CN110698529A - Preparation method of eplerenone intermediate △ 9,11 alkenyl ester - Google Patents
Preparation method of eplerenone intermediate △ 9,11 alkenyl ester Download PDFInfo
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- C07J—STEROIDS
- C07J21/00—Normal steroids containing carbon, hydrogen, halogen or oxygen having an oxygen-containing hetero ring spiro-condensed with the cyclopenta(a)hydrophenanthrene skeleton
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Abstract
The invention provides a preparation method of an eplerenone intermediate △,11 alkenyl ester, which comprises the steps of carrying out esterification reaction on raw materials and methanesulfonyl chloride to generate mesylate, and carrying out elimination reaction on the mesylate to obtain the eplerenone intermediate.
Description
Technical Field
The invention relates to the technical field of pharmacy, in particular to a preparation method of eplerenone intermediate △ 9,11 enol ester.
Background
Eplerenone (Eplerenone), prepared in 1984 by Ciba-GeigyAg of Switzerland, was approved by the FDA in 2002 and first marketed in 2004 in the United states under the trade name Inspra. Eplerenone is a selective aldosterone receptor antagonist and is mainly used as a medicament for the treatment of essential hypertension and post-myocardial infarction heart failure. It has good selectivity to aldosterone, long half-life and good tolerance. Eplerenone can increase survival in patients with congestive heart failure after an acute heart attack.
Canrenone is a raw material for producing spironolactone, has a production history of decades, and is mature in process. The common synthesis method of eplerenone is to adopt canrenone as a raw material, introduce hydroxyl group through fermentation to obtain 11 a-hydroxycarenone, and then synthesize eplerenone by taking 11 a-hydroxycarenone as a raw material, wherein the process route is as follows:
in the above synthetic route, compound I is required to be subjected to dehydroxylation to obtain compound III, the process is disclosed in WO1997021720A2, wherein compound I is reacted with methanesulfonyl chloride to generate methanesulfonate, and the methanesulfonate is removed from formic acid, acetic anhydride and potassium formate to obtain 82.1% of compound III, and the product contains 7.4% of △ 11,12 alkenyl ester and 5.7% of lactone and other impurities.
The impurity has the following structural formula:
other methods of desulfonation, such as elimination of the mesylate with acetic acid and sodium acetate at 100 deg.C, are also taught in WO1997021720A2 to provide 70.4% of compound III, a product containing 12.3% of △ 11,12 alkenyl ester and 10.8% of lactone as impurities and 5.7% of unreacted starting materials, and elimination of the mesylate by heating, such as △ 11,12 alkenyl ester and lactone, are all very substantial.
In patent document CN1749266A, the preparation of compound III from compound I is described by eliminating the 11 a-hydroxy group with phosphorus oxychloride or phosphorus pentachloride. The yield is 60 percent when phosphorus oxychloride is adopted to eliminate hydroxyl, and 45 percent when phosphorus pentachloride is adopted to eliminate hydroxyl, and the yields of the two methods are too low and have no industrial significance. The process route is as follows:
in patent document CN104725461A, the above dehydroxylation process is improved, and the use of boron trihalide and phosphorus pentachloride for dehydroxylation can reduce the generation of △ 11,12 alkene ester and lactone impurities, for the process, the inventors have carried out experimental verification, and the verification result shows that a large amount of raw materials are degraded in the process of preparing compound III from compound I, the generated impurities are more, the reaction selectivity is not good, and the yield is only 60-70%, so the process does not have the conditions of large-scale industrial production.
Disclosure of Invention
In view of the above, the present invention aims to provide a method for preparing eplerenone intermediate △ 9,11 alkenyl ester, so as to solve the technical problems of low yield and many impurities in the preparation process of eplerenone intermediate △ 9,11 alkenyl ester.
