Method for preparing pyrrole carboxylic acid compound

Abstract

The invention discloses a method for preparing a pyrrole carboxylic acid compound. The pyrrole formic acid compound provided by the invention can be used for preparing a pyrrole amide compound used as a mineralocorticoid receptor antagonist. Specifically, the preparation method provided by the invention is mild in condition, simple to operate, safe, controllable, high in yield and suitable for industrial production.

Description

Technical Field

[0001] The present invention relates to the field of pharmaceutical chemistry, in particular to a method for preparing a pyrrol carboxylic acid compound, and also to a method for preparing a pyrrolamide compound using the pyrrol carboxylic acid compound as an important intermediate. The pyrrol carboxylic acid compound of the present invention can be used to prepare a pyrrolamide compound used as a mineralocorticoid receptor antagonist. Background Art

[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 aldosteronism, hypertension, chronic heart failure, sequelae of myocardial infarction, cirrhosis, non-alcoholic fatty hepatitis, 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: 4-methyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrrole-3-carboxylic acid ethyl ester is used as a raw material, and a racemic compound of the compound of formula (A) is obtained through substitution, hydrolysis, chlorination, condensation, and deprotection reactions, and then the compound of formula (A) is obtained through chiral column separation. The method uses a chiral separation method to separate stereoisomers, and the separation method has high requirements for instruments and low yield; overall, the preparation method has high production cost, poor atom economy, large environmental pollution, and harsh reaction conditions, and is not suitable for industrial scale-up production.

[0003]

[0004] International patent application WO2022228215A1 discloses a method for preparing a compound of formula (A), in which a lipase is used to perform chiral resolution on the racemic raw material 1-(2-hydroxyethyl)-4-methyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrrole-3-carboxylic acid methyl ester to prepare the intermediate (S)-1-(2-hydroxyethyl)-4-methyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrrole-3-carboxylic acid methyl ester, followed by benzyl protection, ester hydrolysis, and amination to obtain the amide intermediate (S)-1-(2-(benzyloxy)ethyl)-4-methyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrrole-3-carboxamide, and finally condensation and deprotection to obtain the compound shown in formula (A). This method obtains the intermediate by enzymatic separation, avoiding the use of chiral column separation, but the total yield of the reaction to prepare the amide intermediate from the racemic raw material is not high, and the total yield of the compound represented by formula (A) is also not high. It is also necessary to provide a method for preparing the compound represented by formula (A) with higher yield and lower cost. Summary of the invention

[0005] The present invention provides an intermediate that can be used to prepare a compound of formula (A) and a preparation method thereof; the intermediate includes compounds represented by the general formulae and / or structural formulae described in the present invention.

[0006] The present invention relates to a method for preparing a pyrrole carboxylic acid compound, and also relates to an important intermediate in the method and a preparation method thereof. The preparation method of the present invention has mild conditions, simple operation, safety and controllability, high yield, and is suitable for industrial production.

[0007] The pyrrolidine carboxylic acid compound prepared by the method of the present invention can be used to prepare the compound represented by formula (A).

[0008] In one aspect, the present invention provides a compound represented by formula (I),

[0009]

[0010] Among them, R 1 OH, NH 2 , C 2-4 Alkoxy or benzyloxy, the C 2-4 Alkoxy and benzyloxy are each optionally substituted by 1, 2, 3 or 4 groups independently selected from halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy and C 1-4 The substituents of the haloalkoxy group are substituted.

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

[0012] In another aspect, the present invention provides a compound having one of the following structures,

[0013]

[0014] Optionally, the present invention relates to the use of the compound represented by formula (IA) or (I-B) in the preparation of the compound represented by formula (II). Optionally, the method for preparing the compound represented by formula (II) is as described in the present invention. Optionally, the compound represented by formula (IA) or (I-B) of the present invention can be used as an intermediate in the method for preparing the compound represented by formula (II) of the present invention.

[0015] In one aspect, the present invention provides a method for preparing a compound represented by formula (II):

[0016]

[0017] Wherein, the method comprises:

[0018] Step c) dechlorinating the compound represented by formula (IB) in a solvent under appropriate conditions to obtain a compound represented by formula (II),

[0019]

[0020] In some embodiments, the reaction solvent of step c) is methanol, ethanol, isopropanol, tert-butyl alcohol or a mixed solvent of them (i.e. methanol, ethanol, isopropanol or tert-butyl alcohol) and other solvents in any combination (such as in any proportion). In other embodiments, the other solvents include but are not limited to tetrahydrofuran, DMF, ethyl acetate, methyl tert-butyl ether, ethylene glycol dimethyl ether, ethylene glycol monomethyl ether, toluene, water or any combination thereof. In some embodiments, the reaction solvent of step c) is methanol, ethanol, ethanol / toluene, ethanol / water, ethanol / toluene / water, ethanol / tetrahydrofuran or ethanol / tetrahydrofuran / water. In some embodiments, the reaction solvent of step c) is ethanol, ethanol / water or ethanol / toluene / water. Optionally, ethanol / water of the present invention refers to a mixed solvent composed of ethanol and water, and ethanol / toluene / water refers to a mixed solvent composed of ethanol, toluene and water. Unless otherwise specified, each solvent is mixed in any proportion in the mixed solvent.

