CN113666985A - Preparation method of triamcinolone acetonide - Google Patents
Preparation method of triamcinolone acetonide Download PDFInfo
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- CN113666985A CN113666985A CN202111230099.0A CN202111230099A CN113666985A CN 113666985 A CN113666985 A CN 113666985A CN 202111230099 A CN202111230099 A CN 202111230099A CN 113666985 A CN113666985 A CN 113666985A
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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
Abstract
The invention belongs to the technical field of medicine synthesis, and particularly relates to a preparation method of triamcinolone acetonide. According to the invention, the epoxy compound I is taken as a raw material, dichloromethane is taken as a solvent, a 70% pyridine hydrofluoric acid solution is taken as a fluorination reagent, and then hydrolysis is carried out in a sodium carbonate aqueous solution, so that the consumption of hydrofluoric acid is reduced, the reaction conditions are simplified, the reaction steps are optimized, the reaction under the fluoridation condition is mild, nitrogen protection is omitted, the reaction is easier to operate, the harm to personnel and energy consumption are reduced, and the pollution to the environment is reduced.
Description
Technical Field
The invention belongs to the technical field of medicine synthesis, and particularly relates to a preparation method of triamcinolone acetonide.
Background
The chemical name of triamcinolone acetonide is: the 9-fluoro-11 beta, 21-dihydroxy-16 alpha, 17- [ (1-methylethylidene) bis (oxy) ] -pregna-1, 4-diene-3, 20-dione is a high-efficiency fluorine-containing corticosteroid, has the similar effect to triamcinolone, has the effects of resisting inflammation, resisting pruritus, contracting blood vessels and the like, has weak water-sodium retention effect, has stronger and longer lasting anti-inflammation and anti-allergy effects than hydrocortisone (10-30 times) and prednisone, and has strong and longer effect in treating bronchial asthma by aerosol inhalation. Has better curative effect on local action than triamcinolone. The chemical structural formula is as follows:
the traditional triamcinolone acetonide production process comprises the steps of carrying out fluoridation reaction at-30 to-25 ℃ by taking fluoridated acid as a reaction solvent, slowly adding reaction liquid into a prepared potassium carbonate solution after the reaction is finished, adjusting the pH value to 7.0-7.5, filtering and discharging, and drying to obtain triamcinolone acetonide acetate. And (3) putting the triamcinolone acetonide into a methanol and dichloromethane system, and hydrolyzing under the protection of inert gas to obtain the triamcinolone acetonide. The route is as follows:
the synthetic method has the defects of large amount of used hydrofluoric acid, complex treatment after reaction, great harm to environment and people, low quality and yield of reactants and high energy consumption. The hydrolysis needs to be finished under the protection of inert gas, has higher requirements on using equipment and is not easy to operate.
Disclosure of Invention
Aiming at the problems, the invention provides a preparation method of triamcinolone acetonide, which reduces the consumption of hydrofluoric acid, enables the reaction to be more operable, reduces the harm and energy consumption to personnel, reduces the pollution to the environment, enables the reaction under the fluoridation condition to be mild, improves the yield, and controls the cost in a phase-changing manner.
The invention relates to a preparation method of triamcinolone acetonide, which comprises the following reaction route:
the method comprises the following specific steps:
(1) adding a compound I into an organic solvent, dropwise adding a pyridine hydrofluoric acid solution at-5-0 ℃, keeping the temperature at 0-5 ℃ for reaction after the dropwise adding is finished, and obtaining a reaction solution after the reaction is finished;
(2) pouring the reaction solution into ice water for quenching, controlling the temperature to be below 10 ℃, dropwise adding an alkaline solution, adjusting the pH of the solution to be =7-8, and separating the solution to obtain an organic phase;
(3) cooling the organic phase, keeping the temperature at 0-5 ℃, dropwise adding a sodium carbonate aqueous solution into the organic phase, reacting at 5-10 ℃ after dropwise adding, controlling the temperature to be below 10 ℃ after the reaction is finished, dropwise adding glacial acetic acid into the organic phase to adjust the pH to be =7-8, concentrating under reduced pressure, cooling to 30 ℃ after the concentration is finished, adding water into the concentrate, stirring, filtering, and drying to obtain a triamcinolone acetonide wet product;
(4) adding the triamcinolone acetonide wet product into a reaction bottle, adding ethanol, heating to 75-80 ℃, stirring, performing suction filtration, cooling the mother solution to 25-30 ℃, continuing stirring for crystallization, filtering, and drying to obtain the triamcinolone acetonide.
