Preparation method of fenerenone

Abstract

The invention discloses a method for preparing fenerenone by a resolution method, which comprises the following steps: resolving racemic 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2, 8-dimethyl-1, 4-dihydro-1, 6-naphthyridine-3-formamide in a mixed organic solvent by adopting (2S, 3S)-2, 3-bis (p-methylphenoxy) succinic acid, and carrying out devitrification and alkali dissociation to obtain the fenerenone. The product prepared through the method is low in impurity content and high in optical purity, the adopted resolving agent is stable under the alkaline condition, the resolving agent can be recycled, and decomposition impurities are not prone to being generated.

Description

TECHNICAL FIELD

[0001] The present application relates to the field of drug synthesis, in particular to a preparation method of finerenone. BACKGROUND

[0002] Finerenone is the first new oral selective non-steroidal mineralocorticoid receptor antagonist developed by Bayer. It was first approved for marketing in the United States in 2021 under the trade name KERENDIA, which can reduce the risk of eGFR decline, end-stage renal disease, cardiovascular death, non-fatal myocardial infarction and heart failure hospitalization in adult patients with type 2 diabetes (T2D) and chronic kidney disease (CKD). Its chemical name is: (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-1,4-dihydro-2,8-dimethyl-1,6-naphthalene-3-carboxamide. Finerenone is the S optical isomer of 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-1,4-dihydro-2,8-dimethyl-1,6-naphthalene-3-carboxamide, and the current preparation method mainly includes resolution method and chiral synthesis method.

[0003] Patent document WO2008104306 discloses a method for preparing finerenone by resolution using chiral liquid chromatography (ChiralPak AS-V, 20 μm) for isomer separation. This type of separation method has high requirements for equipment and instruments, and the production scale is not easy to expand, so its industrial application is limited.

[0004] Patent document CN112041318A discloses a process for preparing pure finerenone by resolving 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-1,4-dihydro-2,8-dimethyl-1,6-naphthalene-3-carboxamide in a solvent by salt crystallization using O-aromatic formyl-substituted tartaric acid as a resolving agent. After obtaining the finerenone salt, sodium phosphate is used to free it. Since O-aromatic formyl-substituted tartaric acid is not very stable under alkaline conditions, it may decompose in an alcohol-water system, affecting the recycling of the resolving agent and possibly introducing new impurities into the product. SUMMARY

[0005] The present application provides a method for preparing finerenone by resolution. The method uses racemic 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-1,4-dihydro-2,8-dimethyl-1,6-naphthalene-3-carboxamide to form a salt with a resolving agent to separate and obtain finerenone. The resolving agent used is O-aromatic-substituted tartaric acid. The product prepared by this process has low impurity content, high optical purity and stable product quality, and does not introduce impurities caused by decomposition of the resolving agent.

[0006]

[0007] The process of the above method is as follows: The racemic 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide is dissolved in solvent A to form a salt with (2S,3S)-2,3-bis(p-methylphenoxy)succinic acid, then solvent B is added and the temperature is lowered to crystallize to obtain non-neramexane (2S,3S)-2,3-bis(p-methylphenoxy)succinate, and the filter cake is obtained by filtration to obtain non-neramexane (2S,3S)-2,3-bis(p-methylphenoxy)succinate; the remaining filtrate is the salt mother liquor. The solvent A is selected from one of ethanol or isopropanol, and the solvent B is selected from one of methyl tert-butyl ether or n-heptane.

[0008] The salt obtained in step (1) is freed with a base in a mixed solvent of ethanol and water, the free temperature is 20-45℃, then the temperature is lowered to 10-20℃ to crystallize and suction filtration, and the filter cake is obtained by filtration to obtain non-neramexane, and the filtrate is the free mother liquor; the total mass ratio of ethanol to water added in the mixed solvent of ethanol and water is 1:10-1:5.

