CN108047299B

CN108047299B - Preparation method of important intermediate of canrenone

Info

Publication number: CN108047299B
Application number: CN201711487970.9A
Authority: CN
Inventors: 蒋青锋; 李家宝
Original assignee: Guangxi Wande Pharmaceutical Co ltd
Current assignee: Guangxi Wande Pharmaceutical Co ltd
Priority date: 2017-12-29
Filing date: 2017-12-29
Publication date: 2021-11-09
Anticipated expiration: 2037-12-29
Also published as: CN108047299A

Abstract

The invention provides a preparation method of an important intermediate of canrenone, which comprises the following steps: adding the compound I into a reaction container, adding a mixed solvent and a buffer solution, cooling to-80 to-30 ℃, slowly adding dichlorodicyanobenzoquinone, reacting for 1-3 hours at-80 to-30 ℃, adding an alkali solution to stop the reaction after the reaction is finished, and performing post-treatment operation to obtain a compound II. The preparation process provided by the invention overcomes the defects that in the prior art, when tetrachlorocyanquinone and dichlorodicyanoquinone are used as reducing agents in the dehydrogenation reaction process, impurity compounds III and IV are generated due to poor selectivity, so that the content of impurities in the product is high and the yield is low.

Description

Preparation method of important intermediate of canrenone

Technical Field

The invention belongs to the field of medicine preparation, and particularly relates to a preparation method of an important intermediate of canrenone.

Background

Canrenone (canrenone), chemically 17 β -hydroxy-3-oxo-17 α -pregna-4, 6-diene-21-carboxylic acid-Y-lactone, is a commonly used diuretic and also an important intermediate in the synthesis of the aldosterone receptor antagonist spironolactone. The canrenone can also be widely applied to the preparation of important body retention raw material medicines such as the cardiovascular disease medicine-eplerenone and the like. The compound II is an important intermediate in the production process of canrenone, and the synthesis method thereof has the following side reactions due to poor selectivity by using tetrachlorocyanquinone and dichlorodicyanoquinone as reducing agents reported in documents:

meanwhile, after dichloro dicyano benzoquinone reacts, acidic DDHQ is generated, and a substrate compound I is hydrolyzed, wherein the reaction is as follows:

the compound III and the compound IV react at normal temperature, and the purity of each compound III and compound IV is about 4 percent, so that the subsequent production is greatly influenced. Patent CN105037475A discloses a similar dehydrogenation method using tetrachlorobenzoquinone or dichlorodicyanobenzoquinone as a reducing agent, which has the following reaction formula:

in the reaction, dichlorodicyanobenzoquinone is used as a reducing agent, but side reactions which similarly generate impurity compounds III and IV are not explained, and the purity is greatly influenced in actual production. In the related literature, no report is made on the use of a buffer reagent for inhibiting the compound IV.

The above background disclosure is only for the purpose of assisting understanding of the inventive concept and technical solutions of the present invention, and does not necessarily belong to the prior art of the present patent application, and should not be used for evaluating the novelty and inventive step of the present application in the case that there is no clear evidence that the above content is disclosed at the filing date of the present patent application.

Disclosure of Invention

The invention aims to solve the technical problem of providing a preparation method of an important intermediate of canrenone, so as to overcome the defects that in the prior art, when tetrachlorocyanquinone and dichlorodicyanoquinone are used as reducing agents in the dehydrogenation reaction process, impurity compounds III and IV are generated due to poor selectivity, so that the impurity content is high, and the product yield is reduced.

The invention is realized by the following technical scheme.

The preparation method of the important intermediate of canrenone comprises the following steps: adding the compound I into a reaction container, adding a mixed solvent and a buffer solution, cooling to-80 to-30 ℃, slowly adding dichlorodicyanobenzoquinone, reacting for 1-3 hours at-80 to-30 ℃, adding an alkali solution to stop the reaction after the reaction is finished, and performing post-treatment operation to obtain a compound II.

Further, the structural formula of the compound I is as follows:

further, the structural formula of the compound II is as follows:

further, the reaction for obtaining the compound ii involves a chemical reaction equation as follows:

furthermore, the feeding ratio of the compound I to the mixed solvent is that the mass-to-volume ratio of the compound I (g) to the mixed solvent (ml) is 1: 5-10.

Furthermore, the mixed solvent comprises toluene and acetone, and the input amount of the toluene and the acetone is 1: 1-2 according to the volume ratio.

Further, the buffer solution is a phosphate buffer solution with the pH value of 8-10,

further, the compound I and the buffer solution are added in a weight ratio of 1: 0.1-1

Furthermore, the charging amount of the compound I and the dichlorodicyano benzoquinone is that the compound I and the dichlorodicyano benzoquinone are 1: 0.5-2 in weight ratio.

Furthermore, the compound I and the dichlorodicyano benzoquinone are added in a weight ratio of 1: 1.

Further, the alkali liquor is 1-5% sodium hydroxide solution.

The invention has the beneficial effects that:

1. in the prior art, when tetrachlorocyanquinone and dichlorodicyanoquinone are used as reducing agents in a dehydrogenation reaction process, due to poor selectivity, impurities 1 (compound III) and 2 (compound IV) with the contents respectively accounting for 4% are generated, so that the impurity content is high, and the product yield is reduced.

2. The preparation method has low requirement on equipment, is easy for industrial production and operation, simultaneously provides TLC tracking reaction, has simple operation requirement, and can effectively judge the end point of the reaction.

Drawings

FIG. 1 is a reaction equation of a preparation method of an important intermediate of canrenone according to the present invention;

FIG. 2 is a liquid chromatogram of the final product of example 1 according to the present invention.

