Synthesis method of felinone intermediate

Abstract

The invention discloses a synthesis method of a felinone intermediate, and relates to the technical field of medicine synthesis. The synthesis method comprises the following steps: firstly, taking a 500ml four-neck flask, adding 200ml of dichloromethane, adding 40g of 3-hydroxypropionitrile, finally adding 5g of a DMAP solid material, and stirring for 1 hour; continuously dropwise adding 50 g of ketene dimer, and after temperature-controlled dropwise adding is completed, carrying out heat preservation reaction for 2 hours to obtain a reaction solution; and taking the reaction liquid, washing with 200ml of saturated saline solution, preserving heat, taking the lower-layer material, washing with 200ml of purified water, preserving heat, taking the lower-layer material, finally washing with 200ml of saturated saline solution, taking the lower-layer material, distilling, and desolventizing to obtain the target product. The preparation method comprises the following steps: putting 40g of a target product and 200ml of DMF (Dimethyl Formamide) into a 500ml four-mouth flask, stirring, then adding 50g of 4-cyano-2-methoxybenzaldehyde into a constant-pressure dropping funnel and the like; the synthesis method is stable in reaction, low in raw material price, reasonable in synthesis route, basically free of by-products in the synthesis process, and high in target product purity.

Description

Technical Field

[0001] The present invention relates to the technical field of drug synthesis, and particularly to a synthesis method of (Z)-2-cyanoethyl 2-(4-cyano-2-methoxybenzylidene)-3-oxobutyrate. Background Art

[0002] (Z)-2-cyanoethyl 2-(4-cyano-2-methoxybenzylidene)-3-oxobutyrate is an intermediate of finerenone. Finerenone is a non-steroidal selective mineralocorticoid receptor antagonist, which shows in preclinical studies that it can block the harmful effects caused by overactivation of the mineralocorticoid receptor. In diabetic patients, overactivation of the mineralocorticoid receptor is considered to lead to the progression of chronic kidney disease and cardiovascular damage, which may be driven by factors such as metabolism, hemodynamics, or inflammation and fibrosis. The finerenone intermediate can be used to synthesize a series of drugs with anti-diabetic nephropathy effects, such as febuxostat, etc. These drugs can inhibit the renin-angiotensin system, reduce the excretion of urinary protein, thereby protecting kidney function and delaying the progression of diabetic nephropathy;

[0003] Currently, there is no standardized and effective synthesis scheme for the intermediate of finerenone. The preparation cost of this product is high, by-products are easily generated, and the purity is insufficient. Therefore, this scheme proposes a synthesis method for the intermediate of finerenone. Summary of the Invention

[0004] The purpose of the present invention is to provide a synthesis method for the intermediate of finerenone to solve the problems raised in the background art.

[0005] The present invention is achieved through the following technical solutions:

[0006] The present invention provides a synthesis method for the intermediate of finerenone, including the synthesis of ethyl 2-cyanoacetoacetate and the synthesis of (Z)-2-cyanoethyl 2-(4-cyano-2-methoxybenzylidene)-3-oxobutyrate;

[0007] The synthesis method of ethyl 2-cyanoacetoacetate includes the following steps:

[0008] S1: Take a 500 ml four-necked flask. First, add 200 ml of dichloromethane to the four-necked flask, then add 40 g of 3-hydroxypropionitrile, and finally add 5 g of DMAP solid. Stir for 1 hour, and the reaction temperature is 50 °C during the stirring process. After the reaction is completed, cool down to 0 °C;

[0009] S2: Based on the above S1, continue to dropwise add 50 g of diketene. After the temperature control dropping is completed, keep the temperature for reaction for 2 hours to obtain a reaction solution, and then use the GC monitoring method for status monitoring;

[0010] S3: Perform post-treatment. Take the reaction solution, wash it with 200 ml of saturated brine, keep it warm after washing, take the lower layer material, wash it again with 200 ml of purified water, keep it warm, take the lower layer material again, and finally wash it with 200 ml of saturated brine. Take the lower layer material for distillation and desolvation to obtain the target product, and then detect it by HPLC detection method (the product is stored at low temperature);

[0011] The synthesis method of (Z)-2-cyanoethyl 2-(4-cyano-2-methoxybenzylidene)-3-oxobutyrate includes the following steps:

[0012] S4: Put 40 g of the target product obtained in S3 and 200 ml of DMF into a 500 ml four-necked flask, start stirring, and then add 50 g of 4-cyano-2-methoxybenzaldehyde to the constant pressure dropping funnel;

[0013] S5: Drop it into the four-necked flask through the constant pressure dropping funnel and heat it to 80 °C for reaction for 2 hours (monitored by TLC);

[0014] S6: After the reaction is completed, filter. First, add 300 ml of water to the filtrate, then perform the filtration operation. The filter cake obtained after filtration is washed with water, and finally dried to obtain the required product. The content of the obtained product is 98%, and the yield is 90%.

