Synthesis method of 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-1, 4-dihydro-2, 8-dimethyl-1, 6-naphthyridine-3-formamide

Abstract

The invention relates to a synthesis method of 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-1, 4-dihydro-2, 8-dimethyl-1, 6-naphthyridine-3-formamide, which comprises the following four steps: carrying out a Knoevenagel condensation reaction, carrying out a Hantzsch dihydropyridine synthesis method, carrying out an O-ethylation reaction and carrying out a deprotection reaction to synthesize the 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-1, 4-dihydro-2, 8-dimethyl-1, 6-naphthyridine-3-formamide, and carrying out a reaction to obtain the 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-1, 4-dihydro-2, 8-dimethyl-1, 6-naphthyridine-3-formamide. The preparation method of the 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-1, 4-dihydro-2, 8-dimethyl-1, 6-naphthyridine-3-formamide has the advantages that the selectivity is high, the post-treatment is simple, the yield and the purity of the product are high, a new synthesis route and method are developed for synthesizing the 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-1, 4-dihydro-2, 8-dimethyl-1, 6-naphthyridine-3-formamide, the amplified production is conveniently realized, and the method is suitable for industrial production. The method has good application potential and research value.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of pharmaceutical chemistry synthesis, in particular to the synthesis of polysubstituted 1,4-dihydropyridine compounds, and particularly to a synthesis method of 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-1,4-dihydro-2,8-dimethyl-1,6-naphthyridine-3-carboxamide. BACKGROUND

[0002] Mineralocorticoid receptors exist in the distal tubule and collecting duct epithelial cells of the kidney, and over-activation of the mineralocorticoid receptors by some endogenous hormones can cause diseases such as hypertension, cardiovascular disease and chronic kidney disease. Aldosterone, as the main mineralocorticoid, is produced in the glomerular region of the adrenal cortex and is the product after activation of the renin-angiotensin system, and can induce activation of the mineralocorticoid receptor to cope with hyperkalemia or sodium depletion. Aldosterone can promote the reabsorption of sodium and the excretion of potassium in the kidney, and plays a role in regulating the balance of water and part of the electrolytes in the body. Excessive secretion of aldosterone will increase inflammation, fibrosis and oxidative stress in the kidney, leading to various diseases, including chronic kidney disease, heart failure, coronary artery disease and hypertension, etc., so drugs that block the action of aldosterone on the mineralocorticoid receptor have the effect of treating, for example, hypertension, heart failure and chronic kidney disease.

[0003] Mineralocorticoid receptor antagonists can be divided into steroidal and non-steroidal according to their chemical structure. Spironolactone is the first generation of steroidal mineralocorticoid receptor antagonists. Because it has an antagonistic effect on sex hormones, its non-specific binding to sex hormone receptors can cause male breast development and sexual dysfunction, and female patients may experience menstrual irregularities or breast hyperplasia and other adverse reactions, which limits its use. Eplerenone is the second generation of steroidal mineralocorticoid receptor antagonists, which has higher selectivity than spironolactone, but has weaker affinity for the mineralocorticoid receptor, which can easily lead to hyperkalemia. For the above reasons, the third generation of non-steroidal mineralocorticoid receptor antagonists with better efficacy have emerged, and the representative drug is finerenone (Formula 8), which was developed by Bayer and approved for marketing by the US FDA on July 9, 2021, with the trade name Kerendia, for the treatment of chronic kidney disease in adults caused by type II diabetes, and was approved for marketing in China in June 2022.

[0004]

[0005] The synthesis route of the finerenone compound is mainly developed by Bayer, and other new synthesis routes are also reported. According to the way of obtaining chiral compounds, it can be divided into racemate resolution method and asymmetric catalytic synthesis method. Based on cost and operability, the racemate resolution method (compound of formula 1 reacts to give compound of formula 8) is the preferred method.

