Process for the asymmetric catalytic synthesis of naphthyridine carboxamides

Abstract

The application discloses a method for asymmetrically catalytically synthesizing naphthyridine carboxamide drug finerenone, and belongs to the technical field of organic synthesis. In the first step, compound 1 is reacted with S-1-phenylethanol in an organic solvent to generate intermediate 2; in the second step, compound 2 is reacted with 4-cyano-2-methoxybenzaldehyde in an organic solvent to generate intermediate 3; in the third step, compound 3 is reacted with 4-amino-5-methylpyridin-2-ol in the presence of a chiral catalyst in an organic solvent to generate crude intermediate 4, the crude intermediate 4 is then salified by adding a resolving agent, and after being freed, the intermediate 4 is obtained; in the fourth step, compound 4 is reacted with triethyl orthoformate in an organic solvent under the catalysis of an acid to generate intermediate 5; in the fifth step, compound 5 is catalytically hydrogenated in the presence of a palladium catalyst to generate intermediate 6; and in the sixth step, compound 6 is reacted with hexamethyldisilazane in the presence of a condensing agent, and after treatment, the product I is obtained. The application provides an improved preparation method for finerenone and has the prospect of industrial production.

Description

TECHNICAL FIELD

[0001] The application relates to an improved method for preparing a naphthyridine carboxamide drug, finerenone, by asymmetric catalysis, and belongs to the technical field of organic synthesis. TECHNICAL BACKGROUND

[0002] The naphthyridine carboxamide drug, finerenone, is a "first-in-class" non-steroidal selective mineralocorticoid receptor antagonist under the Bayer Company. In July 2021, the U.S. Food and Drug Administration approved finerenone for marketing in the United States, which is used for treating type 2 diabetes patients with chronic kidney disease (CKD). The clinical trial (FIDELIO-DKD) of finerenone proves that finerenone can bring double benefits of heart and kidney to type 2 diabetes nephropathy patients, and has good safety.

[0003] Based on this, in 2021, China issued the "Diabetic Kidney Disease Clinical Diagnosis and Treatment China Guidelines", which recommended finerenone as a treatment drug for reducing urinary albumin in diabetic nephropathy patients and for treating cardiovascular complications. This is the latest drug recommended by the guidelines for the treatment of diabetic nephropathy after renin-angiotensin system inhibitors (RASi) and sodium-glucose cotransporter 2 inhibitors (SGLT2i). The drug was first approved for marketing in July 2021 and was marketed in the Chinese market in June 2022. Its synthesis method mainly includes the following:

[0004] Route one: In the preparation of the mother nucleus intermediate A, two racemic components are formed, which need to be separated by purification preparation in the later stage, and the total yield is low.

[0005]

[0006] Route two: The preparation of the mother nucleus intermediate is still racemic, and there is no selectivity, and the last step needs chiral resolution.

[0007]

[0008] Route three: The mother nucleus intermediate construction has no selectivity, and finally needs chiral preparation purification; or the reported method uses enzyme method to selectively hydrolyze the substrate ester to realize resolution.

[0009] The main problems with the above-mentioned synthetic routes are as follows: 1) Route 1 has poor alkylation selectivity and low amidation yield; 2) Route 2 has an uncommon 2-cyanoethyl 3-oxobutyrate and limited raw material sources, which limits its preparation; 3) Route 3 uses a high-pressure reaction for XVIII, which is highly risky and not conducive to scale-up production; 4) The above-mentioned routes share common problems, including chiral resolution, complex process flow, and low atom economy. Summary of the Invention

[0010] The present invention aims to provide an improved preparation method for finerenone, which uses chiral adjuvants and different chiral catalysts to make the reaction more economical and efficient, thereby overcoming many drawbacks of existing synthesis methods, such as long time consumption, large amounts of solvent waste, and uneconomical atomic resolution of racemates.

[0011] The present invention first provides a key intermediate of finerenone, the structure of which is as follows:

[0012]

[0013] The technical solution provided by the present invention is as follows: an improved synthesis method of finerenone using asymmetric catalysis of quinine derivatives, the reaction equation is as follows:

[0014]

[0015] In the first step, compound 1 is reacted with S-1-phenylethanol in an organic solvent at elevated temperature to generate intermediate 2;

[0016] Furthermore, in the above technical solution, the organic solvent is selected from toluene or xylene.

[0017] Furthermore, in the above technical solution, the temperature of the reaction is 100-140°C.

[0018] Furthermore, in the above technical solution, the molar ratio of the compound 1 to S-1-phenylethanol is 1:1-1.2.

[0019] In the second step, compound 2 is reacted with 4-cyano-2-methoxybenzaldehyde in an organic solvent to generate intermediate 3;

[0020] Furthermore, in the above technical solution, the organic solvent is selected from ethanol or isopropanol.

