Process for the preparation of pyrrole amide compounds and intermediates thereof

Abstract

The application discloses a method for preparing a pyrrole amide compound and an intermediate thereof. The pyrrole amide compound and / or the intermediate thereof can be used for preparing a pyrrole amide compound used as a salt corticoid receptor antagonist. In particular, the preparation method provided by the application is mild in conditions, simple in operation, safe and controllable, high in yield, and suitable for industrial production.

Description

Technical Field

[0001] This invention relates to the field of medicinal chemistry, specifically to methods for preparing pyrrolamide compounds, and also to important intermediates therein and their preparation methods. The pyrrolamide compounds and / or their intermediates described in this invention can be used to prepare pyrrolamide compounds used as mineralocorticoid receptor antagonists. Background Technology

[0002] International patent application WO2021078135A1 discloses a class of pyrrolamide compounds and their uses. These compounds can be used as mineralocorticoid receptor antagonists and have potential therapeutic effects on diseases such as hyperaldosteronism, hypertension, chronic heart failure, sequelae of myocardial infarction, cirrhosis, non-alcoholic steatohepatitis, chronic kidney disease, diabetic nephropathy, renal failure, fibrosis and / or stroke. Specifically, the international application discloses a compound as shown in formula (A) (i.e., compound (S)-N-(3-fluoro-4-(methylsulfonyl)phenyl)-1-(2-hydroxyethyl)-4-methyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrrole-3-carboxamide), and also discloses the following preparation method: using ethyl 4-methyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrrole-3-carboxylate as a starting material, a racemic compound of formula (A) is obtained through substitution, hydrolysis, acylation, condensation, and deprotection reactions, followed by chiral column resolution to obtain compound (A). The method employs chiral resolution to separate stereoisomers, which requires sophisticated equipment and has low yield. Overall, this preparation method has high production costs, poor atom economy, significant environmental pollution, and harsh reaction conditions, making it unsuitable for industrial-scale production.

[0003]

[0004] International patent application WO2022228215A1 discloses a method for preparing compound (A). In this method, lipase is used to chirally resolve the racemic raw material methyl 1-(2-hydroxyethyl)-4-methyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrrole-3-carboxylate to obtain intermediate (S)-1-(2-hydroxyethyl)-4-methyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrrole-3-carboxylate. Then, after benzyl protection, ester hydrolysis, and amination, amide intermediate (S)-1-(2-(benzyloxy)ethyl)-4-methyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrrole-3-carboxamide is obtained. Finally, the compound is obtained by condensation and deprotection to obtain the compound shown in formula (A). This method obtains the intermediate by enzymatic resolution, avoiding the use of chiral column resolution. However, the overall yield of the reaction to prepare the amide intermediate from the racemic raw material is not high, and the overall yield of the compound shown in formula (A) is also not high. A method for preparing the compound shown in formula (A) with higher yield and lower cost is needed. Summary of the Invention

[0005] This invention provides intermediates that can be used to prepare compounds of formula (A) and methods thereof; the intermediates include compounds represented by the general formulas and / or structural formulas described in this invention.

[0006] This invention relates to a method for preparing pyrrolamide compounds, and also to an important intermediate used in the method and its preparation method. The preparation method described in this invention features mild conditions, simple operation, safety and controllability, high yield, and is suitable for industrial production.

[0007] The pyrrolamide compound prepared by the method described in this invention can be used to prepare the compound shown in formula (A).

[0008] On the one hand, the present invention provides the compound shown in formula (I),

[0009]

[0010] Among them, R 1 For OH, NH2, C 2-4 alkoxy or benzyloxy, the C 2-4 The alkoxy and benzyloxy groups are optionally selected by 1, 2, 3 or 4 independently chosen from halogens, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy and C 1-4 Substituents of haloalkoxy groups.

[0011] In some implementations, the R 1 For OH, NH2, C 2-4 Alkoxy (such as ethoxy, n-propoxy, isopropoxy, n-butoxy, or tert-butoxy) or benzyloxy.

[0012] On the other hand, the present invention provides a compound having one of the following structures:

[0013]

[0014] On one hand, the present invention provides a method for preparing the compound shown in formula (A),

[0015]

[0016] The method includes:

[0017] Step e) The compound of formula (III) reacts to give the compound of formula (A).

[0018]

[0019] In some embodiments, step e) includes a debenzylation reaction and / or a dechlorination reaction.

[0020] In some embodiments, the reaction solvent for step e) is methanol, ethanol, isopropanol, tert-butanol, tetrahydrofuran, DMF, ethyl acetate, methyl tert-butyl ether, ethylene glycol dimethyl ether, ethylene glycol monomethyl ether, toluene, water, or any combination thereof. Unless otherwise specified, the solvents in the mixed solvent are mixed in any proportion.

[0021] In some embodiments, the reaction in step e) of the present invention is carried out in the presence of a transition metal catalyst. Optionally, the transition metal catalyst is palladium on carbon, other palladium-containing catalysts such as palladium acetate, nickel, or nickel-containing catalysts such as nickel chloride. In other embodiments, the reaction in step e) of the present invention is carried out in the presence of a transition metal catalyst, wherein the transition metal catalyst is a palladium on carbon catalyst, a palladium acetate catalyst, or a nickel catalyst.

[0022] In some embodiments, the reaction in step e) of the present invention is carried out in the presence of a palladium-on-carbon catalyst. Optionally, the amount of the palladium-on-carbon catalyst is 1% to 20% of the mass of the compound shown in formula (III); in other embodiments, the amount of the palladium-on-carbon catalyst is 5% to 20% of the mass of the compound shown in formula (III); and in still other embodiments, the amount of the palladium-on-carbon catalyst is 10% to 20% of the mass of the compound shown in formula (III).

[0023] In some embodiments, the reaction in step e) of the present invention is carried out under a hydrogen atmosphere. In other embodiments, in step e), after the debenzylation reaction is completed, the remaining hydrogen in the reaction system is vented.

[0024] In some embodiments, the reaction in step e) of the present invention is carried out in the presence of ammonium formate, sodium formate, sodium hydrogen phosphate (such as disodium hydrogen phosphate), acid, triethylamine, or hydrogen.