[0006]

[0007] However, the currently disclosed synthetic method is affected by complicated reaction steps and post-processing methods, resulting in poor selectivity, low product yield and purity, and complicated operation steps, long reaction time, and difficult to realize large-scale production. SUMMARY

[0008] The first technical problem to be solved by the present application is to provide a synthetic method of 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-1,4-dihydro-2,8-dimethyl-1,6-naphthyridine-3-formamide which can effectively improve the selectivity and thus improve the product yield and purity.

[0009] The first technical problem to be solved by the present application is to provide a synthetic method of 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-1,4-dihydro-2,8-dimethyl-1,6-naphthyridine-3-formamide which can greatly simplify the operation steps and shorten the reaction time, thus facilitating the realization of large-scale production.

[0010] The technical solution adopted by the present application to solve at least one of the above technical problems is:

[0011] A synthetic method of 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-1,4-dihydro-2,8-dimethyl-1,6-naphthyridine-3-formamide, comprising the following steps:

[0012] (1) Knoevenagel condensation reaction: in an organic solvent, under the joint action of an organic base and an organic acid, a compound of formula (2) and a compound of formula (3) undergo Knoevenagel condensation reaction at 10-30°C to synthesize a compound of formula (4);

[0013]

[0014] After the reaction is completed, filtration, organic solvent washing, drying, and vacuum drying at 40-50°C, a pure compound of formula (4) is obtained (HPLC purity > 98.5%);

[0015] (2) Hantzsch dihydropyridine synthesis reaction: at 80-130°C, a compound of formula (4) and a compound of formula (5) undergo cyclization reaction in an organic solvent to synthesize a compound of formula (6);

[0016]

[0017] After the reaction is completed, the temperature is lowered to 20-30°C, and the reaction solution is dropped into a crystallization solvent to crystallize, and the crystallization is maintained for 1-3 hours. After the crystallization is completed, the product is filtered, washed with an organic solvent, dried, and vacuum dried at 50-60°C to obtain the pure compound of formula (6); (HPLC purity > 98.5%);

[0018] (3) O-ethylation reaction: the obtained compound of formula (6) and an ethylating reagent are dissolved in an organic solvent, and an O-ethylation reaction is carried out at 70-100°C in the presence of an acid catalyst to synthesize a compound of formula (7);

[0019]

[0020] After the reaction is completed, the temperature is lowered to 20-30°C, and the reaction solution is dropped into a crystallization solvent to crystallize, and the crystallization is maintained for 1-3 hours. After the crystallization is completed, the product is filtered, washed with an organic solvent, dried, and vacuum dried at 50-60°C to obtain the pure compound of formula (7); (HPLC purity > 99%);

[0021] (4) Deprotection reaction: the compound of formula (7) is dissolved in an organic solvent, and a deprotection reaction is carried out at 70-100°C under the action of an acid to synthesize a compound of formula (1);

[0022]

[0023] After the reaction is completed, the temperature is lowered to 20-30°C, and the reaction solution is dropped into a crystallization solvent to crystallize, and the crystallization is maintained for 1-3 hours. After the crystallization is completed, the product is filtered, washed with an organic solvent, dried, and vacuum dried at 50-60°C to obtain the pure compound of formula (7); (HPLC purity > 99%);

[0024] wherein Ar is a mono-alkoxy-substituted phenyl or an aromatic five-membered heterocyclic group; the mono-alkoxy-substituted phenyl is substituted at an ortho position, a meta position, or a para position, and the aromatic five-membered heterocyclic group is one of 2-furyl, 2-thienyl, 2-pyrrolyl, 2-imidazolyl, and 2-oxazolyl;

[0025] R is a C1-C6 alkyl group.

[0026] Preferably, Ar is selected from:

[0027]

[0028] R is selected from:

[0029] methyl, ethyl, propyl, isopropyl, cyclopropyl, n-butyl, 2-butyl, t-butyl, cyclobutyl, pentyl, isopentyl, neopentyl, cyclopentyl, hexyl, and cyclohexyl.

