Preparation method of fenerenone intermediate

Abstract

The invention discloses a method for preparing a fenerenone intermediate, which comprises the following steps: taking 4-amino-5-methyl-2-ethoxypyridine and 2-butenoic acid-2-formyl ethyl ester as initial raw materials, carrying out addition reaction to obtain an intermediate 1, reacting the intermediate 1 with Boc2O under an alkaline condition to obtain an intermediate 2, and reacting the intermediate 2 with Boc2O under the alkaline condition to obtain the fenerenone intermediate. The preparation method comprises the following steps: carrying out a coupling reaction on an intermediate 2 and 4-bromo-3-methoxyphenol to prepare an intermediate 3, carrying out a bromination reaction on the intermediate 3 and a brominating agent to prepare an intermediate 4, carrying out a cyanidation reaction on the intermediate 4 and K3Fe (CN) 6 under catalysis of palladium acetate to prepare an intermediate 5, carrying out a Boc removal reaction on the intermediate 5 under an acidic condition to prepare an intermediate 6, and carrying out a purification reaction on the intermediate 6 to prepare the intermediate 3. And adding alkali into the intermediate 6, and hydrolyzing to obtain the fenerenone intermediate. The two starting materials used in the method are easy to purchase, and the preparation method of the fenerenone intermediate is simple in post-treatment operation, high in yield and beneficial to industrial production. # imgabs0 #

Description

Technical Field

[0001] The invention relates to a preparation method of a finerenone intermediate (4-(4-cyano-2-methoxyphenyl)-5-ethoxy-1,4-dihydro-2,8-dimethyl-1,6-naphthyridine-3-carboxylic acid), belonging to the technical field of medicine. Background Art

[0002] Finerenone is the first non-steroidal selective mineralocorticoid receptor antagonist, which can be used to treat diabetic nephropathy, chronic kidney disease and end-stage renal disease, and can reduce proteinuria and improve glomerular filtration rate. Finerenone, chemical name: (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-1,4-dihydro-2,8-dimethyl-1,6-naphthyridine-3-carboxamide, has the following structural formula.

[0003]

[0004] Currently, there are multiple documents reporting the preparation method of finerenone, among which the synthesis route disclosed in WO2016016287 is: using 3-methoxy-4-cyanobenzaldehyde as the starting material, finerenone is obtained through 7 steps of reaction, and its synthesis route is shown in Scheme 1.

[0005]

[0006] The synthesis route disclosed in WO2017032673 is: using 3-methoxy-4-cyanobenzaldehyde as a starting material, phenerenone is obtained through a five-step reaction, and its synthesis route is shown in Scheme 2.

[0007]

[0008] The above two routes all use the raw material 4-amino-5-methyl-2-hydroxypyridine, which is expensive due to the high temperature and high pressure reaction, oxidation reaction, nitration reaction, etc. (references: Synthesis 1984 9 765-76641935-71-1; CN113474332A; CN103193704B, etc.), and there are few manufacturers on the market, so it is not easy to buy. In addition, the two existing routes have relatively complicated operation steps, resulting in a low yield, which is not suitable for industrial production. Summary of the invention

[0009] In view of the above problems, the present invention provides a method for preparing a finerenone intermediate, wherein the method uses 4-amino-5-methyl-2-ethoxypyridine and 2-butenoic acid-2-formylethyl ester as starting materials to obtain intermediate 1 through addition reaction, intermediate 1 reacts with Boc2O under alkaline conditions to obtain intermediate 2, intermediate 2 reacts with 4-bromo-3-methoxyphenol through coupling reaction to obtain intermediate 3, intermediate 3 reacts with a brominating agent through bromination reaction to obtain intermediate 4, intermediate 4 reacts with K3Fe(CN)6 under the catalysis of palladium acetate through cyanation reaction to obtain intermediate 5, intermediate 5 reacts with Boc removal reaction under acidic conditions to obtain intermediate 6, and intermediate 6 is hydrolyzed with alkali to obtain a finerenone intermediate. The prepared finerenone intermediate can be subjected to amidation reaction and resolution to obtain finerenone.

