CN113214348A - Preparation method of ciclesonide - Google Patents
Preparation method of ciclesonide Download PDFInfo
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- CN113214348A CN113214348A CN202110514702.1A CN202110514702A CN113214348A CN 113214348 A CN113214348 A CN 113214348A CN 202110514702 A CN202110514702 A CN 202110514702A CN 113214348 A CN113214348 A CN 113214348A
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- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J71/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton is condensed with a heterocyclic ring
- C07J71/0005—Oxygen-containing hetero ring
- C07J71/0026—Oxygen-containing hetero ring cyclic ketals
- C07J71/0031—Oxygen-containing hetero ring cyclic ketals at positions 16, 17
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Abstract
The invention discloses a preparation method of ciclesonide, which comprises the following steps: acetalization, first purification, hydrolysis, esterification and second purification; carrying out an acetalization reaction: adding 16 alpha-hydroxy prednisolone-21-acetate into a polar solvent, stirring and dissolving, controlling the temperature to a proper temperature, adding an acid catalyst, controlling the reaction temperature to be in a proper range, keeping the temperature at a proper temperature, and obtaining an acetal (1) after the reaction is completed by condensation reaction (R/S is 90: 10). The invention selects 16 alpha-hydroxy prednisolone-21-acetate as the starting material, and can obtain ciclesonide with higher purity by the transformation of 16,17 and 21 positions and the separation of isomers.
Description
Technical Field
The invention relates to the technical field of medicinal chemistry, in particular to a preparation method of ciclesonide.
Background
Ciclesonide, which has the chemical name of 16 alpha, 17 alpha-22R-cyclohexylmethylene-11 beta-hydroxy-1, 4-pregnanedione-3, 20-diketone-21-isobutyrate, is a new generation of inhaled non-halogenated enzyme glucocorticoid steroid, has high local anti-inflammatory capability, and can effectively relieve the inflammation of the lung and respiratory tract of a patient. Ciclesonide is administered in an inactive form, is activated in situ by endogenous esterases in the airways, is converted into the active ingredient upon reaching the lungs of the target organ, and once activated, exhibits high local anti-inflammatory activity.
At present, ciclesonide prepared at home and abroad is mainly synthesized by taking 16 alpha-hydroxy prednisolone as a raw material. Gutterer firstly condenses 16 alpha-hydroxy prednisolone with cyclohexyl formaldehyde to obtain acetal (US5733901), then introduces 21-bit isobutyrate to obtain a ciclesonide crude product, and increases the R/S ratio through recrystallization (WO98009982), but because the 21-bit hydroxy of 16 alpha-hydroxy prednisolone exists, impurities are generated in the acetalization process and are not easy to separate, the purification difficulty is high, and the yield is poor;
US5728826 improved the process of siliconizing the acetal followed by recrystallization to increase the R/S ratio and then hydrolyzing the silyl ether to yield ciclesonide, resulting in an overall reaction increased by two steps.
Disclosure of Invention
The invention aims to solve the defects that the 21-position hydroxyl of 16 alpha-hydroxy prednisolone generates impurities and is difficult to separate, the purification difficulty is high and the yield is poor in the acetalization process, and provides a preparation method of ciclesonide.
In order to achieve the purpose, the invention adopts the following technical scheme:
a preparation method of ciclesonide comprises the following steps: carrying out an acetalization reaction, carrying out primary purification, carrying out a hydrolysis reaction, carrying out an esterification reaction and carrying out secondary purification;
carrying out an acetalization reaction: adding 16 alpha-hydroxy prednisolone-21-acetate into a polar solvent, stirring and dissolving, controlling the temperature to a proper temperature, adding an acid catalyst, controlling the reaction temperature to be in a proper range, keeping the temperature at a proper temperature, and obtaining an acetal (1) through a condensation reaction after the reaction is completed (R/S is 90: 10);
first purification: adding the acetal compound (1) obtained in the acetalization reaction into a polar mixed solvent, heating and stirring, then cooling to a certain temperature, recrystallizing, and filtering to obtain a compound (2) (R/S is 99: 1);
and (3) hydrolysis reaction: adding the compound (2) obtained by the first purification into an organic solvent, introducing nitrogen, cooling to a certain temperature, adding alkali, adjusting the pH value to be neutral, concentrating under reduced pressure for crystallization, and reacting to obtain a hydrolysate (3);
esterification reaction: adding the hydrolysate (3) obtained in the hydrolysis reaction into a polar organic solvent, stirring, adding an alkali, controlling the temperature to be proper, filtering, and drying to obtain an ester (4) (R/S is 99: 1);
and (3) second purification: the esterified compound (4) obtained in the esterification reaction is added to a polar mixed solvent, heated to a suitable temperature while being stirred and dissolved, and recrystallized to obtain ciclesonide (II) (S < 0.3%).
