An improved preparation method of finerenone

Abstract

The invention belongs to the field of drug synthesis, and specifically relates to an improved preparation method of finerenone. The reaction process includes five steps, which are: 1) compound 1 and compound 2 undergo Knoevenagel condensation to obtain compound 3; 2) compound 3 and compound 4 undergo ring closure to obtain compound 5; 3) compound 5 reacts with triethyl orthoformate to obtain compound 6; 4) compound 6 and HMDS undergo condensation to obtain amide compound 7; 5) compound 7 and a resolving agent 8 undergo salt separation, and then dissociate to obtain finerenone. The overall route is short, the yield is high, the pollution is small, the equipment requirements are not high, and it is suitable for industrial production.

Description

Technical Field

[0001] The invention belongs to the technical field of drug synthesis, and in particular relates to an improved preparation method of finerenone. Background Art

[0002] Finerenone (FIN, BAY94-8862) is a third-generation aldosterone receptor antagonist developed by Bayer, Germany, also known as a mineralocorticoid receptor antagonist (MRA). Finerenone has a dihydronaphthyridine core. Mineralocorticoid receptors can be overactivated by factors such as elevated aldosterone, causing sodium retention, increased blood pressure, promoting kidney inflammation, and accelerating kidney fibrosis (renal failure). Antagonizing mineralocorticoid receptors to improve inflammation and fibrosis has been a therapeutic target that has been the focus of nephrology in recent years, and finerenone was the first to achieve a real breakthrough. 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, can reduce patients' proteinuria, and increase glomerular filtration rate. It has the potential to be used to treat cardiorenal diseases such as type II diabetes and chronic kidney disease.

[0003] Existing literature [Angewandte Chemie-International Edition, 2020, vol.59, #51, p.23107-23111] reports that 4-amino-5-methyl-2-hydroxypyridine is used as a raw material, firstly selectively O-alkylated under the action of silver carbonate, then protected with PivCl under the action of acid-binding agent triethylamine to obtain amide, then reacted with the aldehyde group in 4-cyano-2-methoxybenzaldehyde under the action of n-butyl lithium at ultra-low temperature, followed by hydrochloric acid deprotection to obtain amino alcohol, and finally cyclized with 1,3-butanedioneamine at chiral phosphorus to obtain enantiopure phenerenone. The synthetic reaction route is as follows:

[0004]

[0005] The literature also reports that naphthyridine compounds with enantiomeric characteristics are synthesized by nitric acid oxidation, and then split by selective catalytic hydrogenation reaction of 3,5-dicarboethoxy-2,6-dimethyl-1,4-dihydropyridine and chiral phosphoric acid catalyst (R / S)-3,3'-bis(9-anthryl)-1,1'-binaphthol phosphate to prepare finerenone. The reaction route is as follows:

[0006]

[0007] The synthesis method in this document has short steps, but the yield is low and the product ee value is low. Part of the method is a small-scale experiment and has little reference value for industrial guidance. Summary of the invention

[0008] In order to solve the problems existing in the above-mentioned prior art, the present invention provides an improved preparation method of finerenone. The reaction process includes five steps, which are: 1) compound 1 and compound 2 undergo Knoevenagel condensation to obtain compound 3; 2) compound 3 and compound 4 undergo ring closure to obtain compound 5; 3) compound 5 reacts with triethyl orthoformate to obtain compound 6; 4) compound 6 and HMDS undergo condensation to obtain amide compound 7; 5) compound 7 and resolving agent 8 undergo salt separation, and then dissociate to obtain finerenone. The overall route is short, the yield is high, the pollution is small, the equipment requirements are not high, and it is suitable for industrial production.

[0009] The improved preparation method of finerenone of the present invention is expressed by the following reaction equation:

[0010]

[0011] The following steps are involved:

[0012] Step A: Compound 1, compound 2, piperidine, acetic acid and an organic solvent are mixed, and the mixture is refluxed to separate water to obtain compound 3;

[0013] Step B: Compound 3 and compound 4 are mixed with an organic solvent and reacted at elevated temperature to obtain compound 5;

[0014] Step C: Compound 5, triethyl orthoformate and an organic solvent are mixed, concentrated sulfuric acid is added, and the temperature is raised to react to obtain compound 6;

[0015] Step D: Compound 6 is reacted with hexamethyldisilazane in the presence of a catalyst under heating and reflux, and after the reaction is completed, alcohol and acid are added to obtain compound 7;

[0016] Step E: Compound 7 is salified with a resolving agent 8, and then freed by adding a base to obtain finerenone.