[0021] In some embodiments, the reaction solvent of step c) of the present invention is ethanol / toluene / water, wherein the volume ratio of ethanol to water is 4:1 to 20:1, preferably 4:1 to 18:1, and more preferably 4:1 to 17:1; more preferably, the volume ratio of ethanol to water is 5:1 to 16:1. In other embodiments, the reaction solvent of step c) of the present invention is ethanol / toluene / water, wherein the volume ratio of ethanol to water is 8:1 to 12:1, 9:1 to 11:1. In other embodiments, the reaction solvent of step c) of the present invention is ethanol / toluene / water, wherein the volume ratio of ethanol to water is 5:1, 6:1, 8:1, 9:1, 10:1 or 12:1.

[0022] In some embodiments, the reaction solvent of step c) of the present invention is ethanol / toluene / water, wherein the volume ratio of toluene to water is 1:1 to 15:1, preferably 1:1 to 12:1, and more preferably 1:1 to 11:1; more preferably, the volume ratio of toluene to water is 1:1 to 10:1. In other embodiments, the reaction solvent of step c) of the present invention is ethanol / toluene / water, wherein the volume ratio of toluene to water is 3:1 to 7:1, or 4:1 to 6:1. In other embodiments, the reaction solvent of step c) of the present invention is ethanol / toluene / water, wherein the volume ratio of toluene to water is 1:1, 2:1, 4:1, 5:1, 6:1 or 10:1.

[0023] In some embodiments, the reaction solvent of step c) of the present invention is ethanol / toluene / water, wherein the volume ratio of the ethanol to water is 4:1 to 20:1, and the volume ratio of the toluene to water is 1:1 to 15:1; preferably, the volume ratio of the ethanol to water is 4:1 to 17:1, and the volume ratio of the toluene to water is 1:1 to 11:1; or preferably, the volume ratio of the ethanol to water is 5:1 to 16:1, and the volume ratio of the toluene to water is 1:1 to 10:1; more preferably, the volume ratio of the ethanol to water is 6:1 to 10:1, and the volume ratio of the toluene to water is 1:1 to 5:1.

[0024] In some other embodiments, the reaction solvent of step c) of the present invention is ethanol / toluene / water, wherein the volume ratio of ethanol, toluene and water is 10:5:1, 10:2:1, 6:4:1, 8:2:1 or 9:1:1.

[0025] In some embodiments, the reaction of step c) of the present invention is carried out in the presence of a transition metal catalyst. Optionally, the transition metal catalyst is palladium carbon, other palladium-containing catalysts (such as palladium acetate, etc.), nickel, or nickel-containing catalysts (such as nickel chloride), etc. In other embodiments, the reaction of step c) of the present invention is carried out in the presence of a transition metal catalyst, wherein the transition metal catalyst is a palladium carbon catalyst, a palladium acetate catalyst or a nickel catalyst.

[0026] In some embodiments, the reaction of step c) of the present invention is carried out in the presence of a palladium-carbon catalyst. Optionally, the palladium-carbon catalyst is used in an amount of 1% to 20% by mass of the compound represented by formula (IB); in some embodiments, the palladium-carbon catalyst is used in an amount of 2% to 15% or 2% to 11% by mass of the compound represented by formula (IB); in other embodiments, the palladium-carbon catalyst is used in an amount of 3% to 10% by mass of the compound represented by formula (IB).

[0027] In some embodiments, the reaction of step c) of the present invention is carried out in the presence of ammonium formate, sodium formate, sodium hydrogen phosphate (such as disodium hydrogen phosphate, etc.), acid, triethylamine or hydrogen.

[0028] In some embodiments, the reaction of step c) of the present invention is carried out in the presence of ammonium formate, sodium formate or hydrogen. In other embodiments, the reaction of step c) of the present invention is carried out in the presence of ammonium formate or sodium formate, and the amount of ammonium formate or sodium formate is 1 equivalent to 5 equivalents, preferably 1 equivalent to 3 equivalents, further preferably 1 equivalent to 2 equivalents, and more preferably 1 equivalent to 1.5 equivalents. In some other embodiments, the reaction of step c) of the present invention is carried out in the presence of sodium formate, and the amount of sodium formate is 1 equivalent to 2 equivalents, preferably 1 equivalent to 1.5 equivalents. In some embodiments, the reaction of step c) of the present invention is carried out in the presence of sodium formate, and the amount of sodium formate is 1.5 equivalents. Optionally, the sodium formate of the present invention may be sodium formate dihydrate or anhydrous sodium formate. Unless otherwise stated, the equivalents mentioned herein refer to the ratio of the molar amount of the reagent sodium formate to the molar amount of the compound represented by formula (IB) as the reaction substrate; for example, "the amount of sodium formate used is 1.5 equivalents" means that the ratio of the molar amount of sodium formate to the molar amount of the compound represented by formula (IB) is 1.5.