Preferably, the temperature control and the heat preservation in the acetalization reaction are both-2-2 ℃.
Preferably, the polar solvent for the acetalization reaction comprises water, alcohols and amides, one or more of the solvents are selected, and the acid catalyst for the acetalization reaction comprises one or more of hydrobromic acid, hydrofluoric acid, perchloric acid and phosphoric acid.
Preferably, the heating temperature of the first purification is 55 ℃ and the temperature is reduced to-5 ℃, and the recrystallization temperature of the first purification is 40-75 ℃.
Preferably, the polar solvent for the first purification includes lower aliphatic alcohols, halogenated hydrocarbons, ketones, ethers, and a mixed solvent of two or more of these solvents is selected.
Preferably, the organic solvent for the hydrolysis reaction comprises lower aliphatic alcohol, halogenated hydrocarbon and ether, and one or more of the organic solvents are selected; the alkali in the hydrolysis reaction comprises one or more of sodium hydroxide, potassium hydroxide, sodium carbonate or potassium carbonate, and the addition mode of the alkali is a solution form with a certain concentration.
Preferably, the temperature is reduced to 0 ℃ in the hydrolysis reaction, NaOH and methanol solution need to be dropped in one hour, the temperature is kept between 0 ℃ and 5 ℃ for reaction for 2 hours, and recrystallization in methanol is needed in the hydrolysis reaction.
Preferably, the organic solvent for the esterification reaction comprises one or more of ketones, amines and amides, the organic solvent comprises one or more of potassium carbonate, sodium acetate, triethylamine and pyridine, and the alkali is added at one time.
Preferably, after the temperature is controlled to be 0-5 ℃ in the esterification reaction, a certain amount of isobutyric anhydride is added dropwise, the reaction is carried out for 4 hours at the temperature of 0-5 ℃ until the thin layer is analyzed to be free of raw materials, and the solution needs to be diluted in ice water before being filtered in the esterification reaction.
Preferably, the polar mixed solvent for the second purification includes lower aliphatic alcohols including methanol, ethanol and isopropanol, halogenated hydrocarbons including chloroform, dichloromethane, tetrachloromethane and 1, 2-dichloroethane, ketones being acetone, and ethers including diethyl ether, dioxane and tetrahydrofuran, and two or more of these solvents are selected.
Compared with the prior art, the invention has the beneficial effects that:
1. selecting 16 alpha-hydroxy prednisolone-21-acetate as a starting material, and obtaining the ciclesonide with higher purity through the transformation of 16,17 and 21 positions and the separation of isomers
2. The existing intermediate of a company is used as a starting material, the line is stable and easy to control, the R/S ratio is controlled from the intermediate stage, the loss in the purification process is greatly reduced, and the yield and the cost are obviously superior to those of other synthesis methods;
3. the invention has simple and convenient process, easily obtained raw materials, no expensive auxiliary materials, greatly reduced industrialization cost and strong operability, and the intermediates in each step can be obtained by purifying by a general chemical method.
Drawings
Fig. 1 is a flow chart of the preparation method of ciclesonide according to the present invention.
Detailed Description
The technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the drawings in the embodiments of the present invention, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all embodiments.