[0017] Furthermore, in step A, the organic solvent is selected from dichloromethane or 1,2-dichloroethane, and isopropanol is used for post-treatment, and the temperature is raised and then lowered for precipitation.

[0018] Furthermore, in step A, the molar ratio of compound 1, compound 2, piperidine and acetic acid is 1:1.1-1.2:0.1:0.1.

[0019] Furthermore, in step B, the organic solvent is selected from NMP or dioxane.

[0020] Furthermore, in step B, the molar ratio of compound 3 to compound 4 is 1:0.98-1.02, and the temperature is raised to 108-113°C.

[0021] Furthermore, in step C, the organic solvent is selected from N,N-dimethylacetamide (DM Ac) or a sulfolane / hexamethylphosphoramide mixed solvent. During the reaction, excess ethanol is distilled off under normal pressure while reacting.

[0022] Furthermore, in step C, the molar ratio of compound 5, triethyl orthoformate and sulfuric acid is 1:5.0-5.5:0.05-0.08.

[0023] Furthermore, in step D, the catalyst is selected from potassium tert-butoxide, lithium amide, lithium hexamethyldisilazide; the alcohol is selected from methanol or ethanol, and the acid is selected from hydrochloric acid or p-toluenesulfonic acid.

[0024] Furthermore, in step D, the molar ratio of compound 6, HMDS and catalyst is 1:2.5-3.0:0.15-0.20.

[0025] Furthermore, in step E, the mixed solvent is a mixture of ethyl acetate and isopropanol, and the volume ratio of the two is 2-3:1.

[0026] Furthermore, in step E, the molar ratio of compound 7 to compound 8 is 1:0.45-0.55.

[0027] Advantageous Effects of the Invention

[0028] The invention avoids the use of high-pressure reaction and metal palladium catalyst in the preparation process, has low equipment requirements, is easy to operate, and is suitable for industrial production. The invention has a short preparation route for rifenarene, high yield, and good product quality. DETAILED DESCRIPTION

[0029] The present invention is further illustrated below through the description of specific implementation modes, but this is not a limitation of the present invention. Those skilled in the art can make various modifications or improvements based on the basic idea of ​​the present invention, but as long as they do not deviate from the basic idea of ​​the present invention, they are all within the scope of the present invention.

[0030] Example 1: Preparation of Compound 5: {4-(4-cyano-2-methoxy-phenyl)-2,8-dimethyl-5-oxo-1,4,5,6-tetrahydro-[1,6]naphthyridine-3-carboxylic acid trifluoroethyl ester}

[0031]

[0032] Add 120.9 g (0.75 mol) of 4-cyano-2-methoxybenzaldehyde, 6.4 g (0.075 mol) of piperidine and 950 mL of dichloromethane to the reaction bottle, stir evenly, then add 4.5 g (0.075 mol) of glacial acetic acid (KF ≤ 0.1%) and 165.9 g (0.9 mol) of ethyl 2,2,2-trifluoro-3-oxobutyrate, raise the bath temperature to 45 ° C, reflux and dehydrate, and add dichloromethane at the same time. The process is reacted for 7 hours and the temperature is lowered to 10-20 ° C. , add 5% sodium bicarbonate aqueous solution and water to wash the organic phase, reduce the pressure of the organic phase (-0.1MPa~-0.09MPa / 35-45℃) to evaporate dichloromethane until 340g remains, add 1L of isopropanol, continue to reduce the pressure and replace the dichloromethane, add 1L of isopropanol and slowly cool to room temperature, filter and dry to obtain 226.6g of off-white intermediate 2-(4-cyano-2-methoxy-benzylidene)-3-oxobutyric acid trifluoroethyl ester, with a yield of 92.3%, HPLC (normal phase) 99.3%. 1 H-NMR (400MHz, DMSO-d6)δ:8.71-8.69(m,1H),7.61(s,1H),7.50-7.42(m,2H),5.08-4.99(m,2H),3.91(s,3H),2.44(s,3H).

