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WO2025011627A1 - 制备吡咯甲酸化合物的方法 - Google Patents

制备吡咯甲酸化合物的方法 Download PDF

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Publication number
WO2025011627A1
WO2025011627A1 PCT/CN2024/105063 CN2024105063W WO2025011627A1 WO 2025011627 A1 WO2025011627 A1 WO 2025011627A1 CN 2024105063 W CN2024105063 W CN 2024105063W WO 2025011627 A1 WO2025011627 A1 WO 2025011627A1
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Prior art keywords
formula
reaction
compound represented
optionally
ethanol
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English (en)
French (fr)
Inventor
王建成
张英勋
阳传文
陈红分
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 WO2025011627A1 publication Critical patent/WO2025011627A1/zh
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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
    • 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, 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.
  • 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 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.
  • formula (A) i.e., compound (S)-N-(3-fluoro-4-(methylsulfonyl)phenyl)-1-(2-hydroxyethyl)-4-methyl-5-(2-(
  • 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 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.
  • the pyrrolidine carboxylic acid 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, etc.) or benzyloxy.
  • the present invention provides a compound having one of the following structures,
  • the present invention relates to the use of the compound represented by formula (I-A) or (I-B) in the preparation of the compound represented by formula (II).
  • the method for preparing the compound represented by formula (II) is as described in the present invention.
  • the compound represented by formula (I-A) 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.
  • the present invention provides a method for preparing a compound represented by formula (II):
  • the method comprises:
  • 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).
  • 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.
  • the reaction solvent of step c) is methanol, ethanol, ethanol/toluene, ethanol/water, ethanol/toluene/water, ethanol/tetrahydrofuran or ethanol/tetrahydrofuran/water.
  • the reaction solvent of step c) is ethanol, ethanol/water or ethanol/toluene/water.
  • ethanol/water of the present invention refers to a mixed solvent composed of ethanol and water
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the reaction of step c) 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, etc.), nickel, or nickel-containing catalysts (such as nickel chloride), etc.
  • 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.
  • the reaction of step c) of the present invention is carried out in the presence of a palladium-carbon catalyst.
  • the palladium-carbon catalyst is used in an amount of 1% to 20% by mass of the compound shown in formula (I-B); 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 shown in formula (I-B); in other embodiments, the palladium-carbon catalyst is used in an amount of 3% to 10% by mass of the compound shown in formula (I-B).
  • 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.
  • 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.
  • 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.
  • the sodium formate of the present invention may be sodium formate dihydrate or anhydrous sodium formate.
  • the equivalents described herein refer to the ratio of the molar amount of the reagent sodium formate to the molar amount of the compound represented by the reaction substrate formula (I-B); 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 (I-B) is 1.5.
  • the reaction of step c) 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 represented by formula (II) of the present invention further comprises a post-treatment method of the reaction of step c).
  • 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.
  • the filtration can be suction filtration or filtration through diatomaceous earth.
  • 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.
  • a reaction solvent such as washing with ethanol
  • the second washing can be optionally performed, such as optionally washing with water.
  • other solvents such as DMAC (i.e., N,N-dimethylacetamide) can be added before the concentration.
  • the drying can be vacuum drying or heated vacuum drying (e.g., vacuum drying at 45°C-60°C).
  • other suitable post-treatment methods can be used for treatment.
  • 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.
  • the method for preparing the compound of formula (II) of the present invention also includes a 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.
  • step a) is performed in the presence of sodium tert-amylate.
  • reaction solvent of step a) is N,N-dimethylacetamide.
  • 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.
  • 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 some 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 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;
  • X is Br or I.
  • the compound represented by (II) of the present invention can be prepared according to the method of the present invention.
  • 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.
  • 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),
  • 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)).
  • 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).
  • 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).
  • 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), (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.
  • All the reaction steps described in the present invention are subjected to post-processing 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 reaction can be carried out by conventional methods such as thin layer chromatography (TLC), high performance liquid chromatography (HPLC), gas chromatography (GC), etc. Detect the degree of reaction.
  • the reaction solution can be post-treated by conventional methods, for example, by vacuum evaporation or conventional distillation of the reaction solvent, the crude product is collected and directly put into the next reaction; or the crude product is directly filtered to obtain the crude product, which is directly put into the next reaction; or after standing, the supernatant is poured out to obtain the crude product, which is directly put into the next 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.
  • 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.
