A preparation method of halcinonide intermediate

Abstract

The present invention is applicable to the technical field of chemical drug synthesis, and provides a preparation method of halcinonide intermediate, comprising the following steps: adding acetic acid to anecortave acetate in an organic solvent, reacting under the common catalysis of p-toluenesulfonic acid and trifluoroacetic anhydride, adjusting the pH value with ammonia, separating, washing, concentrating under reduced pressure, beating, filtering, and drying to obtain D-1; adding D-1 to dimethyl sulfoxide, reacting under the catalysis of potassium acetate, cooling, precipitating a solid, filtering, and drying to obtain D-2; adding an aqueous solution of sodium hydroxide or lithium hydroxide to D-2 in a reaction solvent, and hydrolyzing the reaction to obtain D-3; reacting D-3 with an acyl chloride in an aprotic solvent under alkaline conditions to obtain D-4; adding D-4 to DMF, and reacting with lithium chloride under nitrogen protection to obtain D-5. The raw material anecortave acetate used in the present invention is easily available and cheap, and the method for preparing D-5 is efficient, green, safe, and has a high yield.

Description

Technical Field

[0001] The invention belongs to the technical field of chemical drug synthesis, and in particular relates to a preparation method of a halcinonide intermediate. Background Art

[0002] Halcinonide, chemically known as 16α,17-[(1-methylethylidene)bis(oxy)]-11β-hydroxy-21-chloro-9-fluoropregnan-4-ene-3,20-dione, is a synthetic, potent glucocorticoid with strong local anti-inflammatory effects and little systemic side effects. It is primarily used for psoriasis and eczematous dermatitis, with significant efficacy. Halcinonide intermediate D-5 is the raw material for the production of halcinonide, and its chemical structure is as follows:

[0003]

[0004] The existing synthetic route for halcinonide uses hydrocortisone-21-methanesulfonate as the starting material and is prepared through seven steps: dinitration at the 11 and 17 positions, elimination of chlorination, dihydroxylation, ketalization, bromohydroxylation, epoxidation, and hydrogen fluoride ring opening. However, the raw materials for this process are difficult to obtain, and a nitration step is required for the preparation of the key intermediate D-5. This makes industrial operation unsafe and unfavorable for industrial production. Summary of the Invention

[0005] The purpose of the embodiments of the present invention is to provide a method for preparing a halcinonide intermediate, aiming to solve the problems raised in the above background technology.

[0006] The embodiment of the present invention is achieved by a method for preparing a halcinonide intermediate, and the reaction scheme is as follows:

[0007]

[0008] The preparation method comprises the following steps:

[0009] Acetylation: Add acetic acid to anecortave acetate in an organic solvent, and react under the co-catalysis of p-toluenesulfonic acid and trifluoroacetic anhydride. After the reaction, adjust the pH value to 6-8 with ammonia water, separate the liquids, wash with water, and concentrate under reduced pressure to obtain a solid. Then, slurry with water, filter, and dry to obtain D-1.

[0010] Dehydrogenation: Add D-1 to dimethyl sulfoxide and react under nitrogen protection with potassium acetate as the catalyst. After the reaction is completed, cool the reaction solution and pour it into water to precipitate a solid. Filter and dry to obtain a light yellow solid D-2.

[0011] Hydrolysis: D-2 is dissolved in an alcohol or THF reaction solvent at a reaction temperature of 0-40°C, and 1.0-1.5 eq of an aqueous solution of sodium hydroxide or lithium hydroxide is added to hydrolyze to obtain D-3;

[0012] Sulfonation: D-3 reacts with an acyl chloride in an aprotic solvent under alkaline conditions at a reaction temperature of 0-40°C to give D-4;

[0013] Chlorination: Add D-4 to DMF at a reaction temperature of 80-130°C and react with 2.0-10.0 eq of lithium chloride under nitrogen for 2-6 h to obtain D-5.

