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Preparation method of betamethasone intermediate

A gas and inert gas technology, applied in the field of preparation of betamethasone intermediates, can solve the problems of high energy consumption, unsafe production, incomplete reaction, etc., and achieve the effects of reducing environmental pollution, saving production costs, and reducing reaction time

Active Publication Date: 2014-05-28
SHANGHAI NEW HUALIAN PHARMA
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] However, in the process of industrial preparation of the Grignard reagent methylmagnesium bromide in the prior art, the following common defects occur: after the reaction is started, the reaction is violent, so that the internal pressure suddenly rises so that the material is sprayed, and the production is extremely unsafe; The phenomenon of encapsulation often occurs in Mg shavings, resulting in incomplete reaction, or the reaction is quenched when the coolant is used for cooling due to violent reaction, and the reaction cannot be continued, which directly leads to the low purity and yield of the obtained methylmagnesium bromide. , which in turn leads to a decrease in the purity and yield of the subsequent betamethasone intermediate 5-pregnene-16β-methyl-11α, 17α-dihydroxy-3,20-diethylene glycol ketal (II), and the purification Handling is loaded down with trivial details; And methyl bromide gas utilization rate is low (the utilization rate of methyl bromide gas in the prior art is only 40~50%), consumption is big, and reaction time is long, and energy consumption is high

Method used

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  • Preparation method of betamethasone intermediate
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  • Preparation method of betamethasone intermediate

Examples

Experimental program
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Effect test

Embodiment 1

[0028] In a 2000ml four-necked flask, add 1200ml of THF, 58g of magnesium granules, and 0.2g of iodine granules, and replace with nitrogen twice; control the temperature at 40-45°C, stir, and slowly introduce 5g of methyl bromide gas (the gas flow rate is 0.1- 0.5kg / min), after triggering the Grignard reaction, at this temperature, the remaining 220g of methyl bromide gas was passed into the flask for about 12 hours to react. Concentrate under high pressure, collect the fraction after 60°C, when the concentration temperature rises to 79-85°C, open the nitrogen system, stop the concentration, and naturally cool down to room temperature, take a sample to detect that the content of methylmagnesium bromide is 99.4%, and then slowly dissolve 150g of compound 5 -pregnene-16α, 17α-epoxy-11α-hydroxyl-3,20-diethylene glycol ketal (I) was put into the flask, replaced by nitrogen twice, and heated to 60-90°C for reflux reaction for 15 hours, HPLC detects that the chemical substance (I) i...

Embodiment 2

[0031]In a 2000ml four-necked flask, add 800ml tetrahydrofuran, 100g magnesium granules, 0.6g iodine granules, replace with nitrogen twice; control the temperature at 30-40°C, stir, and slowly introduce 8g of methyl bromide gas (gas flow rate is 0.6-1kg / min) , after triggering the Grignard reaction, at this temperature, pass the remaining 217g of methyl bromide gas into the flask for about 12 hours to react. After passing through, reflux for 3 hours until the magnesium particles are completely dissolved, close the nitrogen valve, heat up and concentrate under normal pressure, and collect 60 For the fraction after ℃, when the concentration temperature rises to 79-85 ℃, turn on the nitrogen system, stop the concentration, and naturally drop to room temperature, take a sample to detect that the content of methylmagnesium bromide is 99.3%, and then slowly add 150g of the compound 5-pregnene- 16α, 17α-epoxy-11α-hydroxyl-3,20-diethylene glycol ketal (I) was dropped into the flask, an...

Embodiment 3

[0034] In a 2000L reactor, after adding 1200L, 58kg of magnesium pellets, and 0.2kg of iodine pellets, replace it with nitrogen twice; control the temperature at 45-50°C, stir, and slowly introduce 5kg of methyl bromide gas (the gas flow rate is 0.5-0.7kg / min) , after triggering the Grignard reaction, at this temperature, the remaining 220kg of methyl bromide gas was passed into the flask for about 12 hours to react, and after completion of the passage, the reaction was refluxed for 3 hours until the magnesium particles were completely dissolved, the nitrogen valve was closed, the temperature was raised and concentrated under normal pressure, and 60 For the fraction after ℃, when the concentration temperature rises to 79-85 ℃, turn on the nitrogen system, stop the concentration, and naturally drop to room temperature, take a sample to detect that the content of methylmagnesium bromide is 99.2%, and then slowly add 150kg of the compound 5-pregnene- 16α, 17α-epoxy-11α-hydroxyl-3,...

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Abstract

The invention provides a preparation method of a betamethasone intermediate. According to the method, magnesium granules are used as a raw material, and reacted with halogenated methane gas under the action of a proper amount of iodine granules to obtain a high-purity Grignard reagent methylmagnesium halide, preferably CH3MgBr, and the betamethasone intermediate 5-methylpregna-16beta-methyl-11alpha,17alpha-dihydroxy-3,20-diethylene ketal (II) is obtained by introducing methyl into a compound 5-methylpregna-16beta,17alpha-epoxy-11alpha-hydroxy-3,20-diethylene ketal (I). The method increases the purity of the CH3MgBr and the purity of the betamethasone intermediate (II), significantly reduces the consumption of methyl bromide gas, largely enhances reaction safety and reduces environment pollution.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and in particular relates to a preparation method of an improved betamethasone intermediate. Background technique [0002] In the synthesis process of the hormone drug betamethasone and its analogs, the Grignard reagent methylmagnesium bromide (CH3MgBr) is prepared by reacting with methyl bromide gas with the participation of an appropriate amount of iodine particles as a catalyst. Sterene-16α, 17α-epoxy-11α-hydroxyl-3,20-diethylene glycol ketal (I) introduces a methyl group to prepare betamethasone intermediate 5-pregnene-16β-methyl-11α, 17α-dihydroxyl-3,20-diethylene glycol ketal (II), its reaction process is as follows: [0003] [0004] However, in the process of industrial preparation of the Grignard reagent methylmagnesium bromide in the prior art, the following common defects occur: after the reaction is started, the reaction is violent, so that the internal pressure suddenly rises s...

Claims

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Application Information

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IPC IPC(8): C07F3/02C07J21/00
Inventor 曹飞卿文彬吴庆安周秋火
Owner SHANGHAI NEW HUALIAN PHARMA
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