[0025] In some embodiments, the reaction in step e) of the present invention is carried out in the presence of ammonium formate, sodium formate, or hydrogen. In other embodiments, the reaction in step e) of the present invention is carried out in the presence of ammonium formate or sodium formate, wherein the amount of ammonium formate or sodium formate is 1 to 20 equivalents, preferably 1 to 18 equivalents, more preferably 2 to 15 equivalents. In still other embodiments, the reaction in step e) of the present invention is carried out in the presence of sodium formate, wherein the amount of sodium formate is 1 to 16 equivalents, preferably 2 to 15 equivalents. In some embodiments, the reaction in step e) of the present invention is carried out in the presence of sodium formate, wherein the amount of sodium formate is 2, 5, 10, or 15 equivalents. Optionally, the sodium formate of the present invention may be sodium formate dihydrate or anhydrous sodium formate. Unless otherwise stated, the equivalent amount referred to herein means the ratio of the molar amount of sodium formate to the molar amount of the reaction substrate compound represented by formula (III); for example, the statement "the amount of sodium formate is 2.0 equivalents" means that the molar amount of sodium formate is 2.0 to the molar amount of the compound represented by formula (III).

[0026] In some embodiments, the reaction in step e) of the present invention is carried out under heating conditions. In some embodiments, the heating conditions are heating to 45°C-75°C; in some embodiments, the heating conditions are heating to 55°C-70°C; in some embodiments, the heating conditions are heating to 60°C-65°C.

[0027] In some embodiments, the method for preparing the compound of formula (III) of the present invention further includes a post-treatment method for the reaction in step e). In other embodiments, the post-treatment method for the reaction in step e) of the present invention includes, but is not limited to: after the reaction, filtering, washing, concentrating to remove the solvent, dissolving the residue in ethanol, adjusting the pH with hydrochloric acid, adding the resulting solution dropwise to ice water, stirring at room temperature, filtering, optionally washing, collecting the filter cake, and drying to obtain the target compound. Optionally, the filtration can be vacuum filtration or diatomaceous earth filtration. Optionally, the first washing is performed using a reaction solvent, such as ethanol; the second washing is optionally performed, such as washing with water. Optionally, other solvents, such as DMAC (i.e., N,N-dimethylacetamide), can be added before concentration. Optionally, the drying can be vacuum drying or heated vacuum drying (e.g., vacuum drying at 45°C-60°C). Optionally, other suitable post-treatment methods can be used after the reaction in step e).

[0028] In some embodiments, the method for preparing the compound represented by formula (A) of the present invention further includes a method for preparing the compound represented by formula (III), wherein the method for preparing the compound represented by formula (III) includes:

[0029] Step c) The compound of formula (IB) is amination under suitable conditions to give the compound of formula (IC).

[0030]

[0031] Step d) The compound shown in formula (IC) reacts with the compound shown in formula (II) under suitable conditions to give the compound shown in formula (III).

[0032]

[0033] Where X is Br or I.

[0034] In some embodiments, in step c), the compound of formula (IB) reacts with thionyl chloride, oxalyl chloride, or N,N'-carbonyldiimidazole (i.e., 1-(1H-imidazolium-1-carbonyl)-1H-imidazolium) and then reacts with an amination reagent to obtain the compound of formula (IC); optionally, the amination reagent is ammonia or an ammonium salt reagent; preferably, the amination reagent is ammonia, ammonium bromide, or NH4SCN.

[0035] In some embodiments, the reaction in step c) is carried out in a solvent, namely N,N-dimethylformamide or N,N-dimethylacetamide; optionally, the reaction in step c) is carried out at room temperature.

[0036] In some embodiments, the reaction in step d) is carried out in the presence of a base. Preferably, the base is potassium carbonate, cesium carbonate, sodium carbonate, potassium tert-butoxide, or potassium phosphate.

[0037] In some embodiments, the reaction in step d) is carried out in the presence of a catalyst, such as a transition metal catalyst like a palladium catalyst; preferably, the palladium catalyst is Pd₂(dba)₃ or Pd(dppf)Cl₂. . CH2Cl2 or Pd(OAc)2.

[0038] In some embodiments, the reaction in step d) is carried out in the presence of a ligand; preferably, the ligand is Xantphos, X-phos, or S-phos.

[0039] In some embodiments, the reaction in step d) is carried out in a solvent, which is toluene, dioxane, tert-butanol (t-BuOH), tert-amyl alcohol (t-AmOH), dimethyl ether (DME), cyclopentyl methyl ether (CPME), N,N-dimethylacetamide (DMAC), N,N-dimethylformamide (DMF), water, or any combination thereof.

[0040] In some embodiments, the reaction temperature of step d) is 55°C-110°C; in some embodiments, the reaction temperature of step d) is 55°C-100°C; in some embodiments, the reaction temperature of step d) is 55°C-83°C.

[0041] In some embodiments, the method for preparing the compound represented by formula (III) further includes a method for preparing the compound represented by formula (IB), wherein the method for preparing the compound represented by formula (IB) includes:

[0042] Step a) The compound shown in formula (I-1) reacts with a benzyl protecting group reagent to give the compound shown in formula (IA).

[0043]

[0044] Step b) The compound of formula (IA) is debenzyl protecting group removed under suitable conditions to obtain the compound of formula (IB);

[0045]

[0046] In some embodiments, the benzyl protecting group reagent in step a) is a halobenzyl group, optionally benzyl bromide.

[0047] In some embodiments, step a) is carried out in the presence of sodium tert-amyl alcohol.

[0048] In some embodiments, the reaction solvent for step a) is N,N-dimethylacetamide.

[0049] In some embodiments, the reaction temperature of step a) is 25°C to 60°C. In other embodiments, the reaction temperature of step a) is 35°C to 55°C. In still other embodiments, the reaction temperature of step a) is 45°C to 55°C.

[0050] In some embodiments, the reaction in step b) is carried out in the presence of an alkali, which is sodium carbonate, potassium carbonate, cesium carbonate, potassium phosphate, lithium hydroxide, potassium hydroxide, or sodium hydroxide.