[0014] Preferably, in the acetylation step, the organic solvent is an alkyl halide, the reaction temperature is 10 to 40° C., and the reaction time is 3 to 9 hours.

[0015] Preferably, in the dehydrogenation step, the reaction temperature is 60-120° C., and the reaction time is 3-8 h.

[0016] Preferably, in the hydrolysis step, the reaction solvent is methanol, the reaction temperature is 10-20° C., and the equivalent of the aqueous solution of sodium hydroxide or lithium hydroxide is 1.0 eq.

[0017] Preferably, in the sulfonation step, the aprotic solvent is DCM or chloroform, the base in the alkaline condition is triethylamine or pyridine, and the acyl chloride is methanesulfonyl chloride or p-toluenesulfonyl chloride.

[0018] Preferably, in the sulfonation step, the reaction temperature is 0-10°C.

[0019] Preferably, the aprotic solvent is DCM, the base in the alkaline condition is triethylamine, and the acyl chloride is methanesulfonyl chloride.

[0020] Preferably, in the chlorination step, the reaction temperature is 100° C., the reaction time is 3 to 4 hours, and the equivalent of lithium chloride is 6 eq.

[0021] The embodiment of the present invention provides a method for preparing a halcinonide intermediate. The raw material anecortave acetate used is easily available and inexpensive. The method for preparing the halcinonide intermediate D-5 is efficient, green, safe, and has a high yield. DETAILED DESCRIPTION

[0022] In order to make the purpose, technical solutions and advantages of the present invention more clearly understood, the present invention is further described in detail below in conjunction with the embodiments. It should be understood that the specific embodiments described herein are only used to explain the present invention and are not intended to limit the present invention.

[0023] The specific implementation of the present invention is described in detail below with reference to specific embodiments.

[0024] Example 1: A method for preparing intermediate D-1, comprising the following steps:

[0025]

[0026] The specific steps are as follows: 1L of dichloromethane, 210g of trifluoroacetic anhydride, 34.4g of p-toluenesulfonic acid and 386ml of glacial acetic acid are added to a 2L single-necked flask in sequence, and after stirring and dispersion, 77.3g of anecortave acetate is added, and then 500ml of dichloromethane is added. The solid dissolves clearly, and the temperature is controlled at 25±5°C for 3 hours. The reaction is complete by TLC detection, and the reaction liquid is slowly added dropwise to 3.5L of ammonia water (500ml of ammonia water + 3L of water), and the pH of the solution is adjusted to 6-8. The layers are separated, the aqueous phase is extracted with 500ml of dichloromethane, the organic phases are combined and washed with 500ml*2 water, and the organic phase is concentrated under reduced pressure. After a large amount of solid precipitates, 500ml of water is added and the mixture is slurried at room temperature for 1h, filtered, the filter cake is washed with water, and dried in a 50°C forced drying oven to obtain 84.6g of an off-white solid with a yield of 98.7%.

[0027] Example 2: A method for preparing intermediate D-2, comprising the following steps:

[0028]

[0029] The specific steps are as follows: 80g of D-1 and 55g of potassium acetate were added to a 1L single-necked flask, followed by 560g of dimethyl sulfoxide. After nitrogen substitution three times, the reaction was allowed to proceed at 80±5°C for 5h. TLC confirmed the reaction was complete. The temperature was then lowered and the reaction mixture was poured into 2.5L of water, resulting in the precipitation of a large amount of viscous solid. The aqueous phase was extracted with 750ml of dichloromethane, and the organic phase was washed twice with 600ml of water. The mixture was concentrated under reduced pressure to remove the bulk of the dichloromethane, yielding a brown oil. 150ml of acetone was added to dissolve the oil at 60°C, followed by the slow dropwise addition of 100ml of water. Crystallization was then allowed to proceed at room temperature for 1h. Filtration was performed, and the filter cake was rinsed twice with 50ml of a 1:1 mixture of acetone and water. The filter cake was then dried in a forced air oven at 50°C to yield 63.0g of a pale yellow solid, a yield of 91.64%.

