Method for asymmetric catalytic synthesis of naphthyridine formamide drugs

Abstract

The invention discloses a method for asymmetric catalytic synthesis of a naphthyridine formamide drug fenerenone, and belongs to the technical field of organic synthesis. The method comprises the following steps: 1, heating a compound 1 and S-1-phenethyl alcohol in an organic solvent for reaction to generate an intermediate 2; 2, reacting the compound 2 with 4-cyano-2-methoxybenzaldehyde in an organic solvent to generate an intermediate 3; 3, the compound 3 and 4-amino-5-methylpyridine-2-alcohol are subjected to a heating reaction in an organic solvent in the presence of a chiral catalyst, a crude product of an intermediate 4 is generated, then a resolving agent is added into the crude product for salification, and the intermediate 4 is obtained after dissociation; 4, adding the compound 4 and triethyl orthoformate into an organic solvent, and carrying out heating reaction under the catalysis of acid to generate an intermediate 5; 5, carrying out catalytic hydrogenation reaction on the compound 5 in the presence of a palladium catalyst to generate an intermediate 6; and 6, carrying out a reaction on the compound 6 and hexamethyldisilazane in the presence of a condensing agent, and carrying out treatment to obtain a product I. The invention provides an improved preparation method for the fenerenone, and the method has an industrial production prospect.

Description

Technical Field

[0001] The invention relates to an improved method for preparing naphthyridine carboxamide drug phenerenone by asymmetric catalysis, and belongs to the technical field of organic synthesis. Technical Background

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

[0003] Based on this, my country has recommended finerenone as a therapeutic drug for reducing urinary albumin and cardiovascular complications in patients with diabetic nephropathy in the "Chinese Guidelines for Clinical Diagnosis and Treatment of Diabetic Kidney Disease" released in 2021. 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 launched in the Chinese market in June 2022. Its synthesis methods mainly include the following:

[0004]

[0005] Route 1: This method forms two racemic components during the preparation of the core intermediate A, which need to be purified and prepared later to be separated, and the overall yield is low.

[0006]

[0007] Route 2: The preparation of the core intermediate in this method is still racemic and non-selective, and the last step requires chiral separation.

[0008]

[0009] Route 3: This method has no selectivity in constructing the core intermediate, and ultimately requires chiral preparation and purification; or it has been reported that an enzymatic method is used to selectively hydrolyze the substrate ester to achieve separation.

[0010] The main problems in the above synthetic routes are as follows: 1) The alkylation selectivity in route 1 is poor and the amidation yield is low; 2) 2-cyanoethyl 3-oxobutyrate in route 2 is uncommon, the raw material source is scarce, and the preparation has certain limitations; 3) XVIII in route 3 adopts high-pressure reaction, which has a high risk factor and is not conducive to large-scale production; 4) There are common problems in the above routes, such as chiral separation, complex process flow, low atom economy and many other defects. Summary of the invention

[0011] The purpose of the present invention is to provide an improved preparation method of finerenone, which adopts chiral auxiliary agents and different chiral catalysts to make the reaction more economical and efficient, and overcome many defects of existing synthesis methods, such as long time consumption, large waste of solvents, uneconomical atomic separation of racemates, etc.

[0012] The present invention first provides a key intermediate of finerenone, the structure of which is as follows:

[0013]

[0014] The technical solution provided by the present invention is as follows: an improved synthesis method of finerenone using asymmetric catalysis of quinine derivatives, and the reaction equation is as follows:

[0015]

[0016] In the first step, compound 1 is reacted with S-1-phenylethanol in an organic solvent at elevated temperature to generate intermediate 2;

[0017] Furthermore, in the above technical solution, the organic solvent is selected from toluene or xylene.

[0018] Furthermore, in the above technical solution, the temperature of the reaction is 100-140°C.

[0019] Furthermore, in the above technical solution, the molar ratio of the compound 1 to S-1-phenylethanol is 1:1-1.2.