[0051] In some embodiments, the reaction in step b) is carried out in a solvent, which is acetone, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, DMSO, methanol, ethanol, THF, methyl tert-butyl ether, water, or any combination thereof.

[0052] In some embodiments, the reaction in step b) is carried out under heating conditions, which means heating to 60°C to 80°C; in other embodiments, the heating conditions mean heating to 65°C to 75°C.

[0053] On the other hand, the present invention provides the use of compounds having one of the following structures in the preparation of pyrrolamide compounds used as mineralocorticoid receptor antagonists.

[0054]

[0055] In some embodiments, the pyrrolidone compound used as a mineralocorticoid receptor antagonist is (S)-N-(3-fluoro-4-(methylsulfonyl)phenyl)-1-(2-hydroxyethyl)-4-methyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrrole-3-carboxamide (i.e., the compound shown in formula (A)).

[0056] Purification of the compound represented by formula (A) in this invention can be achieved by recrystallization or multiple recrystallizations, with the conditions for each recrystallization being the same or different. If necessary, the compound represented by formula (A) in this invention can be further purified by other commonly used purification methods in the art, for example, by using palladium-removing silica gel and / or activated carbon to remove residual palladium. The recrystallization can involve first dissolving the crude product in a benign solvent, stirring to dissolve it, then adding a poor solvent, or adding the solution of the crude product to a poor solvent and stirring to precipitate a solid. The dissolution process can be carried out at room temperature or under heating conditions. Preferably, after dissolving the crude product in a benign solvent, impurities can be removed first using palladium-removing silica gel and / or activated carbon, and then the solution of the crude product can be added to a poor solvent to precipitate a solid. Preferably, in the above recrystallization, the benign solvent can be ethanol or isopropyl acetate, and the poor solvent can be water or toluene. In some embodiments, the benign solvent is ethanol and the unfavorable solvent is water; preferably, the total volume ratio of ethanol to water can be from about 1:1.5 to about 1:15, specifically from about 1:1.8 to about 1:15. In other embodiments, the benign solvent is isopropyl acetate and the unfavorable solvent is toluene; preferably, the total volume ratio of isopropyl acetate to toluene can be from about 1:2 to about 1:15, specifically from about 1:4 to about 1:5.

[0057] On the one hand, the method for preparing the compound of formula (A), the method for preparing the compound of formula (III), and / or the method for preparing the compound of formula (IB) each independently further includes the method for preparing the compound of formula (I-1).

[0058]

[0059] The method includes:

[0060] 1a) The compound shown in formula (I-0) reacts with a photoactive amine to give a salt of the photoactive amine of the corresponding compound of formula (I-1), and

[0061] 1b) The salt obtained in step 1a) reacts to give the compound shown in formula (I-1);

[0062]

[0063] In some embodiments, the photoactive amine of the present invention is an optically active amine having a quinine skeleton.

[0064] In some embodiments, the optically active amine with a quinine skeleton described in this invention is quinine, hydrogenated quinine, quinidine, cinchonine, or cinchonidine.

[0065] In some embodiments, the salt of the photoactive amine of the compound of formula (I-1) of the present invention is a salt formed by the compound of formula (I-1) and the photoactive amine. In other embodiments, the salt of the photoactive amine of the compound of formula (I-1) of the present invention is a quinine salt of formula (I-1), a hydrogenated quinine salt of formula (I-1), a quinidine salt of formula (I-1), a cinchonine salt of formula (I-1), or a cinchonine salt of formula (I-1).

[0066] In some embodiments, the reaction in step 1b) of the present invention is a hydrolysis reaction.

[0067] In some embodiments, the reaction in step 1b) of the present invention is carried out under acidic conditions.

[0068] In some embodiments, the acidic conditions described in this invention are conditions in the presence of hydrochloric acid, sulfuric acid, hydrobromic acid, or citric acid.

[0069] In some embodiments, the reaction solvent in step 1b) of the present invention is N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMAC), acetonitrile, tetrahydrofuran (THF), ethanol, acetone, isopropyl acetate, ethyl acetate, methyl tert-butyl ether, water, dimethoxyethane, or any combination thereof.

[0070] In some embodiments, the reaction solvent of step 1a) of the present invention is N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMAC), acetonitrile, tetrahydrofuran (THF), ethanol, acetone, isopropyl acetate, ethyl acetate, methyl tert-butyl ether, water, dimethoxyethane, or any combination thereof.

[0071] In some embodiments, the reaction temperature of step 1a) of the present invention is room temperature to 100°C; in some embodiments, the reaction temperature of step 1a) is 50°C to 80°C; in some embodiments, the reaction temperature of step 1a) is 55°C to 65°C.

[0072] In some embodiments, the method for preparing the compound of formula (I-1) of the present invention further includes: evaporating the mixture obtained after removing the salt of the photoactive amine of the compound of formula (I-1) in step 1a) to dryness, adding a suitable solvent, and heating for isomerization to obtain a racemic compound of formula (I-0), which is then reacted with the photoactive amine to obtain a salt of the photoactive amine of the compound of formula (I-1). Typically, the photoactive amine described herein is the same as the photoactive amine used in step 1a). Optionally, the suitable solvent includes, but is not limited to, DMF, etc.

[0073] In other embodiments, optionally, the isomerization refers to the racemization of the blocked isomer in solution by means of heating or the like to obtain a racemic compound (i.e., compound of formula (I-0)). Optionally, the racemic compound can be prepared as a salt of the photoactive amine of formula (I-1) by the method of step 1a) of the present invention. Optionally, the salt of the photoactive amine of formula (I-1) can be prepared as a compound of formula (I-1) by the method of step 1b) of the present invention.

[0074] The preparation method of compound (I-1) shown in this invention is simple to operate, has a high yield, and the ee / de value of the obtained product is high; moreover, the R configuration byproduct obtained by this method can be recycled by racemization as described in this invention, which further improves the yield of compound (I-1) (up to 60% or more).

[0075] On the other hand, the present invention provides a salt formed by the compound of formula (I-1) and a photoactive amine.

[0076]

[0077] In some embodiments, the photoactive amine of the present invention is quinine, hydrogenated quinine, quinidine, cinchonine, or cinchonidine. Optionally, the photoactive amine has the following structure.