The organic solvent in the step (1) is dichloromethane; the mass-to-volume ratio of the compound I to the organic solvent is 1 g: 3-5 ml.
The mass fraction of the pyridine hydrofluoric acid solution in the step (1) is 70%, and the mass-volume ratio of the compound I to the pyridine hydrofluoric acid solution is 1 g: 3-5 ml.
In the step (2), the alkaline solution is a sodium hydroxide aqueous solution, and the mass fraction of the alkaline solution is 10%.
The mass fraction of the sodium carbonate aqueous solution in the step (3) is 10%, and the sodium carbonate is calculated by the molar ratio of pure substances: compound I =1.5-2: 1.
And (3) when water is added into the concentrate in the step (3), the mass of the water is 10-15 times of that of the compound I.
In the step (4), the mass of the ethanol is 5-8 times of that of the compound I. The ethanol is absolute ethanol.
Compared with the prior art, the invention has the following beneficial effects:
(1) compared with anhydrous hydrogen fluoride, the method has better selectivity by adopting 70% pyridine hydrofluoric acid solution;
(2) the invention changes the condition that hydrofluoric acid is a solvent and a reactant into a common solvent of dichloromethane, and dichloromethane has better solubility, so that the fluoride is dissolved in dichloromethane and can be directly used for the next step, the reaction condition is simplified, and the reaction step is optimized;
(3) the nitrogen protection is to prevent the reaction from being oxidized under the strong alkali condition, and the alkali of the sodium carbonate is much weaker than that of the sodium hydroxide under the same concentration and is not easy to be oxidized.
Detailed Description
Example 1
A preparation method of triamcinolone acetonide comprises the following steps:
the method comprises the following specific steps:
(1) adding a compound I (10 g) into an organic solvent, dropwise adding a pyridine hydrofluoric acid solution at-5 ℃, keeping the temperature at 0 ℃ for reaction after the dropwise adding is finished, and obtaining a reaction solution after the reaction is finished;
(2) pouring the reaction solution into ice water for quenching, controlling the temperature to be below 10 ℃, dropwise adding an alkaline solution, adjusting the pH of the solution to be =7, and separating the solution to obtain an organic phase;
(3) cooling the organic phase, keeping the temperature at 0 ℃, dropwise adding a sodium carbonate aqueous solution into the organic phase, reacting at 5 ℃, controlling the temperature to be below 10 ℃ after the reaction is finished, dropwise adding glacial acetic acid into the organic phase to adjust the pH to be =8, concentrating under reduced pressure, cooling to 30 ℃ after the concentration is finished, adding water into the concentrate, stirring, filtering, and drying to obtain a triamcinolone acetonide wet product;
(4) adding the triamcinolone acetonide wet product into a reaction bottle, adding ethanol, heating to 75 ℃, stirring, performing suction filtration, cooling the mother solution to 30 ℃, continuing stirring for crystallization, filtering, and drying to obtain 9.02g of triamcinolone acetonide, wherein the yield is 94.8% and the purity is 99.82%.
The organic solvent in the step (1) is dichloromethane; the mass-to-volume ratio of the compound I to the organic solvent is 1 g: 4 ml.
The mass fraction of the pyridine hydrofluoric acid solution in the step (1) is 70%, and the mass-volume ratio of the compound I to the pyridine hydrofluoric acid solution is 1 g: 4 ml.
In the step (2), the alkaline solution is a sodium hydroxide aqueous solution, and the mass fraction of the alkaline solution is 10%.
The mass fraction of the sodium carbonate aqueous solution in the step (3) is 10%, and the sodium carbonate is calculated by the molar ratio of pure substances: compound I =1.5: 1.
When water is added to the concentrate in step (3), the mass of water is 15 times that of the compound I.
The mass of the ethanol in the step (4) is 6.5 times of that of the compound I.
Example 2
A method for preparing triamcinolone acetonide, the route of which is the same as that in example 1.