In view of the above, the present invention provides a process for preparing eplerenone intermediate △ 9,11 alkenyl ester, comprising:
carrying out esterification reaction on the raw material and methanesulfonyl chloride to generate mesylate;
the mesylate is subjected to elimination reaction to obtain eplerenone intermediate △ 9,11 alkenyl ester;
wherein the structural formula of the raw material is
The structural formula of the mesylate is
The structural formula of eplerenone intermediate △ 9,11 alkenyl ester is shown in the specification
In some embodiments of the invention, the starting material is reacted with methanesulfonyl chloride to form a mesylate by an esterification reaction comprising:
putting the raw materials into an organic solvent, adding methanesulfonyl chloride and an acid-binding agent, and carrying out esterification reaction to generate mesylate.
In some embodiments of the present invention, the organic solvent is selected from one of dichloromethane, chloroform, dichloroethane, n-hexane, n-heptane, toluene, acetonitrile, tetrahydrofuran, dioxane.
In some embodiments of the present invention, the acid scavenger is selected from one of triethylamine, N-methylmorpholine, pyridine, imidazole, diisopropylethylamine, dimethylaminopyridine, sodium carbonate, potassium carbonate, and sodium bicarbonate.
In some embodiments of the invention, the mass ratio of the acid-binding agent to the intermediate raw material is 0.2-1: 1.
In some embodiments of the present invention, the esterification reaction is carried out at a temperature of 0 to 30 ℃ for 1 to 5 hours.
In some embodiments of the invention, the mesylate ester is eliminated to provide eplerenone intermediate △ 9,11 alkenyl ester, comprising:
the mesylate was placed in trifluoroacetic acid solvent and base and anhydride were added to provide eplerenone intermediate △ 9,11 alkenyl ester by elimination.
In some embodiments of the invention, the alkali is selected from one of potassium acetate, sodium acetate, potassium formate, sodium bicarbonate and potassium bicarbonate, and the mass ratio of the alkali to the mesylate is 0.2-2: 1.
In some embodiments of the invention, the acid anhydride is selected from one of acetic anhydride, trifluoroacetic anhydride and methanesulfonic anhydride, and the mass ratio of the acid anhydride to the methanesulfonic acid ester is 0.5-2: 1.
In some embodiments of the present invention, the temperature of the elimination reaction is 20 to 60 ℃ and the reaction time is 15 to 30 hours.
From the above, it can be seen that the preparation method of eplerenone intermediate △ 9,11 alkenyl ester provided in the embodiment of the present invention starts from raw materials, reacts with methanesulfonyl chloride to obtain methanesulfonate, and efficiently eliminates methanesulfonate under the action of alkali and acetic anhydride in a trifluoroacetic acid solvent, so that △ 9,11 alkenyl ester (i.e., eplerenone intermediate) is obtained, the obtained product has high yield and good product purity, and △ 11,12 alkenyl ester and lactone generated by the reaction have small impurities, so that the method is a method for efficiently eliminating methanesulfonate.
Compared with the prior art, the method has the advantages that the process yield is about 90 percent, and the product purity is obviously higher than the purity reported in the prior literature, the △ 11,12 alkenyl ester and lactone generated in the embodiment of the invention have fewer impurities and high yield, are an economic and environment-friendly synthetic route, are greatly improved on the prior art, and are suitable for industrial production.
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more apparent, the present invention is further described in detail with reference to specific embodiments below.
It is to be noted that technical terms or scientific terms used in the embodiments of the present invention should have the ordinary meanings as understood by those having ordinary skill in the art to which the present disclosure belongs, unless otherwise defined. The use of "first," "second," and similar terms in this disclosure is not intended to indicate any order, quantity, or importance, but rather is used to distinguish one element from another.
The embodiment of the invention provides a preparation method of eplerenone intermediate △ 9,11 alkenyl ester, which comprises the steps of carrying out esterification reaction on raw materials and methanesulfonyl chloride to generate mesylate, and carrying out elimination reaction on the mesylate to obtain eplerenone intermediate △ 9,11 alkenyl ester.
Wherein the structural formula of the raw material is
The structural formula of the mesylate is
The structural formula of eplerenone intermediate △ 9,11 alkenyl ester is shown in the specification
The eplerenone intermediate △,11 alkenyl ester with less impurities can be obtained through esterification reaction and elimination reaction, and the method has the advantages of short route, high yield and low cost, and is suitable for industrial production.
