Preparation method of 4-cyano-3-methoxybenzaldehyde

Abstract

The invention discloses a method for preparing an intermediate 4-cyano-3-methoxybenzaldehyde of fenerenone, which is characterized in that 4-methyl-3-methoxybenzoic acid which is low in price and easy to obtain is used as a starting raw material and is subjected to amidation, dehydration and oxygen catalytic oxidation to obtain the 4-cyano-3-methoxybenzaldehyde, the use of toxic reagents and expensive metal catalysts is avoided, the cost is reduced, and the method is suitable for industrial production. The method has the advantages of short route, high yield, low cost and the like, meanwhile, the raw materials are cheap and easy to obtain, the reaction is safe, the problems of low yield, relatively high risk and the like in the prior art are solved, and the method has a relatively good industrial application prospect.

Description

Technical Field

[0001] The invention relates to a method for preparing 4-cyano-3-methoxybenzaldehyde, an intermediate of finerenone. Background Art

[0002] Finerenone, chemical name (S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide, is a selective nonsteroidal mineralocorticoid receptor antagonist (MRA) developed by Bayer AG of Germany. It is suitable for adult patients with type 2 diabetes (T2D) accompanied by chronic kidney disease and albuminuria. It can effectively reduce the estimated glomerular filtration rate (eGFR) of these patients that continues to decline, and reduce their risk of developing end-stage renal disease, cardiovascular death, non-fatal myocardial infarction and heart failure. Compared with the early steroidal corticosteroid antagonists spironolactone and eplerenone, the unique nonsteroidal structure of finerenone not only ensures high receptor selectivity but also greatly avoids the hyperkalemia caused by steroidal MRA. The structure of finerenone is as follows:

[0003]

[0004] There are currently several methods for preparing 4-cyano-2-methoxybenzaldehyde, an intermediate of finerenone: In the literature (ChemMedChem, 2012, 7(8): 1385-1403), 4-hydroxy-3-methoxybenzaldehyde is used as a raw material, and cyanation, esterification, substitution, and oxidation reactions are performed to obtain 4-cyano-2-methoxybenzaldehyde. The reaction uses highly toxic osmium tetroxide and a strong oxidant, sodium periodate, and the reaction is highly exothermic and dangerous, which is not conducive to industrial production.

[0005]

[0006] The literature (J. Med. Chem., 2007, 50 (10): 2468-2485) uses 3-methoxy-4-methylbenzonitrile as a raw material, brominates with NBS to obtain a dibromo product, and then dehalogenates and hydrolyzes it with silver nitrate to obtain 4-cyano-2-methoxybenzaldehyde. This method uses relatively expensive silver nitrate, which has certain toxicity and corrosiveness and is not suitable for industrial production.

[0007]

[0008] Patent CN102020587A uses 4-methyl-3-methoxybenzoic acid as a raw material, and obtains the product through amidation, dehydration, bromination and hydrolysis. This method will produce a large amount of toxic and harmful wastewater and is not suitable for industrial production.

[0009]

[0010] Patent CN107721869A uses 4-methyl-3-methoxybenzoic acid as a raw material, and obtains the product through amidation, dehydration, bromination, hydrolysis, and oxidation. This route is complicated, time-consuming, and costly, and is not suitable for industrial production.

[0011]

[0012] Patent WO20166287 uses 4-bromo-2-hydroxybenzoic acid as a raw material, and obtains 4-cyano-2-methoxybenzaldehyde through esterification, reduction, and cyanation. The raw materials of this preparation method are not easy to obtain, and a relatively expensive metal palladium catalyst is required, which is costly and not suitable for industrialization.

[0013]

[0014] The above methods have many disadvantages: including expensive raw materials or reagents, difficult to obtain, complex reaction operation, harsh conditions, low yield, high risk, etc. Therefore, the present invention hopes to develop a new method for preparing 4-cyano-3-methoxybenzaldehyde. Summary of the invention

[0015] In view of the deficiencies in the prior art, the present invention provides a method for preparing 4-cyano-3-methoxybenzaldehyde, an intermediate of phenaretin.

