CN114075258B - Preparation method of hydrocortisone - Google Patents
Preparation method of hydrocortisone Download PDFInfo
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- CN114075258B CN114075258B CN202010804268.6A CN202010804268A CN114075258B CN 114075258 B CN114075258 B CN 114075258B CN 202010804268 A CN202010804268 A CN 202010804268A CN 114075258 B CN114075258 B CN 114075258B
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- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J5/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond
- C07J5/0046—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond substituted in position 17 alfa
- C07J5/0053—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond substituted in position 17 alfa not substituted in position 16
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Abstract
The invention relates to the technical field of pharmacy, and discloses a preparation method of hydrocortisone, which comprises the steps of taking a hydrocortisone acetate crude product as an initial raw material, and performing hypochlorite impurity removal reaction and IRA-400 resin hydrolysis reaction to prepare the hydrocortisone. The preparation method reduces the generation of impurities in the reaction process by the hypochlorite impurity removal reaction step and the matched resin hydrolysis treatment, avoids using iodine with higher toxicity and unfriendliness to the environment, reduces the pollution to the environment, has simple and convenient operation, is suitable for industrial production, and has high yield (the total mass yield is higher than 75%) and high purity (higher than 99.5%) of the obtained product, thereby having wide market prospect.
Description
Technical Field
The invention relates to the technical field of pharmacy, in particular to a preparation method of hydrocortisone.
Background
Hydrocortisone and derivatives thereof are adrenocortical hormone medicaments, have high activity, have the effects of influencing glycometabolism, resisting inflammation, resisting allergy, resisting shock and the like, are widely applied to the treatment of anaphylactic diseases such as adrenocortical insufficiency, rheumatoid disease, lupus erythematosus, bronchial asthma, dermatitis and the like, and have wide market prospect.
Chinese patent ZL200710061260.X discloses a chemical synthesis route of hydrocortisone, which takes 17-hydroxy-4,9-diene-pregna-3, 20-diketone as a starting material, and the hydrocortisone is finally prepared by bromination, debromination, iodination, replacement and hydrolysis, and the route is as follows:
chinese patent ZL201110201729.1 discloses a preparation method of hydrocortisone, which takes an intermediate 17 alpha-hydroxy-4-pregnene-3, 11, 20-trione (II) of a rhizopus nigricans method as a raw material, and finally prepares the hydrocortisone by ketal, reduction, hydrolysis, iodination, replacement and hydrolysis, wherein the reaction route is as follows:
the two chemical synthesis routes have long synthesis steps, iodine with high toxicity and unfriendly environment is needed in the reaction process, and more impurities are generated in the iodine replacement process and are difficult to remove, so that the two chemical synthesis routes are not suitable for industrial production.
In the prior art, anecortave acetate is also taken as a starting material, and is subjected to hydrobromation, debromination and hydrolysis to prepare hydrocortisone, but a large impurity is generated in the process, and is difficult to refine and remove in a final product, and the generation process of the impurity is shown as follows:
the impurity has a structure similar to that of hydrocortisone, is difficult to remove by the conventional general refining method, and seriously restricts the large-scale industrial production of the synthetic route, so that a better method for removing the impurity is found, which becomes a problem to be solved urgently.
Chinese patent CN104610407B discloses a refining method of hydrocortisone acetate, which uses chlorine or hypochlorite, glacial acetic acid and sodium chloride to purify the crude hydrocortisone acetate, and the route is as follows:
one way of this purification method is to treat hydrocortisone acetate directly with chlorine gas having a high chemical activity, which, although the relevant impurities can be removed, adds many new impurities, which makes the purification process difficult; the other mode of the method is that hypochlorite and sodium chloride are added into hydrocortisone acetate, and glacial acetic acid is added dropwise, because the hypochlorite is very alkaline, most of the hydrocortisone acetate is hydrolyzed into hydrocortisone, the obtained product is mixed with the hydrocortisone acetate and the hydrocortisone, and the two substances are difficult to analyze, so that the method cannot achieve the purpose of purifying the hydrocortisone acetate, and the actual operability is not strong.