Alternatively, the starting material is reacted with methanesulfonyl chloride by an esterification reaction to produce a mesylate comprising: putting the raw materials into an organic solvent, adding methanesulfonyl chloride and an acid-binding agent, and carrying out esterification reaction to generate mesylate. In the embodiment of the invention, raw materials are used as substrates, and the raw materials and methanesulfonyl chloride are subjected to a heat preservation reaction in an organic solvent in the presence of methanesulfonyl chloride and an acid-binding agent to generate an esterification reaction to generate the mesylate. Optionally, the organic solvent is selected from one of dichloromethane, trichloromethane, dichloroethane, n-hexane, n-heptane, toluene, acetonitrile, tetrahydrofuran, dioxane, preferably dichloromethane and trichloromethane. Optionally, the mass ratio of the organic solvent to the intermediate raw material is 2-10: 1. Optionally, the acid-binding agent is selected from one of triethylamine, N-methylmorpholine, pyridine, imidazole, diisopropylethylamine, dimethylaminopyridine, sodium carbonate, potassium carbonate and sodium bicarbonate, and triethylamine is preferred. Optionally, the mass ratio of the acid-binding agent to the intermediate raw material is 0.2-1: 1. Optionally, the reaction temperature of the esterification reaction in the step is 0-30 ℃, and the reaction time is 1-5 hours.
Alternatively, the mesylate is subjected to elimination to provide an eplerenone intermediate comprising placing the mesylate in trifluoroacetic acid solvent, adding a base and an anhydride, and subjecting the mesylate to elimination to provide an eplerenone intermediate △ 9,11 enol ester.
According to the method, methanesulfonic acid ester is used as a substrate, and the thermal insulation reaction is carried out in trifluoroacetic acid solvent under the action of alkali and acid anhydride, so that eplerenone intermediate △ 9,11 alkene ester is obtained.
To aid in understanding the protocol of the present invention, several specific preparative procedures are set forth below. The various chemicals and reagents used in the examples were all commercially available unless otherwise specified.
Example 1:
this example provides a method for preparing eplerenone intermediate △ 9,11 alkenyl ester, comprising the steps of:
step (1) esterification reaction
150ml of dichloromethane, 25g of raw materials and 12g of triethylamine are added into a three-neck flask, stirred and dissolved, and nitrogen is introduced to exhaust air. And cooling the system to 10-15 ℃, dripping 8.8g of methanesulfonyl chloride, and keeping the temperature for reacting for 2 hours after dripping. The reaction was followed by TLC and was complete. Adding 75ml of water to quench the reaction, carrying out layering, extracting a water layer for 1 time by using 50ml of dichloromethane, combining organic phases, washing for 1 time by using water, steaming to a small amount, adding 75ml of isopropyl ether, separating out a large amount of white solid, filtering to obtain mesylate, and drying to obtain 29 g. Yield 97.7% and purity 98.2% (HPLC).
Step (2) Elimination reaction
Adding 12g of potassium acetate, 100ml of trifluoroacetic acid and 20ml of acetic anhydride into a three-necked bottle, introducing nitrogen to exhaust air, heating the system to 40-45 ℃, stirring for 2h, adding 20g of methanesulfonate, carrying out heat preservation reaction for 20 h, carrying out TLC tracking reaction, completely reacting, adding 200ml of water, quenching the reaction, adding 80ml of ethyl acetate, layering, extracting a water layer for 2 times by using 40ml of ethyl acetate 2, combining organic phases, washing for 1 time by using water, steaming to a small amount, adding 60ml of isopropyl ether, separating out a large amount of white-like solid, filtering to obtain an eplerenone intermediate, drying to obtain 14.5g of an eplerenone intermediate, obtaining a product with the yield of 90%, the product purity of 91.6%, △ 11, 3.62% of 12-alkenyl ester and 1.86% of lactone (HPLC).