[0029] In some embodiments, the reaction of step c) of the present invention is carried out under heating conditions. Optionally, the heating conditions are heated to 45°C-75°C; in some embodiments, the heating conditions are heated to 55°C-70°C; in some embodiments, the heating conditions are heated to 60°C-65°C.

[0030] In some embodiments, the method for preparing the compound represented by formula (II) of the present invention further comprises a post-treatment method of the reaction of step c). In other embodiments, the post-treatment method of the reaction of step c) of the present invention includes but is not limited to: after the reaction is completed, the reaction solution is filtered, washed, concentrated to remove the solvent (such as ethanol and toluene), the residue is dissolved in ethanol, the pH is adjusted with hydrochloric acid, the resulting solution is added dropwise to ice water, stirred at room temperature, filtered, optionally washed, the filter cake is collected, and dried to obtain the target compound. Optionally, the filtration can be suction filtration or filtration through diatomaceous earth. Optionally, the first washing is washing with a reaction solvent, such as washing with ethanol; the second washing can be optionally performed, such as optionally washing with water. Optionally, other solvents, such as DMAC (i.e., N,N-dimethylacetamide) can be added before the concentration. Optionally, the drying can be vacuum drying or heated vacuum drying (e.g., vacuum drying at 45°C-60°C). Optionally, after the reaction of step c) is completed, other suitable post-treatment methods can be used for treatment.

[0031] The method of the present invention can effectively control the generation of reaction impurities and obtain the intermediate compound represented by formula (II) with high purity and high yield.

[0032] In some embodiments, the method for preparing the compound of formula (II) of the present invention also includes a method for preparing the compound of formula (IB), wherein the method for preparing the compound of formula (IB) comprises:

[0033] Step a) The compound represented by formula (I-1) reacts with a benzyl protecting group reagent to obtain a compound represented by formula (IA),

[0034]

[0035] Step b) removing the benzyl protecting group from the compound represented by formula (IA) under appropriate conditions to obtain the compound represented by formula (IB);

[0036]

[0037] In some embodiments, the benzyl protecting group reagent in step a) is a halogenated benzyl, optionally benzyl bromide.

[0038] In some embodiments, step a) is performed in the presence of sodium tert-amylate.

[0039] In some embodiments, the reaction solvent of step a) is N,N-dimethylacetamide.

[0040] In some embodiments, the reaction temperature of step a) is 25°C to 60°C. In other embodiments, the reaction temperature is 35°C-55°C. In other embodiments, the reaction temperature is 35°C-45°C. In other embodiments, the reaction temperature is 45°C-55°C.

[0041] In some embodiments, the reaction of step b) is carried out under the action of a base, and the base is sodium carbonate, potassium carbonate, cesium carbonate, potassium phosphate, lithium hydroxide, potassium hydroxide or sodium hydroxide.

[0042] In some embodiments, the reaction of step b) is carried out in a solvent, and the solvent is acetone, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, DMSO, methanol, ethanol, THF, methyl tert-butyl ether, water or any combination thereof.

[0043] In some embodiments, the reaction of step b) is carried out under heating conditions, and the heating conditions refer to heating to 60°C to 80°C; in some embodiments, the heating conditions refer to heating to 65°C to 75°C.

[0044] In another aspect, the present invention provides the use of a compound having one of the following structures in the preparation of a pyrrolamide compound used as a mineralocorticoid receptor antagonist,

[0045]

[0046] In some embodiments, the pyrrolamide 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 represented by formula (A)).

[0047] In some embodiments, the use of the compound of formula (II) of the present invention in the preparation of the compound of formula (A), wherein the compound of formula (II) is prepared by the following method to obtain the compound of formula (A) (i.e., (S)-N-(3-fluoro-4-(methylsulfonyl)phenyl)-1-(2-hydroxyethyl)-4-methyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrrole-3-carboxamide):

[0048]

[0049] The compound represented by formula (II) is aminated under appropriate conditions to obtain the compound represented by formula (III), which is then reacted with the compound represented by formula (IV) to obtain the compound represented by formula (V), and the compound represented by formula (V) is subjected to a deprotection reaction to remove the benzyl group to obtain the target compound;

[0050]

[0051] Wherein, X is Br or I.

[0052] Optionally, the compound represented by (II) of the present invention can be prepared according to the method of the present invention.

[0053] Optionally, the compound represented by formula (A) can be prepared using the compound represented by formula (II) of the present invention by referring to the prior art such as the method disclosed in WO2022228215A1.

[0054] On the one hand, the method for preparing the compound of formula (II) or the method for preparing the compound of formula (IB) of the present invention also includes the method for preparing the compound of formula (I-1),

[0055]

[0056] Wherein, the method comprises:

[0057] 1a) reacting the compound represented by formula (I-0) with a photoactive amine to obtain a photoactive amine salt of the corresponding compound represented by formula (I-1), and

[0058] 1b) reacting the salt obtained in step 1a) to obtain a compound represented by formula (I-1);

[0059]

[0060] In some embodiments, the photoactive amine described in the present invention is an optically active amine having a quinine skeleton.

[0061] In some embodiments, the optically active amine having a quinine skeleton of the present invention is quinine, hydroquinine, quinidine, cinchonine or cinchonidine.

