A method for preparing hydrocortisone acetate

Abstract

This application discloses a method for preparing hydrocortisone acetate, comprising at least the following steps: reacting a raw material containing 11β,17α,21-trihydroxypregn-4-ene-9α-bromo-3,20-dione-21-acetate with a debromination agent to obtain hydrocortisone acetate; wherein the debromination agent is an organophosphorus salt. This application uses an organophosphorus salt as a debromination agent in the preparation of hydrocortisone acetate, avoiding the use of chromium-containing compounds in traditional processes, reducing the environmental costs of the process, and the reaction process is simple and easy to operate, showing good prospects for industrial application.

Description

Technical Field

[0001] This application relates to a method for preparing hydrocortisone acetate, which belongs to the field of pharmaceutical preparation. Background Technology

[0002] Hydrocortisone acetate (11β,17α,21-trihydroxypregn-4-ene-3,20-dione-21 acetate) is a corticosteroid drug with anti-inflammatory, anti-allergic, and immunosuppressive effects. It is commonly used to treat various inflammatory and allergic diseases. Hydrocortisone acetate is mainly used topically, usually as an ingredient in eye drops or ointments, to treat eye inflammation, allergic conjunctivitis, and other eye diseases. It can relieve symptoms such as redness, swelling, pain, and itching caused by eye inflammation, and has good efficacy.

[0003] The traditional route for preparing corticosteroids uses diosgenin as a raw material. However, due to the high pollution and cost associated with diosgenin extraction, phytosterols are now used as a raw material both domestically and internationally. In the preparation of hydrocortisone acetate, 11β,17α,21-trihydroxypregn-4-ene-9α-bromo-3,20-dione-21-acetate (compound II) is often reacted with a debrominating agent to obtain hydrocortisone acetate (compound I).

[0004]

[0005] US Patent 5426198A discloses the use of chromium-containing compounds as debromination agents in the preparation of hydrocortisone acetate, which is also the currently used industrial method. However, due to the high toxicity and significant environmental threat posed by chromium-containing compounds, their use has been increasingly restricted both domestically and internationally in recent years. Summary of the Invention

[0006] According to one aspect of this application, a method for preparing hydrocortisone acetate is provided, wherein the method comprises the following steps in the preparation of hydrocortisone acetate.

[0007] The method for preparing the hydrocortisone acetate includes at least the following steps:

[0008] The raw material containing 11β,17α,21-trihydroxypregn-4-ene-9α-bromo-3,20-dione-21-acetate was subjected to a debromination reaction in the presence of a debromination agent to obtain hydrocortisone acetate.

[0009] The general formula of the debromination agent is:

[0010]

[0011] Where M is an alkali metal element;

[0012] R1 and R2 may be the same or different, and each is independently selected from alkyl groups with 1-5 carbon atoms, aryl groups with 6-12 carbon atoms that are substituted or unsubstituted, and cycloalkyl groups with 5-6 carbon atoms.

[0013] Optionally, M is selected from any one of Li, Na, and K. Preferably, M is K.

[0014] Optionally, the substituents of the aryl group are each independently selected from alkyl groups having 1 to 6 carbon atoms.

[0015] Optionally, R1 and R2 are the same, and each is independently selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, n-pentyl, phenyl, cyclohexyl, and cyclopentyl.

[0016] Preferably, R1 and R2 are the same and are selected from phenyl or cyclopentyl.

[0017] Optionally, the debrominating agent is selected from any one of the following substances;

[0018]

[0019] Optionally, the molar ratio of the 11β,17α,21-trihydroxypregn-4-ene-9α-bromo-3,20-dione-21-acetate to the debrominator is 1:2 to 5.

[0020] Preferably, the molar ratio of 11β,17α,21-trihydroxypregn-4-ene-9α-bromo-3,20-dione-21-acetate to the debrominator is 1:2 to 2.5.

[0021] Specifically, the molar ratio of 11β,17α,21-trihydroxypregn-4-ene-9α-bromo-3,20-dione-21-acetate to the debrominator can be independently selected from 1:2, 1:2.5, 1:3, 1:3.5, 1:4, 1:4.5, 1:5, or any ratio between the above values.

[0022] Optionally, the debromination reaction is carried out at a temperature of 20–100°C.

[0023] Preferably, the debromination reaction is carried out at a temperature of 30–50°C.

[0024] Specifically, the lower limit of the temperature for the debromination reaction can be independently selected from 20°C, 25°C, 30°C, 40°C, and 45°C, and the upper limit of the temperature for the debromination reaction can be independently selected from 50°C, 60°C, 80°C, 90°C, and 100°C.

