Preparation method of fenerenone

Abstract

According to the preparation method, a palladium-carbon catalyst is not used, a cheap chemical reagent such as tert-butyl acetoacetate is adopted, chiral tartrate is adopted as a resolving agent, and hydrolysis is carried out by using organic acid, so that the yield of the finerenone is increased. The influence of a palladium-carbon catalyst on the medicine safety can be avoided while the production cost is remarkably saved, and the preparation method of the fenerenone, which is more economical, safer, green and suitable for large-scale production, is provided.

Description

Technical Field

[0001] This invention relates to the field of drug synthesis, and specifically to a method for preparing fenelone. Background Technology

[0002] Fennellone is the first novel oral selective nonsteroidal mineralocorticoid receptor antagonist developed by Bayer. It was first approved for marketing in the United States in 2021 under the brand name KERENDIA. It reduces the risk of persistently declining eGFR, end-stage renal disease, cardiovascular death, non-fatal myocardial infarction, and hospitalization for heart failure in adult patients with type 2 diabetes (T2D)-related chronic kidney disease (CKD). Its chemical name is (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-1,4-dihydro-2,8-dimethyl-1,6-naphthidine-3-carboxamide.

[0003] Fennellone is the S-optical isomer of 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-1,4-dihydro-2,8-dimethyl-1,6-naphthidine-3-carboxamide. Several synthetic routes for fenelone have been reported in the literature, such as Chinese patents CN202210063391.6, CN202310517308.2, and CN202310040409.5. All of these synthetic routes use palladium-on-carbon catalysts. However, palladium-on-carbon catalysts are not only expensive but also highly hazardous in practical operation, resulting in high costs for large-scale industrial production. Furthermore, residual palladium catalyst during the reaction may pose a risk to the fenelone active pharmaceutical ingredient. Therefore, considering both cost and drug safety, it is not suitable for large-scale commercial production.

[0004] Therefore, the existing synthetic routes for fenelinone have problems such as high cost, expensive reagents, and threats to the safety of fenelinone drugs. Summary of the Invention

[0005] To address the shortcomings of existing synthetic routes for finelone, this invention provides a method for preparing finelone that does not use a palladium-on-carbon catalyst but instead employs inexpensive chemical reagents. This significantly reduces production costs while avoiding the impact of palladium-on-carbon catalysts on drug safety. Compared to existing technologies, this invention provides a more economical, safer, greener method for preparing finelone that is suitable for scale-up production.

[0006] This invention provides a method for preparing fenelazol, comprising the following steps: (1) Racemic 4-(4-cyano-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthidine-3-carboxylic acid tert-butyl ester and one of D-(+)-dibenzoyl tartaric acid or (2S,3S)-2,3-bis(p-methylphenoxy)succinic acid are heated and stirred in solution A, heated to 40~60℃, and then cooled and crystallized to obtain (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthidine-3-carboxylic acid tert-butyl ester; (2) Dissolve the (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthidine-3-carboxylic acid tert-butyl ester salt obtained in step (1) in solvent B, add alkali, cool and crystallize to obtain (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthidine-3-carboxylic acid tert-butyl ester; (3) The (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthidine-3-carboxylic acid tert-butyl ester obtained in step (2) was reacted in a trifluoroacetic acid dichloromethane solution with a concentration of 0.5-1 M to obtain (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthidine-3-carboxylic acid; (4) The (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthidine-3-carboxylic acid obtained in step (3) is dissolved in tetrahydrofuran with 1,1-carbonyldiimidazole and 4-dimethylaminopyridine, and ammonia is added. The mixture is heated to react and phenelzine is obtained.

[0007]

[0008] Ar can be phenyl or benzoyl.

[0009] Further, in step (1), solvent A is a mixture of ethanol and water, wherein the volume ratio of ethanol to water is 3:1; Furthermore, in step (2), solvent B is a mixture of ethanol and water, wherein the volume ratio of ethanol to water is 1:4.

[0010] Furthermore, the alkali used in step (2) is one of sodium hydroxide, potassium hydroxide, sodium phosphate, or potassium phosphate.

[0011] Furthermore, the crystallization temperature is 5℃~30℃.

[0012] Further, in step (1), the molar ratio of tert-butyl 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyl-3-carboxylic acid to D-(+)-dibenzoyl tartaric acid or (2S,4S)-2,3-bis(p-methylphenoxy)succinic acid is 1:1 to 1:2.

