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WO2025011628A1 - Procédé de préparation d'un composé pyrrole amide et intermédiaire de celui-ci - Google Patents

Procédé de préparation d'un composé pyrrole amide et intermédiaire de celui-ci Download PDF

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Publication number
WO2025011628A1
WO2025011628A1 PCT/CN2024/105074 CN2024105074W WO2025011628A1 WO 2025011628 A1 WO2025011628 A1 WO 2025011628A1 CN 2024105074 W CN2024105074 W CN 2024105074W WO 2025011628 A1 WO2025011628 A1 WO 2025011628A1
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formula
reaction
compound represented
optionally
solvent
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Chinese (zh)
Inventor
王建成
张英勋
阳传文
左应林
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Sunshine Lake Pharma Co Ltd
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Sunshine Lake Pharma Co Ltd
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Publication of WO2025011628A1 publication Critical patent/WO2025011628A1/fr
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers

Definitions

  • the present invention relates to the field of pharmaceutical chemistry, and in particular to a method for preparing a pyrrolamide compound, and also to an important intermediate and a preparation method thereof.
  • the pyrrolamide compound and/or its intermediate of the present invention can be used to prepare a pyrrolamide compound used as a mineralocorticoid receptor antagonist.
  • 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.
  • 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.
  • 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 the racemic compound of the compound of formula (A) is obtained by substitution, hydrolysis, chlorination, condensation, and deprotection reaction, and then the compound of formula (A) is obtained by chiral column separation.
  • formula (A) i.e., compound (S)-N-(3-fluoro-4-(methylsulfonyl)phenyl)-1-(2-hydroxyethyl)-4-methyl-5-(2-(tri
  • 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.
  • 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.
  • 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 the general formula and/or compounds represented by various structural formulas.
  • the present invention relates to a method for preparing a pyrrolamide 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.
  • the pyrrolamide compound prepared by the method of the present invention can be used to prepare the compound represented by formula (A).
  • the present invention provides a compound represented by formula (I),
  • R 1 is OH, NH 2 , C 2-4 alkoxy or benzyloxy, and the C 2-4 alkoxy and benzyloxy are optionally substituted by 1, 2, 3 or 4 substituents independently selected from halogen, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy and C 1-4 haloalkoxy.
  • the R 1 is OH, NH 2 , C 2-4 alkoxy (such as ethoxy, n-propoxy, isopropoxy, n-butoxy or tert-butoxy) or benzyloxy.
  • the present invention provides a compound having one of the following structures,
  • the present invention provides a method for preparing a compound represented by formula (A):
  • the method comprises:
  • Step e) The compound of formula (III) is reacted to obtain a compound of formula (A),
  • the reaction of step e) comprises a debenzylation reaction and/or a dechlorination reaction.
  • the reaction solvent of step e) is methanol, ethanol, isopropanol, tert-butyl alcohol, tetrahydrofuran, DMF, ethyl acetate, methyl tert-butyl ether, ethylene glycol dimethyl ether, ethylene glycol monomethyl ether, toluene, water or any combination thereof.
  • the solvents in the mixed solvent are mixed in any proportion.
  • the reaction of step e) of the present invention is carried out in the presence of a transition metal catalyst.
  • the transition metal catalyst is palladium carbon, other palladium-containing catalysts such as palladium acetate, nickel, or nickel-containing catalysts such as nickel chloride.
  • the reaction of 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 carbon catalyst, a palladium acetate catalyst or a nickel catalyst.
  • the reaction of step e) of the present invention is carried out in the presence of a palladium-carbon catalyst.
  • the amount of the palladium-carbon catalyst is 1% to 20% of the mass of the compound shown in formula (III); in other embodiments, the amount of the palladium-carbon catalyst is 5% to 20% of the mass of the compound shown in formula (III); in other embodiments, the amount of the palladium-carbon catalyst is 10% to 20% of the mass of the compound shown in formula (III).
  • 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 discharged.
  • the reaction of step e) of the present invention is carried out in the presence of ammonium formate, sodium formate or hydrogen. In other embodiments, the reaction of step e) 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 20 equivalents, preferably 1 equivalent to 18 equivalents, and more preferably 2 equivalents to 15 equivalents. In some other embodiments, the reaction of step e) of the present invention is carried out in the presence of sodium formate, and the amount of sodium formate is 1 equivalent to 16 equivalents, preferably 2 equivalents to 15 equivalents.
  • the reaction of step e) of the present invention is carried out under heating conditions.
  • 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.
  • the method for preparing the compound of formula (A) of the present invention also includes a method for preparing the compound of formula (III), wherein the method for preparing the compound of formula (III) includes:
  • Step d) the compound represented by formula (IC) reacts with the compound represented by formula (II) under appropriate conditions to obtain the compound represented by formula (III),
  • X is Br or I.
  • step c) the compound represented by formula (IB) reacts with thionyl chloride, oxalyl chloride or N,N'-carbonyldiimidazole (i.e., 1-(1H-imidazole-1-carbonyl)-1H-imidazole), and then reacts with an amination reagent to obtain the compound represented by formula (IC);
  • the amination reagent is ammonia water or an ammonium salt reagent; preferably, the amination reagent is ammonia water, ammonium bromide or NH4SCN .
  • the reaction of step c) is carried out in a solvent, and the solvent is N,N-dimethylformamide or N,N-dimethylacetamide; optionally, the reaction of step c) is carried out at room temperature.
  • the reaction of step d) is carried out in the presence of a base.
  • the base is potassium carbonate, cesium carbonate, sodium carbonate, potassium tert-butoxide or potassium phosphate.
  • the reaction of step d) is carried out in the presence of a ligand; preferably, the ligand is Xantphos, X-phos or S-phos.
  • the reaction of step d) is carried out in a solvent, and the solvent is toluene, dioxane, tert-butyl alcohol (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.
  • the solvent is toluene, dioxane, tert-butyl alcohol (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.
  • the method for preparing the compound of formula (III) further includes the method for preparing the compound of formula (I-B), wherein the method for preparing the compound of formula (I-B) 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);
  • the benzyl protecting group reagent in step a) is a halogenated benzyl, optionally benzyl bromide.
  • reaction solvent of step a) is N,N-dimethylacetamide.
  • 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.
  • 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.
  • the solvent is acetone, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, DMSO, methanol, ethanol, THF, methyl tert-butyl ether, water or any combination thereof.
  • 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 other embodiments, the heating conditions refer to heating to 65°C to 75°C.