[0025] Whether the debromination reaction is complete can be determined by thin-layer chromatography. In this application, the specific reaction time is 4 to 6 hours.

[0026] Optionally, the raw material may also include an organic solvent;

[0027] The organic solvent is selected from at least one of acetonitrile, pyridine, dimethyl sulfoxide, dimethylformamide, ether solvents, chlorinated hydrocarbon solvents, and aromatic hydrocarbon solvents.

[0028] Optionally, the ether solvent is selected from at least one of 1,4-dioxane, tetrahydrofuran, and ethers having 1-5 carbon atoms;

[0029] The chlorinated hydrocarbon solvent is a chlorinated alkane with 1-3 carbon atoms;

[0030] The aromatic hydrocarbon solvent is selected from benzene or toluene.

[0031] Specifically, ethers with 1-5 carbon atoms can be methyl ether, diethyl ether, isopropyl ether, methyl tert-butyl ether, etc.

[0032] Chlorinated alkanes with 1-3 carbon atoms can be dichloromethane, chloroform, carbon tetrachloride, 1,1,1-trichloroethane, etc.

[0033] Optionally, in the raw material, the mass-to-volume ratio of 11β,17α,21-trihydroxypregn-4-ene-9α-bromo-3,20-dione-21-acetate to the organic solvent is 1:5 to 50.

[0034] Preferably, the mass-to-volume ratio of 11β,17α,21-trihydroxypregn-4-ene-9α-bromo-3,20-dione-21-acetate to the organic solvent is 1:8 to 20.

[0035] Optionally, the method further includes purifying the hydrocortisone acetate.

[0036] The purification process includes: extracting and separating the hydrocortisone acetate, taking the organic phase, washing, filtering, and drying to obtain the purified hydrocortisone acetate.

[0037] Specifically, the hydrocortisone acetate was dissolved in dichloromethane, then water was added, and the pH was adjusted to neutral with 10wt% dilute sulfuric acid. The mixture was allowed to stand and separate into phases. The organic layer was taken and dried. Then methanol was added for washing, filtration, and drying to obtain purified hydrocortisone acetate.

[0038] The amount of each solvent used in the purification process can be determined by those skilled in the art based on the actual situation. In the specific implementation of this application, the volume ratio of dichloromethane to water is 1:1, and the amount of dichloromethane added is based on the amount of hydrocortisone acetate dissolved; during the methanol washing process, the system temperature is controlled at -15℃ to -5℃ (preferably -10℃).

[0039] The beneficial effects that this application can produce include:

[0040] 1) The method for preparing hydrocortisone acetate provided in this application uses organophosphorus salts as debrominating agents to prepare hydrocortisone acetate, which avoids the use of chromium-containing compounds in traditional processes, reduces the environmental cost of the process, and the reaction process is simple and easy to operate, and has good prospects for industrial application.

[0041] 2) Hydroxycortisone acetate can be prepared using the method provided in this application with a yield of over 90% and a purity of 99.5%. Detailed Implementation

[0042] The present application is described in detail below with reference to the embodiments, but the present application is not limited to these embodiments.

[0043] In this application, the number of carbon atoms in a group refers to the total number of carbon atoms.

[0044] In this application, alkyl groups may include straight-chain alkyl groups or branched alkyl groups. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, etc.

[0045] In this application, aryl refers to any optional functional group or substituent derived from an aromatic carbon ring. An aryl group can be a monocyclic aryl (e.g., phenyl) or a polycyclic aryl; in other words, an aryl group can be a monocyclic aryl, a fused-ring aryl, two or more monocyclic aryl groups conjugated by carbon-carbon bonds, a monocyclic aryl and a fused-ring aryl group conjugated by carbon-carbon bonds, or two or more fused-ring aryl groups conjugated by carbon-carbon bonds. That is, unless otherwise stated, two or more aromatic groups conjugated by carbon-carbon bonds can also be considered as aryl groups in this application. Fused-ring aryl groups may include, for example, bicyclic fused aryl groups (e.g., naphthyl). The aryl group does not contain heteroatoms such as B, N, O, S, P, Se, and Si.

[0046] Unless otherwise specified, all raw materials used in the embodiments of this application were purchased commercially.

[0047] Among them, compound 11β,17α,21-trihydroxypregn-4-ene-9α-bromo-3,20-dione-21-acetate was purchased from Xi'an Guokang Ruijin Pharmaceutical Co., Ltd.

[0048] In this application, the debromination agent is prepared according to the method disclosed in the literature Chemische Berichte Volume 92, Issue 5, 1959, Pages 1118-1126.