[0030] Preferably, the organic solvent in the Knoevenagel condensation reaction is one or more of methanol, ethanol, propanol, isopropanol, n-butanol, 2-butanol, ethylene glycol, diethylene glycol, polyethylene glycol 300-400, methyl tert-butyl ether, ethylene glycol dimethyl ether, tetrahydrofuran, 1,4-dioxane, toluene, xylene;

[0031] The organic base in the Knoevenagel condensation reaction is one of diethylamine, dipropylamine, diisopropylamine, dibutylamine, piperidine, tetrahydropyrrole, morpholine, piperazine; the organic acid is one of formic acid, acetic acid, propionic acid, butyric acid, oxalic acid, malonic acid, trifluoroacetic acid, citric acid; the combination of the organic base and the organic acid is any combination, the molar ratio is 1:1, and the amount is 0.1-1.0 eq of the molar amount of the compound of formula (3).

[0032] Most preferably, the above-mentioned organic base is piperidine; the organic acid is acetic acid.

[0033] Preferably, the organic solvent in the Hantzsch dihydropyridine synthesis reaction is one or more of methanol, ethanol, propanol, isopropanol, n-butanol, 2-butanol, ethylene glycol, diethylene glycol, polyethylene glycol 300-400, 1,4-dioxane, ethylene glycol dimethyl ether, DMF, DMAc, DMSO, NMP, toluene, xylene.

[0034] Most preferably, the organic solvent in the Hantzsch dihydropyridine synthesis reaction is DMSO.

[0035] Preferably, the crystallization solvent in step (2) is one or more of toluene, methanol, ethanol, isopropanol, tetrahydrofuran, ethylene glycol dimethyl ether, dichloromethane, purified water. Most preferably, the crystallization solvent is purified water, and the amount is 1-10V of DMSO.

[0036] Preferably, the organic solvent in the O-ethylation reaction is one or more of methanol, ethanol, propanol, isopropanol, n-butanol, 2-butanol, ethylene glycol, diethylene glycol, polyethylene glycol 300-400, 1,4-dioxane, ethylene glycol dimethyl ether, DMF, DMAc, DMSO, NMP, toluene, xylene. Most preferably, the organic solvent is DMF.

[0037] Preferably, the ethylation reagent in the O-ethylation reaction is one or more of bromoethane, iodoethane, ethyl methanesulfonate, diethyl sulfate, diethyl carbonate, triethyl orthoformate, triethyl orthoacetate, triethylsilyl tetrafluoroborate. Most preferably, the ethylation reagent is triethyl orthoformate.

[0038] Preferably, the acid catalyst in the O-ethylation reaction is one of sulfuric acid, phosphoric acid, perchloric acid, acetic acid, trichloroacetic acid, trifluoroacetic acid, and most preferably, the acid catalyst is sulfuric acid, and the amount used is 0.1-1.0 eq of the molar amount of the compound of formula (6).

[0039] Preferably, the organic solvent in the deprotection reaction is one or more of ethanol, propanol, isopropanol, n-butanol, 2-butanol, ethylene glycol, diethylene glycol, polyethylene glycol 300-400, 1,4-dioxane, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, DMF, DMAc, DMSO, NMP, toluene, xylene, 1,2-dichloroethane. Most preferably, the organic solvent is 1,2-dichloroethane.

[0040] Preferably, the acid in the deprotection reaction is one of trifluoroacetic acid, trichloroacetic acid, hydrochloric acid, hydrobromic acid, sulfuric acid, perchloric acid, phosphoric acid, methanesulfonic acid, p-toluenesulfonic acid, and the amount used is 0.1-10 eq of the molar amount of the compound of formula (7). Most preferably, the acid is trifluoroacetic acid.

[0041] Preferably, the beating and purifying organic solvent in the deprotection reaction is one or more of ethyl acetate, isopropyl acetate, butyl acetate, methanol, ethanol, n-propanol, isopropanol, n-butanol, 2-butanol, acetonitrile, methyl tert-butyl ether, tetrahydrofuran, ethylene glycol dimethyl ether, 1,4-dioxane, toluene, xylene. Most preferably, the organic solvent is isopropyl acetate.