[0033] 226 g (0.69 mol) of 2-(4-cyano-2-methoxy-benzylidene)-3-oxobutyric acid trifluoroethyl ester, 84 g (0.677 mol) of 4-amino-5-methyl-2-hydroxypyridine and 900 mL of NMP were added to the reaction bottle, and the bath temperature was raised to 108-113 ° C. The process was reacted for 14 hours, cooled to 10-20 ° C, and the reaction solution was poured into 2.4 L of water, filtered, and the filter cake was rinsed with water and n-heptane and dried to obtain an off-white intermediate 4-(4-cyano-2-methoxy-phenyl)-2,8-dimethyl-5-oxo-1,4,5,6-tetrahydro-[1,6]naphthyridine-3-carboxylic acid trifluoroethyl ester 265.9 g, with a total yield of 81.8%, HPLC 98.5%. 1 H-NMR(400MHz,DMSO-d6)δ:11.03(s,1H),8.26(s,1H),7.72-7.41(m,3H),7.10-7. 08(m,1H),5.09(s,1H),4.98-4.86(m,2H),3.69(s,3H),2.48(s,3H),2.10(s,3H).

[0034] Example 2: Preparation of Compound 5: {4-(4-cyano-2-methoxy-phenyl)-2,8-dimethyl-5-oxo-1,4,5,6-tetrahydro-[1,6]naphthyridine-3-carboxylic acid trifluoroethyl ester}:

[0035]

[0036] Add 120.9 g (0.75 mol) of 4-cyano-2-methoxybenzaldehyde, 6.4 g (0.075 mol) of piperidine and 1000 mL of 1,2-dichloroethane to the reaction bottle, stir evenly, add 4.5 g (0.075 mol) of glacial acetic acid (KF≤0.1%) and 152.8 g (0.83 mol) of ethyl 2,2,2-trifluoro-3-oxobutyrate, raise the bath temperature to 40-45 ° C, reflux under slight vacuum to separate water (re-place the refluxed lower layer solvent in the reaction bottle), react for 3 hours, cool to 10-20 ° C, add 5% sodium bicarbonate aqueous solution and water to wash the organic phase, and the organic phase is The reaction mixture was evaporated under reduced pressure (-0.1 MPa to -0.09 MPa / 40-45°C) to remove 1,2-dichloroethane until 356 g of 1,2-dichloroethane remained. 1 L of isopropanol was added, and the pressure was further reduced to replace the dichloromethane. 1 L of isopropanol was added and the mixture was slowly cooled to room temperature. The mixture was filtered and dried to obtain 230 g of an off-white intermediate, 2-(4-cyano-2-methoxy-benzylidene)-3-oxobutanoic acid trifluoroethyl ester. The yield was 93.7% and the HPLC (normal phase) was 99.5%. 229 g (0.70 mol) of 2-(4-cyano-2-methoxy-benzylidene)-3-oxobutyric acid trifluoroethyl ester, 85.1 g (0.686 mol) of 4-amino-5-methyl-2-hydroxypyridine and 950 mL of NMP were added to the reaction flask, and the bath temperature was raised to 108-113 ° C. The process was reacted for 14 hours, cooled to 10 ° C to 20 ° C, and the reaction solution was poured into 2.4 L of water, filtered, and the filter cake was rinsed with water and n-heptane and dried to obtain an off-white intermediate 4-(4-cyano-2-methoxy-phenyl)-2,8-dimethyl-5-oxo-1,4,5,6-tetrahydro-[1,6]naphthyridine-3-carboxylic acid trifluoroethyl ester 270.8 g, with a total molar yield of 83.3%, and HPLC 98.8%.

[0037] Example 3: Preparation of Compound 6: [4-(4-cyano-2-methoxyphenyl)-5-ethoxy-1,4-dihydro-2,8-dimethyl-1,6-naphthyridine-3-carboxylic acid trifluoroethyl ester]:

[0038]

[0039] In a reaction flask with atmospheric distillation, add 260g (0.6mol) of 4-(4-cyano-2-methoxy-phenyl)-2,8-dimethyl-5-oxo-1,4,5,6-tetrahydro-[1,6]naphthyridine-3-carboxylic acid trifluoroethyl ester, 489.1g (3.3mol) of triethyl orthoformate and 1050mL of DMAc, stir evenly, add 4.7g (0.048mol) of concentrated sulfuric acid, raise the bath temperature to 100-115°C, react for 12 hours, cool to 10-20°C, slowly pour the reaction solution into 25g of sodium bicarbonate and 3.0L of water, filter, rinse the filter cake with ethanol water and n-heptane, and dry to obtain 241.7g of off-white 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-1,4-dihydro-2,8-dimethyl-1,6-naphthyridine-3-carboxylic acid trifluoroethyl ester, with a total yield of 87.3%, HPLC95.8%. 1 H-NMR(400MHz,DMSO-d6)δ:8.38(s,1H),7.70(s,1H),7.31-7.24(m,3H),5.18(s,1H),5.02 -4.90(m,2H),4.40-4.36(m,2H),3.70(s,3H),2.30(s,3H),2.01(s,3H),1.37-1.34(m,3H).