[0062] 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 a 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 the compound of formula (I-1), a hydroquinine salt of the compound of formula (I-1), a quinidine salt of the compound of formula (I-1), a cinchonine salt of the compound of formula (I-1), or a cinchonine salt of the compound of formula (I-1).

[0063] In some embodiments, the reaction of step 1b) of the present invention is a hydrolysis reaction.

[0064] In some embodiments, the reaction of step 1b) of the present invention is carried out under acidic conditions.

[0065] In some embodiments, the acidic conditions of the present invention are conditions in the presence of hydrochloric acid, sulfuric acid, hydrobromic acid or citric acid.

[0066] In some embodiments, the reaction solvent of 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.

[0067] 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.

[0068] 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-80°C; in some embodiments, the reaction temperature of step 1a) is 55°C-65°C.

[0069] In some embodiments, the preparation method of the compound of formula (I-1) of the present invention further comprises: removing the salt of the photoactive amine of the compound of formula (I-1) in step 1a) and drying the mixed solution, adding a suitable solvent, and heating isomerization to obtain a racemic compound of formula (I-0), and then reacting with a photoactive amine to obtain a salt of the photoactive amine of the compound of formula (I-1). Generally, the photoactive amine described here is the same as the photoactive amine used in step 1a). Optionally, the suitable solvent includes, but is not limited to, DMF and the like.

[0070] In other embodiments, optionally, the isomerization refers to racemization of the atropisomer in the solution by heating or the like to obtain a racemic compound (i.e., a compound of formula (I-0)). Optionally, the racemic compound can be prepared by the method of step 1a) of the present invention to obtain a salt of a photoactive amine of a compound of formula (I-1). Optionally, the salt of a photoactive amine of a compound of formula (I-1) can be prepared by the method of step 1b) of the present invention to obtain a compound of formula (I-1).

[0071] The preparation method of the compound of formula (I-1) shown in the present invention is simple to operate, has a high yield, and the ee / de value of the obtained product is high; and the R-configured by-product obtained by this method can be racemized as described in the present invention to achieve recycling, thereby further improving the yield of the compound of formula (I-1) (up to more than 60%).

[0072] In another aspect, the present invention provides a salt formed by a compound represented by formula (I-1) and a photoactive amine,

[0073]

[0074] In some embodiments, the photoactive amine of the present invention is quinine, hydroquinine, quinidine, cinchonine or cinchonidine. Optionally, the photoactive amine has the structure shown below.

[0075]

[0076] Preferably, the salt formed by the compound represented by formula (I-1) of the present invention and a photoactive amine is a quinine salt of the compound of formula (I-1), a hydrogenated quinine salt of the compound of formula (I-1), a quinidine salt of the compound of formula (I-1), a cinchonine salt of the compound of formula (I-1), or a cinchonidine salt of the compound of formula (I-1).

[0077] The compounds of formula (I-0), (I-1), (IA), (IB), (II) and / or (III) of the present invention are used to prepare the compound of formula (A) of the present invention. Preferably, the method for preparing the compound of formula (A) using the aforementioned compounds is as described in the present invention.

[0078] Definitions and general terms

[0079] In the present invention, "room temperature" refers to a temperature from about 10°C to about 40°C. In some embodiments, "room temperature" refers to a temperature from about 20°C to about 30°C; in some other embodiments, "room temperature" refers to 20°C, 22.5°C, 25°C, 27.5°C, etc.

[0080] In the context of the present invention, all numbers disclosed herein are approximate. The value of each number may differ by 1%, 2%, 5%, 7%, 8% or 10%. Whenever a number having a value of N is disclosed, any number within the value of N+ / -1%, N+ / -2%, N+ / -3%, N+ / -5%, N+ / -7%, N+ / -8% or N+ / -10% is explicitly disclosed, where "+ / -" means plus or minus. Whenever a lower limit, DL, and an upper limit, DU, are disclosed in a numerical range, any value within the disclosed range is explicitly disclosed.

[0081] All the reaction steps described in the present invention are subjected to post-treatment after the reaction reaches a certain degree, such as when the raw material consumption is about greater than 70%, greater than 80%, greater than 90%, greater than 95%, or after the reaction raw material is detected to have been completely consumed, such as cooling, collecting, extracting, filtering, separating, purifying or a combination thereof. The degree of reaction can be detected by conventional methods such as thin layer chromatography (TLC), high performance liquid chromatography (HPLC), gas chromatography (GC) and the like. The reaction solution can be post-treated by conventional methods, for example, after vacuum evaporation or conventional distillation of the reaction solvent, the crude product is collected and directly put into the next step of reaction; or the crude product is directly filtered to obtain the crude product and directly put into the next step of reaction; or after standing, the supernatant is poured out to obtain the crude product and directly put into the next step of reaction; or an appropriate organic solvent or a combination thereof is selected to perform extraction, distillation, crystallization, column chromatography, rinsing, beating and other purification steps.