[0049] This application discloses a method for preparing hydrocortisone acetate, which involves reacting 11β,17α,21-trihydroxypregn-4-ene-9α-bromo-3,20-dione-21-acetate (compound II) with an organophosphorus salt to debrominate and obtain hydrocortisone acetate (compound I). The reaction formula is as follows:

[0050]

[0051] The general formula for organophosphorus salts is:

[0052]

[0053] R1 and R2 may be the same or different, and each is independently selected from alkyl groups with 1-5 carbon atoms, aryl groups with 6-12 carbon atoms that are substituted or substituted, and alkoxy groups with 1-5 carbon atoms.

[0054] Furthermore, the alkyl group having 1-5 carbon atoms is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, 2-methylbutyl, and 2,2-dimethylpropyl;

[0055] The substituents of the aryl group are selected from any one of the alkyl groups having 1-6 carbon atoms; the substituted or substituted aryl groups having 6-12 carbon atoms are selected from phenyl, biphenyl, naphthyl, and benzyl.

[0056] Alkoxy groups with 1-5 carbon atoms are selected from methoxy, ethoxy, n-propyloxy, and n-butyloxy.

[0057] Preferably, R1 and R2 are the same and each is independently selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, n-pentyl, phenyl, cyclohexyl, and cyclopentyl.

[0058] The specific steps are as follows:

[0059] Step 1: Add compound II to an organic solvent at a mass-volume ratio of 1:5 to 50 g / ml. After stirring and dissolving, add the organic phosphine salt at a controlled reaction temperature of 20 to 100°C, according to a molar ratio of compound II to organophosphine salt of 1:2 to 5, and carry out the debromination reaction for 4 to 6 hours to obtain the crude product.

[0060] Step 2: Extract and separate the crude product, wash, filter, and dry the organic phase to obtain the purified product.

[0061] Example 1

[0062] The organophosphorus salts used are

[0063] In a three-necked flask, 2.4 g of compound II, 2.5 g of organophosphorus salt, and 20 ml of dimethyl sulfoxide were added sequentially. The mixture was reacted at 50 °C for 4 h. After the reaction was monitored by thin-layer chromatography, 100 ml of water was added to the system, and the pH was adjusted to 6.5 with 10 wt% dilute sulfuric acid. Then, 100 ml of dichloromethane was added twice for extraction. The organic phases were then combined.

[0064] The organic phase was washed once with 100 ml of water, dried over anhydrous magnesium sulfate, filtered, and evaporated to dryness. Then, 5 ml of methanol was added, the mixture was stirred for 2 hours, cooled to -10°C, filtered, and dried to obtain 1.9 g of the product. The yield was 95%, and the HPLC purity was 99.5%.

[0065] Example 2

[0066] The organophosphorus salt used is

[0067] In a three-necked flask, 2.4 g of compound II, 2.2 g of organophosphorus salt, and 20 ml of dimethyl sulfoxide were added sequentially. The mixture was reacted at 40 °C for 6 h. After the reaction was monitored by thin-layer chromatography, 100 ml of water was added to the system, and the pH was adjusted to 6.0 with 10 wt% dilute sulfuric acid. Then, 100 ml of dichloromethane was added twice for extraction. The organic phases were then combined.

[0068] The organic phase was washed once with 100 ml of water, dried over anhydrous magnesium sulfate, filtered, and evaporated to dryness. Then, 5 ml of methanol was added, the mixture was stirred for 2 hours, cooled to -10°C, filtered, and dried to obtain 1.7 g of the product. The yield was 85%, and the HPLC purity was 99.2%.

[0069] Example 3

[0070] The organophosphorus salts used are

[0071] In a three-necked flask, 2.4 g of compound II, 2.0 g of organophosphorus salt, and 20 ml of dimethyl sulfoxide were added sequentially. The mixture was reacted at 40 °C for 6 h. After the reaction was monitored by thin-layer chromatography, 100 ml of water was added to the system, and the pH was adjusted to 7.0 with 10 wt% dilute sulfuric acid. Then, 100 ml of dichloromethane was added for extraction twice, and the organic phases were combined.

[0072] The organic phase was washed once with 100 ml of water, dried over anhydrous magnesium sulfate, filtered, and evaporated to dryness. Then, 5 ml of methanol was added, the mixture was stirred for 2 hours, cooled to -10°C, filtered, and dried to obtain 1.7 g of product. The yield was 85%, and the HPLC purity was 99.0%.