[0021] Furthermore, in the above technical solution, the temperature of the reaction is 0-40°C.

[0022] Furthermore, in the above technical solution, the molar ratio of the compound 2 to 4-cyano-2-methoxybenzaldehyde is 1:1-1.2.

[0023] Third step, compound 3 and 4-amino-5-methylpyridine-2-ol, in the presence of a chiral catalyst, in an organic solvent, the reaction is heated to generate intermediate 4 crude, then add the salt to the crude product after the free intermediate 4 is obtained;

[0024] Further, in the above technical solution, the chiral catalyst structure is as follows:

[0025]

[0026] Further, in the above technical solution, the organic solvent is selected from dimethyl sulfoxide, N,N-dimethylformamide or N,N-dimethylacetamide; the resolving agent is selected from D-tartaric acid.

[0027] Further, in the above technical solution, the heating reaction is 80-120 DEG C.

[0028] Further, in the above technical solution, the molar ratio of compound 3, 4-amino-5-methylpyridine-2-ol and catalyst is 1:1-1.2:0.001-0.05.

[0029] Fourth step, compound 4 and triethyl orthoformate in an organic solvent, under acid catalysis, the reaction is heated to generate intermediate 5;

[0030] Further, in the above technical solution, the organic solvent is selected from dimethyl sulfoxide, N,N-dimethylformamide or N,N-dimethylacetamide.

[0031] Further, in the above technical solution, the heating reaction is 80-140 DEG C.

[0032] Further, in the above technical solution, the acid is selected from sulfuric acid.

[0033] Fifth step, compound 5 and catalytic hydrogenation under palladium catalyst to generate intermediate 6;

[0034] Further, in the above technical solution, the palladium catalyst is selected from 5% palladium-carbon, 10% palladium-carbon or 10% palladium hydroxide-carbon.

[0035] Sixth step, compound 6 and hexamethyl disilazane, in the presence of a condensing agent, after treatment to obtain product I.

[0036] Further, in the above technical solution, the condensing agent is selected from 1,1-carbonyl diimidazole.

[0037] Inventive beneficial effects

[0038] A, intermediate 2 introduces S-phenyl ethanol, which is beneficial to the subsequent cyclization reaction to improve the selectivity of the target configuration;

[0039] B. The selectivity of 1,2-dihydropyridine compound 4, a key intermediate of finerenone in the cyclization reaction, is further improved under the action of a chiral catalyst, enabling the selective preparation of intermediate 4. This chiral advantage is then transferred to the final product.

[0040] C. The product has advantageous selectivity and can be purified by conventional crystallization to ultimately reach a chiral purity of more than 99%, which can meet pharmaceutical quality requirements. DETAILED DESCRIPTION

[0041] Example 1

[0042]

[0043] 22.1 g (155.4 mmol) of trimethyldioxanone and 19 g (155.5 mmol) of (S)-1-phenylethanol were added to a three-necked flask, followed by 66 mL of xylene. The atmosphere was replaced with nitrogen and the temperature was raised to 110°C for 2 hours. TLC confirmed the completion of the reaction. The reaction solution was directly concentrated until it became viscous, 100 mL of petroleum ether was added, and the mixture was washed with 50 mL of water and 50 mL of saturated ammonium chloride. The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 29 g (140.6 mmol) of yellow liquid intermediate 2, which was used directly in the next step. 1 H NMR (CDCl3, 400M Hz): 7.41-7.22 (m, 5H), 5.94 (q, J = 6.6Hz, 1H), 3.45 (s, 2H), 2.22 (s, 3H); 1.56 (d, J = 6.6Hz, 3H).

[0044] Example 2

[0045] 22.1 g (155.4 mmol) of trimethyldioxanone and 19 g (155.5 mmol) of (S)-1-phenylethanol were added to a three-necked flask, followed by 66 mL of toluene. The atmosphere was replaced with nitrogen and the temperature was raised to 110°C for 2 hours. TLC confirmed the completion of the reaction. The reaction solution was directly concentrated until viscous, 100 mL of petroleum ether was added, and the mixture was washed with 50 mL of water and 50 mL of saturated ammonium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 26.8 g (129.9 mmol) of yellow liquid intermediate 2, which was used directly in the next step.

[0046] Example 3

[0047]

[0048] Under nitrogen, 21 g (130.3 mmol) of 4-cyano-2-methoxybenzaldehyde, 29.5 g (143 mmol) of intermediate 2, 1.10 g (12.9 mmol) of piperidine, 0.78 g (12.9 mmol) of acetic acid, and 50 mL of isopropanol were added sequentially to a three-necked flask and stirred overnight at room temperature. TLC confirmed the completion of the reaction. The reaction solution was poured into 50 mL of water and extracted twice with 25 mL of ethyl acetate. The organic phases were combined and washed with 50 mL of saturated sodium bisulfite solution. The organic phase was dried over anhydrous sodium sulfate and concentrated to obtain 40.9 g (117 mmol) of intermediate 3 as a light yellow solid.