[0082] The term "approximately" or "about" in the present invention is used to modify a numerical value that differs by 10% up and down. In some embodiments, "approximately" or "about" is used to modify a numerical value that differs by 5% up and down. In some embodiments, "approximately" or "about" is used to modify a numerical value that differs by 3% or 2% or 1% up and down. It is understood that the numerical error range modified by "approximately" or "about" is an actual or reasonable error range depending on the numerical value modified by it.

[0083] The terms "optionally", "optionally" or "optional" mean that the subsequently described event or circumstance may but need not occur, ie, the description includes instances where said event or circumstance occurs and instances where it does not.

[0084] In each step of the reaction process described in the present invention, the reaction raw materials or other reagents can be added to the reaction system by dropwise addition. Each dropwise addition process and each step of the reaction are carried out under a certain temperature condition, and any temperature suitable for use in each dropwise addition process or each reaction process is included in the present invention. In addition, many similar modifications, equivalent replacements, or temperatures and temperature ranges equivalent to those described in the present invention are considered to be included in the present invention. The present invention provides a preferred temperature or temperature range for each dropwise addition process, and a preferred reaction temperature or reaction temperature range for each reaction.

[0085] The expressions "solvent 1", "solvent 2", "solvent a", "solvent b", "base a", "base b" and the like described in the present invention use Arabic numerals 1, 2, 3 ... or letters a, b, c ... after "solvent" or "base" only to better distinguish the solvents or bases used in each step, and the Arabic numerals or letters used have no special meanings. For example, solvent 1 includes all solvents suitable for the reaction of preparing the compound of formula (II) by reacting the compound of formula (III) with the compound represented by formula (IV), including but not limited to toluene, dioxane, dimethyl sulfoxide, tert-butyl alcohol, tert-amyl alcohol, dimethyl ether (DME), cyclopentyl methyl ether (CPME), N,N-dimethylacetamide, water or any combination thereof.

[0086] The solvent used in each reaction step described in the present invention is not particularly limited, and any solvent that can dissolve the starting material to a certain extent and does not inhibit the reaction is included in the present invention. In addition, many similar modifications, equivalent replacements, or solvents, solvent combinations, and different proportions of solvent combinations equivalent to those described in the present invention in the art are considered to be included in the scope of the present invention. The present invention provides preferred solvents used in each reaction step.

[0087] The products of each reaction step described in the present invention can be purified by recrystallization under appropriate conditions. The recrystallization solvent used is not particularly limited, and any solvent that can dissolve the crude product to a certain extent and precipitate crystals under certain conditions is included in the present invention. In addition, many similar modifications, equivalent replacements, or solvents, solvent combinations, and different proportions of solvent combinations equivalent to those described in the present invention in the art are considered to be included in the scope of the present invention. Among them, the solvent can be alcohols, ethers, alkanes, halogenated hydrocarbons, esters, ketones, aromatic hydrocarbons, acetonitrile, acetic acid, water, DMF or a combination thereof. For example, 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, ethyl ether, isopropyl ether, dioxane, methyl tert-butyl ether, dimethoxyethane, 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 a combination thereof.

[0088] The content of water in the solvent of the present invention is not particularly limited, that is, the content of water in the solvent does not affect the occurrence of the reaction of the present invention. Any solvent containing a certain amount of water that can be used in the present invention to a certain extent is regarded as the solvent of the present invention. For example, the content of water 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, the water content of the solvent is within a certain range, which 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, the water content of the solvent exceeds a certain range, which may affect the reaction (for example, affecting the yield of the reaction), but does not affect the occurrence of the reaction.

[0089] General Synthesis Methods

[0090] In this specification, if there is any discrepancy between a chemical name and a chemical structure, the structure prevails.

[0091] In the examples described below, all temperatures are in degrees Celsius (°C) unless otherwise indicated. Unless otherwise indicated, various materials and reagents were purchased from commercial suppliers and used without further purification; some materials can be prepared according to methods known in the art.

[0092] The NMR spectral data were measured by Bruker Avance 400 NMR spectrometer or Bruker Avance IIIHD 600 NMR spectrometer, with CDC13 ,d 6 -DMSO,CD 3 OD,D 2 O or d 6 - Acetone is the solvent (in ppm), TMS (0 ppm) or chloroform (7.25 ppm) is used as the reference standard. When multiple peaks are present, the following abbreviations are used: s (singlet), d (doublet), t (triplet), m (multiplet), br (broadened), dd (doublet of doublets), dt (doublet of triplets), td (triplet of doublets), ddd (doublet of doublet of doublets), ddt (doublet of doublet of triplets), dddd (doublet ofdoublet of doublet of doublets). Coupling constants are expressed in Hertz (Hz).

[0093] Low-resolution mass spectrometry (MS) data were determined by an Agilent 6320 series LC-MS spectrometer equipped with a G1312A binary pump and a G1316A TCC (column temperature was maintained at 30 °C). A G1329A autosampler and a G1315B DAD detector were used for analysis, and an ESI source was applied to the LC-MS spectrometer.

[0094] Low-resolution mass spectrometry (MS) data were determined by an Agilent 6120 series LC-MS spectrometer equipped with a G1311A quaternary pump and a G1316A TCC (column temperature was maintained at 30 °C). A G1329A autosampler and a G1315D DAD detector were used for analysis, and an ESI source was applied to the LC-MS spectrometer.