Example 2:
the embodiment provides a preparation method of eplerenone intermediate △ 9,11 alkenyl ester, which is different from the preparation method of embodiment 1 in that 140ml of trichloromethane, 20g of raw material and 10g of N-methylmorpholine are added into a three-neck flask in step (1), the mixture is stirred and dissolved clearly, nitrogen is introduced to exhaust air, the temperature of the system is reduced to 5-10 ℃, 6.2g of methanesulfonyl chloride is dripped, after dripping, the heat preservation reaction is carried out for 3.5 hours, 23.4g of methanesulfonate is finally obtained, the yield is 98.5%, and the purity is 98.6% (HPLC).
Example 3:
the embodiment provides a preparation method of eplerenone intermediate △ 9,11 alkenyl ester, which is different from the preparation method of embodiment 1 in that 160ml of n-hexane, 28g of raw material and 18g of imidazole are added into a three-neck flask in step (1), the mixture is stirred, dissolved and cleared, nitrogen is introduced to exhaust air, the temperature of the system is reduced to 20-25 ℃, 7.5g of methanesulfonyl chloride is dripped, the reaction is carried out for 1.5 hours after dripping, 28.8g of methanesulfonate is finally obtained, the yield is 86.6%, and the purity is 97.4% (HPLC).
Example 4:
the embodiment provides a preparation method of eplerenone intermediate △ 9,11 alkenyl ester, which is different from the preparation method of embodiment 1 in that in step (1), 120ml of dioxane, 26g of raw material and 26g of potassium carbonate are added into a three-neck flask, the mixture is stirred, dissolved and cleared, nitrogen is introduced to exhaust air, the temperature of the system is reduced to 0-8 ℃, 7g of methanesulfonyl chloride is dripped, the temperature is kept for 5 hours after dripping, 27.8g of methanesulfonate is finally obtained, the yield is 90.0%, and the purity is 98.7% (HPLC).
Example 5:
the embodiment provides a preparation method of eplerenone intermediate △ 9,11 alkenyl ester, which is different from the preparation method of embodiment 1 in that in step (1), 155ml of toluene, 22g of raw material and 5g of diisopropylethylamine are added into a three-neck flask, the mixture is stirred and dissolved clearly, nitrogen is introduced to the three-neck flask to exhaust air, the temperature of the system is reduced to 5-10 ℃, 8g of methanesulfonyl chloride is dripped, the temperature is kept for reaction for 3 hours after dripping, and finally 24.4g of methanesulfonate is obtained, the yield is 93.4%, and the purity is 98.4% (HPLC).
Example 6:
the embodiment provides a preparation method of eplerenone intermediate △ 9,11 alkenyl ester, which is different from the preparation method of embodiment 1 in that in step (2), 15g of sodium acetate, 80ml of trifluoroacetic acid and 22ml of acetic anhydride are added into a three-neck flask, nitrogen is introduced to exhaust air, the system is heated to 30-35 ℃ and stirred for 2.5h, 20g of methanesulfonate is added, the heat preservation reaction is carried out for 25 h, TLC tracking reaction is carried out, 200ml of water is added to quench the reaction, 80ml of ethyl acetate is added to carry out layering, a water layer is extracted for 2 times by 40ml of ethyl acetate 2, an organic phase is combined, water is used for washing for 1 time, evaporation is carried out till a small amount is obtained, 60ml of isopropyl ether is added to precipitate a large amount of white-like solid, filtration is carried out to obtain an eplerenone intermediate, drying is carried out to obtain 14.9g, yield 92.5%, product purity is 90.3%, △ 11,12 alkenyl ester is 2.79%, and lactone is 1.57% (.
Example 7:
the embodiment provides a preparation method of eplerenone intermediate △ 9,11 alkenyl ester, which is different from the preparation method of embodiment 1 in that 12g of sodium formate, 90ml of trifluoroacetic acid and 26.5ml of trifluoroacetic anhydride are added into a three-neck flask in step (2), nitrogen is introduced to exhaust air, the temperature of the system is raised to 20-30 ℃, stirring is carried out for 2h, 20g of methanesulfonate is added, the temperature is kept for reaction for 15 h, 14.6g of eplerenone intermediate is finally obtained, the yield is 90.6%, the product purity is 89.7%, △ 11,12 alkenyl ester is 3.72%, and lactone is 2.86% (HPLC).