[0009] (3) A 20% sulfuric acid solution is added dropwise to the free mother liquor to adjust the pH to 4-5, a large amount of solid is precipitated, suction filtration is performed, the filter cake is washed with water, and after drying, the resolution agent (2S,3S)-2,3-bis(p-methylphenoxy)succinate is recovered; sodium hydroxide is added to the salt mother liquor to adjust the pH to alkaline, then extracted with ethyl acetate, take the water layer, add a 20% sulfuric acid solution, adjust the pH to 4-5, and filter the precipitated solid to obtain the resolution agent (2S,3S)-2,3-bis(p-methylphenoxy)succinate; the organic layer is removed to obtain non-neramexane enantiomers.

[0010] Further, the mass ratio of the two solvents in step (1) is: solvent A:solvent B=1:1-3:1, and the mass ratio of racemic 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide to the alcohol solvent used is 1:4-1:2.

[0011] Further, the amount-of-substance ratio of racemic 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide to (2S,3S)-2,3-bis(p-methylphenoxy)succinic acid used in step (1) is 1:2.

[0012] Further, the cooling temperature in the crystallization step in step (1) is 10-20℃, and the cooling time is 6-8 hours.

[0013] Furthermore, the base in step (2) is selected from sodium hydroxide and sodium bicarbonate.

[0014] The structure of the resolving agent (2S, 3S)-2,3-bis(p-methylphenoxy)succinic acid is shown below:

[0015] More specifically, a typical preparation process is: To a three-necked flask, add 2 equivalents of (2S,3S)-2,3-bis(p-tolyloxy)succinic acid (based on 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide). Add ethanol and stir for 5-10 minutes. Add 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide. Heat to 55-65°C and stir for 1 hour. Add water, cool to 10-20°C, and maintain the temperature for crystallization. Filter, drain, and air dry at 50°C to constant weight to obtain finerenone (2S,3S)-2,3-bis(p-tolyloxy)succinate.

[0016] Add water and ethanol to a three-necked flask, add phenerenone (2S, 3S)-2,3-bis(p-tolyloxy) succinate solvent, and stir for 10 to 20 minutes; control the temperature at 20 to 45°C, add sodium hydroxide solution dropwise, and stir for 30 to 40 minutes after addition; cool to 10 to 20°C, filter, and obtain phenerenone.

[0017] A 20% sulfuric acid solution is added dropwise to the free mother liquor to adjust the pH to 4-5, a large amount of solid is precipitated, the solid is filtered, the filter cake is washed with water, and the solution is dried and recovered to obtain the resolving agent (2S, 3S)-2,3-bis(p-methylphenoxy)succinate; sodium hydroxide is added to the salt-forming mother liquor to adjust the pH to alkaline, followed by extraction with ethyl acetate, the aqueous layer is collected, a 20% sulfuric acid solution is added dropwise to adjust the pH to 4-5, the precipitated solid is filtered, and the filter cake is collected to obtain the resolving agent (2S, 3S)-2,3-bis(p-methylphenoxy)succinate; the organic layer is collected and the solvent is removed to obtain the crude phenerenone enantiomer.

[0018] As a comparative study of the decomposition of O-acyl substituted tartaric acid resolving agent under alkaline conditions, the following test was conducted under the alkaline free conditions of the existing literature: 1 g of O,O-dibenzoyl tartaric acid was added to a 50 ml flask, 10 ml of ethanol and 10 ml of 10% sodium phosphate solution were added, and heated to 80 degrees Celsius, and kept for 3 hours. The reaction liquid was detected, and it was found that more than 10% of the dibenzoyl tartaric acid in the product mixture decomposed, and the content of the decomposition impurities was 14.81%. It can be seen that even under relatively mild reaction conditions, dibenzoyl tartaric acid will still decompose during the free process, which will have a negative impact on the process, causing the recovery rate of the resolving agent to decrease, and introducing a large amount of additional impurities into the product, which will pose a hidden danger to drug safety. The process using the present scheme hardly decomposes the resolving agent, and the resolving agent can be recovered almost quantitatively.