[0020] In the second step, compound 2 is reacted with 4-cyano-2-methoxybenzaldehyde in an organic solvent to generate intermediate 3;

[0021] Furthermore, in the above technical solution, the organic solvent is selected from ethanol or isopropanol.

[0022] Furthermore, in the above technical solution, the temperature of the temperature rise reaction is 0-40°C.

[0023] Furthermore, in the above technical solution, the molar ratio of the compound 2 to 4-cyano-2-methoxybenzaldehyde is 1:1-1.2.

[0024] The third step is to react compound 3 with 4-amino-5-methylpyridin-2-ol in the presence of a chiral catalyst in an organic solvent at elevated temperature to generate a crude intermediate 4. A resolving agent is then added to the crude intermediate to form a salt, and the intermediate 4 is obtained after being freed.

[0025] Furthermore, in the above technical solution, the chiral catalyst has the following structure:

[0026]

[0027] Furthermore, in the above technical solution, the organic solvent is selected from dimethyl sulfoxide, N,N-dimethylformamide or N,N-dimethylacetamide; and the resolving agent is selected from D-tartaric acid.

[0028] Furthermore, in the above technical solution, the temperature of the temperature rise reaction is 80-120°C.

[0029] Furthermore, in the above technical solution, the molar ratio of the compound 3, 4-amino-5-methylpyridine-2-ol to the catalyst is 1:1-1.2:0.001-0.05.

[0030] Step 4: Compound 4 is reacted with triethyl orthoformate in an organic solvent under acid catalysis at elevated temperature to generate intermediate 5;

[0031] Furthermore, in the above technical solution, the organic solvent is selected from dimethyl sulfoxide, N,N-dimethylformamide or N,N-dimethylacetamide.

[0032] Furthermore, in the above technical solution, the temperature of the temperature rise reaction is 80-140°C.

[0033] Furthermore, in the above technical solution, the acid is selected from sulfuric acid.

[0034] The fifth step is to react compound 5 with a palladium catalyst to generate an intermediate 6 through catalytic hydrogenation.

[0035] Furthermore, in the above technical solution, the palladium catalyst is selected from 5% palladium-carbon, 10% palladium-carbon or 10% palladium hydroxide-carbon.

[0036] In the sixth step, compound 6 is reacted with hexamethyldisilazane in the presence of a condensing agent to obtain product I after treatment.

[0037] Furthermore, in the above technical solution, the condensation agent is selected from 1,1-carbonyldiimidazole.

[0038] Advantageous Effects of the Invention

[0039] A. The introduction of S-phenylethanol as a chiral auxiliary into intermediate 2 is beneficial to improve the selectivity of the target configuration in the subsequent cyclization reaction;

[0040] B. The selectivity of the key intermediate 1,2-dihydropyridine compound 4 of finerenone in the cyclization reaction is further improved under the action of a chiral catalyst; the intermediate 4 can be selectively prepared with advantage, and the chiral advantage is transferred to the final product.

[0041] C. The product has advantageous selectivity and can be purified by conventional crystallization to eventually reach a chiral purity of more than 99%, which can meet the quality requirements for pharmaceutical use. DETAILED DESCRIPTION

[0042] Example 1

[0043]

[0044] 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, and then 66 mL of xylene was added, and the atmosphere was replaced with nitrogen. The temperature was raised to 110°C for reaction for 2 hours, and TLC confirmed that the reaction was complete. The reaction solution was directly concentrated to a viscous state, 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 29 g (140.6 mmol) of yellow liquid intermediate 2, which was directly used 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).

[0045] Example 2

[0046] 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, and then 66 mL of toluene was added, and the atmosphere was replaced with nitrogen. The temperature was raised to 110°C for reaction for 2 hours, and TLC confirmed that the reaction was complete. The reaction solution was directly concentrated to a viscous state, 100 mL of petroleum ether was added, and 50 mL of water and 50 mL of saturated ammonium chloride were used to wash in turn, dried over anhydrous sodium sulfate, filtered and concentrated to obtain 26.8 g (129.9 mmol) of yellow liquid intermediate 2, which was directly used in the next step.