  • 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,
  • 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)).
  • the purification of the compound shown in formula (A) described in the present invention can be achieved by recrystallization or multiple recrystallizations, and the conditions of each recrystallization can be the same or different.
  • the compound shown in formula (A) described in the present invention can be further removed from impurities 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 be to first dissolve the crude product in a good solvent, stir and dissolve, add a poor solvent or add the solution of the crude product to a poor solvent, and stir to precipitate a solid.
  • the dissolution process can be carried out at room temperature or under heating conditions.
  • the good solvent can be ethanol or isopropyl acetate
  • the poor solvent can be water or toluene.
  • the good solvent is ethanol and the poor solvent is water; preferably, the total volume ratio of ethanol to water can be about 1:1.5 to about 1:15, specifically, about 1:1.8 to about 1:15.
  • the good solvent is isopropyl acetate and the poor solvent is toluene; preferably, the total volume ratio of isopropyl acetate to toluene can be about 1:2 to about 1:15, specifically, about 1:4 to about 1:5.
  • 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) of the present invention each independently includes a method for preparing the compound of formula (I-1).
  • the method comprises:
  • step 1b) reacting the salt obtained in step 1a) to obtain a compound represented by formula (I-1);
  • the optically active amine described in the present invention is an optically active amine having a quinine skeleton.
  • the optically active amine having a quinine skeleton of the present invention is quinine, hydroquinine, quinidine, cinchonine or cinchonidine.
  • 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.
  • 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).
  • the reaction of step 1b) of the present invention is a hydrolysis reaction.
  • reaction of step 1b) of the present invention is carried out under acidic conditions.
  • the acidic conditions of the present invention are conditions in the presence of hydrochloric acid, sulfuric acid, hydrobromic acid or citric acid.
  • 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.
  • 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.
  • 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.
  • 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).
  • the photoactive amine described here is the same as the photoactive amine used in step 1a).
  • the suitable solvent includes, but is not limited to, DMF and the like.
  • 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)).
  • a racemic compound i.e., a compound of formula (I-0)
  • the racemic compound can be subjected to step 1a) of the present invention.
  • the method is to prepare a photoactive amine salt of the compound of formula (I-1).
  • the photoactive amine salt of the compound of formula (I-1) can be prepared by the method of step 1b) of the present invention to obtain the compound of formula (I-1).
  • 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%).
  • the present invention provides a salt formed by a compound represented by formula (I-1) and a photoactive amine,
  • the photoactive amine of the present invention is quinine, hydroquinine, quinidine, cinchonine or cinchonidine.
  • the photoactive amine has the structure shown below.
  • 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).
  • the compounds of formula (I-0), (I-1), (I-A), (I-B), (I-C), (II), and/or (III) of the present invention are used to prepare the compound of formula (A) of the present invention.
  • the method for preparing the compound of formula (A) using the aforementioned compounds is as described 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.
  • reaction steps described in the present invention react to a certain extent, such as the consumption of raw materials is greater than 70%, greater than 80%, greater than 90%, greater than 95%, or after the reaction raw materials have been detected to have been completely consumed, post-treatment is performed, 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, by collecting the crude product after reduced pressure evaporation or conventional distillation of the reaction solvent, and directly putting it into the next step of reaction; or directly filtering to obtain the crude product, and directly putting it into the next step of reaction; or after standing, pouring out the supernatant to obtain the crude product, and directly putting it into the next step of reaction; or selecting an appropriate organic solvent or a combination thereof for extraction, distillation, crystallization, column chromatography, rinsing, beating and other purification steps.
  • 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.
  • 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.
  • 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.
  • 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.
  • DME dimethyl ether
  • CPME
  • 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.
  • 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.
  • the products of each reaction step described in the present invention can be purified by recrystallization under appropriate conditions.
  • recrystallization solvent used, 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.
  • many similar modifications, equivalent substitutions, 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 solvent can be alcohols, ethers, alkanes, halogenated hydrocarbons, esters, ketones, aromatic hydrocarbons, acetonitrile, acetic acid, water, DMF or a combination thereof.
  • 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.
  • 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%.
  • 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.
  • 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.
  • the NMR spectral data were measured by Bruker Avance 400 NMR spectrometer or Bruker Avance III HD 600 NMR spectrometer, using CDC1 3 , d 6 -DMSO, CD 3 OD, D 2 O or d 6 -acetone as solvent (in ppm), and TMS (0 ppm) or chloroform (7.25 ppm) as reference standard.
  • MS data were determined using an Agilent 6320 series LC-MS spectrometer equipped with a G1312A binary pump and a G1316A TCC (column temperature was maintained at 30 °C).
  • G1329A autosampler and a G1315B DAD detector were used for the analysis, and an ESI source was applied to the LC-MS spectrometer.
  • MS data were measured using 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 the analysis, and an ESI source was applied to the LC-MS spectrometer.
  • the high performance liquid chromatography instrument can be an Agilent high performance liquid chromatography, and the chromatographic column can be selected from Xbridge Phenyl (4.6 ⁇ 150mm, 3.5 ⁇ m), ZORBAX Extend-C18 (4.6 ⁇ 150mm, 5 ⁇ m) or Waters Xbridge phenyl (4.6 ⁇ 150mm, 3.5 ⁇ m); phosphoric acid aqueous solution (optionally containing potassium dihydrogen phosphate) and acetonitrile are used as mobile phases for gradient elution.
  • 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, 5 ⁇ m), DAICEL CHIRALPAK IC (4.6 ⁇ 250mm, 5 ⁇ m), and Phenol CHIRAL NY (4.6 ⁇ 250mm, 5 ⁇ m); trifluoroacetic acid-acetonitrile solution and n-hexane are used as mobile phases for gradient elution.
  • 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.
  • the phase was 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%.
  • 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%.
  • the filter cake was filtered and washed with toluene (15 mL).
  • the filter cake was 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 an isomer of 0.74%.