[0078]

[0079] Preferably, the salt formed by the compound of formula (I-1) and the photoactive amine is a quinine salt of formula (I-1), a hydrogenated quinine salt of formula (I-1), a quinidine salt of formula (I-1), a cinchonine salt of formula (I-1), or a cinchonine salt of formula (I-1).

[0080] The compounds of formulas (I-0), (I-1), (IA), (IB), (IC), (II), and / or (III) of this invention are used to prepare the compound of formula (A) of this invention. Preferably, the method for preparing the compound of formula (A) using the aforementioned compounds is as described in this invention.

[0081] Definitions and general terms

[0082] In this invention, "room temperature" refers to a temperature ranging from approximately 10°C to approximately 40°C. In some embodiments, "room temperature" refers to a temperature ranging from approximately 20°C to approximately 30°C; in other embodiments, "room temperature" refers to 20°C, 22.5°C, 25°C, 27.5°C, etc.

[0083] In the context of this invention, all figures disclosed herein are approximate values. The value of each figure may vary by 1%, 2%, 5%, 7%, 8%, or 10%, etc. Whenever a figure with a value of N is disclosed, any figure having a value within N+ / -1%, N+ / -2%, N+ / -3%, N+ / -5%, N+ / -7%, N+ / -8%, or N+ / -10% is explicitly disclosed, where "+ / -" refers to addition or subtraction. Whenever a lower limit, DL, and an upper limit, DU, of a numerical range are disclosed, any value within that disclosed range is explicitly disclosed.

[0084] All reaction steps described in this invention proceed to post-processing after reaching a certain stage, such as when the raw material consumption is approximately greater than 70%, 80%, 90%, or 95%, or after detection that the raw materials have been completely consumed. This post-processing includes cooling, collection, extraction, filtration, separation, purification, or combinations thereof. The degree of reaction can be detected using conventional methods such as thin-layer chromatography (TLC), high-performance liquid chromatography (HPLC), and gas chromatography (GC). Conventional methods can be used to post-process the reaction solution. For example, the crude product can be collected by vacuum evaporation or conventional distillation of the reaction solvent and directly added to the next reaction step; or the crude product can be obtained by direct filtration and directly added to the next reaction step; or the supernatant can be poured off after settling to obtain the crude product, which can then be directly added to the next reaction step; or appropriate organic solvents or combinations thereof can be selected for extraction, distillation, crystallization, column chromatography, rinsing, slurrying, and other purification steps.

[0085] The term "approximately" or "about" in this invention is used to modify a value that differs by 10%. In some embodiments, "approximately" or "about" is used to modify a value that differs by 5%. In some embodiments, "approximately" or "about" is used to modify a value that differs by 3%, 2%, or 1%. It is understood that the range of error for a value modified by "approximately" or "about" depends on the actual or reasonable range of error of the value it modifies.

[0086] The terms “optionally,” “optionally,” or “optionally” mean that the event or situation described below may, but is not necessarily, occur; that is, the description includes both the possibility that the event or situation will occur and the possibility that it will not occur.

[0087] In each step of the reaction process described in this invention, reactants or other reagents can be added to the reaction system dropwise. Each dropwise addition process and each reaction step is carried out under specific temperature conditions; any temperature suitable for each dropwise addition process or each reaction process is included in this invention. Furthermore, many similar modifications, equivalent substitutions, or temperatures and temperature ranges equivalent to those described in this invention are considered to be within the scope of this invention. This invention provides preferred temperatures or temperature ranges for each dropwise addition process, and preferred reaction temperatures or reaction temperature ranges for each reaction.

[0088] The terms "solvent 1", "solvent 2", "solvent a", "solvent b", "base a", "base b" used in this invention, with Arabic numerals 1, 2, 3... or letters a, b, c... following "solvent" or "base," are merely for better differentiation of the solvents or bases used in each step, and the Arabic numerals or letters used have no special meaning. For example, solvent 1 includes all solvents suitable for the reaction of a compound of formula (III) with a compound shown in formula (IV) to prepare a compound of formula (II), including but not limited to toluene, dioxane, dimethyl sulfoxide, tert-butanol, tert-amyl alcohol, dimethyl ether (DME), cyclopentyl methyl ether (CPME), N,N-dimethylacetamide, water, or any combination thereof.

[0089] The solvents used in the reaction steps described in this invention are not particularly limited; any solvent capable of dissolving the starting materials to a certain extent without inhibiting the reaction is included in this invention. Furthermore, many similar modifications, equivalent substitutions, or solvents, solvent combinations, and different proportions of solvent combinations described in this invention are considered to be within the scope of this invention. This invention provides preferred solvents for each reaction step.

[0090] The products of each reaction step described in this invention can be purified by recrystallization under suitable conditions. There are no particular limitations on the recrystallization solvent used; any solvent capable of dissolving the crude product to a certain extent and precipitating crystals under certain conditions is included in this invention. Furthermore, many similar modifications, equivalent substitutions, or solvents, solvent combinations, and different proportions of solvent combinations described in this invention are considered to be within the scope of this invention. The solvents may be alcohols, ethers, alkanes, halogenated hydrocarbons, esters, ketones, aromatic hydrocarbons, acetonitrile, acetic acid, water, DMF, or combinations thereof. Examples include water, acetic acid, methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tert-butanol, petroleum ether, n-pentane, n-hexane, n-heptane, cyclohexane, DMF, N,N-dimethylacetamide, tetrahydrofuran, diethyl ether, isopropyl ether, dioxane, methyl tert-butyl ether, dimethoxyethylene, diethylene glycol dimethyl ether, triethylene glycol dimethyl ether, dichloromethane, 1,2-dichloroethane, chloroform, carbon tetrachloride, ethyl acetate, isopropyl acetate, acetone, butanone, benzene, toluene, xylene, or combinations thereof.