Example 8:
the embodiment provides a preparation method of eplerenone intermediate △ 9,11 alkenyl ester, which is different from the preparation method of embodiment 1 in that in step (2), 13.5g of potassium bicarbonate, 80ml of trifluoroacetic acid, 20ml of trifluoroacetic anhydride are added into a three-neck flask, nitrogen is introduced to exhaust air, the temperature of the system is raised to 55-60 ℃, stirring is carried out for 1.5h, 20g of mesylate is added, the temperature is kept for 18 h, 14.1g of eplerenone intermediate is finally obtained, the yield is 87.5%, the product purity is 91.2%, △ 11,12 alkenyl ester is 2.58%, and lactone is 2.12% (HPLC).
Example 9:
the embodiment provides a preparation method of eplerenone intermediate △ 9,11 alkenyl ester, which is different from the preparation method of embodiment 1 in that in step (2), 14g of potassium acetate, 100ml of trifluoroacetic acid and 28ml of methanesulfonic anhydride are added into a three-necked bottle, nitrogen is introduced to exhaust air, the temperature of the system is raised to 28-33 ℃, stirring is carried out for 2 hours, 20g of methanesulfonic acid ester is added, the temperature is kept for reaction for 18 hours, 13.9g of eplerenone intermediate is finally obtained, the yield is 86.2%, the product purity is 90.3%, △ 11,12 alkenyl ester is 3.66%, and lactone is 2.71% (HPLC).
Example 10:
the embodiment provides a preparation method of eplerenone intermediate △ 9,11 alkenyl ester, which is different from the preparation method of embodiment 1 in that 16g of potassium formate, 100ml of trifluoroacetic acid and 15ml of acetic anhydride are added into a three-neck flask in step (2), nitrogen is introduced to exhaust air, the temperature of the system is raised to 50-58 ℃ and stirred for 3h, 20g of mesylate is added, and the reaction is kept for 30 h, so that 14.7g of eplerenone intermediate is finally obtained, the yield is 91.2%, the product purity is 91.1%, △ 11,12 alkenyl ester is 2.82%, and lactone is 2.05% (HPLC).
Comparative example 1: elimination reaction
Adding DMF60ml, mesylate 20g, potassium acetate 20g, introducing nitrogen to exhaust air, heating the system to 100-105 ℃ for reaction for 6 hours, detecting the reaction of the raw materials by TLC, pouring into 400ml of water for water precipitation, filtering, washing with water, and drying to obtain the eplerenone intermediate 15.8g, the yield 98.1%, the purity 68.4%, △ 11,12 alkenyl ester 23.7%, and lactone 1.4% (HPLC).
Comparative example 2: elimination reaction
60ml of glacial acetic acid, 20g of mesylate, 20g of sodium acetate and nitrogen are added into a three-neck flask to exhaust air, the system is heated to 105-110 ℃ to react for 9 hours, TLC detects that the raw materials are completely reacted, the raw materials are poured into 400ml of water to be separated out by water, filtered, washed by water and dried to obtain 15.2g of eplerenone intermediate, the yield is 94.3%, the purity is 72.3%, △ 11, 12-alkenyl ester is 14.9%, lactone is 6.7% and mesylate is 3.6% (HPLC).
The preparation method of eplerenone intermediate △ 9,11 alkenyl ester provided by the embodiment of the invention starts from an intermediate raw material, reacts with methanesulfonyl chloride to obtain methanesulfonate, and efficiently eliminates the methanesulfonate under the action of alkali and acetic anhydride in a trifluoroacetic acid solvent, so that △ 9,11 alkenyl ester (namely eplerenone intermediate) is obtained, the obtained product has high yield and good product purity, and △ 11,12 alkenyl ester and lactone generated by the reaction have small impurities, so that the method is a method for efficiently eliminating the methanesulfonate.
Compared with the prior art, the method has the advantages that the process yield is about 90 percent, and the product purity is obviously higher than the purity reported in the prior literature, the △ 11,12 alkenyl ester and lactone generated in the embodiment of the invention have fewer impurities and high yield, are an economic and environment-friendly synthetic route, are greatly improved on the prior art, and are suitable for industrial production.