[0030] Example 3: A method for preparing intermediate D-3, comprising the following steps:

[0031]

[0032] The specific steps are as follows: weigh 100g of D-2 into a 2L single-necked bottle, add 1000ml of methanol, stir and disperse, dissolve 10.9g of sodium hydroxide in 200ml of water, slowly drip the sodium hydroxide solution into the reaction system, and a large amount of solid gradually precipitates. TLC shows that the reaction is complete, add acetic acid to adjust the pH to 7, filter, and rinse the filter cake with 200ml of water to obtain an off-white solid, which is then dried with air at 50°C overnight to obtain 81.7g of a yellow solid with a yield of 92.2%.

[0033] Example 4: A method for preparing intermediate D-3, comprising the following steps:

[0034]

[0035] The specific steps are as follows: weigh 10g of D-2 into a 2L single-necked bottle, add 100ml of THF, stir and disperse, dissolve 0.65g of lithium hydroxide in 20ml of water, slowly drip the lithium hydroxide solution into the reaction system, a large amount of solid precipitates, and TLC shows that the reaction is complete. Acetic acid is added to adjust the pH to 7, filter, rinse the filter cake with 50ml of water, and dry it with air at 50°C to obtain 7.7g of yellow solid, with a yield of 86.9%.

[0036] Example 5: A method for preparing intermediate D-4 (methanesulfonate), the reaction is as follows:

[0037]

[0038] The specific steps are as follows: 13.6g of D-3, 136ml of dichloromethane for dissolution, and 6.7g of triethylamine are sequentially added to a 250ml single-necked flask and cooled to 0-10°C. 6.7g of methanesulfonyl chloride is slowly added dropwise, maintaining the internal temperature at ≤20°C. After completion of the addition, the mixture is transferred to room temperature for 10 minutes. After 20 minutes of reaction, TLC confirms the reaction is complete. 7ml of methanol is added to quench the reaction. The organic phase is washed twice with 100ml of dichloromethane. The aqueous phase is extracted once with 100ml of dichloromethane. The organic phases are combined and concentrated under reduced pressure to obtain a brown-red oil. 80ml of methanol is added, the temperature is raised to 60°C, and the mixture is stirred for 1 hour. The temperature is then cooled to allow crystallization, filtered, and dried to obtain 14.7g of a light yellow solid with a yield of 87.2%.

[0039] Example 6: A method for preparing intermediate D-4 (toluenesulfonate), the reaction is as follows:

[0040]

[0041] The specific steps are as follows: 8.0g of D-3 was added to a 2L three-necked flask, 80ml of dichloromethane was added to dissolve the solid, the reaction solution was cooled to 0-10°C, and 4.0g of triethylamine was slowly added to the reaction system. 4.3g of p-toluenesulfonyl chloride was dissolved in 15ml of dichloromethane and slowly added dropwise to the reaction system, maintaining the internal temperature at ≤20°C. After addition, the reaction system was allowed to warm to room temperature and allowed to react. After 20 minutes, TLC confirmed the reaction was complete, and 1ml of methanol was added to quench the reaction. The organic phase was washed twice with 10ml of dichloromethane, and the aqueous phase was extracted once with 10ml of dichloromethane. The organic phases were combined and concentrated under reduced pressure to obtain a brown-red oil. 60ml of methanol was added, the temperature was raised to 60°C, and the mixture was stirred for 1 hour. The mixture was then cooled to crystallize, filtered, and dried to obtain 10.2g of a light yellow solid (86.6% yield).