  • 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.
  • 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 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 organic phases were combined, washed with water (100 mL) and saturated brine (100 mL) in turn, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a dilute 26.3 g of yellow solid, yield 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%.
  • 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.
  • 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.
  • 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.

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Abstract

本发明公开了制备吡咯甲酸化合物的方法。本发明所述吡咯甲酸化合物可用于制备用作盐皮质激素受体拮抗剂的吡咯酰胺化合物。具体而言，本发明所提供的制备方法条件温和，操作简单，安全可控，收率高，适合工业生产。

Description

制备吡咯甲酸化合物的方法 技术领域
本发明涉及药物化学领域，具体涉及制备吡咯甲酸化合物的方法，还涉及所述吡咯甲酸化合物作为重要的中间体制备吡咯酰胺化合物的方法。本发明所述吡咯甲酸化合物可用于制备用作盐皮质激素受体拮抗剂的吡咯酰胺化合物。
背景技术
国际专利申请WO2021078135A1公开了一类吡咯酰胺类化合物及其用途，该类化合物可以用作盐皮质激素受体拮抗剂，对醛甾酮过多症、高血压、慢性心力衰竭、心肌梗死的后遗症、肝硬化、非酒精性脂肪性肝炎、慢性肾病、糖尿病肾病、肾衰竭、纤维化和/或中风等疾病具有潜在治疗功效。具体地，该国际申请公开了如式(A)所示的化合物(即化合物(S)-N-(3-氟-4-(甲基磺酰基)苯基)-1-(2-羟乙基)-4-甲基-5-(2-(三氟甲基)苯基)-1H-吡咯-3-甲酰胺)，还公开了如下制备方法：以4-甲基-5-(2-(三氟甲基)苯基)-1H-吡咯-3-甲酸乙酯为原料经取代、水解、酰氯化、缩合、脱保护反应得到式(A)化合物的消旋化合物，再经手性柱拆分得到式(A)化合物。所述方法采用手性拆分方法分离立体异构体，所述分离方法对仪器要求高，且产率低；整体而言，该制备方法生产成本高、原子经济性差、环境污染大、反应条件较苛刻，不适合工业放大生产。
国际专利申请WO2022228215A1公开了制备式(A)化合物的制备方法，所述方法中使用脂肪酶对外消旋原料1-(2-羟乙基)-4-甲基-5-(2-(三氟甲基)苯基)-1H-吡咯-3-甲酸甲酯进行手性拆分制备得到中间体(S)-1-(2-羟乙基)-4-甲基-5-(2-(三氟甲基)苯基)-1H-吡咯-3-甲酸甲酯，再经苄基保护、酯水解、氨化制得酰胺中间体(S)-1-(2-(苄氧基)乙基)-4-甲基-5-(2-(三氟甲基)苯基)-1H-吡咯-3-甲酰胺，最后经缩合、脱保护得到式(A)所示化合物。该方法通过酶法拆分制得中间体，避免了使用手性柱拆分，但从外消旋原料制备得到酰胺中间体的反应总产率不高，式(A)所示化合物的总收率也不高，还需提供收率更高、成本更低的制备式(A)所示化合的方法。
发明内容
