Process for the preparation of hydrocortisone impurity L
Hydrocortisone impurity L was prepared by etherification, oxidation, reduction and photocatalytic oxidation reactions, which solved the problem of using highly toxic substances in the existing technology and realized a safe and efficient synthesis route suitable for industrial production.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Patents(China)
- Current Assignee / Owner
- TIANJIN PHARMA GROUP CORP
- Filing Date
- 2021-03-31
- Publication Date
- 2026-08-04
AI Technical Summary
Existing synthetic routes for hydrocortisone impurity L use highly toxic tributyltin hydride, which pollutes the environment and involves dangerous reaction conditions, making it difficult to achieve safe and efficient industrial production.
Using progesterone as a raw material, hydrocortisone impurity L is prepared through etherification, oxidation, reduction, 11-α-hydroxyl conversion and photocatalytic oxidation reactions. Photocatalysts such as TiO2, Nb2O5, ZnO, and CdS are used to avoid highly toxic substances. Bio-fermentation and mild conditions are employed to achieve high-purity synthesis.
It provides a safe and environmentally friendly synthesis route, avoiding the use of highly toxic substances, and the product has high purity, making it suitable for industrial production.
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Abstract
Description
Technical Field
[0001] This invention relates to the field of chemical synthesis technology, and in particular to a method for preparing hydrocortisone impurity L. Background Technology
[0002] Hydrocortisone is a class of adrenocortical hormones that can affect glucose metabolism in the body. It has a wide range of clinical applications. In addition to being used to treat adrenocortical insufficiency, it also has a certain alleviating effect on diseases such as rheumatoid arthritis, gout, chronic nephritis, and systemic lupus erythematosus.
[0003] In the research of active pharmaceutical ingredients (APIs), impurities are essential for the establishment of analytical methods. Impurity reference standards are needed to control the quality of impurities in the API to ensure that the prepared product meets pharmaceutical requirements and can then be used to prepare safe and effective drug formulations. 21-Deoxycortisol, an impurity L in the European Pharmacopoeia (EP) for hydrocortisone, can be used for the qualitative and quantitative analysis of impurities in hydrocortisone, thereby improving the quality standards of hydrocortisone. Therefore, the synthesis of impurity L is of great significance.
[0004] Currently reported synthetic routes mainly use 17-hydroxy-4,9-dienepregn-3,20-dione as a starting material, which is obtained through bromination and debromination. The reaction route is as follows:
[0005]
[0006] This route requires the use of tributyltin hydride, which is highly toxic and easily pollutes the environment.
[0007] In view of this, the present invention is hereby proposed. Summary of the Invention
[0008] The main objective of this invention is to provide a method for preparing hydrocortisone impurity L, in order to at least partially solve at least one of the above-mentioned technical problems.
[0009] This invention provides a method for preparing hydrocortisone impurity L, characterized by comprising the following steps:
[0010] (a) Progesterone was etherified to give intermediate 1;
[0011] (b) Intermediate 1 undergoes oxidation and reduction reactions to obtain intermediate 2;
[0012] (c) Intermediate 2 is converted by the α-hydroxyl group at position 11 to obtain intermediate 3;
[0013] (d) Intermediate 3 undergoes an α-hydroxyl oxidation reaction at position 11 under photocatalysis, oxygen-containing gas and light irradiation to obtain intermediate 4;
[0014] (e) Intermediate 4 is reduced to give hydrocortisone impurity L; the reaction formula is as follows:
[0015] In the intermediate 1, R is selected from C1-C6 alkyl groups.
[0016] Further steps include the following:
[0017] (a) Progesterone reacts with an etherifying agent under the action of an acidic catalyst to give intermediate 1;
[0018] (b) Intermediate 1 reacts with oxygen-containing gas under the action of an alkaline reagent, and is then reduced by a reducing agent to obtain intermediate 2;
[0019] (c) Intermediate 2 is fermented to obtain intermediate 3;
[0020] (d) Intermediate 3 undergoes an α-hydroxyl oxidation reaction at position 11 under photocatalysis, oxygen-containing gas and light irradiation to obtain intermediate 4;
[0021] (e) Intermediate 4 is reduced by a reducing agent to obtain hydrocortisone impurity L.
[0022] Furthermore, in step (a), the acidic catalyst is selected from p-toluenesulfonic acid or pyridine hydrobromide; the etherifying agent is selected from triethyl orthoformate or trimethyl orthoacetate.