The method comprises the following specific steps:
(1) adding a compound I (10 g) into an organic solvent, dropwise adding a pyridine hydrofluoric acid solution at 0 ℃, keeping the temperature at 0 ℃ for reaction after the dropwise adding is finished, and obtaining a reaction solution after the reaction is finished;
(2) pouring the reaction solution into ice water for quenching, controlling the temperature to be below 10 ℃, dropwise adding an alkaline solution, adjusting the pH of the solution to be =8, and separating the solution to obtain an organic phase;
(3) cooling the organic phase, keeping the temperature at 5 ℃, dropwise adding a sodium carbonate aqueous solution into the organic phase, reacting at 10 ℃, controlling the temperature to be below 10 ℃ after the reaction is finished, dropwise adding glacial acetic acid into the organic phase to adjust the pH to be =7, concentrating under reduced pressure, cooling to 30 ℃ after the concentration is finished, adding water into the concentrate, stirring, filtering, and drying to obtain a triamcinolone acetonide wet product;
(4) adding the triamcinolone acetonide wet product into a reaction bottle, adding ethanol, heating to 80 ℃, stirring, performing suction filtration, cooling the mother solution to 25 ℃, continuing stirring for crystallization, filtering, and drying to obtain 8.84g of triamcinolone acetonide, wherein the yield is 92.9 percent and the purity is 99.6 percent.
The organic solvent in the step (1) is dichloromethane; the mass-to-volume ratio of the compound I to the organic solvent is 1 g: 3 ml.
The mass fraction of the pyridine hydrofluoric acid solution in the step (1) is 70%, and the mass-volume ratio of the compound I to the pyridine hydrofluoric acid solution is 1 g: 3 ml.
In the step (2), the alkaline solution is a sodium hydroxide aqueous solution, and the mass fraction of the alkaline solution is 10%.
The mass fraction of the sodium carbonate aqueous solution in the step (3) is 10%, and the sodium carbonate is calculated by the molar ratio of pure substances: compound I =2: 1.
When water is added to the concentrate in the step (3), the mass of the water is 10 times of that of the compound I.
The mass of the ethanol in the step (4) is 5 times of that of the compound I.
Example 3
A method for preparing triamcinolone acetonide, the route of which is the same as that in example 1.
The method comprises the following specific steps:
(1) adding a compound I (10 g) into an organic solvent, dropwise adding a pyridine hydrofluoric acid solution into the organic solvent at-3 ℃, keeping the temperature at 5 ℃ for reaction after the dropwise adding is finished, and obtaining a reaction solution after the reaction is finished;
(2) pouring the reaction solution into ice water for quenching, controlling the temperature to be below 10 ℃, dropwise adding an alkaline solution, adjusting the pH of the solution to be =7, and separating the solution to obtain an organic phase;
(3) cooling the organic phase, keeping the temperature at 3 ℃, dropwise adding a sodium carbonate aqueous solution into the organic phase, reacting at 7 ℃, controlling the temperature to be below 10 ℃ after the reaction is finished, dropwise adding glacial acetic acid into the organic phase to adjust the pH to be =7.5, concentrating under reduced pressure, cooling to 30 ℃ after the concentration is finished, adding water into the concentrate, stirring, filtering, and pumping to dry to obtain a triamcinolone acetonide wet product;
(4) adding the triamcinolone acetonide wet product into a reaction bottle, adding ethanol, heating to 78 ℃, stirring, performing suction filtration, cooling the mother solution to 27 ℃, continuing stirring for crystallization, filtering, and drying to obtain 8.92g of triamcinolone acetonide, wherein the yield is 93.7% and the purity is 99.86%.
The organic solvent in the step (1) is dichloromethane; the mass-to-volume ratio of the compound I to the organic solvent is 1 g: 5 ml.
The mass fraction of the pyridine hydrofluoric acid solution in the step (1) is 70%, and the mass-volume ratio of the compound I to the pyridine hydrofluoric acid solution is 1 g: 5 ml.
In the step (2), the alkaline solution is a sodium hydroxide aqueous solution, and the mass fraction of the alkaline solution is 10%.
The mass fraction of the sodium carbonate aqueous solution in the step (3) is 10%, and the sodium carbonate is calculated by the molar ratio of pure substances: compound I =1.8: 1.
When water was added to the concentrate in step (3), the mass of water was 12 times the mass of compound I.
The mass of the ethanol in the step (4) is 8 times of that of the compound I.
Example 4
The compounds I described herein were prepared using the following route:
the method comprises the following specific steps:
preparation of intermediate B
1. 40kg of tetraene acetate A (purchased under CAS number: 37413-91-5) is manually added into a 1500L enamel reaction kettle, 400kg of acetone, 15kg of formic acid and 100kg of purified water are pumped into the reaction kettle through a closed pipeline by a pneumatic pump, the temperature of jacket brine is indirectly reduced to 5 ℃, then 20kg of potassium permanganate solid is manually added into the enamel reaction kettle, and oxidation reaction is carried out under normal pressure for 60 min.