Referring to fig. 1, a method for preparing ciclesonide includes the following steps: carrying out an acetalization reaction, carrying out primary purification, carrying out a hydrolysis reaction, carrying out an esterification reaction and carrying out secondary purification;
carrying out an acetalization reaction: adding 10g of 11 beta, 16 alpha, 17 alpha-trihydroxy-1, 4-pregnadiene-3, 20-dione-21-acetate, 30ml of N, N-dimethylformamide and 30ml of 47% hydrobromic acid into a reaction bottle, stirring and dissolving, controlling the temperature to be 0 +/-2 ℃, dropwise adding 10ml of cyclohexylformaldehyde, keeping the temperature to be 0 +/-2 ℃ for reaction for 2 hours, carrying out thin layer analysis until no raw material exists, diluting the raw material in ice water, filtering and drying to obtain 12g of acetal (1);
first purification: adding 20g of acetal (1), 30ml of dichloromethane and 40ml of methanol into a reaction bottle, heating to 55 ℃, stirring to dissolve, cooling to-5 ℃, precipitating a large amount of white crystalline solid, and filtering to obtain 16.8g of a compound (2) (R/S is 99: 1);
and (3) hydrolysis reaction: adding 30ml of methanol and 30ml of dichloromethane into a reaction bottle, adding 10g of the compound (2), introducing nitrogen, cooling to 0 ℃, dropwise adding 20ml of 2% NaOH/methanol solution within one hour, keeping the temperature at 0-5 ℃, reacting for 2 hours, carrying out thin layer analysis until no raw material exists, adding an appropriate amount of acetic acid to neutralize until the pH is 7, concentrating under reduced pressure, and recrystallizing in methanol to obtain 8g of hydrolysate (3) (R/S is 99: 1);
esterification reaction: adding 10g of hydrolysate (3) into a reaction bottle, adding 30ml of N, N-dimethylformamide, stirring for dissolving, adding 2g of potassium carbonate, controlling the temperature to be 0-5 ℃, dropwise adding 15ml of isobutyric anhydride, keeping the temperature to be 0-5 ℃, reacting for 4 hours, analyzing a thin layer until no raw material exists, diluting in ice water, filtering, and drying to obtain 11g of esterified substance (4) (R/S is 99: 1);
and (3) second purification: 20g of the esterified product (1), 30ml of dichloromethane and 40ml of isopropanol were added to a reaction flask, heated to 55 ℃ and stirred to dissolve, cooled to-5 ℃, and a large amount of white crystalline solid was precipitated and filtered to obtain 18g of the compound (2) (S < 0.3%).
Example 2
Referring to fig. 1, a method for preparing ciclesonide includes the following steps: carrying out an acetalization reaction, carrying out primary purification, carrying out a hydrolysis reaction, carrying out an esterification reaction and carrying out secondary purification;
carrying out an acetalization reaction: adding 10g of 11 beta, 16 alpha, 17 alpha-trihydroxy-1, 4-pregnadiene-3, 20-dione-21-acetate, 30ml of isopropanol and 30ml of 70% hydrofluoric acid into a reaction bottle, stirring and dissolving, controlling the temperature to be 0 +/-2 ℃, dropwise adding 10ml of cyclohexylformaldehyde, preserving the temperature to be 0 +/-2 ℃ for reacting for 2 hours, carrying out thin layer analysis until no raw material exists, diluting in ice water, filtering, and drying to obtain 11.8g of acetal (1) (R/S is 99: 10);
first purification: 20g of acetal (1), 30ml of chloroform and 40ml of ethanol were added to a reaction flask, heated to 55 ℃ and stirred to dissolve, cooled to-5 ℃, and a large amount of white crystalline solid was precipitated and filtered to obtain 15.8g of compound (2) (R/S: 99: 1);
and (3) hydrolysis reaction: adding 30ml of methanol and 30ml of dichloromethane into a reaction bottle, adding 10g of the compound (2), introducing nitrogen, cooling to 0 ℃, dropwise adding 20ml of 2% KOH/methanol solution within one hour, keeping the temperature at 0-5 ℃ for reaction for 2 hours, carrying out thin layer analysis until no raw material exists, adding an appropriate amount of acetic acid for neutralization until the pH is 7, carrying out reduced pressure concentration, and recrystallizing in methanol to obtain 7.5g of hydrolysate (3) (R/S is 99: 1);
esterification reaction: adding 10g of hydrolysate (3) into a reaction bottle, adding 30ml of isopropylamine, stirring for dissolving, controlling the temperature to be 0-5 ℃, dropwise adding 15ml of isobutyric anhydride, reacting for 4 hours at the temperature of 0-5 ℃, carrying out thin layer analysis until no raw material exists, diluting in ice water, filtering, and drying to obtain 10g of esterified substance (4) (R/S is 99: 1);
and (3) second purification: 20g of the esterified product (1), 30ml of chloroform and 40ml of methanol were added to a reaction flask, heated to 55 ℃ and stirred to dissolve, cooled to-5 ℃, and a large amount of white crystalline solid was precipitated and filtered to obtain 16.8g of the compound (2) (S < 0.3%).
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 person skilled in the art should be able to cover the technical scope of the present invention, the technical solutions and the inventive concepts of the present invention with equivalent or modified alternatives and modifications within the technical scope of the present invention.