[0010] The technical solution of the present invention is: a method for preparing a finerenone intermediate, characterized in that:

[0011] (1) adding 4-amino-5-methyl-2-ethoxypyridine to an organic solvent, and reacting it with 2-butenoic acid-2-formylethyl ester at 30-35° C. in the presence of an organic base, acetic acid, and triethyl orthoformate to obtain intermediate 1;

[0012] (2) In an organic solvent, intermediate 1 reacts with Boc2O in the presence of an organic base to obtain intermediate 2;

[0013] (3) In an organic solvent, intermediate 2 is subjected to a coupling reaction with 4-bromo-3-methoxyphenol (hydrogen extraction with n-butyl lithium) at 60-70° C. to obtain intermediate 3;

[0014] (4) In an organic solvent, intermediate 3 is subjected to a bromination reaction with a brominating agent to obtain intermediate 4;

[0015] (5) In an organic solvent, intermediate 4 is subjected to cyanation reaction with K3Fe(CN)6 under the catalysis of palladium acetate to obtain intermediate 5;

[0016] (6) In an organic solvent, intermediate 5 is subjected to Boc removal under acidic conditions to obtain intermediate 6; then, an alkaline hydrolysis reaction is performed to obtain finerenone intermediate.

[0017] Its synthetic route is as follows:

[0018]

[0019] Preferably, the organic solvent used in steps (1) to (3) is any one of methanol, ethanol, isopropanol and sec-butanol.

[0020] Preferably, the organic solvent used in steps (4) to (6) is any one of DMF and THF.

[0021] Preferably, the organic base used in step (1) is one of piperidine, pyridine and triethylamine, and piperidine is most preferred.

[0022] Preferably, the organic base used in step (2) is one of piperidine, pyridine and triethylamine, and triethylamine is most preferred.

[0023] Preferably, the brominating agent in step (4) is one of phosphorus tribromide, bromine and phosphorus oxybromide, and phosphorus tribromide is most preferred.

[0024] Preferably, the acid used in step (6) is one of trifluoroacetic acid, hydrochloric acid and acetic acid, and trifluoroacetic acid is most preferred.

[0025] Preferably, the specific steps are:

[0026] (1) Add 4-amino-5-methyl-2-ethoxypyridine, piperidine and acetic acid to isopropanol, then dropwise add a mixture of 2-butenoic acid-2-formylethyl ester, triethyl orthoformate and isopropanol, react at 30-35° C. for 0.5-1.5 h, then slowly cool to 0-5° C., filter, wash and dry to obtain intermediate 1;

[0027] (2) In methanol, the intermediate 1, triethylamine and Boc2O are mixed uniformly, then the temperature is raised to reflux for reaction, filtered, washed and dried to obtain the intermediate 2;

[0028] (3) In sec-butyl alcohol, react intermediate 2 with 4-bromo-3-methoxyphenol (hydrogen extraction with n-butyl lithium) at 60-70° C. for 2-6 h, then cool to 0-5° C., filter, wash, and dry to obtain intermediate 3;

[0029] (4) In DMF, intermediate 3 and phosphorus tribromide are reacted at 100-105°C for 2-5h, and then water is added to cool and crystallize to obtain intermediate 4;

[0030] (5) In THF, intermediate 4 is catalyzed by palladium acetate and reacted with K3Fe(CN)6 at 55-65°C for 1-3h, and the palladium acetate and the remaining K3Fe(CN)6 are removed by hot filtration, and then the temperature is lowered to 25-30°C for crystal growth, filtration, washing, and drying to obtain intermediate 5;

[0031] (6) In THF, the intermediate 5 is deprotected by adding trifluoroacetic acid at room temperature for 0.5-2h to obtain the intermediate 6; then, sodium hydroxide solution is added dropwise at a temperature of 0-10°C, and the reaction is continued for 1-3h. The mixture is extracted with dichloromethane, and a dilute hydrochloric acid solution is added dropwise to the aqueous phase to adjust the pH to 6-7. The mixture is cooled for crystallization, filtered, washed, and dried to obtain the phenerenone intermediate.