[0042] Compared with the prior art, the method of the present application has the advantages that: the method of the present application includes four steps of Knoevenagel condensation reaction, Hantzsch dihydropyridine synthesis, O-ethylation reaction and deprotection reaction to synthesize 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-1,4-dihydro-2,8-dimethyl-1,6-naphthyridine-3-formamide, the method has high selectivity, simple post-treatment, high yield and purity of the product, and opens up a new synthetic route and method for synthesizing 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-1,4-dihydro-2,8-dimethyl-1,6-naphthyridine-3-formamide, is convenient for realizing scaled-up production, and has good application potential and research value. DETAILED DESCRIPTION

[0043] The present application will be further described in detail below in conjunction with the examples.

[0044] Example 1:

[0045] The synthesis method of 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-1,4-dihydro-2,8-dimethyl-1,6-naphthyridine-3-formamide in this example includes the following steps:

[0046] (1) Knoevenagel condensation reaction: After nitrogen replacement, N-acetyl acetyl-4-methoxy benzylamine (57.66 g, 260.61 mmol), the compound of formula (3) (40.00 g, 248.20 mmol), piperidine (2.11 g, 24.82 mmol), acetic acid (1.49 g, 24.82 mmol) and isopropyl alcohol (400 mL) were sequentially added to a clean reaction bottle, stirring was started, and the reaction was carried out at 20-30 °C for 24 h; sample detection, HPLC detection of the reaction liquid showed that the compound of formula (3) was ≤1%, the reaction was completed, otherwise the reaction was continued to be incubated, and detection was carried out every 2 h until it was qualified; after the reaction was completed, filtration was carried out, isopropyl alcohol was used for washing, drying was carried out at 40-50 °C under vacuum, and the pure compound of formula (4) (light yellow solid, 80.7 g, 89%, HPLC purity > 98.5%) was obtained;

[0047] (2) Hantzsch dihydropyridine synthesis reaction: After nitrogen replacement, the compound of formula (4) (64.58 g, 177.21 mmol), the compound of formula (5) (20.00 g, 161.10 mmol) and DMSO (200 mL) were sequentially added to a clean reaction bottle, stirring was started, and the reaction was carried out at 80-130 °C for 48 h; sample detection, HPLC detection of the reaction liquid showed that the compound of formula (5) was ≤1%, the reaction was completed, otherwise the reaction was continued to be incubated, and detection was carried out every 2 h until it was qualified; after the reaction was completed, the reaction liquid was dropped into purified water (1000 mL) for crystallization, and incubation was carried out at 20-30 °C for 1-3 h; after the crystallization was completed, filtration was carried out, ice ethanol was used for washing, drying was carried out at 50-60 °C under vacuum, and the pure compound of formula (6) (yellow solid, 61.5 g, 81%, HPLC purity > 98.5%) was obtained;

[0048] (3) O-ethylation reaction: After nitrogen replacement, the compound of formula (6) (60.00 g, 127.52 mmol), triethyl orthoformate (94.49 g, 637.58 mmol), DMF (600 mL) and sulfuric acid (12.51, 127.52 mmol) were sequentially added to a clean reaction bottle, stirring was started, and the reaction was carried out at 100-120 °C for 12 h; sample detection, HPLC detection of the reaction liquid showed that the compound of formula (6) was ≤1%, the reaction was completed, otherwise the reaction was continued to be incubated, and detection was carried out every 2 h until it was qualified; after the reaction was completed, the reaction liquid was dropped into purified water (1200 mL) for crystallization, incubation was carried out at 20-30 °C for 1-3 h, filtration was carried out, purified water and isopropyl alcohol were used for washing, drying was carried out at 50-60 °C under vacuum, and the pure compound of formula (7) (light yellow solid, 52.8 g, 83%, HPLC purity > 99%) was obtained;