[0023] Furthermore, in step (b), the alkaline reagent is selected from one or a combination of several of potassium tert-butoxide, sodium methoxide, sodium ethoxide, sodium hydrogen hydrate, or sodium tert-butoxide; the reducing agent is selected from one or a combination of several of sodium sulfite, sodium bisulfite, triethyl phosphite, or trimethyl phosphite.
[0024] Furthermore, in step (b), the alkaline reagent is selected from potassium tert-butoxide or sodium methoxide; the reducing agent is selected from triethyl phosphite or trimethyl phosphite.
[0025] Furthermore, in step (c), the bio-fermentation is carried out by co-fermentation of Aspergillus ochraceus and Arthrobacter simplex AS1.94.
[0026] Furthermore, in step (d), the photocatalyst is selected from one or a combination of several of TiO2, Nb2O5, ZnO, CdS or Bi2MoO6; the light wavelength is 250-400nm.
[0027] Furthermore, the photocatalyst is nanoscale, with a particle size of 5-20 nm and a specific surface area of 100-200 m². 2 g -1 .
[0028] Furthermore, in step (d), the photocatalyst is selected from one or a combination of several of TiO2, Nb2O5, or CdS; the illumination wavelength is 365 nm.
[0029] Furthermore, in step (d), a soluble silver salt is also added.
[0030] Furthermore, in step (d), the soluble silver salt is selected from silver nitrate.
[0031] Furthermore, the illumination is provided by a mercury lamp.
[0032] Furthermore, in step (d), the molar ratio of intermediate 3 to photocatalyst is (8-12):1.
[0033] Furthermore, in step (e), the reducing agent is selected from sodium borohydride or potassium borohydride.
[0034] Compared with the prior art, the present invention has the following beneficial effects:
[0035] The present invention provides a method for preparing hydrocortisone impurity L, using progesterone as a raw material, through a series of reactions including etherification, oxidation and reduction, conversion of the 11-position α-hydroxyl group, and oxidation and reduction of the 11-position α-hydroxyl group to obtain hydrocortisone impurity L. In the 11-position α-hydroxyl oxidation reaction, the present invention uses photocatalysis to oxidize the hydroxyl group at the 11-position of the steroid compound to a ketone group. The photocatalytic oxidation utilizes holes generated after semiconductor excitation as a strong oxidant to capture electrons from the organic compound, thereby completing the oxidation. The entire reaction route of the present invention is novel, the raw materials are readily available, the reaction conditions are mild, and dangerous operations such as the use of highly toxic substances and gases are avoided. The product has few impurities, high purity, and can be industrialized. Detailed Implementation
[0036] The embodiments of the present invention will be described in detail below with reference to examples. However, those skilled in the art will understand that the following examples are for illustrative purposes only and should not be considered as limiting the scope of the invention. Unless otherwise specified, specific conditions were applied in the examples. Reagents or instruments used, unless otherwise specified, are all commercially available products.
[0037] Example 1
[0038] Example 1-1
[0039]
[0040] 50.0 g of progesterone and 300 mL of ethanol were added to a reaction flask and stirred at room temperature. 0.5 g of p-toluenesulfonic acid monohydrate was added, and the mixture was stirred and cooled to 0 °C. 28.3 g of triethyl orthoformate was added dropwise. After the addition was complete, the mixture was kept at the same temperature and stirred. TLC monitoring showed no further progesterone. The reaction solution was slowly poured into a beaker containing 400 mL of 5% sodium hydroxide solution, washed with 200 mL of water, filtered, and dried to obtain 42.3 g of an off-white solid, which was intermediate 1-1, with a yield of 84.6%.
[0041] Examples 1-2
[0042]
[0043] 50.0 g of progesterone and 500 mL of methanol were added to a reaction flask and stirred at room temperature. 0.4 g of pyridine hydrobromide was added, and the mixture was stirred and cooled to 3°C. 27.5 g of trimethyl orthoacetate was added dropwise. After the addition was complete, the mixture was kept at the same temperature and stirred. TLC monitoring showed no further progesterone. The reaction mixture was slowly poured into a beaker containing 500 mL of 5% potassium hydroxide solution, washed with 200 mL of water, filtered, and dried to obtain 40.0 g of an off-white solid, which is intermediate 1-2, with a yield of 80.0%.