本发明提供了可用于制备式(A)化合物的中间体及其制备方法；所述中间体包括本发明所述的各通式 和/或各结构式所示的化合物。
本发明涉及制备吡咯甲酸化合物的方法，同时还涉及所述方法中的重要中间体及其制备方法。本发明所述的制备方法条件温和，操作简单，安全可控，收率高，适合工业化生产。
本发明所述方法制备得到的吡咯甲酸化合物可用于制备式(A)所示化合物。
一方面，本发明提供了式(I)所示化合物，
其中，R1为OH、NH2、C2-4烷氧基或苄氧基，所述C2-4烷氧基和苄氧基分别任选地被1、2、3或4个独立地选自卤素、C1-4烷基、C1-4卤代烷基、C1-4烷氧基和C1-4卤代烷氧基的取代基取代。
在一些实施方案中，所述R1为OH、NH2、C2-4烷氧基(如乙氧基、正丙氧基、异丙氧基、正丁氧基或叔丁氧基等)或苄氧基。
另一方面，本发明提供了一种化合物，其具有如下其中之一的结构，
任选地，本发明涉及所述式(I-A)或(I–B)所示化合物在用于制备式(II)所示化合物中的用途。任选地，所述制备式(II)所示化合物的方法如本发明所述。任选地，本发明所述式(I-A)或(I–B)所示化合物可用作本发明所述式(II)所示化合物的制备方法中的中间体。
一方面，本发明提供了一种制备式(II)所示化合物的方法，
其中，所述方法包括：
步骤c)式(I-B)所示化合物在合适条件下在溶剂中脱氯得到式(II)所示化合物，
在一些实施方案中，所述步骤c)的反应溶剂为甲醇、乙醇、异丙醇、叔丁醇、或者它们(即甲醇、乙醇、异丙醇或叔丁醇)与其他溶剂任意组合(如以任意比例组合)的混合溶剂。在另一些实施方案中，所述其他溶剂包括但不限于四氢呋喃、DMF、乙酸乙酯、甲基叔丁基醚、乙二醇二甲醚、乙二醇单甲醚、甲苯、水或它们的任意组合。在一些实施方案中，所述步骤c)的反应溶剂为甲醇、乙醇、乙醇/甲苯、乙醇/水、乙醇/甲苯/水、乙醇/四氢呋喃、或乙醇/四氢呋喃/水。在一些实施方案中，所述步骤c)的反应溶剂为乙醇、乙醇/水或乙醇/甲苯/水。任选地，本发明所述乙醇/水是指乙醇和水组成的混合溶剂，所述乙醇/甲苯/水是指乙醇、甲苯和水组成的混合溶剂。除非特别说明，所述混合溶剂中各溶剂以任意比例混合。
在一些实施方案中，本发明所述步骤c)的反应溶剂为乙醇/甲苯/水，其中所述乙醇和水的体积比为4:1至20:1，优选为4:1至18:1，进一步优选为4:1至17:1；更优选地，所述乙醇和水的体积比为5:1至16:1。在另一些所述方案中，本发明所述步骤c)的反应溶剂为乙醇/甲苯/水，其中所述乙醇和水的体积比为8:1至12:1、9:1至11:1。在另一些所述方案中，本发明所述步骤c)的反应溶剂为乙醇/甲苯/水，其中所述乙醇和水的体积比为5:1、6:1、8:1、9:1、10:1或12:1。
在一些实施方案中，本发明所述步骤c)的反应溶剂为乙醇/甲苯/水，其中所述甲苯和水的体积比为1:1至15:1，优选为1:1至12:1，进一步优选为1:1至11:1；更优选地，所述甲苯和水的体积比为1:1至10:1。在另一些所述方案中，本发明所述步骤c)的反应溶剂为乙醇/甲苯/水，其中所述甲苯和水的体积比为3:1至7:1、或4:1至6:1。在另一些所述方案中，本发明所述步骤c)的反应溶剂为乙醇/甲苯/水，其中所述甲苯和水的体积比为1:1、2:1、4:1、5:1、6:1或10:1。
在一些实施方案中，本发明所述步骤c)的反应溶剂为乙醇/甲苯/水，其中所述乙醇和水的体积比为4:1至20:1，所述甲苯和水的体积比为1:1至15:1；优选地，所述乙醇和水的体积比为4:1至17:1，所述甲苯和水的体积比为1:1至11:1；或优选地，所述乙醇和水的体积比为5:1至16:1，所述甲苯和水的体积比为1:1至10:1；更选地，所述乙醇和水的体积比为6:1至10:1，所述甲苯和水的体积比为1:1至5:1。
在另一些所述方案中，本发明所述步骤c)的反应溶剂为乙醇/甲苯/水，其中所述乙醇、甲苯和水的体积比为10:5:1、10:2:1、6:4:1、8:2:1或9:1:1。