[0049] (4) Deprotection reaction: after nitrogen replacement, the clean reaction bottle was added with compound of formula (7) (50.00 g, 104.05 mmol), 1,2-dichloroethane (500 mL) and trifluoroacetic acid (57.17 g, 501.42 mmol) in sequence, stirring was started, and the temperature was increased to 70-100 °C, and the reaction was kept for 16 h; sampling detection showed that the content of compound of formula (7) in the reaction solution was ≤0.5% by HPLC detection, and the reaction was ended, otherwise the reaction was continuously kept, and the detection was performed every 2 h until the content was qualified; after the reaction was ended, the temperature was decreased to 30-45 °C, 1,2-dichloroethane was concentrated out under reduced pressure until the flow was interrupted; the temperature was decreased to 20-30 °C, purified water (100 mL) was added, 10% sodium carbonate aqueous solution was added to adjust the pH to 8-10, and the reaction was kept at 20-30 °C for 1-3 h, then filtration was performed, purified water and dichloromethane were used for elution, the filter cake was dried, and vacuum drying was performed at 50-60 °C to obtain the pure compound of formula (1) (white solid, 33.5 g, 88%, HPLC purity >99%).

[0050] Examples 2-10:

[0051] Examples 2-10 were respectively implemented in the same manner as the Knoevenagel condensation reaction step in Example 1, except that isopropyl alcohol in the examples was respectively replaced with the following solvent, and the used solvent and the yield and purity of the corresponding product are shown in the following table.

[0052]

[0053] Examples 11-22:

[0054] Examples 11-22 were respectively implemented in the same manner as the Knoevenagel condensation reaction step in Example 1, except that piperidine and acetic acid in the examples were respectively replaced with the following organic base and organic acid, and the used organic base, organic acid and the yield and purity of the corresponding product are shown in the following table.

[0055]

[0056] Examples 23-30:

[0057] Examples 23-30 were respectively implemented in the same manner as the Hantzsch dihydropyridine synthesis reaction step in Example 1, except that DMSO in the examples was respectively replaced with the following solvent, and the used solvent and the yield and purity of the corresponding product are shown in the following table.

[0058]

[0059]

[0060] Examples 31-37:

[0061] Examples 31 to 37 were carried out in the same manner as the O-ethylation reaction step in Example 1, except that DMF in each was replaced with the following solvent, and the ethylating agent used and the yield and purity of the corresponding product are shown in the following table.

[0062]

[0063] Examples 38 to 43:

[0064] Examples 38 to 43 were carried out in the same manner as the O-ethylation reaction step in Example 1, except that triethyl orthoformate in each was replaced with the following ethylating agent, and the ethylating agent used and the yield and purity of the corresponding product are shown in the following table.

[0065]

[0066] Examples 44 to 48:

[0067] Examples 44 to 48 were carried out in the same manner as the O-ethylation reaction step in Example 1, except that sulfuric acid in each was replaced with the following acid, and the acid used and the yield and purity of the corresponding product are shown in the following table.

[0068]

[0069]

[0070] Examples 49 to 58:

[0071] Examples 49 to 58 were carried out in the same manner as the deprotection reaction step in Example 1, except that 1,2-dichloroethane in each was replaced with the following solvent, and the solvent used and the yield and purity of the corresponding product are shown in the following table.

[0072]

[0073] Examples 59 to 63:

[0074] Examples 59 to 63 were carried out in the same manner as the deprotection reaction step in Example 1, except that trifluoroacetic acid in each was replaced with the following acid, and the acid used and the yield and purity of the corresponding product are shown in the following table.

[0075]

[0076] Examples 64 to 70:

[0077] Examples 64-70 were carried out in the same manner as Example 1, except that the Ar substituent of the compound of formula (2) therein was replaced by the following substituent, respectively, and the Ar group used and the yield and purity of the product of the corresponding step are shown in the following table.

[0078]

[0079] Example 71:

[0080] The synthetic method of 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-1,4-dihydro-2,8- dimethyl-1,6-naphthyridine-3-carboxamide in this example comprises the following steps:

[0081] (1) Knoevenagel condensation reaction: after nitrogen replacement, N-acetyl acetyl-4- methoxybenzylamine (1.73 kg), the compound of formula (3) (1.2 kg), piperidine (63.4 g), acetic acid (44.7 g) and isopropyl alcohol (12 L) were sequentially added into a clean reaction kettle, stirring was started, and the reaction was carried out at 20-30 °C for 24 h; sampling detection was performed, HPLC detection of the compound of formula (3) in the reaction solution was ≤1%, the reaction was completed, otherwise the reaction was continuously incubated, and detection was performed every 2 h until it was qualified; after the reaction was completed, filtration was performed, isopropyl alcohol was used for washing, the filter cake was dried at 40-50 °C under vacuum, and the pure compound of formula (4) (light yellow solid, 2.47 kg, 91%, HPLC purity >98.5%) was obtained.