[0049] Example 4

[0050] Under nitrogen, 21 g (130.3 mmol) of 4-cyano-2-methoxybenzaldehyde, 29.5 g (143 mmol) of intermediate 2, 1.10 g (12.9 mmol) of piperidine, 0.78 g (12.9 mmol) of acetic acid, and 50 mL of ethanol were added sequentially to a three-necked flask and stirred overnight at room temperature. TLC confirmed the completion of the reaction. The reaction solution was poured into 50 mL of water and extracted twice with 25 mL of ethyl acetate. The organic phases were combined, washed with 50 mL of saturated sodium bisulfite solution, and dried over anhydrous sodium sulfate and concentrated to obtain 38.7 g (110.7 mmol) of intermediate 3 as a light yellow solid.

[0051] Example 5

[0052]

[0053] To a three-necked flask were added 38 g (108.75 mmol) of intermediate 3, 13.5 g of 4-amino-5-methylpyridin-2-ol (108.75 mmol), 0.72 g (1.38 mmol) of chiral catalyst 1, and 190 mL of dimethyl sulfoxide. The atmosphere was purged with nitrogen, and the mixture was heated to 100°C and allowed to react overnight. TLC and HPLC confirmed the completion of the reaction. 200 mL of ethyl acetate was added to the reaction solution, which was washed twice with 50 mL of water. The organic phase was dried and concentrated to yield 42 g of crude product. Chiral HPLC analysis revealed an isomer ratio of 75:25. The crude product was suspended in 240 mL of ethanol and 80 mL of water, followed by the addition of 9.38 g of D-tartaric acid. The atmosphere was purged with nitrogen, and the mixture was heated to reflux with stirring for 45 minutes. The mixture was cooled and filtered to yield 26.4 g (43.6 mmol) of intermediate 4 as an off-white solid. Chiral HPLC analysis revealed an isomer ratio of 97.6:2.4.

[0054] Example 6

[0055] To a three-necked flask were added 38 g (108.75 mmol) of intermediate 3, 13.5 g (108.75 mmol) of 4-amino-5-methylpyridin-2-ol, 0.74 g (1.31 mmol) of chiral catalyst 2, and 190 mL of dimethyl sulfoxide. After nitrogen substitution, the reaction was allowed to proceed at 100°C overnight. TLC and HPLC confirmed the completion of the reaction. 200 mL of ethyl acetate was added to the reaction solution, which was washed twice with 50 mL of water. The organic phase was dried and concentrated to yield 46 g of crude product. Chiral HPLC analysis revealed an isomer ratio of 85:15. The crude product was suspended in 240 mL of ethanol and 80 mL of water, followed by the addition of 9.38 g of D-tartaric acid. After nitrogen substitution, the mixture was stirred at reflux for 45 minutes, cooled, and filtered to yield 29.6 g (48.8 mmol) of intermediate 4 as an off-white solid. Chiral HPLC analysis revealed an isomer ratio of 98.9:1.1.

[0056] Example 7

[0057]

[0058] To a three-necked flask, 25 g (54.88 mmol) of intermediate 4, 40 g (269.9 mmol) of triethyl orthoformate, and 170 mL of N,N-dimethylacetamide were added sequentially. Finally, 2.75 g (27.4 mmol) of concentrated sulfuric acid was slowly added dropwise. The temperature was raised to 120°C and the reaction was allowed to proceed for 4 hours. TLC and HPLC confirmed the completion of the reaction. The reaction solution was cooled to 50°C and slowly poured into 120 mL of water. After stirring for approximately 1 hour, 150 mL of water was added dropwise. The system was cooled to 0-5°C and stirred for 1 hour. The mixture was then filtered, the filter cake was washed twice with water, and then dried to obtain 21.3 g (44.05 mmol) of intermediate 5.

[0059] Example 8

[0060]

[0061] To the reaction flask were added 25 g (51.7 mmol) of Intermediate 5, 125 mL of tetrahydrofuran, and 1.0 g of 10% palladium hydroxide / carbon. The atmosphere was replaced with hydrogen and stirred at room temperature overnight. Completion of the reaction was confirmed by TLC. The product was filtered and concentrated to obtain 19.4 g (51.3 mmol) of Intermediate 6, which was used directly in the next reaction.