[0032] Furthermore, in the step (1), the molar ratio of 4-amino-5-methyl-2-ethoxypyridine, 2-butenoic acid-2-formylethyl ester, piperidine, acetic acid and triethyl orthoformate is 1:1.0-1.1:0.05-0.2:0.05-0.2:0.9-1.1.

[0033] Furthermore, in step (2), the molar ratio of intermediate 1, triethylamine and Boc2O is 1:0.07-0.09:0.8-1.0; preferably 1:0.08:0.9.

[0034] Furthermore, in step (3), the molar ratio of intermediate 2 to 4-bromo-3-methoxyphenol is 1:0.6-0.8; preferably 1:0.7.

[0035] Furthermore, in step (4), the molar ratio of intermediate 3 to phosphorus tribromide is 1:1.0-1.1; preferably 1:1.05.

[0036] Furthermore, in step (5), the molar ratio of intermediate 4 to K3Fe(CN)6 is 1:1.0-1.2; preferably 1:1.1.

[0037] Furthermore, in step (6), the molar ratio of intermediate 5 to trifluoroacetic acid is 1:0.7-0.9; preferably 1:0.8.

[0038] The technical effects of the present invention are:

[0039] 1. The two starting materials used in the present invention are available from many manufacturers on the market and are easy to purchase. In addition, the price is lower than that of the starting material 4-amino-5-methyl-2-hydroxypyridine involved in the background technology, which greatly saves production costs;

[0040] 2. The synthetic route of the present invention does not involve dangerous reactions such as high temperature and high pressure reactions, oxidation reactions, nitration reactions, etc. The post-processing steps only involve a small amount of extraction steps, the operation is simple, and the yield of each step is above 85%, which is more conducive to industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0041] Figure 1 HPLC chart of the intermediate of finerenone, the product of Example 1;

[0042] Figure 2 The intermediate of the product finerenone in Example 1 1 H NMR spectrum;

[0043] Figure 3 for Figure 2 1 A partial enlargement of the H NMR spectrum (>7.2 ppm);

[0044] Figure 4 for Figure 2 1 Magnified portion of the H NMR spectrum (<6.0 ppm). DETAILED DESCRIPTION

[0045] The effects are described below in conjunction with the embodiments and drawings.

[0046] Example 1: Preparation of finerenone intermediate

[0047] (1) Add 30 g of 4-amino-5-methyl-2-ethoxypyridine and 135 ml of isopropanol to a reaction flask, raise the temperature to 30-35° C., continue to add 1.58 g of piperidine and 1.12 g of acetic acid, stir evenly, and control the addition within 3 hours to complete the addition of a mixture of 29.85 g of 2-butenoic acid-2-formylethyl ester, 27.58 g of triethyl orthoformate and 15 ml of isopropanol. After addition, react at 30-35° C. for 1 hour, cool to 0-5° C. and stir for 30 minutes, filter, rinse the filter cake with isopropanol, and dry to obtain 48.93 g of intermediate 1, with a yield of 89.8%;

[0048] (2) Add 48.93 g of intermediate 1, 245 ml of methanol, 1.47 g of triethylamine and 35.94 g of Boc2O to a reaction flask and mix well at room temperature. Then heat the reaction to reflux for 3 h. After the reaction is complete, cool the reaction to 10-20 °C and stir for 0.5 h. Filter, rinse the filter cake with methanol, and dry to obtain 63.44 g of intermediate 2. The yield is 95.1%.