[0082] (2) Hantzsch dihydropyridine synthesis reaction: after nitrogen replacement, the compound of formula (4) (2.26 kg) and the compound of formula (5) (0.70 kg) were sequentially added into a clean reaction kettle, stirring was started, and the temperature was increased to 80-130 °C, and the reaction was incubated for 48 h; sampling detection was performed, HPLC detection of the compound of formula (5) in the reaction solution was ≤1%, the reaction was completed, otherwise the reaction was continuously incubated, and detection was performed every 2 h until it was qualified; after the reaction was completed, the temperature was decreased to 20-30 °C, the reaction solution was dropped into purified water (35 L) for crystallization, and the temperature was incubated at 20-30 °C for 1-3 h; after the crystallization was completed, filtration was performed, ice ethanol was used for washing, the filter cake was dried at 50-60 °C under vacuum, and the pure compound of formula (6) (yellow solid, 2.2 kg, 83%, HPLC purity >98.5%) was obtained.

[0083] (3) O-ethylation reaction: after nitrogen replacement, the clean reaction kettle was sequentially added with the compound of formula (6) (2.2 kg), triethyl orthoformate (3.4 kg), DMF (22 L) and sulfuric acid (0.45 kg), stirring was started, and the temperature was increased to 100-120 DEG C, and the reaction was kept for 12 h; sample detection was performed, HPLC detection showed that the content of the compound of formula (6) in the reaction solution was less than 1%, the reaction was completed, otherwise the reaction was kept for 2 h, and the detection was performed every 2 h until the qualified product was obtained; after the reaction was completed, the temperature was decreased to 20-30 DEG C, the reaction solution was dropped into purified water (44 L) for crystallization, and the temperature was kept at 20-30 DEG C for 1-3 h; filtration was performed, purified water and isopropyl alcohol were used for washing, the filter cake was dried, and vacuum drying was performed at 50-60 DEG C to obtain the compound of formula (7) (light yellow solid, 2.0 kg, 87%, HPLC purity > 99%).

[0084] (4) Deprotection reaction: after nitrogen replacement, the clean reaction kettle was sequentially added with the compound of formula (7) (2.0 kg), 1,2-dichloroethane (20 L) and trifluoroacetic acid (2.3 kg), stirring was started, and the temperature was increased to 70-100 DEG C, and the reaction was kept for 16 h; sample detection was performed, HPLC detection showed that the content of the compound of formula (7) in the reaction solution was less than 0.5%, the reaction was completed, otherwise the reaction was kept for 2 h, and the detection was performed every 2 h until the qualified product was obtained; after the reaction was completed, the temperature was decreased to 30-45 DEG C, 1,2-dichloroethane was concentrated under reduced pressure until the flow was interrupted; the temperature was decreased to 20-30 DEG C, purified water (4 L) was added, 10% sodium carbonate aqueous solution was added to adjust the pH to 8-10, the temperature was kept at 20-30 DEG C for 1-3 h, and filtration was performed; purified water and dichloromethane were used for washing, the filter cake was dried, and vacuum drying was performed at 50-60 DEG C to obtain the compound of formula (1) (white solid, 1.3 kg, 86%, HPLC purity > 99%).

