CN110759962B - Preparation method of high-purity fluocinolone acetonide - Google Patents
Preparation method of high-purity fluocinolone acetonide Download PDFInfo
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- CN110759962B CN110759962B CN201911137209.1A CN201911137209A CN110759962B CN 110759962 B CN110759962 B CN 110759962B CN 201911137209 A CN201911137209 A CN 201911137209A CN 110759962 B CN110759962 B CN 110759962B
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- C—CHEMISTRY; METALLURGY
- 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 belongs to the technical field of steroid hormone preparation, and particularly relates to a preparation method of high-purity fluocinolone acetonide, which comprises the steps of mixing fluocinolone acetonide with a mixed solution, and performing hydrolysis reaction to obtain the mixed solution, wherein the mixed solution is a mixed solution of sulfite and strong alkali, the scheme adopts a system of strong alkali and sulfite to hydrolyze 21-bit ester group, and the sulfite is added, so that the reaction can be performed at 0-30 ℃, the site of the reaction is protected in situ, the problem of product deterioration in the hydrolysis process can be well avoided, the EP9.0 requirement can be met only by simple refining, the purity of the obtained product is obviously higher than that of the prior art, and the purity and yield of a crude product are greatly improved.
Description
Technical Field
The invention belongs to the technical field of preparation of steroid hormones, and particularly relates to a preparation method of high-purity fluocinolone acetonide.
Background
Fluocinolone acetonide is external cortical hormone, is applied to skin affected parts to treat pruritus, mucosal inflammation, neurodermatitis, contact dermatitis, solar dermatitis, psoriasis and the like caused by skin allergy, is particularly suitable for infantile eczema, and has the advantages of remarkable curative effect, less side effect, quick response and good itching relieving effect. The current method for preparing fluocinolone acetonide is to hydrolyze fluocinolone acetonide under alkaline condition. In CN201810181914.0, hydrolysis with lithium hydroxide, hydrazine hydrate, etc. is reported, and in WO2018037423, hydrolysis with sodium hydroxide is reported, the reaction formula is as follows:
corticosteroids containing 1, 3-dihydroxyacetone side chains are easy to degrade side chains under alkaline conditions, and a trace amount of oxygen in a system can accelerate the process, and degradation paths are as follows:
the stronger the alkalinity, the faster the degradation speed, the higher the temperature, the faster the degradation speed, the longer the time, the faster the degradation speed. Therefore, the existing hydrolysis method inevitably leads to low purity and low yield of the hydrolysate, and brings great difficulty to the refining of products in the later period. Because the time for industrial production is long, the temperature control cannot be very accurate, so that the existing method is not suitable for industrial scale-up production.
Disclosure of Invention
The invention aims to provide a preparation method of high-purity fluocinolone acetonide, which improves the purity and yield of the product.
The invention relates to a preparation method of high-purity fluocinolone acetonide, which comprises the following steps of mixing fluocinolone acetonide with a mixed solution, and carrying out hydrolysis reaction to obtain the fluocinolone acetonide, wherein the mixed solution is a mixed solution of sulfite and strong alkali, and the reaction formula is as follows:
the strong base is one or more of sodium hydroxide, potassium hydroxide and lithium hydroxide, and the weight ratio of fluocinonide to the strong base is (10-100): 1.
The weight ratio of fluocinolone acetate to sulfite is (5-10): 1. The sulfite is preferably sodium sulfite.
The reaction solvent for the hydrolysis reaction is a mixed solvent composed of an alcohol solvent and dichloromethane, and the alcohol solvent is preferably methanol. Preferably, the weight volume ratio (g/ml) of the fluocinolone acetate to the mixed solvent is 1 (15-25), and the volume ratio of the alcohol solvent to the dichloromethane is 1: (0.5-2).
The temperature of the hydrolysis reaction is 0-30 ℃, and preferably 5-15 ℃.
And after the hydrolysis reaction is finished, adjusting the pH value of the reaction solution to 6-7, concentrating, cooling to 0-5 ℃, separating out crystals, filtering, washing and drying to obtain the fluocinolone acetonide.