[0047] Example 3

[0048]

[0049] Under nitrogen protection, 21g (130.3mmol) 4-cyano-2-methoxybenzaldehyde, 29.5g (143mmol) intermediate 2, 1.10g (12.9mmol) piperidine, 0.78g (12.9mmol) acetic acid and 50mL isopropanol were added to a three-necked flask in sequence, stirred at room temperature overnight, and TLC confirmed that the reaction was complete. The reaction solution was poured into 50ml water, extracted twice with 25mL ethyl acetate, the organic phases were combined, washed with 50mL saturated sodium bisulfite solution, and the organic phase was dried and concentrated over anhydrous sodium sulfate to obtain 40.9g (117mmol) of light yellow solid intermediate 3.

[0050] Example 4

[0051] Under nitrogen protection, 21g (130.3mmol) 4-cyano-2-methoxybenzaldehyde, 29.5g (143mmol) intermediate 2, 1.10g (12.9mmol) piperidine, 0.78g (12.9mmol) acetic acid and 50mL ethanol were added to a three-necked flask in sequence, stirred at room temperature overnight, and TLC confirmed that the reaction was complete. The reaction solution was poured into 50mL water, extracted twice with 25mL ethyl acetate, the organic phases were combined, washed with 50mL saturated sodium bisulfite solution, and the organic phase was dried and concentrated over anhydrous sodium sulfate to obtain 38.7g (110.7mmol) of light yellow solid intermediate 3.

[0052] Example 5

[0053]

[0054] 38g (108.75mmol) of intermediate 3, 13.5g of 4-amino-5-methylpyridin-2-ol (108.75mmol), 0.72g (1.38mmol) of chiral catalyst 1 and 190mL of dimethyl sulfoxide were added to a three-necked flask in sequence, replaced with nitrogen, and heated to 100°C for overnight reaction. TLC and HPLC confirmed that the reaction was complete. 200mL of ethyl acetate was added to the reaction solution, washed twice with 50mL of water, and the organic phase was dried and concentrated to obtain 42g of crude product. The isomer ratio of chiral HPLC analysis was 75:25. The crude product was suspended in 240mL of ethanol and 80mL of water, and 9.38g of D-tartaric acid was added. The nitrogen was replaced, the temperature was raised to reflux and stirred for 45 minutes, and the temperature was lowered and filtered to obtain 26.4g (43.6mmol) of off-white solid intermediate 4. The isomer ratio of chiral HPLC analysis was 97.6:2.4.

[0055] Example 6

[0056] 38g (108.75mmol) of intermediate 3, 13.5g (108.75mmol) of 4-amino-5-methylpyridin-2-ol, 0.74g (1.31mmol) of chiral catalyst 2 and 190mL of dimethyl sulfoxide were added to a three-necked flask in sequence. After nitrogen substitution, the reaction was carried out at 100°C overnight. TLC and HPLC confirmed that the reaction was complete. 200mL of ethyl acetate was added to the reaction solution, washed twice with 50mL of water, and the organic phase was dried and concentrated to obtain 46g of crude product. The isomer ratio of chiral HPLC analysis was 85:15. The crude product was suspended in 240mL of ethanol and 80mL of water, and 9.38g of D-tartaric acid was added. After nitrogen substitution, the temperature was raised and refluxed for 45 minutes, and the temperature was lowered and filtered to obtain 29.6g (48.8mmol) of off-white solid intermediate 4. The isomer ratio of chiral HPLC analysis was 98.9:1.1.

[0057] Example 7

[0058]

[0059] In 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 in sequence, and finally 2.75 g (27.4 mmol) of concentrated sulfuric acid was slowly added dropwise, and the temperature was raised to 120°C for reaction for 4 hours. TLC and HPLC confirmed that the reaction was complete. The reaction solution was cooled to 50°C and slowly poured into 120 mL of water. After stirring for about 1 hour, 150 mL of water was added dropwise, and the system was cooled to 0-5°C. After stirring for 1 hour, it was filtered, the filter cake was washed with water twice, and dried to obtain 21.3 g (44.05 mmol) of intermediate 5.