Detailed Description

The technical solution of the present invention is further described below, but the scope of the claimed invention is not limited to the described.

The structural formula of compound i described in examples 1-3 is as follows:

the structural formula of the compound II is as follows:

the preparation method of the important intermediate of canrenone is used for preparing a compound II, and the chemical reaction equation is as follows:

example 1

The preparation method of the canrenone important intermediate as shown in figure 1 comprises the following steps: adding 30g of the compound I, 100ml of toluene, 200ml of acetone and 30ml of phosphate buffer (pH is 10) into a three-neck flask, cooling to-80 ℃, slowly adding 60g of dichlorodicyanoquinone, keeping the temperature for reaction for 3 hours, after TLC (PE: EA is 4:1) shows that the reaction is complete (no spot of the compound I), adding 60ml of 5% sodium hydroxide solution, stirring for 2 hours, carrying out suction filtration, rinsing with water until the filtrate is neutral, taking out a filter cake, and drying.

26.4g of product was obtained in 88% yield with 98.1% purity as shown in FIG. 2 and with 0.16% and 0.61% for impurity 1 (compound III) and impurity 2 (compound IV), respectively.

Example 2

The preparation method of the canrenone important intermediate as shown in figure 1 comprises the following steps: adding 50g of compound I, 100ml of toluene, 150ml of acetone and 5ml of phosphate buffer solution (pH 8) into a three-neck flask, cooling to-30 ℃, slowly adding 25g of dichlorodicyanobenzoquinone, carrying out heat preservation reaction at-30 ℃ for 1h, after TLC (PE: EA: 4:1) shows that the reaction is complete (no compound I spots), adding 1000ml of 1% sodium hydroxide solution, stirring for 1h, carrying out suction filtration, rinsing with water until the filtrate is neutral, taking out a filter cake, and drying.

43.5g of the product was obtained in 87% yield and 97.8% purity, with the contents of impurity 1 (compound III) and impurity 2 (compound IV) being 0.22% and 0.79%, respectively.

Example 3

The preparation method of the canrenone important intermediate as shown in figure 1 comprises the following steps: adding 100g of compound I, 350ml of toluene, 450ml of acetone and 100ml of phosphate buffer (pH is 9) into a three-neck flask, cooling to-50 ℃, slowly adding 100g of dichlorodicyanoquinone, keeping the temperature for reaction for 1.5h, adding 2000ml of 3% sodium hydroxide solution after TLC (PE: EA is 4:1) shows that the reaction is complete (no compound I spots), stirring for 1.5h, performing suction filtration, rinsing with water until the filtrate is neutral, taking out a filter cake, and drying.

91.2g of the product was obtained in 91.2% yield with a purity of 98.9% and contents of impurity 1 (compound III) and impurity 2 (compound IV) of 0.15% and 0.43%, respectively.

Comparative example 1

No buffer was added and the remaining conditions were as in example 3.

84.2g of the product was obtained with a yield of 84.2% and a purity of 92.1%, the contents of impurity 1 (compound III) and impurity 2 (compound IV) being 3.5% and 3.8%, respectively.

From the analysis of the yield and purity of the products obtained in examples 1 to 3 and the experimental results of comparative example 1, it is apparent that the yield is significantly improved, the purity is higher, and the content of impurities is lower in examples 1 to 3 and comparative example 1, because the salt buffer is added to assist the dehydrogenation process, the conversion of the compound i into the

impurities

1 and 2 is inhibited, and the conversion of the compound i into the product (compound ii) is further promoted, so that the yield is improved, and the purity of the product is improved.

The foregoing is a more detailed description of the invention in connection with specific/preferred embodiments and is not intended to limit the practice of the invention to those descriptions. It will be apparent to those skilled in the art that various substitutions and modifications can be made to the described embodiments without departing from the spirit of the invention, and such substitutions and modifications are to be considered as within the scope of the invention.

Claims

1. The preparation method of the important intermediate of canrenone is characterized by comprising the following steps: adding a compound I into a reaction container, adding a mixed solvent and a buffer solution, cooling to minus 80 ℃ to minus 30 ℃, slowly adding dichlorodicyanobenzoquinone, reacting for 1-3 hours at minus 80 ℃ to minus 30 ℃, adding an alkali solution to stop the reaction after the reaction is finished, and performing post-treatment operation to obtain a compound II;

the feeding ratio of the compound I to the mixed solvent is that the compound I g and the mixed solvent ml =1: 5-10 according to the mass-volume ratio;

the mixed solvent comprises toluene and acetone, and the input amount of the toluene and the acetone is that the ratio of toluene to acetone =1: 1-2 according to the volume ratio;

the buffer solution is a phosphate buffer solution with the pH = 8-10;

the compound I and the buffer solution are added in a weight ratio of compound I to buffer solution =1: 0.1-1;

the feeding amount of the compound I and the dichloro dicyano benzoquinone is that the compound I and the dichloro dicyano benzoquinone are in a weight ratio of =1: 0.5-2;

the alkali liquor is 1-5% sodium hydroxide solution;

the structural formula of the compound I is as follows:

；

the structural formula of the compound II is as follows:

。

2. the method for preparing the important intermediate of canrenone as claimed in claim 1, wherein the reaction for obtaining the compound II involves the chemical reaction equation:

。

3. the method for preparing the important intermediate of canrenone according to claim 1, wherein the compound I and the dichlorodicyanoquinone are added in a weight ratio of compound I to dichlorodicyanoquinone =1: 1.