[0091] The water content in the solvent described in this invention is not particularly limited; that is, the water content in the solvent does not affect the occurrence of the reaction described in this invention. Any solvent containing a certain amount of water that can be used in this invention to a certain extent is considered a solvent described in this invention. For example, the water content in the solvent is approximately less than 0.05%, less than 0.1%, less than 0.2%, less than 0.5%, less than 5%, less than 10%, less than 25%, less than 30%, or 0%. In some embodiments, a water content in the solvent within a certain range is more conducive to the reaction; for example, in the step of using ethanol as the reaction solvent, using anhydrous ethanol is more conducive to the reaction. In some embodiments, a water content in the solvent exceeding a certain range may affect the reaction (e.g., affect the reaction yield), but does not affect the occurrence of the reaction.

[0092] General synthesis methods

[0093] In this specification, if there are any differences between chemical names and chemical structures, the structure is preferred.

[0094] In the embodiments described below, all temperatures are specified in degrees Celsius (°C) unless otherwise stated. Unless otherwise stated, all materials and reagents were purchased from commercial suppliers and were not further purified before use; some materials can be prepared according to methods known in the art.

[0095] Nuclear magnetic resonance (NMR) spectral data were determined using a Bruker Avance 400 NMR spectrometer or a Bruker Avance IIIHD 600 NMR spectrometer, with CDCl3, d6-DMSO, CD3OD, D2O, or d6-acetone as solvents (in ppm), and TMS (0 ppm) or chloroform (7.25 ppm) as reference standards. When multiple peaks are observed, the following abbreviations are used: s (single peak), d (doublet), t (triplet), m (multiplet), br (broadened), dd (doublet of doublets), dt (doublet of triplets), td (triplet of doublets), ddd (doublet of doublets), ddt (doublet of doublets), dddd (doublet of doublets). The coupling constant is represented by Hertz (Hz).

[0096] Low-resolution mass spectrometry (MS) data were determined using an Agilent 6320 series LC-MS spectrometer equipped with a G1312A binary pump and a G1316A TCC (column temperature maintained at 30°C). A G1329A autosampler and a G1315B DAD detector were used for analysis, and an ESI source was used in the LC-MS spectrometer.

[0097] Low-resolution mass spectrometry (MS) data were determined using an Agilent 6120 series LC-MS spectrometer equipped with a G1311A quaternary pump and a G1316A TCC (column temperature maintained at 30°C). A G1329A autosampler and a G1315D DAD detector were used for analysis, and an ESI source was used in the LC-MS spectrometer.

[0098] Both spectrometers were equipped with an Agilent Zorbax SB-C18 column, 2.1 × 30 mm, 5 μm. Injection volume was determined by sample concentration; flow rate was 0.6 mL / min; HPLC peak values ​​were recorded and read using UV-Vis wavelengths at 210 nm and 254 nm. The mobile phase consisted of 0.1% formic acid-acetonitrile solution (phase A) and 0.1% formic acid ultrapure aqueous solution (phase B). Gradient elution conditions are shown in Table 1.

[0099] Table 1: Gradient elution conditions for mobile phase in low-resolution mass spectrometry

[0100] Time (min) <![CDATA[A(CH3CN,0.1%HCOOH)]]> <![CDATA[B(H2O,0.1%HCOOH)]]> 0-3 5-100 95-0 3-6 100 0 6-6.1 100-5 0-95 6.1-8 5 95

[0101] The purity of the compound, the content of the reaction product, or the content of the intermediate control product were obtained by high-performance liquid chromatography (HPLC). The HPLC instrument used was an Agilent HPLC system, and the chromatographic column could be Xbridge Phenyl (4.6 × 150 mm, 3.5 μm), ZORBAX Extend-C18 (4.6 × 150 mm, 5 μm), or Waters Xbridge phenyl (4.6 × 150 mm, 3.5 μm). Gradient elution was performed using an aqueous phosphoric acid solution (optionally containing potassium dihydrogen phosphate) and acetonitrile as the mobile phase.

[0102] The stereoisomers described in this invention are detected using high-performance liquid chromatography (HPLC). The HPLC instrument can be an Agilent HPLC system, and the chromatographic column can be an OJ-RH (4.6 × 250 mm, 5 μm), a Daicel CHIRALPAKIC (4.6 × 250 mm, 5 μm), or a Philoman CHIRAL NY (4.6 × 250 mm, 5 μm). Gradient elution is performed using trifluoroacetic acid-acetonitrile solution and n-hexane as the mobile phase. Specific implementation methods

[0103] This invention discloses a method for preparing pyrrolamide compounds as shown in formula (A) and their intermediates. Those skilled in the art can refer to this invention and appropriately modify the process parameters to achieve the same result. It should be particularly noted that all similar substitutions and modifications are obvious to those skilled in the art and are considered to be included in this invention. The method of this invention has been described through preferred embodiments, and those skilled in the art will clearly be able to modify or appropriately change and combine the methods described herein without departing from the content, spirit, and scope of this invention to implement and apply the technology of this invention.

[0104] To enable those skilled in the art to better understand the present invention, the present invention will be described in detail below with reference to embodiments. Example

[0105] Example 1 Preparation of 2-chloro-1-(2-hydroxyethyl)-4-methyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrrole-3-carboxylic acid (intermediate 1)

[0106]

[0107] Ethyl 2-chloro-1-(2-hydroxyethyl)-4-methyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrrole-3-carboxylate (29.1 g, 77.44 mmol), prepared according to methods known in the art, was added to a mixed solvent of methanol (90 mL) and water (30 mL), followed by the addition of potassium hydroxide (15.34 g, 232.32 mmol, 85% purity). The mixture was heated to reflux for 3 hours. The solvent was removed under reduced pressure, and water (90 mL) was added to the residue. The residue was washed with methyl tert-butyl ether (90 mL), and the aqueous phase was adjusted to pH 4 with 2 mol / L hydrochloric acid solution. The residue was then extracted with ethyl acetate (150 mL × 2). The combined organic phases were washed successively with water (100 mL) and saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give 26.3 g of a pale yellow solid, with a yield of 97.67%.