[0060] Example 8

[0061]

[0062] 25 g (51.7 mmol) of intermediate 5, 125 mL of tetrahydrofuran and 1.0 g of 10% palladium hydroxide / carbon were added to the reaction flask, hydrogen was replaced and stirred at room temperature overnight, and TLC confirmed the completion of the reaction. Filter and concentrate to obtain 19.4 g (51.3 mmol) of intermediate 6, which was directly used in the next step.

[0063] Example 9

[0064]

[0065] At room temperature, add Example 9 to the reaction bottle to obtain 16g (42.17mmol) of intermediate 6, 7.5g (46.25mmol) of 1,1-carbonyldiimidazole and 80mL of tetrahydrofuran, stir evenly, and then add 0.25g (2mmol) of 4-dimethylaminopyridine. The mixture was stirred at room temperature for 1 hour, and then heated to 50°C and stirred for 2.5 hours. 15g (92.9mmol) of hexamethyldisilazane was added dropwise to the reaction solution and stirred overnight at reflux. The system was cooled to 5°C, 20mL of water was added, and the internal temperature was controlled at 5-20°C. The mixture was then stirred at reflux for 1 hour, slowly cooled to 0°C, stirred at this temperature for 1 hour, and filtered to obtain 13.5g (35.67mmol) of product I as an off-white solid, 99.5% ee; 1 H-NMR (500MHz, DMSO-d6): 7.69(s,1H),7.55(s,1H),7.37(d,J=1.6Hz,1H),7.28(dd,J=7.9,1.5Hz,1H),7.15(d,J=7.8Hz,1H ),6.90-6.55(m,2H),5.38(s,1H),4.01(dq,J=7.2,3.2Hz,2H),3.82(s,3H),2.19(s,3H),2.12(s,3H),1.05(t,J=7.0Hz,3H).

[0066] The above are only preferred embodiments of the present invention. It should be noted that the above preferred embodiments should not be regarded as limiting the present invention, and the protection scope of the present invention should be based on the scope defined by the claims. For ordinary technicians in this technical field, several improvements and modifications can be made without departing from the spirit and scope of the present invention, and these improvements and modifications should also be regarded as the protection scope of the present invention.

Claims

1. A key intermediate of the naphthyridine carboxamide drug phenerenone, characterized in that: The structure is as follows:

2. A method for preparing finerenone by asymmetric catalysis, characterized in that: The reaction equation is as follows:

3. 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 by heating to generate intermediate 2; a second step, reacting compound 2 with 4-cyano-2-methoxybenzaldehyde in an organic solvent by heating to generate intermediate 3; a third step, reacting compound 3 with 4-amino-5-methylpyridine-2-ol in an organic solvent by heating in the presence of a chiral catalyst to generate a crude intermediate 4, and then adding a resolving agent to the crude product to form a salt, and obtaining intermediate 4 after being freed; a fourth step, reacting compound 4 with triethyl orthoformate in an organic solvent by heating under acid catalysis to generate intermediate 5; a fifth step, reacting compound 5 with catalytic hydrogenation under 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 I after treatment.

4. The improved synthesis method of finerenone by asymmetric catalysis according to claim 3, 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.

5. The improved synthesis method of finerenone by asymmetric catalysis according to claim 3, 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.

6. The improved asymmetric catalytic synthesis method of finerenone according to claim 3, characterized in that: In the third step, the chiral catalyst structure is as follows:

7. The improved asymmetric catalytic synthesis method of finerenone according to claim 3, 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 80-120°C.

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

05.

9. The improved asymmetric catalytic synthesis method of finerenone according to claim 3, 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.

10. The improved asymmetric catalytic synthesis method of finerenone according to claim 3, 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.

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