[0016] A method for preparing 4-cyano-3-methoxybenzaldehyde, an intermediate of finerenone, wherein the preparation method is as follows:

[0017]

[0018] (1) Compound I 4-methyl-3-methoxybenzoic acid is dissolved in organic solvent A, and then a solid acid catalyst is added thereto and refluxed to react completely to obtain a mixed solution containing an esterified product, the filtrate is filtered and cooled to -10 to 30°C, concentrated ammonia water is added to react for 6 to 15 hours (preferably 12 hours), and after the reaction is completed, the following post-treatment is performed: the reaction solution is concentrated to remove the organic solvent, and then water is added and stirred at -10 to 10°C (preferably -5 to 5°C) for 0.5 to 2 hours (preferably 1 hour), and the filter cake is filtered and dried to obtain Compound II; wherein the mass of the solid acid catalyst is 10% to 30% (preferably 20%) of the mass of Compound I, and the molar ratio of NH3·H2O contained in the concentrated ammonia water to the compound I is 1 to 10:1 (preferably 5:1);

[0019] (2) dissolving the compound II obtained in step (1) in an organic solvent B, adding a dehydrating agent thereto at a temperature of 20 to 100° C. (preferably 40 to 60° C.), heating to 110 to 120° C. for reaction for 2 to 6 hours (preferably 4 hours), then cooling to 20 to 30° C. and concentrating under reduced pressure to obtain a residue, adding petroleum ether to the residue, stirring at 20 to 30° C. for 2 to 6 hours (preferably 3 hours), and then filtering to obtain a filter cake, washing and drying the filter cake to obtain a compound III; wherein the molar ratio of the compound II to the dehydrating agent is 1:1 to 5 (preferably 1:2);

[0020] (3) Adding the compound III prepared in step (2) and the organic solvent C, an alkaline substance, and a catalyst to a reaction kettle at the same time, introducing air or oxygen to make the pressure in the kettle reach 0.1-2 MPa, and heating to 50-100° C. (preferably 60° C.) to complete the reaction to obtain a reaction solution, then adding water to the reaction kettle to obtain a mixed solution, centrifuging the mixed solution, taking the supernatant and performing reduced pressure distillation, adding water, adjusting the pH to 2-3, cooling and crystallizing, filtering and removing the filtrate, washing and drying to obtain 4-cyano-3-methoxybenzaldehyde; wherein the molar ratio of the compound III, the alkaline substance, and the catalyst is 1:1-2:0.1-0.5 (preferably 1:1.5:0.2); wherein the pH can be adjusted by using one or more of hydrochloric acid, sulfuric acid, phosphoric acid, and acetic acid, preferably hydrochloric acid.

[0021] Furthermore, the organic solvent A in step (1) is one or more of methanol, ethanol, propanol, butanol, and tert-butanol (preferably methanol), and the volume amount of the organic solvent A is 1 to 2 mL / mmol (preferably 1.5 mL / mmol) based on the amount of compound I.

[0022] Furthermore, the solid acid catalyst in step (1) is an acidic resin. Preferably, the solid acid catalyst can be an acidic cation exchange resin produced by Zhengguang Company, model CD650.

[0023] Furthermore, the mass percentage of NH3·H2O in the concentrated ammonia water in step (1) is 27-30%.

[0024] Furthermore, the organic solvent B in step (2) is one or more of dichloromethane, dichloroethane, acetonitrile and toluene, preferably toluene, and the volume amount of the organic solvent B is 1 to 2 mL / mmol (preferably 1.5 mL / mmol) based on the amount of compound II.

[0025] Furthermore, the dehydrating agent in step (2) is one or more of acetic anhydride, thionyl chloride, sulfuric acid, and phosphine oxychloride, preferably thionyl chloride.

[0026] Furthermore, the organic solvent C in step (3) is one or more of methanol, ethanol, isopropanol, and tetrahydrofuran, preferably methanol; wherein the volume amount of the organic solvent C is 1 to 2 mL / mmol (preferably 1.5 mL / mmol) based on the amount of compound III.

[0027] Furthermore, the alkaline substance in step (3) is one or more of potassium hydroxide, sodium hydroxide, and ammonia water, preferably sodium hydroxide.

[0028] Furthermore, the catalyst in step (3) is one or more of cobalt acetate, cobalt triacetylacetonate, cobalt stearate, cobalt sulfate, and cobalt trioxide, preferably cobalt acetate.

[0029] Furthermore, after removing the filtrate in step (3), the filter cake is filtered out by suction, washed with saturated brine, and vacuum dried at 30° C. to obtain the target product IV.

[0030] Furthermore, the reflux reaction time in step (1) is 6 to 10 hours, and the reaction time in step (3) is 12 to 20 hours.