[0108] Example 2: Preparation of (S)-2-chloro-1-(2-hydroxyethyl)-4-methyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrrole-3-carboxylic acid (intermediate 2)

[0109]

[0110] Method 1:

[0111] Weigh quinine (7.28 g, 22.43 mmol) into a reaction flask, add N,N-dimethylacetamide (6.5 mL), ethyl acetate (65 mL), and water (3.9 mL), and heat to 60 °C. Add 2-chloro-1-(2-hydroxyethyl)-4-methyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrrole-3-carboxylic acid (intermediate 1) (13.00 g, 37.39 mmol) to N,N-dimethylacetamide (6.5 mL) and ethyl acetate (48 mL), heat until dissolved, and then add dropwise to the aforementioned quinine solution. Turn off the heat, cool to room temperature, filter, wash with ethyl acetate (13 mL × 2), and dry the filter cake under vacuum. The filter cake was added to a mixed solvent of ethyl acetate (80 mL) and water (60 mL), and 2 mol / L hydrochloric acid solution (18.7 mL) was added while stirring. After 10 minutes, the aqueous phase was separated, and the organic phase was washed successively with water (50 mL) and saturated brine (40 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 6.35 g of a pale yellow solid with an ee value of 96.04%, a purity of 99.65%, and a yield of 48.84%.

[0112] Method 2:

[0113] N,N-dimethylacetamide (75 mL), ethyl acetate (1050 mL), and water (45 mL) were added to quinine (83.97 g, 172.55 mmol), and the system was heated to 65 °C. 2-chloro-1-(2-hydroxyethyl)-4-methyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrrole-3-carboxylic acid (intermediate 1) (150.0 g, 287.59 mmol) was added to N,N-dimethylacetamide (75 mL) and ethyl acetate (255 mL), dissolved, and then added dropwise to the quinine reaction solution. After the addition was complete, the mixture was kept at 65 °C with stirring for 1 hour, and then cooled to room temperature. The mixture was filtered, and the filter cake was washed with ethyl acetate (50 mL × 2). The filter cake was collected and dried under vacuum at 45 °C for 11 hours to obtain a white solid (131.96 g). 4M hydrochloric acid solution was added to the obtained white solid until the pH was ≤3, and the mixture was stirred at room temperature for 5 hours. The filter cake was filtered, washed with water (500 mL), collected, and vacuum dried at 60 °C for 17 hours to obtain the target product as a white solid (64.83 g, 43.22%).

[0114] Identification of intermediate 2:

[0115] MS(ESI,pos.ion)m / z:314.2(M+1);

[0116] 1 H NMR (400MHz, CDCl3) δ7.82 (d, J=7.6Hz, 1H), 7.64 (dt, J=21.3, 7.4Hz, 2H), 7.43 (d,J=7.3Hz,1H),4.05(dt,J=10.5,6.0Hz,1H),3.84–3.60(m,3H),2.01(s,3H).

[0117] Example 3: Preparation of (S)-1-(2-(benzyloxy)ethyl)-2-chloro-4-methyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrrole-3-carboxylic acid benzyl ester (intermediate 3)

[0118]

[0119] Method 1:

[0120] Under nitrogen protection, intermediate 2 (100 g, 287.59 mmol) and benzyl bromide (147.56 g, 862.77 mmol) were dissolved in N,N-dimethylacetamide (2 L), and sodium tert-amyl alcohol (95.02 g, 862.77 mmol) was added. The mixture was then heated to 40 °C and reacted overnight. The reaction solution was poured into water (4000 mL) and extracted with MTBE (800 mL × 3). The organic phases were combined, washed with saturated brine (600 mL × 2), and concentrated under reduced pressure to remove the solvent, yielding a pale yellow transparent oil (151 g, 99.45%).

[0121] Method 2:

[0122] Intermediate 2 (8.25 g, 23.73 mmol), benzyl bromide (12.18 g, 71.19 mmol), N,N-dimethylacetamide (83 mL), and sodium tert-amyl alcohol (7.84 g, 71.19 mmol) were added to the reaction flask. After completion, the mixture was purged with nitrogen three times, and then heated to 50 ± 5 °C for 4 hours under nitrogen protection. The reaction solution was diluted with water (250 mL), extracted with methyl tert-butyl ether (75 mL × 2), and the organic phase was washed with 20% saline (200 mL × 2). The solution was concentrated under reduced pressure to obtain the target product as a pale yellow transparent oil (12.52 g, 99.95%).

[0123] Example 4: Preparation of (S)-1-(2-(benzyloxy)ethyl)-2-chloro-4-methyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrrole-3-carboxylic acid (intermediate 4)

[0124]

[0125] Ethanol (240 mL), potassium hydroxide (35.01 g, 530.36 mmol, 85% purity) and water (60 mL) were added to intermediate 3 (70 g, 132.59 mmol). The reaction mixture was then heated to 70 °C for 6 hours. The temperature was lowered to 45 °C, and water (240 mL) was added to dilute the reaction solution. Ethanol was removed by rotary evaporation under reduced pressure. Methyl tert-butyl ether (400 mL) and heptane (200 mL) were added to a beaker, and the two solvents were mixed thoroughly. Approximately half of the above-mentioned mixed solvent was added to the residue after reduced evaporation. The mixture was stirred for 5 minutes, allowed to stand, and the upper organic phase was separated, retaining the aqueous phase. The remaining half of the above-mentioned mixed solvent was added to the aqueous phase, stirred for 5 minutes, allowed to stand, and the upper organic phase was separated, retaining the aqueous phase. Dilute hydrochloric acid (2M, purchased from Chengdu Kelon) was added to the retained aqueous phase to adjust the pH to ≤3. Ethyl acetate was used for extraction (500 mL). The organic phase was washed with water (200 mL) and saturated brine (200 mL), respectively. The organic phase was concentrated under reduced pressure to obtain the target product as a brownish-yellow oil (58.03 g, 99.96%). MS (ESI, pos.ion) m / z: 438.1 (M+1).

[0126] Example 5: Preparation of (S)-1-(2-(benzyloxy)ethyl)-2-chloro-4-methyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrrole-3-carboxamide (intermediate 5)

[0127]

[0128] Intermediate 4 (66 g, 150.74 mmol), N,N-dimethylacetamide (135 mL), and 1-(1H-imidazolium-1-carbonyl)-1H-imidazolium (36.66 g, 226.11 mmol) were added to the reaction flask. After reacting at room temperature for 2 hours, ammonia (312.91 g, 2410.4 mmol) was added, and the mixture was stirred at room temperature for 20 hours. The reaction solution was diluted with water (300 mL), extracted with isopropyl acetate (200 mL × 2), and the organic phase was washed with water (300 mL) and saturated brine (300 mL). The solution was concentrated under reduced pressure to obtain the target product as a brownish-yellow oil (65.80 g, 99.99%). MS (ESI, pos.ion) m / z: 437.5 (M+1).