[0095] Both spectrometers were equipped with an Agilent Zorbax SB-C18 column with a size of 2.1×30 mm, 5 μm. The injection volume was determined by the sample concentration; the flow rate was 0.6 mL / min; the HPLC peak was recorded and read at UV-Vis wavelengths at 210 nm and 254 nm. The mobile phase was 0.1% formic acid acetonitrile solution (phase A) and 0.1% formic acid ultrapure water solution (phase B). The gradient elution conditions are shown in Table 1:

[0096] Table 1: Gradient elution conditions for low resolution mass spectrometry mobile phase

[0097]

[0098]

[0099] Data such as compound purity, reaction product content or in-process control product content are obtained by high performance liquid chromatography (HPLC). The high performance liquid chromatography instrument can be an Agilent high performance liquid chromatography, and the chromatographic column can be selected from XbridgePhenyl (4.6×150mm, 3.5μm), ZORBAX Extend-C18 (4.6×150mm, 5μm) or Waters Xbridgephenyl (4.6×150mm, 3.5μm); phosphoric acid aqueous solution (optionally containing potassium dihydrogen phosphate) and acetonitrile are used as mobile phases for gradient elution.

[0100] The stereoisomers described in the present invention are detected by high performance liquid chromatography. The high performance liquid chromatography instrument can be an Agilent high performance liquid chromatography, and the chromatographic column can be selected from OJ-RH (4.6×250mm, 5μm), DAICEL CHIRALPAKIC (4.6×250mm, 5μm), and Phenol CHIRAL NY (4.6×250mm, 5μm); trifluoroacetic acid-acetonitrile solution and n-hexane are used as mobile phases for gradient elution. Specific implementation methods

[0102] The embodiments of the present invention disclose methods for preparing pyrrolamide compounds and intermediates thereof as shown in formula (A). Those skilled in the art can refer to the content of the present invention and appropriately improve the process parameters to achieve the above. 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 the present invention. The method of the present invention has been described through preferred embodiments, and relevant personnel can obviously modify or appropriately change and combine the methods described herein without departing from the content, spirit and scope of the present invention to achieve and apply the technology of the present invention.

[0103] In order to enable those skilled in the art to better understand the present invention, the present invention is described in detail below in conjunction with embodiments. Example

[0104] Example 1 Preparation of 2-chloro-1-(2-hydroxyethyl)-4-methyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrrole-3-carboxylic acid (Intermediate 1)

[0105]

[0106] 2-Chloro-1-(2-hydroxyethyl)-4-methyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrrole-3-carboxylic acid ethyl ester (29.1 g, 77.44 mmol) prepared by a method known in the art was added to a mixed solvent of methanol (90 mL) and water (30 mL), and then potassium hydroxide (15.34 g, 232.32 mmol, purity 85%) was added, and the mixture was heated to reflux for 3 hours. The solvent was evaporated under reduced pressure, water (90 mL) was added to the residue, and the mixture was washed with methyl tert-butyl ether (90 mL), the aqueous phase was adjusted to pH=4 with 2 mol / L hydrochloric acid solution, and then extracted with ethyl acetate (150 mL×2), the organic phases were combined, washed with water (100 mL) and saturated brine (100 mL) in sequence, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 26.3 g of a light yellow solid with a yield of 97.67%.

[0107] Example 2 Preparation of (S)-2-chloro-1-(2-hydroxyethyl)-4-methyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrrole-3-carboxylic acid (Intermediate 2)

[0108]

[0109] Method 1:

[0110] 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 to dissolve, and then add dropwise to the above quinine solution. Turn off the heating, cool to room temperature, filter, rinse with ethyl acetate (13 mL × 2), and vacuum dry the filter cake. 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 with stirring. The aqueous phase was separated after 10 minutes, and the organic phase was washed with water (50 mL) and saturated brine (40 mL) in turn, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 6.35 g of a light yellow solid with an ee value of 96.04%, a purity of 99.65%, and a yield of 48.84%.

[0111] Method 2:

[0112] Add N,N-dimethylacetamide (75mL), ethyl acetate (1050mL) and water (45mL) to quinine (83.97g, 172.55mmol), and heat the system to 65℃ after completion. Add 2-chloro-1-(2-hydroxyethyl)-4-methyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrrole-3-carboxylic acid (intermediate 1) (150.0g, 287.59mmol) to N,N-dimethylacetamide (75mL) and ethyl acetate (255mL), dissolve and add dropwise to the quinine reaction solution. After the addition is complete, stir at 65℃ for 1 hour and then cool to room temperature. Filter by suction, rinse the filter cake with ethyl acetate (50mL×2), collect the filter cake, and vacuum dry at 45℃ for 11 hours to obtain a white solid (131.96g). Add 4M hydrochloric acid solution to the obtained white solid until pH ≤ 3, and stir at room temperature for 5 hours. The filter cake was collected and vacuum dried at 60°C for 17 hours to obtain the target product as a white solid (64.83 g, 43.22%).