[0042] Example 7: A method for preparing intermediate D-5, comprising the following steps:

[0043]

[0044] The specific steps are as follows: 9.1 g of D-4 methanesulfonate, 45 ml of DMF, and 2.1 g of lithium chloride were added sequentially to a 100 ml three-necked flask and the atmosphere was replaced with nitrogen three times. The external temperature was set to 100°C, and the solid gradually dissolved. The reaction was allowed to react for 3 hours. After completion by TLC, the temperature was lowered to 60°C, and the reaction solution was slowly added dropwise to 90 ml of water. The mixture was stirred for 1 hour to allow crystallization to proceed. The filter cake was then filtered with suction, rinsed with 50 ml of water, dried, and dried in a 50°C air oven to yield 7.39 g of a khaki solid (95.2% yield).

[0045] Example 8: A method for preparing intermediate D-5, comprising the following steps:

[0046]

[0047] The specific steps are as follows: 4.5 g of D-4 methanesulfonate, 22 ml of DMF, and 1.6 g of lithium chloride were added sequentially to a 100 ml three-necked flask and the atmosphere was replaced with nitrogen three times. The external temperature was set to 90°C, and the solid gradually dissolved. The reaction was allowed to react for 5 hours. When TLC indicated complete reaction, the temperature was lowered to 60°C, and the reaction solution was slowly added dropwise to 90 ml of water. The mixture was stirred for 1 hour to crystallize, and then filtered. The filter cake was rinsed with 50 ml of water, dried, and dried in a 50°C air drying oven to yield 3.5 g of solid, with a yield of 90.2%.

[0048] Example 9: A method for preparing intermediate D-5, comprising the following steps:

[0049]

[0050] The specific steps are as follows: 5g of D-4 p-toluenesulfonate, 25ml of DMF, and 1.5g of lithium chloride were added to a 100ml reaction flask and the atmosphere was replaced with nitrogen three times. The reaction was maintained at 100°C for 4 hours. TLC confirmed the reaction was complete. The temperature was then lowered to 60°C, and the reaction solution was slowly added dropwise to 50ml of water. The mixture was stirred for 1 hour to allow crystallization. The filter cake was then filtered and rinsed with 100ml of water, drained, and dried in a 50°C air oven to yield 3.2g of a khaki solid (89.1% yield).

[0051] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions and improvements made within the spirit and principles of the present invention should be included in the scope of protection of the present invention.

Claims

1. A method for preparing a halcinonide intermediate, characterized in that: The reaction route is as follows: The preparation method comprises the following steps: Acetylation: Add acetic acid to anecortave acetate in an organic solvent, and react under the co-catalysis of p-toluenesulfonic acid and trifluoroacetic anhydride. After the reaction, adjust the pH to 6-8 with aqueous ammonia. Then, separate the liquids, wash with water, and concentrate under reduced pressure to obtain a solid. Then, slurry the solid with water, filter, and dry to obtain D-1. The organic solvent is an alkyl halide. The reaction temperature is 10-40°C and the reaction time is 3-9 hours. Dehydrogenation: Add D-1 to dimethyl sulfoxide and react under nitrogen protection with potassium acetate as the catalyst. After the reaction is completed, cool the reaction solution and pour it into water to precipitate solids. Filter and dry to obtain a light yellow solid D-2. The reaction temperature is 60-120°C and the reaction time is 3-8 hours. Hydrolysis: D-2 is dissolved in methanol at a reaction temperature of 10-20°C, and 1.0 eq of an aqueous solution of sodium hydroxide or lithium hydroxide is added to hydrolyze to obtain D-3; Sulfonation: D-3 is reacted with an acyl chloride in an aprotic solvent under alkaline conditions at a reaction temperature of 0-10°C to obtain D-4. The aprotic solvent is DCM or chloroform, the base in the alkaline conditions is triethylamine or pyridine, and the acyl chloride is methanesulfonyl chloride or p-toluenesulfonyl chloride. Chlorination: Add D-4 to DMF at 100°C and react with 6 eq of lithium chloride under nitrogen for 3-4 h to obtain D-5.

2. The method for preparing a halcinonide intermediate according to claim 1, wherein The aprotic solvent is DCM, the base in the alkaline condition is triethylamine, and the acyl chloride is methanesulfonyl chloride.

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