在一些实施方案中，本发明所述步骤c)的反应在过渡金属催化剂的存在下进行。任选地，所述过渡金属催化剂为钯碳、其它含钯的催化剂(如醋酸钯等)、镍、或含镍催化剂(如氯化镍)等。在另一些实施方案中，本发明所述步骤c)的反应在过渡金属催化剂的存在下进行，其中所述过渡金属催化剂为钯碳催化剂、醋酸钯催化剂或镍催化剂。
在一些实施方案中，本发明所述步骤c)的反应在钯碳催化剂的存在下进行。任选地，所述钯碳催化剂的用量是式(I-B)所示化合物质量的1％至20％；在一些实施方案中，所述钯碳催化剂的用量是式(I-B)所示化合物质量的2％至15％或2％至11％；在另一些实施方案中，所述钯碳催化剂的用量是式(I-B)所示化合物质量的3％至10％。
在一些是实施方案中，本发明所述步骤c)的反应是在甲酸铵、甲酸钠、磷酸氢钠(如磷酸氢二钠等)、酸、三乙胺或氢气的存在下进行。
在一些是实施方案中，本发明所述步骤c)的反应是在甲酸铵、甲酸钠或氢气的存在下进行。在另一些实施方案中，本发明所述步骤c)的反应是在甲酸铵或甲酸钠的存在下进行，所述甲酸铵或甲酸钠的用量是1当量至5当量，优选为1当量至3当量，进一步优选为1当量至2当量，更优选为1当量至1.5当量。在又一些实施方案中，本发明所述步骤c)的反应是在甲酸钠的存在下进行，所述甲酸钠的用量是1当量至2当量，优选为1当量至1.5当量。在一些实施例中，本发明所述步骤c)的反应是在甲酸钠的存在下进行，所述甲酸钠的用量是1.5当量。任选地，本发明所述甲酸钠可为二水合甲酸钠或无水甲酸钠。除非另外说明，此处所述当量是指试剂甲酸钠与反应底物式(I-B)所示化合物的摩尔量的比值；例如，所述“甲酸钠的用量是1.5当量”是指甲酸钠摩尔量与式(I-B)所示化合物的摩尔量的比值是1.5。
在一些实施方案中，本发明所述步骤c)的反应是在加热条件下进行的。任选地，所述加热条件是加热至45℃-75℃；在一些实施方案中，所述加热条件是加热至55℃-70℃；在一些实施方案中，所述加热条件是加热至60℃-65℃。
在一些实施方案中，本发明制备式(II)所示化合物的方法还包括所述步骤c)反应的后处理方法。在另一些实施方案中，本发明所述步骤c)反应的后处理方法包括但不限于：反应结束后，反应液过滤，洗涤，浓缩除去溶剂(如乙醇和甲苯)，残留物溶于乙醇中，盐酸调节pH，所得溶液滴加至冰水中，室温搅拌，过滤，任选地洗涤，收集滤饼，干燥得到目标化合物。任选地，所述过滤可以是抽滤，还可以是经硅藻土过滤。任选地，所述第一次洗涤是使用反应溶剂进行洗涤，例如使用乙醇进行洗涤；所述第二次洗涤可以任选地进行，例如任选地用水洗涤。任选地，所述浓缩前可以加入其他溶剂，例如DMAC(即N,N-二甲基乙酰胺)。任选地，所述干燥可以是真空干燥或加热真空干燥(例如45℃-60℃真空干燥)。任选地，所述步骤c)反应结束后可以采用其他合适的后处理方式进行处理。
使用本发明所述方法可以有效控制反应杂质的生成，高纯度高收率地得到式(II)所示的中间体化合物。
在一些实施方案中，本发明制备式(II)所示化合物的方法还包括式(I-B)所示化合物的制备方法，其中，所述式(I-B)所示化合物的制备方法包括：
步骤a)式(I-1)所示化合物与苄基保护基试剂反应得到式(I-A)所示化合物，
步骤b)式(I-A)所示化合物在合适条件下脱去苄基保护基得到式(I-B)所示化合物；
在一些实施方案中，所述步骤a)中的苄基保护基试剂为卤代苄基，任选地为苄基溴。
在一些实施方案中，所述步骤a)是在叔戊醇钠的存在下进行的。
在一些实施方案中，所述步骤a)的反应溶剂是N,N-二甲基乙酰胺。
在一些实施方案中，所述步骤a)的反应温度是25℃至60℃。在另一些实施方案中，所述反应温度是35℃-55℃。在另一些实施方案中，所述反应温度是35℃-45℃。在另一些实施方案中，所述反应温度是45℃-55℃。
在一些实施方案中，所述步骤b)的反应是在碱的作用下进行的，所述碱为碳酸钠、碳酸钾、碳酸铯、磷酸钾、氢氧化锂、氢氧化钾或氢氧化钠。