[0040] Example 4: Preparation of Compound 6: [4-(4-cyano-2-methoxyphenyl)-5-ethoxy-1,4-dihydro-2,8-dimethyl-1,6-naphthyridine-3-carboxylic acid trifluoroethyl ester]:

[0041]

[0042] In a reaction flask with atmospheric distillation, add 260g (0.6mol) of 4-(4-cyano-2-methoxy-phenyl)-2,8-dimethyl-5-oxo-1,4,5,6-tetrahydro-[1,6]naphthyridine-3-carboxylic acid trifluoroethyl ester, 444.6g (3.0mol) of triethyl orthoformate, 700mL of cyclopentane sulfone and 260mL of hexamethylphosphoramide, stir evenly, add 3.4g (0.035mol) of concentrated sulfuric acid, and raise the bath temperature to 10 5-115°C, the process reacts for 5.5 hours, cools to 10-20°C, slowly pours the reaction solution into 25g of sodium bicarbonate and 2.0L of water, filters, rinses the filter cake with ethanol water and n-heptane, and dries to obtain 259.7g of an off-white intermediate 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-1,4-dihydro-2,8-dimethyl-1,6-naphthyridine-3-carboxylic acid trifluoroethyl ester, with a molar yield of 93.8% and an HPLC of 98.7%.

[0043] Example 5: Preparation of Compound 7: [4-(4-cyano-2-methoxyphenyl)-5-ethoxy-1,4-dihydro-2,8-dimethyl-1,6-naphthyridine-3-carboxamide]:

[0044]

[0045] Add 230.7g (0.5mol) of 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-1,4-dihydro-2,8-dimethyl-1,6-naphthyridine-3-carboxylic acid trifluoroethyl ester and 242.1g (1.5mol) of hexamethyldisilazane into the reaction bottle, add 11.2g (0.1mol) of potassium tert-butoxide at room temperature, heat to reflux for 6 hours, cool to 10-15°C, add 600mL of methanol to quench, add 500mL of water, adjust pH to 5-6 with hydrochloric acid, and add 1500mL of DCM, stirred for 0.5 hours, allowed to stand, the upper organic phase was retained, the organic phase was washed with 50% methanol aqueous solution and water, the organic phase (-0.1MPa ~ -0.09MPa / 30-35°C) was evaporated to remove DCM until 453g remained, and n-heptane was added for replacement, and dried to obtain 184.7g of off-white intermediate 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-1,4-dihydro-2,8-dimethyl-1,6-naphthyridine-3-carboxamide, with a total yield of 97.6%, HPLC97.8%. 1 H-NMR(400MHz,DMSO-d6)δ:7.67(s,1H),7.54(s,1H),7.36(s,1H),7.28-7.26(m,1H),7.24-7.22(m, 1H),6.70(s,2H),4.36(s,1H),4.05-3.97(m,2H),3.81(s,3H),2.17-2.11(m,6H),1.05-1.02(m,3H).

[0046] Example 6: Preparation of Compound 7: [4-(4-cyano-2-methoxyphenyl)-5-ethoxy-1,4-dihydro-2,8-dimethyl-1,6-naphthyridine-3-carboxamide]:

[0047]

[0048] 230.7 g (0.5 mol) of 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-1,4-dihydro-2,8-dimethyl-1,6-naphthyridine-3-carboxylic acid trifluoroethyl ester and 242.1 g (1.5 mol) of hexamethyldisilazane were added to the reaction bottle, and 1.72 g (0.075 mol) of lithium amide was added at room temperature. The reaction was heated to reflux for 4 hours, and the temperature was lowered to 10-15 ° C., 600 mL of methanol was added to quench, 500 mL of water was added, and the pH was adjusted to 5-6 with hydrochloric acid, and 1500 mL of DCM was added. The mixture was stirred for 0.5 hours and allowed to stand. The upper organic phase was retained, and the organic phase was washed with 50% methanol aqueous solution and water. The organic phase (-0.1 MPa~-0.09 M Pa / 30-35°C) to evaporate DCM under reduced pressure, add 10% methanol aqueous solution, cool to 0-5°C, filter, rinse the filter cake with water, and dry to obtain 180.3 g of light yellowish white intermediate 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-1,4-dihydro-2,8-dimethyl-1,6-naphthyridine-3-carboxamide, with a total yield of 95.3% and HPLC 95.8%.