Disclosure of Invention
In order to solve the technical problems, the invention provides a preparation method of hydrocortisone, which has the advantages of short reaction route, simple reaction process and low pollution, and the obtained hydrocortisone acetate and hydrocortisone have high yield (the total mass yield is respectively higher than 90% and 75%) and high purity (respectively higher than 99.2% and 99.5%).
The specific technical scheme of the invention is as follows:
a preparation method of hydrocortisone comprises the following steps:
preferably, the synthesis process specifically comprises the following steps:
1) Impurity removal reaction: dissolving the crude hydrocortisone acetate in an organic solvent A, adding acid, controlling the temperature to be 15-40 ℃, dropwise adding a sodium hypochlorite aqueous solution, continuously stirring for reaction after dropwise adding, adding a sodium metabisulfite aqueous solution after the reaction is completed through high performance liquid chromatography, concentrating, elutriating, filtering to obtain a wet product, and refining the wet product once (recrystallizing) by using the organic solvent A to obtain a fine hydrocortisone acetate product.
2) And (3) hydrolysis reaction: dissolving the fine hydrocortisone acetate product obtained in the step 1) in an organic solvent A, cooling to-10 ℃, adding IRA-400 resin, stirring for reaction, filtering after the reaction is finished, concentrating the filtrate to remove the organic solvent, cooling for crystallization, filtering, and drying to obtain a finished hydrocortisone product.
The principle of the invention is as follows: in the step 1), hypochlorous acid is formed by sodium hypochlorite under a weak acid condition, then the hypochlorous acid reacts with impurities which are difficult to refine and remove in the hydrocortisone acetate crude product to form impurities which are easy to refine and remove, the impurities are removed by refining, and then the residual hypochlorous acid is neutralized by sodium metabisulfite aqueous solution. In the step 2), the resin hydrolysis treatment is particularly used, so that the generation of impurities is further reduced, the purity of the product obtained by the method is higher than 99.5%, and the total mass yield is higher than 75%.
As described in the background art, chinese patent CN104610407B discloses a refining method of hydrocortisone acetate, which uses chlorine or hypochlorite, glacial acetic acid and sodium chloride to purify the crude hydrocortisone acetate, and when the method uses hypochlorite, the concrete steps are to add hypochlorite and sodium chloride to the hydrocortisone acetate, and then add glacial acetic acid dropwise. Due to the fact that hypochlorite has strong alkalinity, most of hydrocortisone acetate is hydrolyzed into hydrocortisone, the obtained product is mixed with hydrocortisone acetate and hydrocortisone, and the two substances are difficult to analyze, cannot achieve the purpose of purification, and is not strong in actual operability. Although sodium hypochlorite is also used in the present invention, the addition sequence is different, and therefore, the present invention is completely different in principle, and the addition sequence in the patent CN104610407B mentioned in the background is to use hypochlorite to generate chlorine gas for subsequent treatment. In contrast, the method of the invention has better effect.
Preferably, the organic solvent A is a mixed solvent of dichloromethane and at least one alcohol of methanol, ethanol or isopropanol; the volume ratio of the dichloromethane to the alcohols is 1: 0.5-3.
Preferably, the volume ratio of the dichloromethane to the alcohols is 1: 0.5-3.
Preferably, in step 1): the volume dosage of the organic solvent A is 10-30 times of the crude hydrocortisone acetate product.
Since hydrocortisone acetate has poor solubility in a single solvent, hydrocortisone acetate can be completely dissolved by using a mixed solvent within the above range.
Preferably, in step 1): the acid is glacial acetic acid, and the volume dosage of the glacial acetic acid is 0.03-0.1 time of that of the hydrocortisone acetate crude product.
The acetic acid is equivalent to a buffer system, the weak acidity of the system is maintained, too little addition is not enough, too much addition is carried out, and the acidity is too strong.
Preferably, in step 1): the mass concentration of the sodium hypochlorite aqueous solution is 5-13%, and the volume consumption of the sodium hypochlorite aqueous solution is 0.1-0.5 time of that of the hydrocortisone acetate crude product.
If sodium hypochlorite is added too little, the reaction is incomplete, and if sodium hypochlorite is added too much, reaction impurities are increased.