[0129] Example 6: Preparation of (S)-1-(2-(benzyloxy)ethyl)-2-chloro-N-(3-fluoro-4-(methanesulfonyl)phenyl)-4-methyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrrole-3-carboxamide (intermediate 6)

[0130]

[0131] Intermediate 5 (5.0 g, 11.45 mmol), 4-bromo-2-fluoro-1-(methanesulfonyl)benzene (2.98 g, 11.79 mmol), palladium acetate (0.077 g, 0.34 mmol), Xantphos (0.20 g, 0.34 mmol), cesium carbonate (7.46 g, 22.9 mmol), and tert-amyl alcohol (40 mL) were added to the reaction flask. After the addition was complete, the mixture was purged with nitrogen four times, and the reaction was heated to 65 ± 5 °C for 5 hours under a nitrogen atmosphere. The reaction solution was diluted with tap water (25 mL), stirred for 3 minutes, and then isopropyl acetate (20 mL) was added. After stirring for another 3 minutes, the mixture was allowed to stand and separate into layers. The upper organic phase was collected and concentrated under reduced pressure to obtain the target product as a brownish-yellow oil (6.97 g, 99.99%). MS (ESI, pos.ion) m / z: 610.2 (M+1).

[0132] Example 7 Preparation of (S)-1-(2-hydroxyethyl)-N-(3-fluoro-4-methylsulfonyl)phenyl)-4-methyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrrole-3-carboxamide (compound shown in formula (A))

[0133]

[0134] Intermediate 6 (10 g, 16.42 mmol), ethanol (100 mL), and palladium on carbon (2.08 g, 10%) were added to the reaction flask. After completion, the mixture was heated to 60 °C for 6.5 hours under a hydrogen atmosphere. The hydrogen atmosphere was then released, and sodium formate dihydrate (2.07 g, 32.84 mmol) and water (5 mL) were added. The reaction was continued at 60 °C for 6 hours. The reaction solution was filtered through diatomaceous earth. The filter cake was washed with ethanol (20 mL), and the filtrate was concentrated under reduced pressure. Ethanol (25 mL) and water (10 mL) were added to the residue. After dissolving the residue, it was added dropwise to water (200 mL). After the addition was complete, the mixture was stirred at room temperature for 30 minutes. The mixture was then filtered, and the filter cake was washed with water (20 mL). The filter cake was collected and dried under vacuum at 50 °C for 24 hours to obtain the crude product. The crude product and isopropyl acetate (22.5 mL) were added to the reaction flask, and the mixture was heated to 55 ± 5 °C to completely dissolve the crude product. Toluene (68 mL) was added dropwise. After completion, the mixture was kept at 55 °C and stirred until a solid precipitated. Toluene (22.5 mL) was added dropwise again, and stirring was continued at 55 °C for 2 hours. The heating was turned off, and the mixture was allowed to cool to room temperature and stirred for another 12 hours. The mixture was filtered, and the filter cake was washed with toluene (15 mL). The cake was then dried under vacuum at 60 °C for 24 hours to obtain the target product as a white solid (5.56 g, 69.9%) with a purity of 98.30% and 0.74% isomers.

[0135] MS(ESI,pos.ion)m / z:485.1(M+1).

[0136] 1 H NMR(400MHz, DMSO-d6)δ(ppm)10.15(s,1H),7.98(dd,J=13.5,1.3Hz,1H),7.90(d,J=7.8Hz,1H),7.81(s,1H),7.78(d,J=8.3Hz,2H),7 .75–7.67(m,2H),7.47(d,J=7.4Hz,1H),4.95(dd,J=6.3,3.6Hz,1H),3.73–3.64(m,1H),3.58–3.44(m,3H),3.28(s,3H),1.92(s,3H).

[0137] 19 F NMR(376MHz,DMSO-d6)δ(ppm)-59.56(s),-109.31(s).

[0138] In the description of this specification, references to terms such as "one embodiment," "some embodiments," "example," "specific example," or "some examples," etc., refer to specific features, structures, materials, or characteristics described in connection with that embodiment or example, which are included in at least one embodiment or example of the invention. In this specification, the illustrative expressions of the above terms do not necessarily refer to the same embodiment or example.

[0139] Although embodiments of the present invention have been shown and described above, it is understood that the above embodiments are exemplary and should not be construed as limiting the present invention. Those skilled in the art can make changes, modifications, substitutions and variations to the above embodiments within the scope of the present invention.

Claims

1. The compound shown in formula (I), (I)， in, R 1 For NH2, C 2-4 alkoxy or benzyloxy, the C 2-4 The alkoxy and benzyloxy groups are optionally selected by 1, 2, 3 or 4 independently chosen from halogens, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy and C 1-4 Substituents of haloalkoxy groups.

2. A compound having one of the following structures, (I-A), (I-C), or (III).

3. A method for preparing the compound shown in formula (A), (A)， in, The method includes: Step e) The compound of formula (III) reacts to give the compound of formula (A). (III)。 4. The method according to claim 3, wherein, The reaction solvent in step e) is methanol, ethanol, isopropanol, tert-butanol, or any combination thereof with other solvents, wherein the other solvents are tetrahydrofuran, DMF, ethyl acetate, methyl tert-butyl ether, ethylene glycol dimethyl ether, ethylene glycol monomethyl ether, toluene, water, or any combination thereof.

5. The method according to claim 3, wherein, The reaction in step e) is carried out in the presence of a transition metal catalyst; optionally, the transition metal catalyst is a palladium on carbon catalyst, a palladium acetate catalyst, or a nickel catalyst.

6. The method according to claim 3, wherein, The reaction in step e) is carried out under a hydrogen atmosphere.

7. The method according to claim 3, wherein, The reaction in step e) is carried out in the presence of ammonium formate, sodium formate, disodium hydrogen phosphate, acid, triethylamine, or hydrogen.