[0113] Identification of Intermediate 2:

[0114] MS(ESI,pos.ion)m / z:314.2(M+1);

[0115] 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).

[0116] 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)

[0117]

[0118] Method 1:

[0119] 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), sodium tert-amyl alcohol (95.02 g, 862.77 mmol) was added and heated to 40 ° C for overnight reaction. The reaction solution was poured into water (4000 mL), then extracted with MTBE (800 mL × 3), the organic phases were combined, washed with saturated brine (600 mL × 2), and the solvent was removed by concentration under reduced pressure to obtain a light yellow transparent oil (151 g, 99.45%).

[0120] Method 2:

[0121] Add 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) to the reaction flask, replace with nitrogen three times after completion, and then heat to 50±5°C under nitrogen protection for 4 hours. Add water (250 mL) to the reaction solution for dilution, extract with methyl tert-butyl ether (75 mL×2), wash the organic phase with 20% brine (200 mL×2), and concentrate under reduced pressure to obtain the target product as a light yellow transparent oil (12.52 g, 99.95%).

[0122] Example 4 Preparation of (S)-1-(2-(benzyloxy)ethyl)-2-chloro-4-methyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrrole-3-carboxylic acid (Intermediate 4)

[0123]

[0124] Add ethanol (240mL), potassium hydroxide (35.01g, 530.36mmol, purity 85%) and water (60mL) to intermediate 3 (70g, 132.59mmol), and heat to 70℃ for 6 hours. Cool to 45℃, add water (240mL) to dilute the reaction solution, and remove ethanol by vacuum rotary evaporation. Add methyl tert-butyl ether (400mL) and heptane (200mL) to a beaker, and mix the two solvents for later use. Add about half of the above mixed solvent to the reduced steam residue, stir for 5 minutes, let stand to separate the upper organic phase, and retain the aqueous phase. Add the other half of the above mixed solvent to the aqueous phase, stir for 5 minutes, let stand to separate the upper organic phase, and retain the aqueous phase. Add dilute hydrochloric acid (2M, purchased from Chengdu Kelong) to the retained aqueous phase to adjust the pH to ≤ 3, extract with ethyl acetate (500 mL), wash the organic phase with water (200 mL) and saturated brine (200 mL), respectively, and concentrate the organic phase under reduced pressure to obtain the target product as a brown oil (58.03 g, 99.96%). MS (ESI, pos.ion) m / z: 438.1 (M+1).

[0125] Example 5 Preparation of (S)-1-(2-(benzyloxy)ethyl)-4-methyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrrole-3-carboxylic acid (Intermediate 5)

[0126]

[0127] Example 1:

[0128] Intermediate 4 (12.0 g, 27.41 mmol), sodium formate dihydrate (4.28 g, 41.12 mmol), palladium carbon (1.20 g, 1.12 mmol, purity 10%) were dissolved in a mixed solvent of ethanol (120 mL), toluene (60 mL) and water (12 mL), and the temperature was raised to 65 ° C for reaction for 3.5 hours. The reaction solution was filtered through diatomaceous earth, and the filter cake was washed with ethanol. The filtrate was concentrated under reduced pressure to remove the solvent, and the residue was dissolved in ethanol (40 mL), adjusted to pH = 2 with 2.5 mol / L hydrochloric acid, and the solution was added dropwise to ice water (400 mL), naturally warmed to room temperature and stirred overnight. Filtered, the filter cake was collected, and vacuum dried at 60 ° C to obtain the target product as an off-white solid (9.6 g, 86.83%). HPLC: 96.81%, MS (ESI, pos.ion) m / z: 404.2 (M+1).

[0129] 1 H NMR (400 MHz, DMSO-d 6 )δ11.69(s,1H),7.91–7.84(m,1H),7.74–7.65(m,2H),7.53(s,1H),7.38–7.25(m,4H),7. 21(d,J=6.8Hz,2H),4.46–4.35(m,2H),3.92–3.81(m,1H),3.60–3.44(m,3H),1.88(s,3H).

[0130] Example 2-5:

[0131] Referring to the method of Example 1, the method conditions for preparing intermediate 5 were tested, wherein the reaction temperature was 60°C, the amount of sodium formate was 1.5 equivalents (i.e., the molar amount of sodium formate was 1.5 times the molar amount of intermediate 4), and the amount of palladium carbon was 10% (calculated as a percentage of the mass of the raw material intermediate 4); the experimental results are shown in the following table.

[0132] Table A

[0133] Example Feeding amount Reaction solvent Reaction time Content of in-process controlled products Example 2 10g Toluene 24h Not tested, more than 50% of raw materials remain Example 3 10g Ethanol / water=10 / 1 3h 78.22％ Example 3 1g Ethanol / toluene / water=6 / 4 / 1 6h 83.17％ Example 4 1g Ethanol / toluene / water=8 / 2 / 1 6h 81.76％ Example 5 1g Ethanol / toluene / water=10 / 5 / 1 4h 93.88％

[0134] Note: In the above table, the ratio of mixed solvents refers to the volume ratio; the content of the intermediate controlled product refers to the content of the product in the reaction system after the reaction is completed and before post-treatment, which is the peak area ratio of the product obtained by sampling from the reaction system and detecting by HPLC.