Claims (10)
1. The preparation method of ciclesonide is characterized by comprising the following steps: acetalization, first purification, hydrolysis, esterification and second purification;
carrying out an acetalization reaction: adding 16 alpha-hydroxy prednisolone-21-acetate into a polar solvent, stirring and dissolving, controlling the temperature to a proper temperature, adding an acid catalyst, controlling the reaction temperature to be in a proper range, keeping the temperature at a proper temperature, and obtaining an acetal (1) through a condensation reaction after the reaction is completed (R/S is 90: 10);
first purification: adding the acetal compound (1) obtained in the acetalization reaction into a polar mixed solvent, heating and stirring, then cooling to a certain temperature, recrystallizing, and filtering to obtain a compound (2) (R/S is 99: 1);
and (3) hydrolysis reaction: adding the compound (2) obtained by the first purification into an organic solvent, introducing nitrogen, cooling to a certain temperature, adding alkali, adjusting the pH value to be neutral, concentrating under reduced pressure for crystallization, and reacting to obtain a hydrolysate (3);
esterification reaction: adding the hydrolysate (3) obtained in the hydrolysis reaction into a polar organic solvent, stirring, adding an alkali, controlling the temperature to be proper, filtering, and drying to obtain an ester (4) (R/S is 99: 1);
and (3) second purification: the esterified compound (4) obtained in the esterification reaction is added to a polar mixed solvent, heated to a suitable temperature while being stirred and dissolved, and recrystallized to obtain ciclesonide (II) (S < 0.3%).
2. The method for preparing ciclesonide according to claim 1, wherein the temperature control and the temperature maintenance in the acetalization reaction are both between-2 ℃ and 2 ℃.
3. The method for preparing ciclesonide according to claim 1, wherein the polar solvent for the acetalization comprises water, alcohols, amides, one or more of these solvents are selected, and the acid catalyst for the acetalization comprises one or more of hydrobromic acid, hydrofluoric acid, perchloric acid, phosphoric acid.
4. The method for preparing ciclesonide according to claim 1, wherein the heating temperature for the first purification is 55 ℃ and the temperature is reduced to-5 ℃, and the recrystallization temperature for the first purification is 40-75 ℃.
5. The method according to claim 1, wherein the polar solvent for the first purification comprises lower aliphatic alcohols, halogenated hydrocarbons, ketones, ethers, and a mixture of two or more of these solvents is selected.
6. The method for preparing ciclesonide according to claim 1, wherein the organic solvent for the hydrolysis reaction comprises lower aliphatic alcohols, halogenated hydrocarbons, ethers, and one or more of these organic solvents are selected; the alkali in the hydrolysis reaction comprises one or more of sodium hydroxide, potassium hydroxide, sodium carbonate or potassium carbonate, and the addition mode of the alkali is a solution form with a certain concentration.
7. The method for preparing ciclesonide according to claim 1, wherein the temperature of the hydrolysis reaction is reduced to 0 ℃, and the NaOH and methanol solution is dropped in one hour, the holding temperature is 0-5 ℃ for 2 hours, and the hydrolysis reaction is recrystallized in methanol.
8. The method for preparing ciclesonide according to claim 1, wherein the organic solvent for the esterification reaction comprises one or more of ketones, amines and amides, the organic solvent comprises one or more of potassium carbonate, sodium acetate, triethylamine and pyridine, and the base is added at one time.
9. The method for preparing ciclesonide according to claim 1, wherein the temperature of the esterification reaction is controlled to 0-5 ℃, and then a certain amount of isobutyric anhydride is added dropwise, and then the esterification reaction is carried out for 4 hours at 0-5 ℃ until the thin layer is analyzed to be free of raw materials, and the solution is diluted in ice water before being filtered in the esterification reaction.
10. The method as claimed in claim 1, wherein the polar mixed solvent for the second purification includes lower aliphatic alcohols including methanol, ethanol and isopropanol, halogenated hydrocarbons including chloroform, dichloromethane, tetrachloro-methane and 1, 2-dichloroethane, ketones including acetone, ethers including diethyl ether, dioxane and tetrahydrofuran.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP2064227A2 (en) * | 2006-09-19 | 2009-06-03 | Cipla Ltd. | Processes for the preparation of ciclesonide and its crystal form |
| CN107778343A (en) * | 2016-08-30 | 2018-03-09 | 天津太平洋制药有限公司 | A kind of preparation method of ciclesonide |
| CN109293730A (en) * | 2018-10-23 | 2019-02-01 | 山东泰华生物科技股份有限公司 | A kind of preparation method of ciclesonide |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP2064227A2 (en) * | 2006-09-19 | 2009-06-03 | Cipla Ltd. | Processes for the preparation of ciclesonide and its crystal form |
| CN107778343A (en) * | 2016-08-30 | 2018-03-09 | 天津太平洋制药有限公司 | A kind of preparation method of ciclesonide |
| CN109293730A (en) * | 2018-10-23 | 2019-02-01 | 山东泰华生物科技股份有限公司 | A kind of preparation method of ciclesonide |
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