[0013] Racemic tert-butyl 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyl-3-carboxylic acid was prepared by the following steps: a) The compound of formula 1 reacts with tert-butyl 3-oxobutyrate compound under the action of piperidine and acetic acid to give the compound of formula 2;

[0014] b) Reaction of the compound of formula 2 obtained in step a) with 4-amino-5-methyl-1,2-dihydropyridin-2-one yields the compound of formula 3;

[0015] c) The compound of formula 3 obtained in step b) is reacted with triethyl orthoformate under sulfuric acid catalysis to obtain the racemic compound of formula 4, namely racemic 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthidine-3-carboxylic acid tert-butyl ester.

[0016]

[0017] Existing synthetic routes for finelone suffer from high costs, expensive reagents, and risks to the safety of finelone products. To address these shortcomings, this invention provides a method for preparing finelone that avoids the use of a palladium-on-carbon catalyst. Instead, it employs inexpensive chemical reagents such as tert-butyl acetoacetate, uses chiral tartrate esters as resolving agents, and hydrolyzes the product with an organic acid. This method significantly reduces production costs while avoiding the safety risks associated with palladium-on-carbon catalysts, providing a more economical, safe, environmentally friendly, and scalable method for preparing finelone. Specific implementation methods

[0018] Example 1 Preparation of (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthidine-3-carboxylic acid tert-butyl ester: 20 g of 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyl-3-carboxylic acid tert-butyl ester was added to ethanol / water (225 ml / 75 ml), and D-(+)-dibenzoyl tartaric acid was added with stirring. The mixture was heated to 60 °C and reacted for 5 hours. The mixture was then cooled to room temperature for 2 hours to allow crystals to precipitate. The mixture was filtered, and the filter cake was washed with ethanol / water (75 ml / 25 ml). The filter cake was dried to obtain the resolving salt of formula IIa. The resolving salt of formula IIa (17.9 g) was added to ethanol / water (36 ml / 144 ml), and the pH was adjusted to 7.5 by adding 5% sodium hydroxide aqueous solution dropwise with stirring. The mixture was heated to 50 °C and reacted for 3 hours. After cooling to room temperature, the mixture was filtered, and the filter cake was washed with ethanol / water (10 ml / 40 ml) and dried to obtain 9.5 g of (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthidine-3-carboxylic acid tert-butyl ester with an ee value of 99.6%.

[0019] Example 2 Preparation of (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthidine-3-carboxylic acid tert-butyl ester: 20 g of 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyl-3-carboxylic acid tert-butyl ester was added to ethanol / water (225 ml / 75 ml), and (2S,3S)-2,3-bis(p-methylphenoxy)succinic acid (13.9 g) was added with stirring. The mixture was heated to 60 °C and reacted for 6 hours. The mixture was then cooled to room temperature and allowed to crystallize for 2 hours. The mixture was filtered, and the filter cake was washed with ethanol / water (75 ml / 25 ml). The filter cake was dried to obtain the resolving salt of formula IIa. The resolving salt of formula IIa was added to ethanol / water (36 ml / 144 ml), and the pH was adjusted to 7.5 by adding 5% sodium hydroxide aqueous solution dropwise with stirring. The mixture was heated to 50 °C and reacted for 3 hours. After cooling to room temperature, the mixture was filtered, and the filter cake was washed with ethanol / water (10 ml / 40 ml) and dried to obtain 9.4 g of (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthidine-3-carboxylic acid tert-butyl ester with an ee value of 99.8%.

[0020] Example 3 Preparation of (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthidine-3-carboxylic acid: 9 g of (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthidine-3-carboxylic acid tert-butyl ester was added to dichloromethane (50 ml), followed by 3.6 g of trifluoroacetic acid. The mixture was reacted at room temperature for 2 hours. Most of the reaction solution was evaporated, and 50 g of ethanol was added. The mixture was heated to reflux, cooled to room temperature, filtered, and the filter cake was dried to obtain 7.6 g of (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthidine-3-carboxylic acid, with a yield of 97.6%.

[0021] Example 4 Preparation of fenelone Add (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthidine-3-carboxylic acid (7.6 g) to tetrahydrofuran (38 ml), stir, add 1,1-carbonyldiimidazole (4.1 g) and 4-dimethylaminopyridine (0.25 g), stir at room temperature for 1 hour, then heat to 50°C and react for 2.5 hours. Add ammonia (5.4 g), heat to reflux, react for 22 hours, cool to 5°C, slowly add tetrahydrofuran / water (6 ml / 4 ml), stir, heat to reflux, stir for 1 hour, then slowly cool to 0°C, filter, and use tetrahydrofuran (11 ml*) to filter cake. 2) Wash twice, then rinse with water (15ml*2) The filter cake was washed twice and dried to give 7.4 g of feneline, a white solid, with a yield of 97.6% and an ee value of 99.6%.