TLC (thin-layer chromatography) was used to monitor the oxidation reaction, and after completion of the reaction, 100kg of tetrahydrofuran was pumped into a 1500L enamel reactor by a pneumatic pump and stirred at room temperature and normal pressure for 30 min. Then opening a kettle bottom valve, transferring the feed liquid into a 50L sealed centrifuge through a sealed pipeline, performing centrifugal separation, and keeping filtrate (water phase and solvent phase are mutually soluble).
3. Transferring the centrifuged filtrate into a 500L enamel reaction kettle through a closed pipeline for concentration, heating jacket steam to 50 ℃, concentrating under vacuum negative pressure (vacuum degree of-0.085 kPa to-0.1 kPa) for 2h until no liquid is evaporated, condensing by a condenser matched with the reaction kettle (the evaporation rate is 99%, the tetrahydrofuran condensation efficiency is 92%, and the acetone condensation efficiency is 95%), cooling by primary common water to 0 ℃, and removing tetrahydrofuran and acetone in the filtrate. And pumping the concentrated feed liquid into a 50L sealed centrifuge through a sealed pipeline for centrifugal separation, and keeping solids to obtain an intermediate B crude product.
4. Manually transferring the concentrated intermediate B crude product to a 500L enamel reaction kettle, pumping 100kg methanol into the reaction kettle by using a pneumatic pump for recrystallization, heating jacket steam to 50 ℃, stirring at normal pressure for 2 hours, indirectly cooling jacket salt water to 20 ℃, stirring for 1 hour, pumping the stirred feed liquid into a 50L sealed centrifuge through a sealed pipeline for centrifugal separation, and obtaining an intermediate B wet product.
5. Transferring the wet intermediate B product to a vacuum drying oven, electrically heating, vacuum drying at 50 deg.C for 12h, and drying to obtain 20kg intermediate B white powder product.
Preparation of Compound I
1. Manually adding 20kg of white powdery intermediate B into a 500L enamel reaction kettle, pumping 200kg of acetone and 5kg of 70% perchloric acid solution into the reaction kettle through a closed pipeline by using a pneumatic pump, starting stirring at room temperature, and carrying out ketalization reaction at normal pressure for 1 h.
And 2, monitoring the reaction by TLC, pumping 60kg of purified water into a 500L enamel reaction kettle after the reaction is finished, then manually adding 5kg of powdered bromosuccinimide (NBS), starting stirring at room temperature, carrying out bromination addition reaction at normal pressure, and reacting for 3 h.
Monitoring the reaction by TLC, after the reaction is finished, adding 27.5kg of prepared sodium hydroxide solution (sodium hydroxide: water =1:10, mass ratio) into a 500L enamel reaction kettle, starting stirring at room temperature, and carrying out bromination addition reaction at normal pressure for 3 h.
And 4, monitoring the reaction by TLC, adding 2.145kg of glacial acetic acid into a 500L enamel reaction kettle after the reaction is finished, adjusting the pH to be neutral, concentrating, heating jacket steam to 50 ℃, concentrating for 2h under vacuum negative pressure (vacuum degree is-0.085 kPa to-0.1 kPa) until no liquid is evaporated out, condensing by a condenser matched with the reaction kettle (the evaporation rate is 99 percent, the acetone condensation efficiency is 95 percent), and removing the acetone by adopting primary common water cooling at 0 ℃. And pumping the concentrated suspension into a 50L sealed centrifuge through a sealed pipeline for centrifugal separation, and retaining solids to obtain a crude product of the compound I.
5. Manually transferring the crude product of the compound I to a 500L enamel reaction kettle, pumping 100kg of methanol into the reaction kettle by using a pneumatic pump for recrystallization, heating jacket steam to 50 ℃, stirring at normal pressure for 2 hours, indirectly cooling jacket salt water to 20 ℃, stirring for 1 hour, and pumping the stirred feed liquid into a 50L sealed centrifuge through a sealed pipeline for centrifugal separation to obtain a wet product of the compound I.
6. Transferring the wet product of the compound I into a vacuum drying oven, electrically heating, vacuum drying at 50 ℃ for 12h, and drying to obtain 10kg of a white powdery product of the compound I.