Those of ordinary skill in the art will understand that: the discussion of any embodiment above is meant to be exemplary only, and is not intended to intimate that the scope of the disclosure, including the claims, is limited to these examples; within the idea of the invention, also features in the above embodiments or in different embodiments may be combined, steps may be implemented in any order, and there are many other variations of the different aspects of the invention as described above, which are not provided in detail for the sake of brevity.
The embodiments of the invention are intended to embrace all such alternatives, modifications and variances that fall within the broad scope of the appended claims. Therefore, any omissions, modifications, substitutions, improvements and the like that may be made without departing from the spirit and principles of the invention are intended to be included within the scope of the invention.
Claims (10)
1. A method for preparing eplerenone intermediate △ 9,11 alkenyl ester, comprising:
carrying out esterification reaction on the raw material and methanesulfonyl chloride to generate mesylate;
the mesylate is subjected to elimination reaction to obtain eplerenone intermediate △ 9,11 alkenyl ester;
wherein the structural formula of the raw material is
The structural formula of the mesylate is
The structural formula of eplerenone intermediate △ 9,11 alkenyl ester is shown in the specification
2. The process for preparing eplerenone intermediate △ 9,11 alkenyl ester of claim 1, wherein the esterification of a starting material with methanesulfonyl chloride to form a mesylate comprises:
putting the raw materials into an organic solvent, adding methanesulfonyl chloride and an acid-binding agent, and carrying out esterification reaction to generate mesylate.
3. The method of claim 2, wherein the organic solvent is selected from the group consisting of dichloromethane, chloroform, dichloroethane, n-hexane, n-heptane, toluene, acetonitrile, tetrahydrofuran, and dioxane.
4. The method of claim 2, wherein the acid-binding agent is selected from the group consisting of triethylamine, N-methylmorpholine, pyridine, imidazole, diisopropylethylamine, dimethylaminopyridine, sodium carbonate, potassium carbonate, and sodium bicarbonate.
5. The method for preparing eplerenone intermediate △ 9,11 alkenyl ester according to claim 2, wherein a mass ratio of the acid-binding agent to the intermediate raw material is 0.2-1: 1.
6. The method of claim 2, wherein the esterification reaction is carried out at a temperature of 0-30 ℃ for 1-5 hours.
7. The process for the preparation of eplerenone intermediate △ 9,11 alkenyl ester of claim 1 wherein the mesylate ester is subjected to elimination to provide eplerenone intermediate △ 9,11 alkenyl ester comprising:
and (3) putting the mesylate in a trifluoroacetic acid solvent, adding a base and an acid anhydride, and obtaining an eplerenone intermediate through elimination reaction.
8. The method for preparing the eplerenone intermediate △ 9,11 alkenyl ester according to claim 7, wherein the base is one selected from the group consisting of potassium acetate, sodium acetate, potassium formate, sodium bicarbonate, and potassium bicarbonate, and a mass ratio of the base to the mesylate is 0.2-2: 1.
9. The method for preparing the △ 9,11 ene ester as an eplerenone intermediate according to claim 7, wherein the acid anhydride is one selected from acetic anhydride, trifluoroacetic anhydride and methanesulfonic anhydride, and the mass ratio of the acid anhydride to the methanesulfonic ester is 0.5-2: 1.
10. The method of claim 7, wherein the elimination reaction is carried out at a temperature of 20-60 ℃ for a time of 15-30 hours.
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| CN104725461A (en) * | 2015-04-02 | 2015-06-24 | 山东新华制药股份有限公司 | Preparation method of eplerenone |
| CN105753930A (en) * | 2016-03-30 | 2016-07-13 | 北京万全德众医药生物技术有限公司 | Synthesizing method of eplerenone |
| CN106349326A (en) * | 2016-07-29 | 2017-01-25 | 北京万全德众医药生物技术有限公司 | Preparation method of eplerenone impurity A |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115433252A (en) * | 2022-08-24 | 2022-12-06 | 浙江亚瑟医药有限公司 | Preparation method of delta 9 (11) -canrenone |
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