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  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

La présente invention concerne un procédé de préparation d'un composé pyrrole amide et un intermédiaire de celui-ci. Le composé pyrrole amide et/ou son intermédiaire selon la présente invention peuvent être utilisés pour préparer un composé pyrrole amide utilisé en tant qu'antagoniste du récepteur minéralocorticoïde. En particulier, le procédé de préparation selon la présente invention est doux en termes de conditions, simple à utiliser, sûr et contrôlable, élevé en termes de rendement et approprié pour une production industrielle.
PCT/CN2024/105074 2023-07-12 2024-07-12 Procédé de préparation d'un composé pyrrole amide et intermédiaire de celui-ci Pending WO2025011628A1 (fr)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20160096803A1 (en) * 2013-04-10 2016-04-07 Daiichi Sankyo Company, Limited Crystal of pyrrole derivative and method for producing the same
CN112707854A (zh) * 2019-10-25 2021-04-27 广东东阳光药业有限公司 吡咯酰胺类化合物及其用途
CN115246785A (zh) * 2021-04-26 2022-10-28 年衍药业(珠海)有限公司 吡咯酰胺化合物的制备方法
CN115784961A (zh) * 2021-09-10 2023-03-14 上海鼎雅药物化学科技有限公司 埃沙西林酮及其中间体的合成方法

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA3248246A1 (fr) * 2022-01-14 2025-07-10 Sunshine Lake Pharma Co Ltd Procédé de préparation d'un composé pyrrole et intermédiaire de celui-ci

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20160096803A1 (en) * 2013-04-10 2016-04-07 Daiichi Sankyo Company, Limited Crystal of pyrrole derivative and method for producing the same
CN112707854A (zh) * 2019-10-25 2021-04-27 广东东阳光药业有限公司 吡咯酰胺类化合物及其用途
CN115246785A (zh) * 2021-04-26 2022-10-28 年衍药业(珠海)有限公司 吡咯酰胺化合物的制备方法
CN115784961A (zh) * 2021-09-10 2023-03-14 上海鼎雅药物化学科技有限公司 埃沙西林酮及其中间体的合成方法

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