[0015] Preferably, the synthesis reaction formula of ethyl 2-cyanoacetoacetate is:

[0016]

[0017] Preferably, the synthesis reaction formula of (Z)-2-cyanoethyl 2-(4-cyano-2-methoxybenzylidene)-3-oxobutyrate is:

[0018]

[0019] The present invention has the following beneficial effects:

[0020] The synthesis method of the intermediate of finerenone in the present invention has a stable reaction, low raw material prices, a reasonable synthesis route, basically no by-products generated during the synthesis process, high purity of the target product, and high promotion value.

[0021] The synthesis method of the intermediate of finerenone in the present invention generates ethyl 2-cyanoacetoacetate by reacting diketene with 3-hydroxypropionitrile, and then reacts ethyl 2-cyanoacetoacetate with 4-cyano-2-methoxybenzaldehyde to generate the target product. The operation is simple, and the reaction is safe and stable.

[0022] Of course, it is not necessary for any product implementing the present invention to simultaneously achieve all the above-mentioned advantages. Brief Description of the Drawings

[0023] To more clearly illustrate the technical solutions of the embodiments of the present invention, the following will briefly introduce the drawings required for the description of the embodiments. Obviously, the drawings in the following description are only some embodiments of the present invention. For those of ordinary skill in the art, without creative efforts, other drawings can be obtained based on these drawings.

[0024] Figure 1 It is a flow chart of a synthesis method of a non-lynabidone intermediate of the present invention. Detailed Embodiments

[0025] The following will clearly and completely describe the technical solutions in the embodiments of the present invention with reference to the drawings in the embodiments of the present invention. Obviously, the described embodiments are only some embodiments of the present invention, rather than all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those of ordinary skill in the art without creative efforts belong to the scope of protection of the present invention.

[0026] Please refer to Figure 1 As shown, the present invention is a synthesis method of a non-lynabidone intermediate, including the synthesis of ethyl 2-cyanoacetoacetate and the synthesis of (Z)-ethyl 2-(4-cyano-2-methoxybenzylidene)-3-oxobutyrate;

[0027] The synthesis reaction formula of ethyl 2-cyanoacetoacetate is:

[0028]

[0029] (Z)-ethyl 2-(4-cyano-2-methoxybenzylidene)-3-oxobutyrate synthesis reaction formula is:

[0030]

[0031] The synthesis method of ethyl 2-cyanoacetoacetate includes the following steps:

[0032] Take a 500 ml four-necked flask. First, add 200 ml of dichloromethane to the four-necked flask, then add 40 g of 3-hydroxypropionitrile, and finally add 5 g of DMAP solid material. Stir for 1 hour, and the reaction temperature is 50 °C during the stirring process. After the reaction is completed, cool down to 0 °C;

[0033] Based on the above steps, continue to dropwise add 50 g of diketene. After the temperature control dropwise addition is completed, keep the temperature for reaction for 2 hours to obtain a reaction solution, and then use the GC monitoring method for status monitoring;

[0034] Post-treatment was carried out. The reaction solution was taken, washed with 200 ml of saturated brine, kept warm after washing, the lower-layer material was taken, then washed with 200 ml of purified water, kept warm again, the lower-layer material was taken again, and finally washed with 200 ml of saturated brine. The lower-layer material was distilled and the solvent was removed to obtain the target product, and then detected by HPLC detection method (the product was stored at low temperature);

[0035] A synthetic method of (Z)-2-cyanoethyl 2-(4-cyano-2-methoxybenzylidene)-3-oxobutyrate, comprising the following steps:

[0036] 40 g of the target product obtained in the above step and 200 ml of DMF were put into a 500-ml four-necked flask, stirring was started, and then 50 g of 4-cyano-2-methoxybenzaldehyde was added to a constant-pressure dropping funnel;

[0037] It was added dropwise to the four-necked flask through the constant-pressure dropping funnel and heated to 80 °C for reaction for 2 hours (monitored by TLC);

[0038] After the reaction was completed, filtration was carried out. First, 300 ml of water was added to the filtrate, and then the filtration operation was carried out. The filter cake obtained after filtration was washed with water, and finally the required product was obtained after drying. The content of the obtained product was 98%, and the yield was 90%.