[0085] In the embodiment of the present application, the compound of formula (2) and the compound of formula (3) are selected as starting materials, Knoevenagel condensation reaction occurs under the joint action of an organic base and an organic acid to synthesize the compound of formula (4); the compound of formula (4) and the compound of formula (5) are subjected to Hantzsch reaction to synthesize the compound of formula (6); the compound of formula (6) is subjected to O-ethylation reaction with an ethylation reagent under acid catalysis to synthesize the compound of formula (7); finally, the compound of formula (7) is subjected to deprotection under the promotion of an acid to synthesize the compound of formula (1). The method of the present application has high selectivity, simple post-treatment, simple operation, can be scaled up, and has high yield and purity of the product, and provides theoretical and technical guidance for the synthesis and production of 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-1,4-dihydro-2,8-dimethyl-1,6-naphthyridine-3-formamide.

Claims

1. A method for synthesizing 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-1,4-dihydro-2,8-dimethyl-1,6-naphthidine-3-carboxamide, characterized in that... Includes the following steps: (1) Knoevenagel condensation reaction: In an organic solvent, under the combined action of an organic base and an organic acid, compound (2) and compound (3) undergo Knoevenagel condensation reaction at 10-30℃ to synthesize compound (4). After the reaction was completed, the mixture was filtered, washed with organic solvent, filtered dry, and vacuum dried at 40-50℃ to obtain the pure compound of formula (4). (2) Hantzsch dihydropyridine synthesis reaction: Compound (4) and compound (5) undergo cyclization reaction in an organic solvent at 80-130℃ to synthesize compound (6); After the reaction is complete, the temperature is lowered to 20-30℃, and the reaction solution is dropped into the crystallization solvent to crystallize. The crystallization is maintained at the temperature for 1-3 hours. After crystallization is complete, the mixture is filtered, washed with organic solvent, filtered dry, and vacuum dried at 50-60℃ to obtain the pure product of compound (6). (3) O-ethylation reaction: The obtained compound (6) and the ethylating agent are dissolved in an organic solvent, and an O-ethylation reaction is carried out at 70-100℃ in the presence of an acid catalyst to synthesize compound (7); After the reaction is complete, the temperature is lowered to 20-30℃, a diluent is added to induce crystallization, and the crystallization is carried out at 20-30℃ for 1-3 hours. The crystals are then filtered, washed, and dried. The wet material is purified by recrystallization and dried under vacuum at 50-60℃ to obtain the pure product of compound (7). (4) Deprotection reaction: Dissolve the compound of formula (7) in an organic solvent and undergo a deprotection reaction at 70-100℃ under the action of acid to synthesize the compound of formula (1); After the reaction is completed, the temperature is lowered to 20-30℃, the organic solvent is concentrated under reduced pressure until the flow stops, an alkaline aqueous solution is added to adjust the pH, and crystals are precipitated at 20-30℃ for 1-3 hours. The mixture is then filtered, washed, and dried. The mixture is then slurried in an organic solvent to obtain a wet material, which is then dried under vacuum at 50-60℃ to obtain the pure product of compound (1). Wherein, Ar is a monoalkoxy-substituted phenyl or an aromatic five-membered heterocyclic group; the substitution position of the monoalkoxy-substituted phenyl is ortho, meta or para, and the aromatic five-membered heterocyclic group is one of 2-furanyl, 2-thienyl, 2-pyrroleyl, 2-imidazolyl, and 2-oxazolyl; R is a C1 to C6 alkyl group.

2. The method for synthesizing 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-1,4-dihydro-2,8-dimethyl-1,6-naphthidine-3-carboxamide according to claim 1, characterized in that: The Ar mentioned is selected from: The R mentioned is selected from: Methyl, ethyl, propyl, isopropyl, cyclopropyl, n-butyl, 2-butyl, tert-butyl, cyclobutyl, pentyl, isopentyl, neopentyl, cyclopentyl, hexyl, cyclohexyl.