[0031] The invention uses cheap and readily available 4-methyl-3-methoxybenzoic acid as a starting material, obtains 4-cyano-3-methoxybenzaldehyde through amidation, dehydration and oxygen catalytic oxidation, avoids the use of toxic reagents and expensive metal catalysts, has the advantages of short route, high yield, low cost and the like, and at the same time, the raw materials are cheap and readily available, and the reaction is safe, thus overcoming the problems of low yield and high risk in the prior art, and having good industrial application prospects. DETAILED DESCRIPTION

[0032] The present invention is further described below by means of specific embodiments, but the protection scope of the present invention is not limited thereto.

[0033] Example 1: Preparation of Compound II

[0034] Compound I (10 g, 60.14 mmol) was dissolved in methanol (90 mL), 2 g of Zhengguang resin (after drying) was added, the temperature was raised to reflux for reaction for 8 h, and the mixture was filtered after cooling. The filtrate was cooled to 0 ° C, 37 mL of 30% concentrated ammonia water was added, and the mixture was stirred for 12 h. After the reaction was completed, the methanol was concentrated to remove the methanol, water (10 mL) was added, and the mixture was stirred at 0 ° C for 1 h, filtered, the filter cake was washed with water, and dried at 55 ° C to obtain 8.57 g of white solid, with a yield of 86.39%. 1 H NMR (500MHz, DMSO-d6): δ = 7.94 (s, 1H), 7.43-7.18 (m, 4H), 3.83 (s, 3H), 2.17 (s, 3H) ppm.

[0035] Example 2: Preparation of Compound II

[0036] Compound I (10 g, 60.14 mmol) was dissolved in methanol (90 mL), and 2 g of epoxy anhydride resin (after drying) was added. The temperature was raised to reflux for reaction for 8 h, and the mixture was filtered after cooling. The filtrate was cooled to 0°C, and 37 mL of 30% concentrated ammonia water was added. The mixture was stirred and heated for 12 h. After the reaction was completed, the methanol was removed by concentration, and water (10 mL) was added and stirred at 0°C for 1 h. The mixture was filtered by suction, and the filter cake was washed with water and dried at 55°C to obtain 7.51 g of a white solid with a yield of 75.66%.

[0037] Example 3: Preparation of Compound II

[0038] Compound I (10 g, 60.14 mmol) was dissolved in methanol (90 mL), 2 g of phenolic resin (after drying) was added, the temperature was raised to reflux for reaction for 8 h, and the mixture was filtered after cooling. The filtrate was cooled to 0 ° C, 37 mL of 30% concentrated ammonia water was added, and the mixture was stirred for 12 h. After the reaction was completed, the methanol was removed by concentration, and water (10 mL) was added and stirred at 0 ° C for 1 h, and the mixture was filtered by suction. The filter cake was washed with water and dried at 55 ° C to obtain 6.38 g of white solid with a yield of 64.28%.

[0039] Example 4: Preparation of Compound III

[0040] Take a 100mL dry three-necked flask, add compound II (5g, 30.29mmol), add toluene (45mL), add thionyl chloride (11.45g, 60.58mmol) dropwise at 40°C, and then heat to 110°C for 4h. After the reaction is completed, the organic solvent and thionyl chloride are recovered by concentration under reduced pressure, and the residue is added with petroleum ether (20mL) for slurry, stirred at 25°C for 3h, filtered, the filter cake is washed with petroleum ether, and dried at 50°C to obtain 4.07g of white solid, with a yield of 91.47%. 1 H NMR (500MHz, DMSO-d6): δ = 7.21-7.16 (dd, J = 7.8-7.65Hz, 2H), 7.03 (s, 1H), 3.85 (s, 3H), 2.26 (s, 3H) ppm.

[0041] Example 5: Preparation of Compound III

[0042] Take a 100mL dry three-necked flask, add compound II (5g, 30.29mmol), add toluene (45mL), add acetic anhydride (6.18g, 60.58mmol) dropwise at 40°C, and then heat to 110°C for 4h. After the reaction is completed, the organic solvent and thionyl chloride are recovered by concentration under reduced pressure, and the residue is added with petroleum ether (20mL) for slurry, stirred at 25°C for 3h, filtered, and the filter cake is washed with petroleum ether and dried at 50°C to obtain 3.44g of white solid, with a yield of 77.16%;