Preferably, in step 1): the mass concentration of the sodium metabisulfite aqueous solution is 5-20%, and the volume consumption of the sodium metabisulfite aqueous solution is 1-5 times of that of the hydrocortisone acetate crude product.
The sodium pyrosulfite is added to neutralize the oxidizing property of hypochlorous acid, and the addition amount is moderate.
Preferably, in step 2): the volume dosage of the organic solvent A is 10-30 times of that of the fine hydrocortisone acetate.
Preferably, in step 2): the weight consumption of the IRA-400 resin is 0.1-1 time of that of the fine hydrocortisone acetate.
The resin has strong alkalinity, and the hydrolysis reaction can be incomplete due to too small dosage, otherwise, waste can be caused, and impurities can be increased.
Compared with the prior art, the invention has the following technical effects:
1. the principle of the invention is that hypochlorous acid is formed by sodium hypochlorite under weak acid condition, then reacts with impurities which are difficult to be removed by refining in the crude hydrocortisone acetate to form impurities which are easy to be removed by refining, and the residual hypochlorous acid is neutralized by sodium metabisulfite aqueous solution. Short process route, convenient operation, no use of iodine with high toxicity and unfriendly environment, and suitability for industrial production.
2. The invention adds the reaction step of removing impurities, can well remove raw materials with incomplete reaction, particularly uses a resin hydrolysis process, further reduces the generation of impurities, and the product purity is higher than 99.5 percent.
3. The invention has mild reaction, is carried out under the condition of low temperature or room temperature, and has the total mass yield higher than 75 percent.
4. Low requirement on a reaction device, low running cost, simple and convenient operation, suitability for industrial production and better market prospect.
5. According to the method disclosed by the invention, the hydrocortisone acetate with high yield and high purity can be obtained, and the hydrocortisone with high yield and high purity can not be obtained by further post-treatment according to the requirements.
Detailed Description
The present invention will be further described with reference to the following examples. The specific experimental procedures or conditions are not described in the examples, and the procedures can be performed according to the conventional experimental methods described in the publications in the field, and the reagents or equipment used are not indicated by manufacturers, and are all conventional products commercially available.
General examples
A preparation method of hydrocortisone comprises the following steps:
1) Impurity removal reaction: dissolving the crude hydrocortisone acetate in an organic solvent A, wherein the volume consumption of the organic solvent A is 10-30 times of that of the crude hydrocortisone acetate. Adding glacial acetic acid, wherein the volume dosage of the glacial acetic acid is 0.03-0.1 time of that of the hydrocortisone acetate crude product; controlling the temperature to be 15-40 ℃, dropwise adding a sodium hypochlorite aqueous solution, wherein the mass concentration of the sodium hypochlorite aqueous solution is 5-13%, the volume consumption of the sodium hypochlorite aqueous solution is 0.1-0.5 time of that of the hydrocortisone acetate crude product, continuously stirring for reaction after the dropwise adding is finished, and adding a sodium metabisulfite aqueous solution after the reaction is finished, wherein the mass concentration of the sodium metabisulfite aqueous solution is 5-20%, and the volume consumption of the sodium metabisulfite aqueous solution is 1-5 times of that of the hydrocortisone acetate crude product; concentrating, elutriating, filtering to obtain a wet product, and refining the wet product once by using an organic solvent A to obtain a fine hydrocortisone acetate product;
2) And (3) hydrolysis reaction: dissolving the fine hydrocortisone acetate obtained in the step 1) in an organic solvent A, wherein the volume consumption of the organic solvent A is 10-30 times of that of the fine hydrocortisone acetate; cooling to-10 ℃, adding IRA-400 resin, stirring and reacting, wherein the weight consumption of the IRA-400 resin is 0.1-1 time of that of the fine hydrocortisone acetate; and after the reaction is finished, filtering, concentrating the filtrate to remove the organic solvent, cooling, crystallizing, filtering, and drying to obtain a finished product of hydrocortisone.
Wherein the organic solvent A is a mixed solvent of dichloromethane and at least one alcohol of methanol, ethanol or isopropanol; the volume ratio of the dichloromethane to the alcohols is 1: 0.5-3. The volume ratio of the dichloromethane to the alcohols is 1: 0.5-3.