[0135] The compound of formula (A) can be prepared using intermediate 5 as a raw material according to a similar method disclosed in the prior art.

[0136] In the description of this specification, the description with reference to the terms "one embodiment", "some embodiments", "example", "specific example", or "some examples" means that the specific features, structures, materials or characteristics described in conjunction with the embodiment or example are included in at least one embodiment or example of the present invention. In this specification, the schematic expressions of the above terms do not necessarily refer to the same embodiment or example.

[0137] Although the embodiments of the present invention have been shown and described above, it is to be understood that the above embodiments are exemplary and are not to be construed as limitations of the present invention. A person skilled in the art may change, modify, replace and vary the above embodiments within the scope of the present invention.

Claims

1. A compound represented by formula (I), in, R 1 OH, NH2, C 2-4 Alkoxy or benzyloxy, the C 2-4 Alkoxy and benzyloxy are each optionally substituted by 1, 2, 3 or 4 groups independently selected from halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy and C 1-4 The substituents of the haloalkoxy group are substituted.

2. A compound having one of the following structures, 3. A method for preparing a compound represented by formula (II), in, The method comprises: Step c) dechlorinating the compound represented by formula (IB) in a solvent under appropriate conditions to obtain a compound represented by formula (II), 4. The method according to claim 3, wherein: The solvent is methanol, ethanol, isopropanol, tert-butyl alcohol, or a mixed solvent composed of any of them and other solvents, wherein the other solvent is tetrahydrofuran, DMF, ethyl acetate, methyl tert-butyl ether, ethylene glycol dimethyl ether, ethylene glycol monomethyl ether, toluene, water or any combination thereof; Optionally, the solvent is methanol, ethanol, ethanol / toluene, ethanol / water, ethanol / toluene / water, ethanol / tetrahydrofuran, or ethanol / tetrahydrofuran / water.

5. The method according to claim 3 or 4, wherein: The reaction in step c) is carried out in the presence of a transition metal catalyst; optionally, the transition metal catalyst is a palladium-carbon catalyst, a palladium acetate catalyst or a nickel catalyst.

6. The method according to any one of claims 3 to 5, wherein: The reaction in step c) is carried out in the presence of ammonium formate, sodium formate, disodium hydrogen phosphate, acid, triethylamine or hydrogen.

7. The method according to any one of claims 3 to 6, wherein: The reaction of step c) is carried out under heating conditions; optionally, the heating conditions of step c) are heating to 45°C-75°C, 55°C-70°C or 60°C-65°C.

8. The method according to any one of claims 3 to 7, further comprising a method for preparing a compound of formula (IB), wherein: The preparation method of the compound represented by formula (IB) comprises: Step a) The compound represented by formula (I-1) reacts with a benzyl protecting group reagent to obtain a compound represented by formula (IA), Step b) removing the benzyl protecting group from the compound represented by formula (IA) under appropriate conditions to obtain the compound represented by formula (IB); 9. The method according to claim 8, wherein: The benzyl protecting group reagent in step a) is a halogenated benzyl, preferably benzyl bromide; Optionally, the step a) is carried out in the presence of sodium tert-amylate; Optionally, the reaction solvent of step a) is N,N-dimethylacetamide; Optionally, the reaction temperature of step a) is 25°C to 60°C, or 35°C-55°C, or 45°C-55°C.

10. The method according to claim 8 or 9, wherein: The reaction in step b) is carried out under the action of a base, which is sodium carbonate, potassium carbonate, cesium carbonate, potassium phosphate, lithium hydroxide, potassium hydroxide or sodium hydroxide; Optionally, the reaction of step b) is carried out in a solvent, and the solvent is acetone, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, DMSO, methanol, ethanol, THF, methyl tert-butyl ether, water or any combination thereof; Optionally, the reaction of step b) is carried out under heating conditions, which refers to heating to 60°C to 80°C or 65°C to 75°C.

11. The method according to any one of claims 8 to 10, further comprising a method for preparing a compound of formula (I-1), wherein: The preparation method of the compound represented by formula (I-1) comprises: 1a) reacting the compound represented by formula (I-0) with a photoactive amine to obtain a photoactive amine salt of the corresponding compound represented by formula (I-1), and 1b) reacting the salt obtained in step 1a) to obtain a compound represented by formula (I-1); 12. The method according to claim 11, wherein: The optically active amine is an optically active amine having a quinine skeleton; optionally, the optically active amine having a quinine skeleton is quinine, hydroquinine, quinidine, cinchonine or cinchonidine.

13. The method according to claim 11 or 12, wherein: The reaction in step 1b) is a hydrolysis reaction; Optionally, the reaction of step 1b) is carried out under acidic conditions; optionally, the acidic conditions are conditions in the presence of hydrochloric acid, sulfuric acid, hydrobromic acid or citric acid; Optionally, the reaction solvent of 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.

14. The method according to any one of claims 11 to 13, wherein: The reaction solvent of 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; preferably, the reaction temperature of step 1a) is 50°C-80°C or 55°C-65°C.

Images