8. The method according to claim 3, wherein, The reaction in step e) is carried out under heating conditions; optionally, the heating conditions are heating to 45°C-75°C, 55°C-70°C, or 60°C-65°C.

9. The method according to claim 3, further comprising a method for preparing the compound of formula (III), wherein, The preparation method of the compound shown in formula (III) includes: Step c) The compound of formula (IB) is amination under suitable conditions to give the compound of formula (IC). (I-B)、 (I-C); Step d) The compound of formula (IC) reacts with the compound of formula (II) under suitable conditions to give the compound of formula (III). (II), Where X is Br or I.

10. The method of claim 9, wherein, In step c), the compound shown in formula (IB) reacts with sulfoxide, oxalyl chloride, or... N,N Following the reaction with '-carbonyldiimidazole, the compound is further reacted with an amination reagent to give the compound shown in formula (IC); optionally, the amination reagent is ammonia or an ammonium salt reagent; Optionally, the reaction in step c) is carried out in a solvent, wherein the solvent is N,N -dimethylformamide or N,N -Dimethylacetamide; optionally, the reaction in step c) is carried out at room temperature.

11. The method according to claim 10, wherein, The amination reagent is ammonia, ammonium bromide, or NH4SCN.

12. The method according to claim 9, wherein, The reaction in step d) is carried out in the presence of a base; Optionally, the reaction in step d) is carried out in the presence of a catalyst, which is a palladium metal catalyst; Optionally, the reaction in step d) is carried out in the presence of a ligand; Optionally, the reaction in step d) is carried out in a solvent, such as toluene, dioxane, tert-butanol, tert-amyl alcohol, dimethyl ether, or cyclopentyl methyl ether. N,N -Dimethylacetamide, N,N -Dimethylformamide, water, or any combination thereof; Optionally, the reaction temperature of step d) is 55℃-110℃, 55℃-100℃, or 55℃-85℃.

13. The method according to claim 12, wherein, The alkali is potassium carbonate, cesium carbonate, sodium carbonate, potassium tert-butoxide, or potassium phosphate.

14. The method according to claim 12, wherein, The palladium metal catalyst is Pd2(dba)3 or Pd(dppf)Cl2. . CH2Cl2 or Pd(OAc)2.

15. The method according to claim 12, wherein, The ligand is Xantphos, X-phos, or S-phos.

16. The method according to claim 9, further comprising a method for preparing the compound of formula (IB), wherein, The method for preparing the compound represented by formula (IB) includes: Step a) The compound shown in formula (I-1) reacts with a benzyl protecting group reagent to give the compound shown in formula (IA). (I-1)、 (I-A); Step b) The compound of formula (IA) is debenzyl protecting group removed under suitable conditions to obtain the compound of formula (IB); (I-B)。 17. The method according to claim 16, wherein, The benzyl protecting group reagent in step a) is a halobenzyl group, optionally benzyl bromide; Optionally, step a) is carried out in the presence of sodium tert-amyl alcohol; Optionally, the reaction solvent in step a) is N,N -Dimethylacetamide; Optionally, the reaction temperature of step a) is 25°C to 60°C.

18. The method according to claim 17, wherein, The reaction temperature for step a) is 35℃-55℃.

19. The method of claim 16, wherein, The reaction in step b) is carried out under the action of an alkali, wherein the alkali is sodium carbonate, potassium carbonate, cesium carbonate, potassium phosphate, lithium hydroxide, potassium hydroxide, or sodium hydroxide; Optionally, the reaction in step b) is carried out in a solvent, such as acetone, acetonitrile, etc. N,N -Dimethylformamide, N,N - Dimethylacetamide, DMSO, methanol, ethanol, THF, methyl tert-butyl ether, water, or any combination thereof; Optionally, the reaction in step b) is carried out under heating conditions, which means heating to 60°C to 80°C or 65°C to 75°C.

20. The method according to claim 16, further comprising a method for preparing the compound of formula (I-1), wherein, The preparation method of the compound shown in formula (I-1) includes: 1a) The compound shown in formula (I-0) reacts with a photoactive amine to give a salt of the photoactive amine of the corresponding compound of formula (I-1), and 1b) The salt obtained in step 1a) reacts to give the compound shown in formula (I-1); (I-0)。 21. The method according to claim 20, wherein, The photoactive amine is an optically active amine with a quinine skeleton; optionally, the optically active amine with a quinine skeleton is quinine, hydrogenated quinine, quinidine, cinchonine, or cinchonine.

22. The method according to claim 20, wherein, The reaction in step 1b) is a hydrolysis reaction; Optionally, the reaction in step 1b) is carried out under acidic conditions; optionally, the acidic conditions are those in the presence of hydrochloric acid, sulfuric acid, hydrobromic acid, or citric acid. Optionally, the reaction solvent in step 1b) is N , N -Dimethylformamide, N , N - Dimethylacetamide, acetonitrile, tetrahydrofuran, ethanol, acetone, isopropyl acetate, ethyl acetate, methyl tert-butyl ether, water, dimethoxyethane, or any combination thereof.

23. The method of claim 20, wherein, The reaction solvent in step 1a) is N,N -Dimethylformamide, N,N - Dimethylacetamide, acetonitrile, tetrahydrofuran, ethanol, acetone, isopropyl acetate, ethyl acetate, methyl tert-butyl ether, water, dimethoxyethane, or any combination thereof; Optionally, the reaction temperature of step 1a) is room temperature to 100°C.

24. The method of claim 20, wherein, The reaction temperature in step 1a) is 50℃-80℃.

25. The method according to claim 20, wherein, The reaction temperature in step 1a) is 55℃-65℃.

26. The use of a compound having one of the following structures in the preparation of a pyrrolidone compound for use as a mineralocorticoid receptor antagonist, (I-A), (I-C) or (III).

27. The use according to claim 26, wherein, The pyrrolidone compound used as a mineralocorticoid receptor antagonist is ( S )- N -(3-fluoro-4-(methanesulfonyl)phenyl)-1-(2-hydroxyethyl)-4-methyl-5-(2-(trifluoromethyl)phenyl)-1 H -Pyrrole-3-carboxamide.

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