[0049] (3) Add 63.44 g of intermediate 2, 24.76 g of 4-bromo-3-methoxyphenol, 22.08 g of n-butyl lithium and 950 ml of sec-butyl alcohol to a reaction flask, raise the temperature to 60-70° C. and react for 4 h, then cool to 0-10° C. and stir for 30 min, filter, rinse the filter cake with sec-butyl alcohol, and dry to obtain 73.10 g of intermediate 3, with a yield of 87.0%;

[0050] (4) Add 73.10 g of intermediate 3, 168 ml of DMF and 41.67 g of phosphorus tribromide to a reaction flask, heat to 100-105° C. and react for 3 h, then cool to 60° C. and dropwise add 300 ml of water for crystallization. After addition, cool to 0-5° C. and stir for 30 min, filter, rinse the filter cake with water, and dry to obtain 74.09 g of intermediate 4, with a yield of 90.0%;

[0051] (5) Add 74.09 g of intermediate 4, 370 ml of tetrahydrofuran, 0.7 g of palladium acetate and 47.79 g of K3Fe(CN)6 to a reaction flask, heat to 60°C for 2 h, remove palladium acetate and remaining K3Fe(CN)6 by hot filtration, then cool to 25-30°C for 2 h, filter and dry to obtain 66.31 g of intermediate 5, with a yield of 99.0%;

[0052] (6) Add 66.31 g of intermediate 5, 11.89 g of trifluoroacetic acid and 330 ml of THF to a reaction flask, stir and react at room temperature for 1 h, filter, rinse the filter cake with THF, and dry to obtain 44.40 g of intermediate 6, with a yield of 85.0%;

[0053] (7) 44.40 g of intermediate 6 and 222 ml of THF were added to the reaction flask and mixed. The mixture was then cooled to 0-10° C. and an aqueous sodium hydroxide solution (6.05 g dissolved in 300 ml of water) was added dropwise. After the addition was completed, the temperature was controlled at 0-10° C. for reaction for 2 h. After the reaction was complete, dichloromethane (2221+89 ml) was added to the reaction system for extraction. The mixture was separated and a dilute hydrochloric acid solution (16.39 g of dilute hydrochloric acid dissolved in 195 ml of water) was added dropwise to the aqueous phase. After the addition was completed, the pH value was 6-7 and a large amount of solid was precipitated. The mixture was stirred at 0-10° C. for 0.5 h, filtered and dried to obtain 39.28 g of finerenone intermediate. The yield was 95.1% and the HPLC purity was 96.75%. 1 H NMR spectrum Figure 2-4 shown.

[0054] Example 2: Finerenone intermediate

[0055] (1) Add 30 g of 4-amino-5-methyl-2-ethoxypyridine and 135 ml of isopropanol to a reaction flask, heat to 30-35° C., continue to add 1.60 g of piperidine and 1.13 g of acetic acid, stir evenly, and add a mixture of 29.90 g of 2-butenoic acid-2-formylethyl ester, 27.55 g of triethyl orthoformate and 15 ml of isopropanol dropwise over 3 h. After addition, react at 30-35° C. for 1 h, cool to 0-5° C. and stir for 30 min, filter, rinse the filter cake with isopropanol, and dry to obtain 48.85 g of intermediate 1, with a yield of 89.88%;

[0056] (2) Add 48.85 g of intermediate 1, 245 ml of methanol, 1.50 g of triethylamine, and 36.01 g of Boc2O to a reaction flask and mix evenly at room temperature. Then heat the reaction to reflux for 3 h. After the reaction is complete, cool the reaction to 10-20 °C and stir for 0.5 h. Filter, rinse the filter cake with methanol, and dry to obtain 63.33 g of intermediate 2, with a yield of 94.68%;

[0057] (3) Add 63.33 g of intermediate 2, 24.83 g of 4-bromo-3-methoxyphenol, 22.16 g of n-butyl lithium, and 950 ml of sec-butyl alcohol to a reaction flask, raise the temperature to 60-70° C. and react for 4 h, then cool to 0-10° C. and stir for 30 min, filter, rinse the filter cake with sec-butyl alcohol, and dry to obtain 73.29 g of intermediate 3, with a yield of 87.35%;