在一些实施方案中，所述步骤b)的反应是在溶剂中进行，所述溶剂为丙酮、乙腈、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、DMSO、甲醇、乙醇、THF、甲基叔丁基醚、水或它们的任意组合。
在一些实施方案中，所述步骤b)的反应是在加热条件下进行的，所述加热条件是指加热至60℃至80℃；在一些实施方案中，所述加热条件是指加热至65℃至75℃。
另一方面，本发明提供了具有如下其中之一结构的化合物在制备用作盐皮质激素受体拮抗剂的吡咯酰胺化合物的用途，
在一些实施方案中，所述用作盐皮质激素受体拮抗剂的吡咯酰胺化合物为(S)-N-(3-氟-4-(甲基磺酰基)苯基)-1-(2-羟乙基)-4-甲基-5-(2-(三氟甲基)苯基)-1H-吡咯-3-甲酰胺(即式(A)所示化合物)。
在一些实施方案中，本发明所述式(II)所示化合物在制备式(A)所式化合物中的用途，其中，式(II)所示化合物经如下方法制备得到式(A)所示化合物(即(S)-N-(3-氟-4-(甲基磺酰基)苯基)-1-(2-羟乙 基)-4-甲基-5-(2-(三氟甲基)苯基)-1H-吡咯-3-甲酰胺)：
式(II)所示化合物在合适条件下氨化得到式(III)所示化合物，然后与式(IV)所示化合物反应得到式(V)所示化合物，式(V)化合物经脱保护反应脱除苄基得到目标化合物；
其中，X为Br或I。
任选地，本发明所述(II)所示化合物可按照本发明所述方法制备得到。
任选地，可以参照现有技术如WO2022228215A1所公开的方法，使用本发明所述式(II)所示化合物制备得到式(A)所示化合物。
一方面，本发明所述制备式(II)所述化合物的方法或所述式(I-B)所示化合物的制备方法还包括了式(I-1)所示化合物的制备方法，
其中，所述方法包括：
1a)式(I-0)所示化合物与光活性胺反应得到相应的式(I-1)化合物的光活性胺的盐，和
1b)步骤1a)所得的盐反应得到式(I-1)所示化合物；
在一些实施方案中，本发明所述光活性胺为具有奎宁骨架的光学活性胺。
在一些实施方案中，本发明所述具有奎宁骨架的光学活性胺为奎宁、氢化奎宁、奎尼丁、辛可宁或辛可尼丁。
在一些实施方案中，本发明所述式(I-1)化合物的光活性胺的盐为式(I-1)所示化合物与光活性胺形成的盐。在另一些实施方案中，本发明所述式(I-1)化合物的光活性胺的盐为式(I-1)化合物的奎宁盐、式(I-1)化合物的氢化奎宁盐、式(I-1)化合物的奎尼丁盐、式(I-1)化合物的的辛可宁盐、或式(I-1)化合物的的辛可宁丁盐。
在一些实施方案中，本发明所述步骤1b)的反应为水解反应。
在一些实施方案中，本发明所述步骤1b)的反应是在酸性条件下进行的。
在一些实施方案中，本发明所述酸性条件是盐酸、硫酸、氢溴酸或柠檬酸存在的条件。
在一些实施方案中，本发明所述步骤1b)的反应溶剂为N,N-二甲基甲酰胺(DMF)、N,N-二甲基乙酰胺(DMAC)、乙腈、四氢呋喃(THF)、乙醇、丙酮、乙酸异丙酯、乙酸乙酯、甲基叔丁基醚、水、二甲氧基乙烷或它们的任意组合。
在一些实施方案中，本发明所述步骤1a)的反应溶剂为N,N-二甲基甲酰胺(DMF)、N,N-二甲基乙酰胺(DMAC)、乙腈、四氢呋喃(THF)、乙醇、丙酮、乙酸异丙酯、乙酸乙酯、甲基叔丁基醚、水、二甲氧基乙烷或它们的任意组合。
在一些实施方案中，本发明所述步骤1a)的反应温度是室温至100℃；在一些实施方案中，所述步骤1a)的反应温度是50℃-80℃；在一些实施方案中，所述步骤1a)的反应温度是55℃-65℃。
在一些实施方案中，本发明所述式(I-1)化合物的制备方法还包括：将步骤1a)中移除所述式(I-1)化合物的光活性胺的盐后得到的混合液旋干，加入合适的溶剂，并加热异构化以得到外消旋的式(I-0)化合物，再与光活性胺反应得到式(I-1)化合物的光活性胺的盐。通常，此处所述光活性胺与步骤1a)使用的光活性胺相同。任选地，所述合适的溶剂包括但不限于，DMF等。