[0019] As can be seen from the above, the resolving agent used in the present scheme is stable under alkaline conditions and is not prone to decomposition; the product prepared by the present process has low impurity content, high optical purity, stable product quality, and the resolving agent can be recycled and used with little decomposition loss. BRIEF DESCRIPTION OF DRAWINGS

[0020] Figure 1 The detection results of the stereoisomers in Example 4 Figure 2 The detection results of the stereoisomers in Example 5 Figure 3 The detection results of the stereoisomers in Example 6 Figure 4 The detection results of the related substances in Example 4 Figure 5 The detection results of the related substances in Comparative Example 1 DETAILED DESCRIPTION Example 1

[0021] Finerenone (2S, 3S)-2,3-bis(p-tolyloxy)succinate Into a 250 ml three-necked flask, 33.0 g (100 mmol) of (2S, 3S)-2,3-bis(p-tolyloxy)succinic acid was added, 66 g of ethanol was added, stirred for 10 min, 18.9 g (50 mmol) of 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-formamide was added, and the temperature was raised to 55°C, and stirred for 1 h. 23 g of water was added, and the temperature was lowered to 20°C in 4 h, and then kept for 4 h. Filtration was performed, and after drying, 50°C air drying was performed to constant weight, and 23.9 g of finerenone (2S, 3S)-2,3-bis(p-tolyloxy)succinate was obtained. Example 2

[0022] Finerenone (2S, 3S)-2,3-bis(p-tolyloxy)succinate Into a 250ml flask, 33.0g (100mmol) (2S, 3S)-2,3-bis(p-tolyloxy)succinic acid was added, then 68g ethanol was added, stirred for 10min, 18.9g (50mmol) 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide was added, the temperature was raised to 55°C, and stirred for 1h. 53g n-heptane was added, and the temperature was lowered to 20°C in 4h, and then kept for 3h. Filtration was performed, and after drying, air-drying was performed at 50°C until the weight was constant. Finerenone (2S, 3S)-2,3-bis(p-tolyloxy)succinate was obtained in a yield of 22.9g. Example 3

[0023] Finerenone (2S, 3S)-2,3-bis(p-tolyloxy)succinate Into a 250ml flask, 33.0g (100mmol) (2S, 3S)-2,3-bis(p-tolyloxy)succinic acid was added, then 69g isopropanol was added, stirred for 5-10min, 18.9g (50mmol) 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide was added, the temperature was raised to 55-65°C, and stirred for 1h. 23g methyl tert-butyl ether was added, and the temperature was lowered to 10°C in 3.5h, and then kept for 3h. Filtration was performed, and after drying, air-drying was performed at 50°C until the weight was constant. Finerenone (2S, 3S)-2,3-bis(p-tolyloxy)succinate was obtained in a yield of 22.3g. Example 4

[0024] Finerenone Into a 250ml flask, 60g drinking water, 10g ethanol, and 20g (18.4mmol) finerenone (2S, 3S)-2,3-bis(p-tolyloxy)succinate prepared according to the method in Example 1 were added, and stirred for 10min. The temperature was controlled at 45°C, and sodium hydroxide solution (1.55g sodium hydroxide dissolved in 3.6g drinking water) was added dropwise, and stirred for 30min after the addition was completed. The temperature was lowered to 10°C, and filtration was performed. Finerenone was obtained in a yield of 9.8g, with an e.e. of 100% and a purity of 99.97%.

[0025] The chromatographic conditions for stereoisomer detection were as follows: the chromatographic column was Daicel ChiralPak AD-H, 4.6*250mm, 5μm; the column temperature was 25°C; the injection volume was 10μL; an ultraviolet detector was used, and the detection wavelength was 255nm; the mobile phase was n-hexane:isopropanol=65:35 (V / V) for isocratic elution, and the flow rate was 1ml / min.