[0058] (4) Add 73.29 g of intermediate 3, 168 ml of DMF, and 41.70 g of phosphorus tribromide to a reaction flask, raise the temperature to 100-105° C. and react for 3 h, then cool to 60° C. and add 300 ml of water dropwise for crystallization. After the addition, cool to 0-5° C. and stir for 30 min, filter, rinse the filter cake with water, and dry to obtain 74.27 g of intermediate 4, with a yield of 90.53%;

[0059] (5) Add 74.27 g of intermediate 4, 370 ml of tetrahydrofuran, 0.7 g of palladium acetate, and 47.70 g of K3Fe(CN)6 to the reaction flask and heat to 60°C for 2 h. Remove the palladium acetate and the remaining K3Fe(CN) by hot filtration. 6， Then the temperature was lowered to 25-30°C and crystals were grown for 2 hours, filtered, and dried to obtain 66.28 g of intermediate 5 with a yield of 99.0%;

[0060] (6) Add 66.28 g of intermediate 5, 11.89 g of trifluoroacetic acid, and 330 ml of THF to a reaction flask, stir at room temperature for 1 h, filter, rinse the filter cake with THF, and dry to obtain 44.56 g of intermediate 6, with a yield of 85.49%;

[0061] (7) 44.56 g of intermediate 6 and 222 ml of THF were added to the reaction flask and mixed. The temperature was lowered to 0-10° C. and an aqueous sodium hydroxide solution (6.05 g dissolved in 300 ml of water) was added dropwise. After the addition was completed, the temperature was controlled at 0-10° C. and the reaction was carried out for 2 h. After the reaction was completed, dichloromethane (2221+89 ml) was added to the reaction system for extraction. The liquids were separated and a dilute hydrochloric acid solution (16.39 g dissolved in 195 ml of water) was added dropwise to the aqueous phase. After the addition was completed, the pH was 6-7 and a large amount of solid was precipitated. The temperature was controlled at 0-10° C. and stirred for 0.5 h. The mixture was filtered and dried to obtain 39.37 g of finerenone intermediate with a yield of 96.11%.

[0062] Example 3: Preparation of finerenone from finerenone intermediates

[0063]

[0064] (1) 46.81 g of finerenone intermediate, 22 g of CDI, and 1.51 g of DMAP were added to a reaction bottle, heated to 55-60° C. for reaction for 3 h, and sampled for detection. After the reaction was completed, 126.06 g of 25% ammonia water was added dropwise, heated to 80° C. for reaction for 12 h, and sampled for detection. After the reaction was completed, the temperature was lowered to 25° C., 235 g of water was added, and then the temperature was lowered to 0-10° C. and stirred for 30 min, filtered, the filter cake was washed with water, and dried to obtain 39.69 g of finerenone intermediate 2, with a yield of 85.0%;

[0065] (2) 39.69 g of finerenone intermediate 2, 595 ml of ethanol, and 20.67 g of dibenzoyltartaric acid were added to a reaction flask, heated to 55° C. for reaction for 1.5 h. After the reaction was complete, the temperature was lowered to 25° C. for crystal growth for 16 h, filtered, and the filter cake was washed with a mixed solution of ethanol and water, and dried to obtain 38.63 g of finerenone dibenzoyltartaric acid, with a yield of 50%;

[0066] (3) Add 38.63 g of finerenone dibenzoyl tartrate, 78 ml of ethanol, 310 ml of water, and 26.91 g of sodium phosphate into a reaction flask, heat to 35° C. and stir for 5 h. Take samples for testing. After the reaction is complete, filter and dry to obtain 18.45 g of finerenone, with a yield of 93.0%.