Example 1
Preparation method of hydrocortisone
1) Dissolving 50 g of crude debrominated substance (hydrocortisone acetate) in 300 ml of dichloromethane and 400 ml of methanol, adding 3.5 ml of glacial acetic acid, dropwise adding 5 ml of 13% sodium hypochlorite aqueous solution, controlling the temperature to be 25 ℃, stirring for reaction, after the reaction is finished, adding 80 ml of 10% sodium metabisulfite aqueous solution, concentrating, performing water precipitation, filtering, refining and drying to obtain 45 g of refined debrominated substance (hydrocortisone acetate), wherein the HPLC content is 99.2% and the yield is 90.0%.
2) And (3) hydrolysis reaction: dissolving 45 g of the refined debrominated substance (hydrocortisone acetate) in a mixed organic solvent of 250 ml of dichloromethane and 200 ml of isopropanol, cooling to-10 ℃, adding 45 g of IRA-400 resin, stirring for reaction, filtering after the reaction is finished, concentrating the filtrate to remove the organic solvent, cooling for crystallization, filtering, and drying to obtain 37.6 g of hydrocortisone, wherein the melting point of the product is 212.2-213.5 ℃, the HPLC content is 99.6%, and the total mass yield is 75.2%.
Example 2
Preparation method of hydrocortisone
1) Dissolving 50 g of crude debrominated substance (hydrocortisone acetate) in 250 ml of dichloromethane and 300 ml of ethanol, adding 1.6 ml of glacial acetic acid, dropwise adding 25 ml of 5% sodium hypochlorite aqueous solution, controlling the temperature to be 40 ℃, stirring for reaction, after the reaction is finished, adding 250 ml of 5% sodium metabisulfite aqueous solution, concentrating, performing water precipitation, filtering, refining and drying to obtain 45.5 g of refined debrominated substance (hydrocortisone acetate), wherein the HPLC content is 99.3%, and the yield is 91.0%.
2) And (3) hydrolysis reaction: dissolving 45.5 g of the refined debrominant (hydrocortisone acetate) in 350 ml of dichloromethane and 600 ml of ethanol mixed organic solvent, cooling to 0 ℃, adding 20 g of IRA-400 resin, stirring for reaction, filtering after the reaction is finished, concentrating the filtrate to remove the organic solvent, cooling for crystallization, filtering, and drying to obtain 37.9 g of hydrocortisone, wherein the melting point of the product is 212.6-213.7 ℃, the HPLC content is 99.7%, and the total mass yield is 75.8%.
Example 3
Preparation method of hydrocortisone
1) Dissolving 50 g of crude debrominated substance (hydrocortisone acetate) in 1000 ml of dichloromethane and 500 ml of isopropanol, adding 5 ml of glacial acetic acid, dropwise adding 15 ml of 10% sodium hypochlorite aqueous solution, controlling the temperature to be 15 ℃, stirring for reaction, after the reaction is finished, adding 50 ml of 20% sodium metabisulfite aqueous solution, concentrating, performing water precipitation, filtering, refining and drying to obtain 44.9 g of refined debrominated substance (hydrocortisone acetate), wherein the HPLC content is 99.2% and the yield is 89.8%.
2) And (3) hydrolysis reaction: dissolving 44.9 g of the refined debrominated substance (hydrocortisone acetate) in a mixed solvent of 500 ml of dichloromethane and 800 ml of methanol, cooling to 10 ℃, adding 5g of IRA-400 resin, stirring for reaction, filtering after the reaction is finished, concentrating the filtrate to remove the organic solvent, cooling for crystallization, filtering, and drying to obtain 37.6 g of hydrocortisone, wherein the melting point of the product is 212.2-213.5 ℃, the HPLC content is 99.5%, and the total mass yield is 75.2%.
Comparative example 150 g of crude debrominated substance (hydrocortisone acetate) was dissolved in 300 ml of dichloromethane and 250 ml of methanol, the system temperature was maintained at 30 ℃, 5g of chlorine gas was introduced, the mixture was stirred for half an hour, concentrated, cooled to 0 ℃ and filtered to obtain 40.2 g of refined hydrocortisone acetate with an HPLC content of 95.0% and a mass yield of 80.4%.
