPLC purity: more than 99 percent.
EXAMPLE 317 preparation of alpha, 21-dihydroxypregn-4-ene-3, 20-dione-17-propionate
Adding 20g of compound I, namely 17 alpha, 21-dihydroxypregn-4-ene-3, 20-dione, into a reaction bottle, sequentially adding 120mL of tetrahydrofuran, 20mL of trimethyl orthopropionate and 2g of benzenesulfonic acid, reacting completely under stirring at 40 ℃, then adding 60mL of formic acid aqueous solution with pH of 5, reacting completely under stirring at 20 ℃, dropwise adding 2 wt% of sodium hydroxide aqueous solution to adjust the pH to be neutral, concentrating, performing elutriation, filtering, drying and refining with ethyl acetate to obtain 18.2g of compound III, namely 17 alpha, 21-dihydroxypregn-4-ene-3, 20-dione-17-propionate, wherein the total mass yield is as follows: 91.0%, HPLC purity: more than 99 percent.
Example 417 preparation of alpha, 21-dihydroxypregn-4-ene-3, 20-dione-17-propionate
Adding 20g of a compound I, namely 17 alpha, 21-dihydroxypregn-4-ene-3, 20-dione, into a reaction bottle, sequentially adding 120mL of dimethylformamide, 20mL of triethyl orthopropionate and 2mL of trifluoroacetic acid, reacting completely under stirring at 40 ℃, then adding 60mL of a mixed solution of acetic acid with pH 3 and potassium acetate, reacting completely under stirring at 20 ℃, dropwise adding a 2 wt% sodium hydroxide aqueous solution to adjust the pH to be neutral, performing elutriation, filtering and drying, and refining ethyl acetate to obtain 18.4g of a compound III, namely 17 alpha, 21-dihydroxypregn-4-ene-3, 20-dione-17-propionate, wherein the total mass yield is as follows: 92.0%, HPLC purity: more than 99 percent.
The above description is only for the preferred embodiment of the present invention, but the scope of the present invention is not limited thereto, and any changes or substitutions that can be easily conceived by those skilled in the art within the technical scope of the present invention are included in the scope of the present invention.
Claims (8)
1. A preparation method of a novel androgen receptor inhibitor is characterized in that the synthetic route of the method is as follows:
wherein R is methyl or ethyl;
the method specifically comprises the following steps:
1) cyclic etherification reaction: dissolving a compound I, namely 17 alpha, 21-dihydroxypregn-4-ene-3, 20-dione in an organic solvent A, sequentially adding an etherification reagent and a catalyst, stirring at 0-60 ℃ to react completely, performing water precipitation or water precipitation after concentration, filtering and drying to obtain a compound II;
2) etherification and hydrolysis reaction: dissolving the compound II in an organic solvent B, adding a hydrolysis reagent, reacting completely under stirring at-10-40 ℃, then adding alkali to adjust the pH value to be neutral, concentrating, precipitating with water, filtering, drying, and refining with ethyl acetate to obtain a compound III, namely 17 alpha, 21-dihydroxypregn-4-ene-3, 20-diketone-17-propionate.
2. The method for preparing the novel androgen receptor inhibitor according to claim 1, characterized in that the method comprises the steps of dissolving a compound I, namely 17 alpha, 21-dihydroxypregn-4-ene-3, 20-dione, in an organic solvent A, sequentially adding an etherification reagent and a catalyst, completely reacting under stirring at 0-60 ℃, then adding a hydrolysis reagent, completely reacting under stirring at-10-40 ℃, adding an alkali to adjust the pH value to be neutral, carrying out water precipitation or after concentration, carrying out water precipitation, filtering, drying, and refining with ethyl acetate to obtain a compound III, namely 17 alpha, 21-dihydroxypregn-4-ene-3, 20-dione-17-propionate.
3. The process for preparing a novel androgen receptor inhibitor according to claim 1 or 2, characterized in that the organic solvent A is one of dimethylformamide, dimethylacetamide, tetrahydrofuran or dioxane, and the volume dosage is 1-10 times of the weight of the substrate compound I.
4. The process for producing a novel androgen receptor inhibitor according to claim 1 or 2, characterized in that the etherification agent is trimethyl orthopropionate or triethyl orthopropionate, and the volume usage amount thereof is 0.3 to 2 times of the weight of the substrate compound i.
5. The process for preparing a novel androgen receptor inhibitor according to claim 1 or 2, characterized in that the catalyst is one of p-toluenesulfonic acid, benzenesulfonic acid, methanesulfonic acid, trichloroacetic acid or trifluoroacetic acid, and the amount by weight or volume thereof is 0.01-0.1 times of the weight of the substrate compound I.
6. The process for preparing a novel androgen receptor inhibitor according to claim 1, wherein the organic solvent B is one of methanol, ethanol, propanol, isopropanol, dichloromethane, chloroform, tetrahydrofuran or dioxane, and the volume amount thereof is 1 to 30 times of the weight of the substrate compound II.
7. The process for the preparation of a novel androgen receptor inhibitor according to claim 1 or 2, characterized in that the hydrolyzing agent is AlCl 3 Formic acid, acetic acid, propionic acid, formic acid and formate mixture, acetic acid and acetate mixture, propionic acid and formic acidOne of a mixture of acid and propionate or a mixture of phosphoric acid and dihydrogen phosphate, wherein the pH range of the hydrolysis reagent aqueous solution is 2-5, and the volume consumption of the hydrolysis reagent aqueous solution is 1-10 times of the weight of the substrate compound II.
8. The preparation method of a novel androgen receptor inhibitor as claimed in claim 1 or 2, characterized in that the alkali is one or more of formate, acetate, bicarbonate, carbonate and hydroxide in water solution, and the mass fraction of the alkali water solution is 2-20%.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115466301A (en) * | 2022-08-29 | 2022-12-13 | 扬州奥锐特药业有限公司 | Steroid compound, crystal form A thereof, and preparation method and application thereof |
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| FR1520264A (en) * | 1966-04-25 | 1968-04-05 | Koninklijke Gist Spiritus | Process for obtaining 11beta-17alpha-hydroxysteroids |
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2022
- 2022-06-01 CN CN202210623403.6A patent/CN115073546A/en active Pending
Patent Citations (6)
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| FR1520264A (en) * | 1966-04-25 | 1968-04-05 | Koninklijke Gist Spiritus | Process for obtaining 11beta-17alpha-hydroxysteroids |
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| CN103450304A (en) * | 2007-08-03 | 2013-12-18 | 科斯莫股份公司 | Enzymatic process for obtaining 17 alpha-monoesters of 11-deoxycortisol and/or 9, 11-dehydro derivatives thereof |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115466301A (en) * | 2022-08-29 | 2022-12-13 | 扬州奥锐特药业有限公司 | Steroid compound, crystal form A thereof, and preparation method and application thereof |
| WO2024045950A1 (en) * | 2022-08-29 | 2024-03-07 | 扬州奥锐特药业有限公司 | Steroid compound and crystal form a thereof, and preparation methods therefor and use thereof |
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