在另一些实施方案中，任选地，所述异构化是指通过如加热等方式将溶液中的阻转异构体外消旋化以得到外消旋体化合物(即，式(I-0)化合物)。任选地，所述外消旋体化合物可经本发明所述步骤1a)的方法制备得到式(I-1)化合物的光活性胺的盐。任选地，所述式(I-1)化合物的光活性胺的盐可经本发明所述步骤1b)的方法制备得到式(I-1)化合物。
本发明所示式(I-1)化合物的制备方法操作简单，收率高，所得产物的ee/de值高；且该方法所得的R构型副产物可以经本发明所述的外消旋化以实现循环利用，进一步提高式(I-1)化合物的收率(可达60％以上)。
另一方面，本发明提供了式(I-1)所示化合物与光活性胺形成的盐，
在一些实施方案中，本发明所述光活性胺为奎宁、氢化奎宁、奎尼丁、辛可宁或辛可尼丁。任选地，所述光活性胺分别具有如下所示结构。
优选地，本发明所述式(I-1)所示化合物与光活性胺形成的盐为式(I-1)化合物的奎宁盐、式(I-1)化合物的氢化奎宁盐、式(I-1)化合物的奎尼丁盐、式(I-1)化合物的的辛可宁盐、或式(I-1)化合物的辛可宁丁盐。
本发明所述式(I-0)、(I-1)、(I-A)、(I-B)、(II)和/或(III)所示化合物用于制备本发明所述的式(A)所示化合物。优选地，使用前述化合物制备式(A)所示化合物的方法如本发明所述。
定义和一般术语
本发明中“室温”指的是温度由大约10℃到大约40℃。在一些实施方案中，“室温”指的是温度由大约20℃到大约30℃；在外一些实施方案中，“室温”指的是20℃，22.5℃，25℃，27.5℃等等。
在本发明的上下文中，所有在此公开了的数字均为近似值。每一个数字的数值有可能会出现1％、2％、5％、7％、8％或10％等差异。每当公开一个具有N值的数字时，任何具有N+/-1％，N+/-2％，N+/-3％，N+/-5％，N+/-7％，N+/-8％或N+/-10％值以内的数字会被明确地公开，其中“+/-”是指加或减。每当公开一个数值范围中的一个下限，DL，和一个上限，DU，时，任何处于该公开了的范围之内的数值会被明确地公开。
本发明所述的所有反应步骤反应到一定程度如原料消耗大约大于70％，大于80％，大于90％，大于95％，或经检测反应原料已经消耗完毕后进行后处理，如冷却，收集，提取，过滤，分离，净化处理或其组合。可以通过常规的方法如薄层层析法(TLC)、高效液相色谱法(HPLC)、气相色谱法(GC)等方法 检测反应程度。可以采用常规的方法对反应溶液进行后处理，例如，通过减压蒸发或常规蒸馏反应溶剂后收集粗产物，直接投入下一步反应；或直接过滤得到粗产物，直接投入下一步反应；或静置后，倾倒出上层清液得到粗产物，直接投入下一步反应；或选择适当的有机溶剂或其组合进行萃取，蒸馏，结晶，柱层析，润洗，打浆等纯化步骤。
本发明中的术语“大约”或“约”是用于修饰一个上下相差10％的数值。在一些实施方案中，“大约”或“约”用于修饰一个上下相差5％的数值。在一些实施方案中，“大约”或“约”用于修饰一个上下相差3％或2％或1％的数值。可以理解的是，“大约”或“约”修饰的数值误差范围是取决于其所修饰的数值的实际或合理的误差范围。
术语“任选地”、“任选”或“任选的”是指随后描述的事件或情形可以但不一定出现，即，该描述包括其中所述事件或情形出现的情况以及不出现的情况。
本发明所述各步反应过程中，反应原料或其他试剂可以通过滴加的方式加入到反应体系中。所述各滴加过程以及所述的各步反应均在一定温度条件下进行，任何适合使用于各滴加过程或各反应过程的温度均包含在本发明中。另外，本领域的许多类似改动，等同替换，或等同于本发明所描述的温度及温度范围，均视为本发明的包含范围。本发明给出了各滴加过程较佳的温度或温度范围，以及各反应较佳的反应温度或反应温度范围。