Claims (9)
1. The preparation method of triamcinolone acetonide is characterized by comprising the following reaction route:
2. the preparation method of triamcinolone acetonide according to claim 1, characterized by comprising the following specific steps:
(1) adding a compound I into an organic solvent, dropwise adding a pyridine hydrofluoric acid solution at-5-0 ℃, keeping the temperature at 0-5 ℃ for reaction after the dropwise adding is finished, and obtaining a reaction solution after the reaction is finished;
(2) pouring the reaction solution into ice water for quenching, controlling the temperature to be below 10 ℃, dropwise adding an alkaline solution, adjusting the pH of the solution to be =7-8, and separating the solution to obtain an organic phase;
(3) cooling the organic phase, keeping the temperature at 0-5 ℃, dropwise adding a sodium carbonate aqueous solution into the organic phase, reacting at 5-10 ℃ after dropwise adding, controlling the temperature to be below 10 ℃ after the reaction is finished, dropwise adding glacial acetic acid into the organic phase to adjust the pH to be =7-8, concentrating under reduced pressure, cooling to 30 ℃ after the concentration is finished, adding water into the concentrate, stirring, filtering, and drying to obtain a triamcinolone acetonide wet product;
(4) adding the triamcinolone acetonide wet product into a reaction bottle, adding ethanol, heating to 75-80 ℃, stirring, performing suction filtration, cooling the mother solution to 25-30 ℃, continuing stirring for crystallization, filtering, and drying to obtain the triamcinolone acetonide.
3. A preparation method of triamcinolone acetonide according to claim 2, wherein the organic solvent in step (1) is dichloromethane; the mass-to-volume ratio of the compound I to the organic solvent is 1 g: 3-5 ml.
4. A preparation method of triamcinolone acetonide according to claim 2, wherein the pyridine hydrofluoric acid solution in the step (1) has a mass fraction of 70%, and the mass-to-volume ratio of the compound I to the pyridine hydrofluoric acid solution is 1 g: 3-5 ml.
5. A preparation method of triamcinolone acetonide according to claim 2, characterized in that the alkaline solution in step (2) is an aqueous sodium hydroxide solution with a mass fraction of 10%.
6. A method for preparing triamcinolone acetonide according to claim 2, wherein the mass fraction of the sodium carbonate aqueous solution in step (3) is 10%, and the ratio of sodium carbonate to sodium carbonate in terms of pure substance is, in terms of mole ratio: compound I =1.5-2: 1.
7. A method for preparing triamcinolone acetonide according to claim 2, wherein the mass of water added to the concentrate in step (3) is 10-15 times the mass of compound I.
8. A preparation method of triamcinolone acetonide according to claim 2, characterized in that the mass of ethanol in step (4) is 5-8 times of the mass of compound I.
9. The method for preparing triamcinolone acetonide according to claim 2, wherein the synthetic route of the compound I is as follows:
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115322243A (en) * | 2022-09-20 | 2022-11-11 | 山东赛托生物科技股份有限公司 | Method for preparing triamcinolone acetonide key intermediate by one-pot method |
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| CN111954525A (en) * | 2018-04-02 | 2020-11-17 | 凯莫森特里克斯股份有限公司 | Prodrugs of fused bicyclic C5aR antagonists |
| CN112142821A (en) * | 2019-06-29 | 2020-12-29 | 天津药业研究院股份有限公司 | Synthesis method and application of 9-fluoro steroid compound |
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Patent Citations (5)
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| CN102863505A (en) * | 2012-10-22 | 2013-01-09 | 宝鸡康乐生物科技有限公司 | Process for synthesizing triamcinolone acetonide acetate |
| CN107778345A (en) * | 2016-08-30 | 2018-03-09 | 天津太平洋制药有限公司 | A kind of preparation method of triamcinolone acetonide acetate |
| CN106632561A (en) * | 2016-12-16 | 2017-05-10 | 广州仁恒医药科技股份有限公司 | Method for preparing difluprednate |
| CN111954525A (en) * | 2018-04-02 | 2020-11-17 | 凯莫森特里克斯股份有限公司 | Prodrugs of fused bicyclic C5aR antagonists |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN115322243A (en) * | 2022-09-20 | 2022-11-11 | 山东赛托生物科技股份有限公司 | Method for preparing triamcinolone acetonide key intermediate by one-pot method |
| CN115322243B (en) * | 2022-09-20 | 2023-10-03 | 山东赛托生物科技股份有限公司 | Method for preparing triamcinolone acetonide key intermediate by one-pot method |
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