[0022] Example 5 Preparation of tert-butyl 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyl-3-carboxylate Step (1): 50 g of 4-cyano-2-methoxybenzaldehyde was added to 275 ml of isopropanol. Piperidine (2.6 g) and acetic acid (1.9 g) were added while stirring. A solution of 99 g of tert-butyl acetoacetate in 25 ml of isopropanol was slowly added at room temperature. After the addition was complete, the mixture was reacted at room temperature for 5 hours. The mixture was filtered, and the filter cake was washed with 150 ml of isopropanol. The filter cake was dried to obtain 85.2 g of (E / Z)-2-(4-cyano-2-methoxybenzyl)-3-oxobutyrate tert-butyl ester, a pale yellow solid with a yield of 90.4%.

[0023] Step (2): 80 g of (E / Z)-2-(4-cyano-2-methoxybenzyl)-3-oxobutyrate tert-butyl ester was added to 2-butanol (800 ml), and 34.4 g of 4-amino-5-methyl-2-hydroxypyridine was added with stirring. The mixture was heated to reflux and reacted for 48 hours. The temperature was then lowered to 0-10 °C, and crystallization was allowed to occur for 30 minutes. The mixture was filtered, and the filter cake was washed with isopropanol (240 ml). The filter cake was dried to obtain 92.4 g of 4-(4-cyano-2-methoxyphenyl)-2,8-dimethyl-5-oxo-1,4,5,6-tetrahydro-1,6-naphthidine-3-carboxylic acid-2-methoxyethyl ester, a pale yellow solid with a yield of 85.7%.

[0024] Step (3): 50g of 4-(4-cyano-2-methoxyphenyl)-2,8-dimethyl-5-oxo-1,4,5,6-tetrahydro-1,6-naphthidine-3-carboxylic acid-2-methoxyethyl ester was added to N,N-dimethylacetamide (300ml), and 100g of triethyl orthoformate was added with stirring. 7.5g of concentrated sulfuric acid was added dropwise. After the addition was complete, the temperature was raised to 110-120℃ and reacted for 2 hours. The temperature was then lowered to 50℃, and 1.2L of water was slowly added dropwise. After the addition was complete, the temperature was lowered to 0-10℃ to allow crystallization for 1 hour. The mixture was filtered, and the filter cake was washed with water (300ml). The filter cake was dried to obtain 50.5g of tert-butyl 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthidine-3-carboxylic acid, a yellow solid with a yield of 98.8%.

Claims

1. A method for preparing phenelzine, characterized in that, Includes the following steps: (1) Racemic 4-(4-cyano-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthidine-3-carboxylic acid tert-butyl ester and one of D-(+)-dibenzoyl tartaric acid or (2S,3S)-2,3-bis(p-methylphenoxy)succinic acid are heated and stirred in A, and then cooled and crystallized to obtain (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthidine-3-carboxylic acid tert-butyl ester; (2) Dissolve the (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthidine-3-carboxylic acid tert-butyl ester salt obtained in step (1) in solvent B, add alkali, cool and crystallize to obtain (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthidine-3-carboxylic acid tert-butyl ester; the alkali is selected from sodium hydroxide, potassium hydroxide, sodium phosphate or potassium phosphate; (3) (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthidine-3-carboxylic acid tert-butyl ester was reacted in a 0.5-1 M trifluoroacetic acid-dichloromethane solution to obtain (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthidine-3-carboxylic acid; (4) (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthidine-3-carboxylic acid, 1,1-carbonyldiimidazole, and 4-dimethylaminopyridine were dissolved in tetrahydrofuran, and ammonia was added. The mixture was heated to obtain phenelzine.

2. The method as described in claim 1, characterized in that, Solvent A is a mixture of ethanol and water, wherein the volume ratio of ethanol to water is 3:1; solvent B is a mixture of ethanol and water, wherein the volume ratio of ethanol to water is 1:

4.

3. The method according to any one of claims 1-2, characterized in that, The crystallization temperature is 5℃~20℃.

4. The method as described in claim 3, characterized in that, The heating temperature in step (1) is 40℃~60℃.

5. The method as described in claim 4, characterized in that, The molar ratio of 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyl-3-carboxylic acid tert-butyl ester to D-(+)-dibenzoyl tartaric acid or (2S,3S)-2,3-bis(p-methylphenoxy)succinic acid is 1:1 to 1:2.

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