The method has the advantages that the ester group at the 21 th position is hydrolyzed by adopting a system of strong alkali and sulfite, the sulfite is added, the reaction can be carried out at 0-30 ℃, the reaction sites are protected in situ, the deterioration problem of the product in the hydrolysis process can be well avoided, the product can meet the requirement of EP9.0 only by simple refining, the purity of the obtained product is obviously higher than that of the prior art, and the purity and yield of the crude product are greatly improved.
Detailed Description
Example 1
Adding 10g of fluocinolone acetonide acetate, 100ml of dichloromethane and 100ml of methanol into a reaction bottle, stirring for dissolving, cooling to 5-10 ℃, introducing nitrogen for protection, dropwise adding alkali liquor (0.2 g of sodium hydroxide, 1.2g of sodium sulfite and 20ml of water), reacting for 1.5 hours at the temperature of 5-15 ℃ after dropwise adding, and sampling and detecting without raw material points. Neutralizing with glacial acetic acid to 6-7, concentrating the system to viscous state, cooling to 0-5 deg.C, crystallizing for 1 hr, filtering, leaching the filter cake with a small amount of methanol, draining, washing with water, draining, and drying at 50-60 deg.C. The weight yield is 91 percent, and the purity is 99.3 percent.
Example 2
Adding 10g of fluocinolone acetonide acetate, 100ml of dichloromethane and 100ml of ethanol into a reaction bottle, stirring for dissolving, cooling to 15-20 ℃, introducing nitrogen for protection, dropwise adding alkali liquor (0.8 g of sodium hydroxide, 1.8g of sodium sulfite and 20ml of water), reacting for 1.5 hours at 15-20 ℃ after dropwise adding, and sampling and detecting without raw material points. Neutralizing with glacial acetic acid to 6-7, concentrating the system to viscous state, cooling to 0-5 deg.C, crystallizing for 1 hr, filtering, leaching the filter cake with a small amount of methanol, draining, washing with water, draining, and drying at 50-60 deg.C. The weight yield is 90%, and the purity is 99.2%.
Example 3
Adding 10g of fluocinolone acetonide acetate, 120ml of dichloromethane and 60ml of methanol into a reaction bottle, stirring for dissolving, cooling to 0-5 ℃, introducing nitrogen for protection, dropwise adding alkali liquor (0.2 g of lithium hydroxide, 1.2g of sodium sulfite and 20ml of water), reacting for 1.5 hours at 0-5 ℃ after dropwise adding, and sampling and detecting without raw material points. Neutralizing with glacial acetic acid to 6-7, concentrating the system to viscous state, cooling to 0 deg.C, crystallizing for 1 hr, filtering, rinsing the filter cake with a small amount of methanol, draining, washing with water, draining, and drying at 50-60 deg.C. The weight yield is 90.5%, and the purity is 99.2%.
Example 4
Adding 10g of fluocinolone acetonide acetate, 80ml of dichloromethane and 140ml of methanol into a reaction bottle, stirring for dissolving, cooling to 5-10 ℃, introducing nitrogen for protection, dropwise adding alkali liquor (0.2 g of sodium hydroxide, 1.0g of sodium sulfite and 20ml of water), reacting for 1.5 hours at the temperature of 5-15 ℃ after dropwise adding, and sampling and detecting without raw material points. Neutralizing with glacial acetic acid to 6-7, concentrating the system to viscous state, cooling to 0-5 deg.C, crystallizing for 1 hr, filtering, leaching the filter cake with a small amount of methanol, draining, washing with water, draining, and drying at 50-60 deg.C. The weight yield is 91%, and the purity is 99.1%.