[0044] Example 2
[0045] Example 2-1
[0046]
[0047] 200 mL of tetrahydrofuran and 13.0 g of potassium tert-butoxide were added to a reaction flask and stirred at room temperature. 19.4 g of triethyl phosphite was added, the mixture was cooled in an ice-water bath, air was bubbled in, and 20.0 g of intermediate 1-1 was added and the mixture was stirred until no intermediate 1-1 was detected by TLC. 40 mL of 6N hydrochloric acid was added to the reaction mixture, and the reaction was continued until complete as detected by TLC. 500 mL of water was added to the reaction mixture, and the mixture was cooled in an ice-water bath with stirring. The mixture was filtered, washed, vacuum filtered, and dried to obtain 18.0 g of intermediate 2, with a yield of 90.0%.
[0048] Example 2-2
[0049]
[0050] 180 mL of ethanol and 6.8 g of sodium methoxide were added to a reaction flask and stirred at room temperature. 15.8 g of trimethyl phosphite was added, the mixture was cooled with an ice bath, air was bubbled in, and 20.0 g of intermediate 1-2 was added. The mixture was stirred and monitored by TLC until no intermediate 1-2 was detected. 50 mL of 5N hydrochloric acid was added to the reaction mixture, and the mixture was stirred at room temperature until the reaction was complete as confirmed by TLC. 400 mL of water was added to the reaction mixture, and the mixture was cooled and stirred in an ice-water bath. The mixture was filtered, washed, vacuum filtered, and dried to obtain 17.6 g of intermediate 2, with a yield of approximately 88.0%.
[0051] Example 3
[0052]
[0053] Add 30.0g of intermediate 2 to 1L of water as the fermentation substrate. The fermentation medium components are: 15.0g glucose, 5.0g silkworm pupa powder, 30.0g corn steep liquor, 1.0g ammonium sulfate, 2.0g potassium dihydrogen phosphate, 5.0g sodium dihydrogen phosphate, and 0.4g bubbly inhibitor. Adjust the pH to 6.0. *Arthrobacter simplex* AS1.94 was cultured in a secondary culture. After 24h of primary seed culture, it was inoculated into the secondary seed medium at a 10% inoculum. After 22h of secondary culture, it was inoculated into the above fermentation medium at a 15% inoculum. *Aspergillus ochraceus* was cultured as a primary seed for 24h and then inoculated into the above fermentation medium at a 30% inoculum. A 5L fermenter was used for conversion, with a liquid volume of 80%, a pressure of 0.05MPa, and an air flow rate of 40m³. 3 / hr, temperature 28℃, stirring 180rpm, TLC monitoring until complete conversion, extraction with ethyl acetate, inactivation of fermentation broth at 85℃, cooling to room temperature, filtration, extraction of filter cake with ethyl acetate, concentration, drying, to obtain white crystals, which is intermediate 3, yield 88.5%.
[0054] Example 4
[0055]
[0056] Example 4-1
[0057] At room temperature, add 600 mL of acetone, 50.0 g of intermediate 3, and 1.0 g of TiO2 (particle size 15 nm, specific surface area 150 m²) to a reaction flask. 2 g -1 0.10 g of silver nitrate was added to the reaction flask, oxygen was introduced and stirred, and the reaction was carried out under the irradiation of a medium-pressure mercury lamp with a wavelength of 365 nm. TLC monitoring showed no intermediate 3. After the reaction was completed, the reaction solution was filtered, the filtrate was concentrated under reduced pressure to about 50 mL, diluted in 20 times water, filtered, washed and dried to obtain 49.0 g of intermediate 4, with a yield of 98%.
[0058] Example 4-2
[0059] At room temperature, add 500 mL of dichloromethane, 50.0 g of intermediate 3, and 4.0 g of Nb₂O₅ (particle size 5 nm, specific surface area 200 m²) to a reaction flask. 2 g -10.12 g of silver nitrate and oxygen were continuously introduced into the reaction flask and stirred. The reaction was carried out under the illumination of a medium-pressure mercury lamp with a wavelength of 250 nm. TLC monitoring showed no intermediate 3. After the reaction was completed, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure to about 50 mL. It was then diluted with 22 times the amount of water, filtered, washed, and dried to obtain 49.1 g of intermediate 4, with a yield of 98.2%.
[0060] Example 4-3
[0061] At room temperature, add 700 mL of tetrahydrofuran, 50 g of intermediate 3, and 1.8 g of CdS (particle size 20 nm, specific surface area 100 m²) to a reaction flask. 2 g -1 Oxygen was introduced into the reaction flask and stirred. The reaction was carried out under the illumination of a medium-pressure mercury lamp with a wavelength of 400 nm. TLC monitoring showed no intermediate 3. After the reaction was completed, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure to about 55 mL. It was then diluted with 18 times the amount of water, filtered, washed, and dried to obtain 47.5 g of intermediate 4, with a yield of 95%.