[0043] Example 6: Preparation of Compound III

[0044] Take a 100mL dry three-necked flask, add compound II (5g, 30.29mmol), add toluene (45mL), add concentrated sulfuric acid (5.94g, 60.58mmol) dropwise at 40°C, and then heat to 110°C for 4h. After the reaction is completed, the organic solvent and thionyl chloride are recovered by concentration under reduced pressure, and the residue is added with petroleum ether (20mL) for slurry, stirred at 25°C for 3h, filtered, the filter cake is washed with petroleum ether, and dried at 50°C to obtain 2.31g of white solid, with a yield of 51.87%;

[0045] Example 7: Preparation of Compound IV

[0046] Add compound III (4g, 27.19mmol) to a 100mL reactor, add methanol (40mL), sodium hydroxide (1.63g, 40.78mmol), and stir at room temperature for 4h. Add cobalt acetate (962mg, 5.44mmol), introduce oxygen until the reaction pressure reaches 1.5MPa, heat to 60℃, and keep warm for 12h. After the reaction, add 20mL of water, keep stirring for 30min, centrifuge to separate the catalyst, and remove the solvent by vacuum distillation of the supernatant. Add 20mL of water to the residue, adjust the pH to 2-3 with 1mol / L hydrochloric acid, cool to 0℃ and stir for 4h, filter, wash the filter cake with saturated brine, and vacuum dry at 30℃ to obtain 3.95g of white solid with a yield of 90.37%. 1 H NMR (400MHz, DMSO-d6): δ = 10.51 (s, 1H), 7.89-7.87 (d, J = 7.6Hz, 1H), 7.31-7.29 (d, J = 7.6Hz, 1H), 7.25 (s, 1H), 3.97 (s, 3H) ppm.

[0047] Example 8: Preparation of Compound IV

[0048] Add compound III (4g, 27.19mmol) to a 100mL reactor, add methanol (40mL), sodium hydroxide (1.63g, 40.78mmol), and stir at room temperature for 4h. Add cobalt acetate (962mg, 5.44mmol), introduce air until the reaction pressure reaches 1.5MPa, heat to 60℃, and keep warm for 12h. After the reaction, add 20mL of water, keep stirring for 30min, centrifuge to separate the catalyst, and remove the solvent by vacuum distillation of the supernatant. Add 20mL of water to the residue, adjust the pH to 2-3 with 1mol / L hydrochloric acid, cool to 0℃ and stir for 4h, filter, wash the filter cake with saturated brine, and vacuum dry at 30℃ to obtain 3.28g of white solid with a yield of 75.04%.

[0049] Example 9: Preparation of Compound IV

[0050] Add compound III (4g, 27.19mmol) to a 100mL reactor, add methanol (40mL), sodium hydroxide (1.63g, 40.78mmol), and stir at room temperature for 4h. Add cobalt trioxide (902mg, 5.44mmol), introduce oxygen until the reaction pressure reaches 1.5MPa, heat to 60℃, and keep warm for 12h. After the reaction, add 20mL of water, keep stirring for 30min, centrifuge to separate the catalyst, and remove the solvent by vacuum distillation of the supernatant. Add 20mL of water to the residue, adjust the pH to 2-3 with 1mol / L hydrochloric acid, cool to 0℃ and stir for 4h, filter, wash the filter cake with saturated brine, and vacuum dry at 30℃ to obtain 3.62g of white solid with a yield of 82.75%.

[0051] Example 10: Preparation of Compound IV

[0052] Add compound III (4g, 27.19mmol) to a 100mL reactor, add methanol (40mL), sodium hydroxide (1.63g, 40.78mmol), and stir at room temperature for 4h. Add cobalt triacetylacetonate (1.986g, 5.44mmol), introduce oxygen until the reaction pressure reaches 1.5MPa, heat to 60℃, and keep warm for 12h. After the reaction, add 20mL of water, keep stirring for 30min, centrifuge to separate the catalyst, and remove the solvent by vacuum distillation of the supernatant. Add 20mL of water to the residue, adjust the pH to 2-3 with 1mol / L hydrochloric acid, cool to 0℃ and stir for 4h, filter, wash the filter cake with saturated brine, and vacuum dry at 30℃ to obtain 3.78g of white solid with a yield of 86.44%.