Example 5
Adding 10g of fluocinolone acetonide acetate, 100ml of dichloromethane and 100ml of methanol into a reaction bottle, stirring for dissolving, cooling to 5-10 ℃, introducing nitrogen for protection, dropwise adding alkali liquor (0.2 g of sodium hydroxide, 2.0g of sodium sulfite and 20ml of water), reacting for 1.5 hours at the temperature of 5-15 ℃ after dropwise adding, and sampling and detecting without raw material points. Neutralizing with glacial acetic acid to 6-7, concentrating the system to viscous state, cooling to 0-5 deg.C, crystallizing for 1 hr, filtering, leaching the filter cake with a small amount of methanol, draining, washing with water, draining, and drying at 50-60 deg.C. The weight yield is 90%, and the purity is 99.3%.
Comparative example 1
Adding 10g of fluocinolone acetonide acetate, 100ml of dichloromethane and 100ml of methanol into a reaction bottle, stirring for dissolving, cooling to 0-5 ℃ (2 ℃ for comparison documents), introducing nitrogen for protection, dropwise adding alkali liquor (0.2 g of sodium hydroxide and 10ml of methanol), keeping the temperature for 2 hours after dropwise adding, and sampling and detecting without raw material points. Neutralizing with glacial acetic acid to 6-7, concentrating the system to viscous state, replacing with 20ml methanol once to viscous state, cooling to 0 deg.C, crystallizing for 1 hr, filtering, leaching the filter cake with a small amount of methanol, pumping, washing with water, pumping, and drying at 50-60 deg.C. The weight yield is 87%, and the purity is 97.5%.
As can be seen from the comparison between the examples of the present application and the comparative example 1, the purity of the product can reach more than 99% by adopting a simple washing, concentrating and drying step, while the purity of the product obtained by the method of the comparative example 1 can only reach 97.5%, and the product purity can meet the requirement only by adopting an additional step for refining, so that the preparation method of the present invention has the advantages of lower cost and higher efficiency.
Claims (8)
1. The preparation method of high-purity fluocinolone acetonide is characterized in that fluocinolone acetonide acetate is mixed with a mixed solution, and the mixture is obtained by hydrolysis reaction, wherein the mixed solution is a mixed solution of sulfite and strong alkali, and the reaction formula is as follows:
the strong base is one or more of sodium hydroxide, potassium hydroxide and lithium hydroxide.
2. The process according to claim 1, wherein the weight ratio of fluocinolone acetonide to sulfite is (5-10): 1.
3. The method according to claim 1 or 2, wherein the weight ratio of fluocinolone acetonide to the strong base is (10-100): 1.
4. The process according to claim 1 or 2, wherein the reaction solvent for the hydrolysis is a mixed solvent of an alcohol solvent and methylene chloride.
5. The method according to claim 4, wherein the alcoholic solvent is methanol.
6. The method according to claim 1 or 2, wherein the temperature of the hydrolysis reaction is 0 to 30 ℃.
7. The method according to claim 6, wherein the temperature of the hydrolysis reaction is 5 to 15 ℃.
8. The preparation method according to claim 1 or 2, wherein after the hydrolysis reaction is completed, the reaction solution is adjusted to pH 6 to 7, concentrated, cooled to 0 to 5 ℃, crystals are precipitated, filtered, washed, and dried to obtain fluocinolone acetonide.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2018037423A1 (en) * | 2016-08-25 | 2018-03-01 | Coral Drugs Pvt. Ltd. | Novel process for preparation of corticosteroids |
| CN108218951A (en) * | 2018-03-06 | 2018-06-29 | 浙江日升昌药业有限公司 | A kind of high-purity fluorine easily preparation method |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2018037423A1 (en) * | 2016-08-25 | 2018-03-01 | Coral Drugs Pvt. Ltd. | Novel process for preparation of corticosteroids |
| CN108218951A (en) * | 2018-03-06 | 2018-06-29 | 浙江日升昌药业有限公司 | A kind of high-purity fluorine easily preparation method |
Non-Patent Citations (1)
| Title |
|---|
| Moon J.Y. et al..Inclusion complex-based solid-phase extraction of steroidal compounds with entrapped β-cyclodextrin polymer.《Steroids》.2008, * |
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