Claims

1. A method for preparing a finerenone intermediate, Its characteristics are: The finerenone intermediate is 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-1,4-dihydro-2,8-dimethyl-1,6-naphthyridine-3-carboxylic acid; and its preparation method comprises the following steps: (1) adding 4-amino-5-methyl-2-ethoxypyridine to an organic solvent, and reacting it with 2-butenoic acid-2-formylethyl ester at 30-35° C. in the presence of an organic base, acetic acid, and triethyl orthoformate to obtain intermediate 1; (2) In an organic solvent, intermediate 1 reacts with Boc in the presence of an organic base. 2 O reacts to obtain intermediate 2; (3) In an organic solvent, n-butyl lithium is used to extract hydrogen, and intermediate 2 is coupled with 4-bromo-3-methoxyphenol to obtain intermediate 3; (4) In an organic solvent, intermediate 3 is subjected to a bromination reaction with a brominating agent to obtain intermediate 4; (5) In an organic solvent, intermediate 4 reacts with K under the catalysis of palladium acetate. 3 Fe(CN) 6 The intermediate 5 is prepared by cyanation reaction; (6) In an organic solvent, intermediate 5 is subjected to removal of Boc under acidic conditions to obtain intermediate 6; then, an alkali hydrolysis reaction is performed to obtain finerenone intermediate; 2. A method for preparing a finerenone intermediate according to claim 1, Its characteristics are: The organic solvent used in the steps (1) to (3) is any one of methanol, ethanol, isopropanol and sec-butanol.

3. A method for preparing a finerenone intermediate according to claim 1, Its characteristics are: The organic solvent used in steps (4) to (6) is any one of DMF and THF.

4. A method for preparing a finerenone intermediate according to claim 1, Its characteristics are: The organic base used in the steps (1) and (2) is one of piperidine, pyridine and triethylamine.

5. A method for preparing a finerenone intermediate as claimed in claim 4, Its characteristics are: The organic base used in the step (1) is pyridine.

6. A method for preparing a finerenone intermediate as claimed in claim 4, Its characteristics are: The organic base used in the step (2) is triethylamine.

7. A method for preparing a finerenone intermediate according to claim 1, Its characteristics are: In the step (4), the brominating agent is one of phosphorus tribromide, bromine and phosphorus oxybromide.

8. A method for preparing a finerenone intermediate according to claim 1, Its characteristics are: The acid used in step (6) is one of trifluoroacetic acid, hydrochloric acid and acetic acid.

9. A method for preparing a finerenone intermediate according to any one of claims 1 to 8, Its characteristics are: (1) Add 4-amino-5-methyl-2-ethoxypyridine, piperidine and acetic acid to isopropanol, then dropwise add a mixture of 2-butenoic acid-2-formylethyl ester, triethyl orthoformate and isopropanol, react at 30-35° C. for 0.5-1.5 h, then slowly cool to 0-5° C., filter, wash and dry to obtain intermediate 1; (2) In methanol, intermediate 1, triethylamine and Boc 2 O are mixed evenly, then the temperature is raised to reflux for reaction, filtered, washed, and dried to obtain intermediate 2; (3) In sec-butyl alcohol, n-butyl lithium is used to extract hydrogen, and the intermediate 2 is reacted with 4-bromo-3-methoxyphenol at 60-70° C. for 2-6 h, then cooled to 0-5° C., filtered, washed, and dried to obtain the intermediate 3; (4) In DMF, intermediate 3 and phosphorus tribromide are reacted at 100-105°C for 2-5h, and then water is added to cool and crystallize to obtain intermediate 4; (5) In THF, the intermediate 4 was catalyzed by palladium acetate and reacted with K 3 Fe(CN) 6 React at 55-65℃ for 1-3h, and remove palladium acetate and remaining K by hot filtration. 3 Fe(CN) 6 Then cool to 25-30°C to grow crystals, filter, wash and dry to obtain intermediate 5; (6) In THF, the intermediate 5 is deprotected by adding trifluoroacetic acid at room temperature for 0.5-2h to obtain the intermediate 6; then, sodium hydroxide solution is added dropwise at a temperature of 0-10°C, and the reaction is continued for 1-3h. The mixture is extracted with dichloromethane, and a dilute hydrochloric acid solution is added dropwise to the aqueous phase to adjust the pH to 6-7. The mixture is cooled for crystallization, filtered, washed, and dried to obtain the phenerenone intermediate.

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