Claims

1. A method for preparing 4-cyano-3-methoxybenzaldehyde, an intermediate of finerenone, characterized in that: The preparation method is as follows: (1) Compound I 4-methyl-3-methoxybenzoic acid is dissolved in organic solvent A, and then a solid acid catalyst is added thereto to reflux and react completely to obtain a mixed solution containing an esterified product, the filtrate is filtered and cooled to -10 to 30°C, concentrated ammonia water is added to react for 6 to 15 hours, the organic solvent is concentrated to remove, and then water is added and stirred at -10 to 10°C for 0.5 to 2 hours, and the filter cake is filtered and dried to obtain compound II; wherein the mass of the solid acid catalyst is 10% to 30% of the mass of compound I, and the molar ratio of NH3·H2O contained in the concentrated ammonia water to the compound I is 1 to 10:1; (2) dissolving the compound II obtained in step (1) in an organic solvent B, adding a dehydrating agent thereto at a temperature of 20 to 100° C., heating to 110 to 120° C. for reaction for 2 to 6 hours, then cooling to 20 to 30° C. and concentrating under reduced pressure to obtain a residue, adding petroleum ether to the residue, stirring at 20 to 30° C. for 2 to 6 hours, and then filtering to obtain a filter cake, washing and drying the filter cake to obtain a compound III; wherein the molar ratio of the compound II to the dehydrating agent is 1:1 to 5; (3) Adding the compound III prepared in step (2) and the organic solvent C, an alkaline substance, and a catalyst to a reaction kettle at the same time, introducing air or oxygen to make the pressure in the kettle reach 0.1-2 MPa, and heating to 50-100° C. to complete the reaction to obtain a reaction solution, then adding water to the reaction kettle to obtain a mixed solution, centrifuging the mixed solution, taking the supernatant and performing reduced pressure distillation, adding water, adjusting the pH to 2-3, cooling and crystallizing, filtering and removing the filtrate, washing and drying to obtain 4-cyano-3-methoxybenzaldehyde; wherein the molar ratio of the compound III, the alkaline substance, and the catalyst is 1:1-2:0.1-0.

5.

2. The method for preparing 4-cyano-3-methoxybenzaldehyde, an intermediate of safenaredonone according to claim 1, characterized in that: The organic solvent A in step (1) is one or more of methanol, ethanol, propanol, butanol and tert-butanol, and the volume amount of the organic solvent A is 1-2 mL / mmol based on the amount of compound I.

3. The method for preparing 4-cyano-3-methoxybenzaldehyde, an intermediate of safenaredonone according to claim 1, characterized in that: The solid acid catalyst in step (1) is an acidic resin.

4. The method for preparing 4-cyano-3-methoxybenzaldehyde, an intermediate of safenaredonone according to claim 1, characterized in that: The mass percentage of NH3·H2O in the concentrated ammonia water described in step (1) is 27-30%.

5. The method for preparing 4-cyano-3-methoxybenzaldehyde, an intermediate of safenaredonone according to claim 1, characterized in that: The organic solvent B in step (2) is one or more of dichloromethane, dichloroethane, acetonitrile and toluene, and the volume amount of the organic solvent B is 1-2 mL / mmol based on the amount of compound II.

6. The method for preparing 4-cyano-3-methoxybenzaldehyde, an intermediate of safenaredonone according to claim 1, characterized in that: The dehydrating agent in step (2) is one or more of acetic anhydride, thionyl chloride, sulfuric acid, and trichlorophosphine oxide.

7. The method for preparing 4-cyano-3-methoxybenzaldehyde, an intermediate of safenaredonone according to claim 1, characterized in that: The organic solvent C in step (3) is one or more of methanol, ethanol, isopropanol, and tetrahydrofuran; wherein the volume amount of the organic solvent C is 1 to 2 mL / mmol based on the amount of compound III.

8. The method for preparing 4-cyano-3-methoxybenzaldehyde, an intermediate of safenaredonone according to claim 1, characterized in that: The alkaline substance in step (3) is one or more of potassium hydroxide, sodium hydroxide and ammonia water.

9. The method for preparing 4-cyano-3-methoxybenzaldehyde, an intermediate of safenaredonone according to claim 1, characterized in that: The catalyst in step (3) is one or more of cobalt acetate, cobalt triacetylacetonate, cobalt stearate, cobalt sulfate, and cobalt trioxide.

10. The method for preparing 4-cyano-3-methoxybenzaldehyde, an intermediate of safenaredonone according to claim 1, characterized in that: The reflux reaction time of step (1) is 6 to 10 hours, and the reaction time of step (3) is 12 to 20 hours.

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