[0049] Embodiment 7: the preparation of finerenone:

[0050]

[0051] Add 170.3 g (0.45 mol) of 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-1,4-dihydro-2,8-dimethyl-1,6-naphthyridine-3-carboxamide, 48 g (0.225 mol) of L-1-(3,3-dimethylbutyryl)pyrrolidine-2-carboxylic acid, 1020 mL of ethyl acetate and 340 mL of isopropanol into the reaction bottle, stir evenly, raise the bath temperature to 75-85 ° C, react for 4.5 hours, and slowly cool to 10-20 ℃, filter, rinse the filter cake with cold ethyl acetate / isopropanol mixed solution, put the filter cake back into the reaction bottle, add 1300mL of methanol, control 20-25℃, add triethylamine to adjust pH=6.5-7.0, filter, rinse the filter cake with 100mL of methanol, evaporate the filtrate (-0.1MPa~-0.09MPa, 30-35℃) under reduced pressure to remove methanol, add ethanol / water to replace, and recrystallize from ethanol / water to obtain 72g of phenerenone with a molar yield of 42.3% and HPLC99.7%. 1H-NMR(400MHz,DMSO-d6)δ:7.69(s,1H),7.55(s,1H),7.37(s,1H),7.29-7.27(m,1H),7.16-7.12(m,1H),6. 76-6.68(m,2H),5.36(s,1H),4.05-3.98(m,2H),3.82(s,3H),2.18(s,3H),2.12(s,3H),1.06-1.03(m,3H).

[0052] The above embodiments describe the basic principles, main features and advantages of the present invention. Those skilled in the art should understand that the present invention is not limited by the above embodiments, and the above embodiments and descriptions are only for explaining the principles of the present invention. Without departing from the scope of the principles of the present invention, the present invention may have various changes and improvements, and these changes and improvements all fall within the scope of protection of the present invention.

Claims

1. An improved preparation method of finerenone, characterized in that: The following steps are involved: Step A: Compound 1, compound 2, piperidine, acetic acid and an organic solvent are mixed, and the mixture is refluxed to separate water to obtain compound 3; Step B: Compound 3 and Compound 4 are mixed with an organic solvent, and the mixture is heated to obtain Compound 5; the molar ratio of Compound 3 to Compound 4 is 1:0.98-1.02; Step C: Compound 5, triethyl orthoformate and an organic solvent are mixed, concentrated sulfuric acid is added, and the temperature is raised to react to obtain compound 6; Step D: Compound 6 and hexamethyldisilazane are heated to reflux in the presence of a catalyst, and after the reaction, alcohol and acid are added to obtain compound 7; the catalyst is selected from potassium tert-butoxide or lithium hexamethyldisilazane; the alcohol is selected from methanol or ethanol, and the acid is selected from hydrochloric acid or p-toluenesulfonic acid; the molar ratio of compound 6, HMDS and catalyst is 1:2.5-3.0:0.15-0.20; Step E: Compound 7 and a resolving agent 8 are salified and resolved in an organic solvent, and alkali is added to free the compound 7 to obtain phenelenone; the organic solvent is selected from a mixed solvent of ethyl acetate and isopropanol; the molar ratio of compound 7 to compound 8 is 1:0.45-0.

55.

2. The improved method for preparing finerenone according to claim 1, characterized in that: In step A, the organic solvent is selected from dichloromethane or 1,2-dichloroethane.

3. The improved preparation method of finerenone according to claim 1, characterized in that: In step A, the molar ratio of compound 1, compound 2, piperidine and acetic acid is 1:1.1-1.2:0.1:0.

1.

4. The improved preparation method of finerenone according to claim 1, characterized in that: In step B, the organic solvent is selected from NMP or dioxane.

5. The improved preparation method of finerenone according to claim 1, characterized in that: In step C, the organic solvent is selected from N,N-dimethylacetamide or a mixed solvent of sulfolane / hexamethylphosphoramide.

6. The improved preparation method of finerenone according to claim 1, characterized in that: In step C, the molar ratio of compound 5, triethyl orthoformate and sulfuric acid is 1:5.0-5.5:0.05-0.08.

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