[0062] Example 5
[0063]
[0064] Example 5-1
[0065] 300 ml of methanol and 30.0 g of intermediate 4 were added to a reaction flask. The temperature was controlled at -5 °C. 3.6 g of sodium borohydride was added in portions. After the addition was complete, the temperature was raised to reflux. TLC monitoring showed no intermediate 4. Saturated sodium sulfate solution was added, followed by a large amount of anhydrous sodium sulfate for drying. The mixture was filtered, and the filtrate was extracted with ethyl acetate. The organic phase was concentrated, and then n-heptane was added. The mixture was filtered and dried to obtain a white solid, which was 24.0 g of hydrocortisone impurity L, with a yield of 80.0%.
[0066] Example 5-2
[0067] 350 ml of methanol and 30.0 g of intermediate 4 were added to a reaction flask. The temperature was controlled at -2 °C. 5.1 g of potassium borohydride was added in portions. After the addition was complete, the temperature was raised to reflux. TLC monitoring showed no intermediate 4. Saturated sodium sulfate solution was added, followed by a large amount of anhydrous sodium sulfate for drying. The mixture was filtered, and the filtrate was extracted with ethyl acetate. The organic phase was concentrated, and then n-heptane was added. The mixture was filtered and dried to obtain a white solid, which was 22.8 g of hydrocortisone impurity L, with a yield of 76.0%.
[0068] Example 5-3
[0069] 300 ml of tetrahydrofuran and 30.0 g of intermediate 4 were added to a reaction flask. The temperature was controlled at -4 °C. 10.2 g of lithium aluminum hydride was added in portions. After the addition was complete, the temperature was raised to reflux. TLC monitoring showed no intermediate 4. Saturated sodium sulfate solution was added, followed by a large amount of anhydrous sodium sulfate for drying. The mixture was filtered, and the filtrate was extracted with ethyl acetate. The organic phase was concentrated, and then n-heptane was added. The mixture was filtered and dried to obtain a white solid, which was 23.0 g of hydrocortisone impurity L, with a yield of approximately 76.7%.
[0070] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, and not to limit them; although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art should understand that modifications can still be made to the technical solutions described in the foregoing embodiments, or equivalent substitutions can be made to some or all of the technical features; and these modifications or substitutions do not cause the essence of the corresponding technical solutions to deviate from the scope of the technical solutions of the embodiments of the present invention.
Claims
1. A method for preparing hydrocortisone impurity L, characterized in that, Includes the following steps: (a) Progesterone reacts with an etherifying agent under the action of an acidic catalyst to give intermediate 1; (b) Intermediate 1 reacts with oxygen-containing gas under the action of an alkaline reagent, and is then reduced by a reducing agent to obtain intermediate 2; (c) Intermediate 2 is fermented to obtain intermediate 3; (d) Intermediate 3 undergoes an 11-position α-hydroxyl oxidation reaction under photocatalysis, oxygen-containing gas, and light irradiation to obtain intermediate 4; (e) Intermediate 4 is reduced to give hydrocortisone impurity L; the reaction formula is as follows: ； R in intermediate 1 is selected from C1-C6 alkyl groups; In step (a), the acidic catalyst is selected from p-toluenesulfonic acid or pyridine hydrobromide; the etherifying agent is selected from triethyl orthoformate or trimethyl orthoacetate. In step (b), the alkaline reagent is selected from one or a combination of several of potassium tert-butoxide, sodium methoxide, sodium ethoxide, sodium hydrogen hydride, or sodium tert-butoxide; the reducing agent is selected from one or a combination of several of triethyl phosphite or trimethyl phosphite. In step (c), the bio-fermentation is carried out by co-fermentation of Aspergillus ochraceus and Arthrobacter simplex AS1.94; In step (d), the photocatalyst is selected from one or a combination of several of TiO2, Nb2O5, and CdS; a soluble silver salt is also added; and the wavelength of the light irradiation is 250-400 nm.
2. The method for preparing hydrocortisone impurity L according to claim 1, characterized in that: In step (d), the photocatalyst is nanoscale, with a particle size of 5-20 nm and a specific surface area of 100-200 m². 2 g -1 .
3. The method for preparing hydrocortisone impurity L according to claim 1, characterized in that: In step (d), the molar ratio of intermediate 3 to photocatalyst is (8-12):
1.
4. The method for preparing hydrocortisone impurity L according to claim 1, characterized in that: In step (e), the reducing agent for the reduction reaction is selected from sodium borohydride or potassium borohydride.