[0062] Example 9

[0063]

[0064] To the reaction flask was added 16 g (42.17 mmol) of intermediate 6, 7.5 g (46.25 mmol) of 1,1-carbonyldiimidazole and 80 mL of tetrahydrofuran at room temperature, after stirring well, 0.25 g (2 mmol) of 4-dimethylaminopyridine was added. The mixture was stirred at room temperature for 1 hour, then heated to 50 °C for 2.5 hours. 15 g (92.9 mmol) of hexamethyldisilazane was added dropwise to the reaction solution, and stirred at reflux overnight. The system was cooled to 5 °C, 20 mL of water was added, and the internal temperature was controlled at 5-20 °C. Then the mixture was stirred at reflux for 1 hour, slowly cooled to 0 °C, and stirred at this temperature for 1 hour, filtered to obtain 13.5 g (35.67 mmol) of product I as a white solid, 99.5% ee; 1 H-NMR (500 MHz, DMSO-d6): 7.69 (s, 1H), 7.55 (s, 1H), 7.37 (d, J = 1.6 Hz, 1H), 7.28 (dd, J = 7.9, 1.5 Hz, 1H), 7.15 (d, J = 7.8 Hz, 1H), 6.90-6.55 (m, 2H), 5.38 (s, 1H), 4.01 (dq, J = 7.2, 3.2 Hz, 2H), 3.82 (s, 3H), 2.19 (s, 3H), 2.12 (s, 3H), 1.05 (t, J = 7.0 Hz, 3H).

[0065] The above merely describes the preferred embodiments of the present application, and it should be noted that the above preferred embodiments should not be regarded as a limitation to the present application, and the protection scope of the present application should be defined by the scope of the claims. For those skilled in the art, several improvements and refinements can be made without departing from the spirit and scope of the present application, and these improvements and refinements should also be regarded as the protection scope of the present application.

Claims

1. An improved synthesis method of finerenone by asymmetric catalysis, characterized in that: The reaction equation is as follows: The third step is to react compound 3 with 4-amino-5-methylpyridin-2-ol in the presence of a chiral catalyst at elevated temperature in an organic solvent to generate a crude intermediate 4. A resolving agent is then added to the crude product to form a salt, which is then freed to obtain intermediate 4. The structure of the chiral catalyst is as follows:

2. The improved synthesis method of finerenone by asymmetric catalysis according to claim 1, characterized in that: The method comprises the following steps: a first step, reacting compound 1 with S-1-phenylethanol in an organic solvent at elevated temperature to generate intermediate 2; a second step, reacting compound 2 with 4-cyano-2-methoxybenzaldehyde in an organic solvent to generate intermediate 3; a third step, the same as that described in claim 1; a fourth step, reacting compound 4 with triethyl orthoformate in an organic solvent at elevated temperature under acid catalysis to generate intermediate 5; a fifth step, catalytically hydrogenating compound 5 in the presence of a palladium catalyst to generate intermediate 6; and a sixth step, reacting compound 6 with hexamethyldisilazane in the presence of a condensing agent, and obtaining product 1 after treatment.

3. The improved synthesis method of finerenone by asymmetric catalysis according to claim 2, characterized in that: In the first step, the organic solvent is selected from toluene or xylene; the temperature of the reaction is 100-140° C.; and the molar ratio of the compound 1 to S-1-phenylethanol is 1:1-1.

2.

4. The improved synthesis method of finerenone by asymmetric catalysis according to claim 2, characterized in that: In the second step, the organic solvent is selected from ethanol or isopropanol; the temperature of the reaction is 0-40° C.; and the molar ratio of the compound 2 to 4-cyano-2-methoxybenzaldehyde is 1:1-1.

2.

5. The improved synthesis method of finerenone by asymmetric catalysis according to claim 1, characterized in that: In the third step, the organic solvent is selected from dimethyl sulfoxide, N,N-dimethylformamide or N,N-dimethylacetamide; the resolving agent is selected from D-tartaric acid; and the temperature of the reaction is raised to 80-120°C.

6. The improved synthesis method of finerenone by asymmetric catalysis according to claim 2, characterized in that: In the third step, the molar ratio of the compound 3, 4-amino-5-methylpyridin-2-ol and the catalyst is 1:1-1.2:0.001-0.

05.

7. The improved synthesis method of finerenone by asymmetric catalysis according to claim 2, characterized in that: In the fourth step, the organic solvent is selected from dimethyl sulfoxide, N,N-dimethylformamide or N,N-dimethylacetamide; the temperature of the reaction is 80-140° C.; and the acid is selected from sulfuric acid.

8. The improved synthesis method of finerenone by asymmetric catalysis according to claim 2, characterized in that: In the fifth step, the palladium catalyst is selected from 5% palladium-carbon, 10% palladium-carbon or 10% palladium hydroxide-carbon; in the sixth step, the condensation agent is selected from 1,1-carbonyldiimidazole.

Images