[0039] In the present invention, the GC monitoring method is a monitoring method of gas chromatography. This method is used for qualitative and quantitative analysis of chemical reaction products. The mixture is separated into individual components through a chromatographic column, and then each component is detected and measured using a detector. The GC monitoring method is widely used in product analysis, impurity control, and quality control in chemical reactions. Through GC monitoring, detailed information of reaction products can be obtained, the reaction conversion rate and selectivity can be understood, and the purity of products can be detected and controlled;

[0040] At the same time, HPLC detection refers to the detection method of high-performance liquid chromatography, which is a commonly used separation and detection technology. HPLC pumps the mobile phase into the chromatographic column filled with the stationary phase through a high-pressure liquid delivery system, separates the compounds in the sample, and then enters the detector for detection. It has the advantages of high separation efficiency, high sensitivity, high analysis speed, etc., and can perform qualitative and quantitative analysis on the compounds in complex mixtures. In chemical reactions, HPLC detection can be used for the separation and detection of reaction products, as well as the control and detection of impurities and by-products, which is of great significance for ensuring product quality and reaction efficiency;

[0041] In addition, TLC monitoring is to track and monitor the reaction process by thin-layer chromatography, which is a commonly used separation and analysis method. By coating a thin layer of stationary phase (such as silica gel, alumina, etc.) on a glass plate or plastic plate, then spotting the sample on the stationary phase and developing it with a solvent, the purpose of separation and detection can be achieved. In a chemical reaction, TLC monitoring is used to analyze the distribution and concentration of reaction products to determine whether the reaction has achieved the desired purpose. By comparing with known standards, the relative positions and proportions of each component can be determined, thereby judging whether the reaction needs to be adjusted or optimized. TLC monitoring has the advantages of simplicity, rapidity, high sensitivity, etc., and is therefore widely used in chemical reactions. It can help researchers discover and solve problems in a timely manner during the experiment, improving the efficiency and success rate of the experiment.

[0042] In the description of this specification, the descriptions referring to terms such as "one embodiment", "example", "specific example", etc. mean that the specific features, structures, materials or characteristics described in connection with the embodiment or example are included in at least one embodiment or example of the present invention. In this specification, the schematic representations of the above terms do not necessarily refer to the same embodiment or example. Moreover, the specific features, structures, materials or characteristics described can be combined in a suitable manner in any one or more embodiments or examples.

[0043] The preferred embodiments of the present invention disclosed above are only used to help explain the present invention. The preferred embodiments do not elaborate on all the details and do not limit the invention to only the specific embodiments. Obviously, many modifications and variations can be made according to the content of this specification. These embodiments are selected and specifically described in this specification to better explain the principles and practical applications of the present invention, so that those skilled in the art can well understand and utilize the present invention. The present invention is only limited by the claims and their full scope and equivalents.

Claims

1. A method for synthesizing a finerenone intermediate, characterized in that, Including the synthesis of ethyl 2-cyanoacetoacetate and the synthesis of (Z)-ethyl 2-cyano-2-(4-cyano-2-methoxybenzylidene)-3-oxobutyrate; The synthesis method of ethyl 2-cyanoacetoacetate includes the following steps: S1: Take a 500 ml four-necked flask. First, add 200 ml of dichloromethane to the four-necked flask, then add 40 g of 3-hydroxypropionitrile, and finally add 5 g of solid DMAP. Stir for 1 hour, and the reaction temperature is 50 °C during the stirring process. After the reaction is completed, cool down to 0 °C; S2: Based on S1 above, continue to dropwise add 50 g of diketene. After the temperature control dropping is completed, keep the temperature and react for 2 hours to obtain a reaction solution, and then use the GC monitoring method for status monitoring; S3: Perform post-treatment. Take the reaction solution, wash it with 200 ml of saturated brine, keep the temperature after washing, take the lower layer material, wash it with 200 ml of purified water, keep the temperature again, take the lower layer material, and finally wash it with 200 ml of saturated brine. Take the lower layer material for distillation and desolvation to obtain the target product, and then use the HPLC detection method for detection; The synthesis method of (Z)-ethyl 2-cyano-2-(4-cyano-2-methoxybenzylidene)-3-oxobutyrate includes the following steps: S4: Put 40 g of the target product obtained in S3 and 200 ml of DMF into a 500 ml four-necked flask, start stirring, and then add 50 g of 4-cyano-2-methoxybenzaldehyde to the constant pressure dropping funnel; S5: Dropwise add it to the four-necked flask through the constant pressure dropping funnel and heat it to 80 °C for reaction for 2 hours; S6: After the reaction is completed, filter. First, add 300 ml of water to the filtrate, then perform the filtration operation. The filter cake obtained after filtration is washed with water, and finally dried to obtain the required product. The content of the obtained product is 98%, and the yield is 90%.

2. The synthesis method of a non- finerenone intermediate according to claim 1, characterized in that, The target product obtained in S3 is stored at low temperature.

3. A method for synthesizing a non- finerenone intermediate according to claim 1, characterized in that, The synthesis reaction formula of ethyl 2-cyanoacetoacetate is:

4. A method for synthesizing a non-fulinidone intermediate according to claim 1, characterized in that, The synthesis reaction formula of (Z)-ethyl 2-cyano-2-(4-cyano-2-methoxybenzylidene)-3-oxobutyrate is:

5. A method for synthesizing a finerenone intermediate according to claim 1, characterized in that, TLC monitoring is used during the heating reaction in S5.

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