3. The method for synthesizing 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-1,4-dihydro-2,8-dimethyl-1,6-naphthidine-3-carboxamide according to claim 1 or 2, characterized in that: The organic solvent in the Knoevenagel condensation reaction is one or more of the following: methanol, ethanol, propanol, isopropanol, n-butanol, 2-butanol, ethylene glycol, diethylene glycol, polyethylene glycol 300-400, methyl tert-butyl ether, ethylene glycol dimethyl ether, tetrahydrofuran, 1,4-dioxane, toluene, and xylene. The organic base in the Knoevenagel condensation reaction is one of diethylamine, dipropylamine, diisopropylamine, dibutylamine, piperidine, tetrahydropyrrole, morpholine, piperazine, and N-methylpiperazine; the organic acid is one of formic acid, acetic acid, propionic acid, butyric acid, oxalic acid, malonic acid, trifluoroacetic acid, and citric acid; the combination of organic base and organic acid is arbitrary, the molar ratio is 1:1, and the amount used is 0.1 to 1.0 eq of the molar amount of the compound in formula (3).

4. The method for synthesizing 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-1,4-dihydro-2,8-dimethyl-1,6-naphthidine-3-carboxamide according to claim 1 or 2, characterized in that: The organic solvent used in the Hantzsch dihydropyridine synthesis reaction is one or more of the following: methanol, ethanol, propanol, isopropanol, n-butanol, 2-butanol, ethylene glycol, diethylene glycol, polyethylene glycol 300-400, 1,4-dioxane, diethylene glycol dimethyl ether, DMF, DMAc, DMSO, NMP, toluene, and xylene.

5. The method for synthesizing 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-1,4-dihydro-2,8-dimethyl-1,6-naphthidine-3-carboxamide according to claim 1 or 2, characterized in that: The organic solvent in the O-ethylation reaction is one or more of the following: methanol, ethanol, propanol, isopropanol, n-butanol, 2-butanol, ethylene glycol, diethylene glycol, polyethylene glycol 300-400, 1,4-dioxane, diethylene glycol dimethyl ether, DMF, DMAc, DMSO, NMP, toluene, and xylene.

6. The method for synthesizing 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-1,4-dihydro-2,8-dimethyl-1,6-naphthidine-3-carboxamide according to claim 1 or 2, characterized in that: The ethylating agent in the O-ethylation reaction is one or more of the following: bromoethane, iodoethane, ethyl methanesulfonate, diethyl sulfate, diethyl carbonate, triethyl orthoformate, triethyl orthoacetate, and triethyloxonium tetrafluoroborate.

7. The method for synthesizing 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-1,4-dihydro-2,8-dimethyl-1,6-naphthidine-3-carboxamide according to claim 1 or 2, characterized in that: The acid catalyst in the O-ethylation reaction is one of sulfuric acid, phosphoric acid, perchloric acid, acetic acid, trichloroacetic acid, or trifluoroacetic acid, and the amount used is 0.1 to 1.0 eq of the molar amount of the compound in formula (6).

8. The method for synthesizing 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-1,4-dihydro-2,8-dimethyl-1,6-naphthidine-3-carboxamide according to claim 1 or 2, characterized in that: The organic solvent used in the deprotection reaction is one or more of the following: ethanol, propanol, isopropanol, n-butanol, 2-butanol, ethylene glycol, diethylene glycol, polyethylene glycol 300-400, 1,4-dioxane, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, DMF, DMAc, DMSO, NMP, toluene, xylene, and 1,2-dichloroethane.

9. The method for synthesizing 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-1,4-dihydro-2,8-dimethyl-1,6-naphthidine-3-carboxamide according to claim 1 or 2, characterized in that: The acid used in the deprotection reaction is one of trifluoroacetic acid, trichloroacetic acid, hydrochloric acid, hydrobromic acid, sulfuric acid, perchloric acid, phosphoric acid, methanesulfonic acid, and p-toluenesulfonic acid, and the amount used is 0.1 to 10 eq of the molar amount of the compound in formula (7).

10. The method for synthesizing 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-1,4-dihydro-2,8-dimethyl-1,6-naphthidine-3-carboxamide according to claim 1 or 2, characterized in that: The organic solvent used in the deprotection reaction for pulping and purification is one or more of the following: ethyl acetate, isopropyl acetate, butyl acetate, methanol, ethanol, n-propanol, isopropanol, n-butanol, 2-butanol, acetonitrile, methyl tert-butyl ether, tetrahydrofuran, ethylene glycol dimethyl ether, 1,4-dioxane, toluene, and xylene.

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