Comparative example 2
Dissolving 50 g of crude debrominated substance (hydrocortisone acetate) in 400 ml of dichloromethane and 300 ml of methanol, keeping the temperature of the system at 40 ℃, adding 25 g of sodium hypochlorite and 5g of sodium chloride, dropwise adding 17.5 g of glacial acetic acid, stirring for half an hour after the addition, concentrating, cooling to 5 ℃, and filtering to obtain 40.7 g of hydrocortisone acetate, wherein the HPLC content is 90.0%, and the mass yield is 81.4%.
The content and yield ratios of hydrocortisone acetate and impurities in the HPLC charts in each example and comparative example are shown in Table 1.
Table 1: content and yield of hydrocortisone acetate and impurities in high performance liquid chromatography in each example and comparative example
As can be seen from the data in table 1: the hydrocortisone acetate prepared by the preparation method has the content higher than 99.2 percent and the impurity (anecortave acetate) content lower than 0.02 percent; the impurity content (anecortave acetate) in the hydrocortisone acetate obtained by the preparation method (comparative examples 1-2) reported in the literature is more than 0.15%, and the content of other impurities is obviously higher than that of the preparation method disclosed by the invention.
In addition, in terms of yield, it can be seen from the data in table 1 that the yields of examples 1 to 3 of the present invention are significantly better than those of comparative examples 1 to 2.
The raw materials and equipment used in the invention are common raw materials and equipment in the field if not specified; the methods used in the present invention are conventional in the art unless otherwise specified.
The above description is only a preferred embodiment of the present invention, and is not intended to limit the present invention, and all simple modifications, alterations and equivalents of the above embodiments according to the technical spirit of the present invention are still within the protection scope of the technical solution of the present invention.
Claims (6)
1. A preparation method of hydrocortisone is characterized by comprising the following steps:
the method specifically comprises the following steps:
1) Impurity removal reaction: dissolving a hydrocortisone acetate crude product in an organic solvent A, adding glacial acetic acid, controlling the temperature to be 15-40 ℃, dropwise adding a sodium hypochlorite aqueous solution, continuously stirring for reaction after dropwise adding, adding a sodium metabisulfite aqueous solution after the reaction is completed, concentrating, elutriating, filtering to obtain a wet product, and refining the wet product once by using the organic solvent A to obtain a hydrocortisone acetate fine product; the mass concentration of the sodium hypochlorite aqueous solution is 5-13%, and the volume consumption of the sodium hypochlorite aqueous solution is 0.1-0.5 time of that of the hydrocortisone acetate crude product; the organic solvent A is a mixed solvent of dichloromethane and at least one alcohol of methanol, ethanol or isopropanol, and the volume ratio of the dichloromethane to the alcohol is 1:0.5 to 3;
2) And (3) hydrolysis reaction: dissolving the fine hydrocortisone acetate product obtained in the step 1) in an organic solvent A, cooling to-10 ℃, adding IRA-400 resin, stirring for reaction, filtering after the reaction is finished, concentrating the filtrate to remove the organic solvent, cooling for crystallization, filtering, and drying to obtain a finished hydrocortisone product.
2. The method of claim 1, wherein: in step 1): the volume dosage of the organic solvent A is 10-30 times of the crude hydrocortisone acetate product.
3. The method of claim 1, wherein: in step 1): the volume dosage of the glacial acetic acid is 0.03-0.1 time of that of the hydrocortisone acetate crude product.
4. The method of claim 1, wherein: in step 1): the mass concentration of the sodium metabisulfite aqueous solution is 5-20%, and the volume consumption of the sodium metabisulfite aqueous solution is 1-5 times of that of the crude hydrocortisone acetate product.
5. The method of claim 1, wherein: in the step 2): the volume dosage of the organic solvent A is 10-30 times of that of the fine hydrocortisone acetate.
6. The production method according to claim 1 or 5, characterized in that: in step 2): the weight consumption of the IRA-400 resin is 0.1-1 time of that of the fine hydrocortisone acetate.
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