[0026] The chromatographic conditions for related substance detection are as follows: the chromatographic column is Bridge Shield RP18, 3.0 mm*150 mm, 3.5 μm; the column temperature is 25 ℃; the injection volume is 5 μL; the ultraviolet detector is used, and the detection wavelength is 251 nm; the mobile phase A is a phosphoric acid solution (300 μL of phosphoric acid is dissolved in 1000 ml of water), the mobile phase B is acetonitrile, gradient elution is used, the elution gradient (V A / V B ): 0-16.5 min = 95:5; 16.5-17 min = 1:1; 17-22 min = 1:4; 22-28 min = 95:5; the flow rate is 1 ml / min. Example 5

[0027] Finerenone Into a 250 ml three-necked flask, 60 g of drinking water, 11 g of ethanol, 20 g (18.4 mmol) of finerenone (2S, 3S)-2,3-bis(p-tolyloxy)succinate prepared according to the method in Example 2 were added, and stirred for 10 min; sodium carbonate solution (3.9 g of sodium carbonate was dissolved in 20 g of water) was added dropwise at 45 ℃, and stirred for 30 min after the addition was completed; the temperature was lowered to 10 ℃, and filtration was performed, to obtain 10.1 g of finerenone. e.e. = 99.72%, purity 99.61%. Example 6

[0028] Finerenone Into a 2 L four-necked flask, 60 g of drinking water, 12 g of ethanol, 20 g (18.4 mmol) of finerenone (2S, 3S)-2,3-bis(p-tolyloxy)succinate prepared according to the method in Example 3 were added, and stirred for 10 min; sodium carbonate solution (3.9 g of sodium carbonate was dissolved in 20 g of water) was added dropwise at 45 ℃, and stirred for 30 min after the addition was completed; the temperature was lowered to 10 ℃, and filtration was performed, to obtain 10.0 g of finerenone. e.e. = 99.69%, purity 99.20%. Example 7

[0029] Resolution agent recovery Into the mother liquor obtained by filtration in Example 4, 20% sulfuric acid solution was added dropwise, the pH was adjusted to 4-5, a large amount of solid was precipitated, filtration was performed, the filter cake was washed with water, and dried to recover the resolution agent (2S, 3S)-2,3-bis(p-methylphenoxy)succinate 9.31 g. Comparative Example 1

[0030] Into a 50 ml flask, 1 g of dibenzoyl tartaric acid was added, 10 ml of ethanol and 10 ml of 10% sodium phosphate solution were added, and heated to 80 ℃, and kept for 3 hours. The reaction liquid was detected, and the purity of dibenzoyl tartaric acid in the product reaction liquid was 85.19%, and the decomposition impurity content was 14.81%.

[0031] Chromatographic conditions: Column: Waters Xterra RP18 4.6 x 150 mm, 3.5 μm; flow rate: 1.0 ml / min; Detection wavelength: 255 nm; injection volume: 10 μl; column temperature: 35 °C; mobile phase A: 20 mM phosphate buffer (pH 8.0); mobile phase B: methanol; gradient elution was used with the elution gradient (V A / V B ): 0-20 min = 80:20, 20-25.1 min = 25:75, 25.1-30 min = 80:20.

Claims

1. A method for preparing finerenone, characterized in that: The following steps are included: (1) dissolving racemic 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide and (2S,3S)-2,3-bis(p-methylphenoxy)succinic acid in solvent A to form a salt, then adding solvent B and cooling to crystallize to obtain phenerenone (2S,3S)-2,3-bis(p-methylphenoxy)succinate; the solvent A is selected from one of ethanol and isopropanol, and the solvent B is selected from one of water, methyl tert-butyl ether, and n-heptane; (2) Dissolve finerenone (2S, 3S)-2,3-bis(p-methylphenoxy)succinate in an ethanol-water mixture, add alkali and heat to liberate it, then cool to 10°C to crystallize and obtain finerenone.

2. The method according to claim 1, wherein: The mass ratio of the solvent A to the solvent B is 1:1-3:1; the mass ratio of the racemic 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide to the solvent A is 1:4-1:

2.

3. The method according to claim 1, wherein: The cooling temperature in the cooling and crystallization step is 10-20°C.

4. The method according to claim 1, wherein: The alkali is selected from sodium hydroxide and sodium carbonate, and the heating temperature is 20-45°C.

5. The method according to claim 1, wherein: The mass ratio of ethanol to water in the ethanol-water mixed solution is 1:10-1:5.

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