[0073] Example 4

[0074] The organophosphorus salt used is

[0075] In a three-necked flask, 2.4 g of compound II, 2.5 g of organophosphorus salt, and 25 ml of dimethyl sulfoxide were added sequentially. The mixture was reacted at 30 °C for 5.5 h. After the reaction was monitored by thin-layer chromatography, 100 ml of water was added to the system, and the pH was adjusted to 6.8 with 10 wt% dilute sulfuric acid. Then, 100 ml of dichloromethane was added twice for extraction, and the organic phases were combined.

[0076] The organic phase was washed once with 100 ml of water, dried over anhydrous magnesium sulfate, filtered, and evaporated to dryness. Then, 5 ml of methanol was added, the mixture was stirred for 2 hours, cooled to -10°C, filtered, and dried to obtain 1.2 g of product. The yield was 60%, and the HPLC purity was 98.5%.

[0077] Example 5

[0078] The organophosphorus salt used is

[0079] In a three-necked flask, 2.4 g of compound II, 2.3 g of organophosphorus salt, and 100 ml of dimethyl sulfoxide were added sequentially. The mixture was reacted at 70 °C for 4 h. After the reaction was monitored by thin-layer chromatography, 100 ml of water was added to the system, and the pH was adjusted to 6.4 with 10 wt% dilute sulfuric acid. Then, 100 ml of dichloromethane was added twice for extraction. The organic phases were then combined.

[0080] The organic phase was washed once with 100 ml of water, dried over anhydrous magnesium sulfate, filtered, and evaporated to dryness. Then, 5 ml of methanol was added, the mixture was stirred for 2 hours, cooled to -10°C, filtered, and dried to obtain 1.1 g of product. The yield was 55%, and the HPLC purity was 95.0%.

[0081] Examples 6-7

[0082] The preparation process of the product in this embodiment is basically the same as that in Example 1, except for the R1 and R2 groups of the organophosphorus salt.

[0083] Example <![CDATA[R1 and R2 groups]]> Product output (g) Yield % HPLC purity % Example 6 n-Butyl 1.25 grams 62％ 98.5％ Example 7 Toluene 1.8 grams 90％ 99.2％

[0084] The above description is merely a few embodiments of this application and is not intended to limit this application in any way. Although this application discloses preferred embodiments as described above, it is not intended to limit this application. Any changes or modifications made by those skilled in the art without departing from the scope of the technical solution of this application using the disclosed technical content are equivalent to equivalent implementation cases and fall within the scope of the technical solution.

Claims

1. A method for preparing hydrocortisone acetate, characterized in that, The method includes at least the following steps: The raw material containing 11β,17α,21-trihydroxypregn-4-ene-9α-bromo-3,20-dione-21-acetate was subjected to a debromination reaction in the presence of a debromination agent to obtain hydrocortisone acetate. The general formula of the debromination agent is: Where M is an alkali metal element; R1 and R2 may be the same or different, and each is independently selected from alkyl groups with 1-5 carbon atoms, aryl groups with 6-12 carbon atoms (substituted or unsubstituted), and cycloalkyl groups with 5-6 carbon atoms. The substituents of the aryl group are each independently selected from alkyl groups having 1 to 6 carbon atoms.

2. The preparation method according to claim 1, characterized in that, M is selected from any one of Li, Na, and K.

3. The preparation method according to claim 1, characterized in that, R1 and R2 are identical and each is independently selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, n-pentyl, phenyl, cyclohexyl, and cyclopentyl.

4. The preparation method according to claim 1, characterized in that, The molar ratio of the 11β,17α,21-trihydroxypregn-4-ene-9α-bromo-3,20-dione-21-acetate to the debrominator is 1:2 to 5.

5. The preparation method according to claim 1, characterized in that, The debromination reaction is carried out at a temperature of 20–100 °C.

6. The preparation method according to claim 1, characterized in that, The raw materials also include organic solvents; The organic solvent is selected from at least one of acetonitrile, pyridine, dimethyl sulfoxide, dimethylformamide, ether solvents, chlorinated hydrocarbon solvents, and aromatic hydrocarbon solvents.

7. The preparation method according to claim 6, characterized in that, The ether solvent is selected from at least one of 1,4-dioxane, tetrahydrofuran, and ethers having 1-5 carbon atoms; The chlorinated hydrocarbon solvent is a chlorinated alkane with 1-3 carbon atoms; The aromatic hydrocarbon solvent is selected from benzene or toluene.

8. The preparation method according to claim 6, characterized in that, In the raw materials, the mass-to-volume ratio of 11β,17α,21-trihydroxypregn-4-ene-9α-bromo-3,20-dione-21-acetate to the organic solvent is 1:5 to 50.

9. The preparation method according to claim 1, characterized in that, It also includes the purification of the hydrocortisone acetate.

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