本发明所述的“溶剂1”、“溶剂2”、“溶剂a”、“溶剂b”、“碱a”、“碱b”等表述，在“溶剂”或“碱”后面使用阿拉伯数字1、2、3……或者字母a、b、c……，仅仅是为了更好的区分各个步骤中使用的溶剂或碱，所使用的阿拉伯数字或字母并无特殊含义。例如，溶剂1，包括所有适用于由式(III)化合物与式(IV)所示化合物反应制备式(II)化合物的反应的溶剂，包括但不限于甲苯、二氧六环、二甲基亚砜、叔丁醇、叔戊醇、二甲醚(DME)、环戊基甲醚(CPME)、N,N-二甲基乙酰胺、水或它们的任意组合。
本发明所述的各反应步骤所使用的溶剂没有特别限制，任何在一定程度上能溶解起始原料并且不抑制反应的溶剂均包含在本发明中。另外，本领域的许多类似改动，等同替换，或等同于本发明所描述的溶剂，溶剂组合，及溶剂组合的不同比例，均视为本发明的包含范围。本发明给出了各反应步骤所使用的较佳的溶剂。
本发明所述的各反应步骤的产物，在合适的条件下，可以通过重结晶的方式进行纯化。所使用的重结晶溶剂没有特别限制，任何在一定程度上能溶解粗产物并且在一定条件下能析出结晶的溶剂均包含在本发明中。另外，本领域的许多类似改动，等同替换，或等同于本发明所描述的溶剂，溶剂组合，及溶剂组合的不同比例，均视为本发明的包含范围。其中，所述的溶剂可以是醇类，醚类，烷烃类，卤代烃类，酯类，酮类，芳烃类，乙腈，乙酸，水，DMF或它们的组合。例如水，乙酸，甲醇，乙醇，正丙醇，异丙醇，正丁醇，异丁醇，叔丁醇，石油醚，正戊烷，正己烷，正庚烷，环己烷，DMF，N,N-二甲基乙酰胺，四氢呋喃，乙醚，异丙醚，二氧六环，甲基叔丁基醚，二甲氧乙烷，二乙二醇二甲醚，三甘醇二甲醚，二氯甲 烷，1,2-二氯乙烷，氯仿，四氯化碳，乙酸乙酯，乙酸异丙酯，丙酮，丁酮，苯，甲苯，二甲苯或它们的组合。
本发明所述的溶剂中水分的含量，没有特别的限制，即，溶剂中水分的含量不影响本发明所述反应的发生。任何在一定程度上能在本发明中使用的含有一定量的水分的溶剂，均视为本发明所述的溶剂。如溶剂中水分的含量大约小于0.05％，小于0.1％，小于0.2％，小于0.5％，小于5％，小于10％，小于25％，小于30％，或为0％。在一些实施方案中，所述溶剂的水分含量在一定范围内，更有利于反应的进行；例如，在以乙醇作为反应溶剂的步骤，使用无水乙醇，更有利反应的进行。在一些实施方案中，所述溶剂的水分含量超出一定范围，可能会影响反应的进行(例如，影响反应的收率)，但并不影响反应的发生。
一般合成方法
在本说明书中，如果在化学名称和化学结构间存在任何差异，结构是占优的。
下面所描述的实施例，除非其他方面表明所有的温度定为摄氏度(℃)。除非其他方面表明，各种物料、试剂购买于商品供应商，使用时都没有经过进一步纯化；部分物料可根据本领域公知的方法制备得到。
核磁共振光谱数据通过Bruker Avance 400核磁共振谱仪或Bruker Avance III HD 600核磁共振谱仪来测定，以CDC13,d6-DMSO,CD3OD,D2O或d6-丙酮为溶剂(以ppm为单位)，用TMS(0ppm)或氯仿(7.25ppm)作为参照标准。当出现多重峰的时候，将使用下面的缩写：s(singlet，单峰),d(doublet，双峰),t(triplet，三重峰),m(multiplet，多重峰),br(broadened，宽峰),dd(doublet of doublets，双二重峰),dt(doublet of triplets，双三重峰),td(triplet of doublets，三双重峰),ddd(doublet of doublet of doublets，双双二重峰),ddt(doublet of doublet of triplets，双双三重峰),dddd(doublet of doublet of doublet of doublets，双双双二重峰)。偶合常数，用赫兹(Hz)表示。
低分辨率质谱(MS)数据通过配备G1312A二元泵和a G1316A TCC(柱温保持在30℃)的Agilent 6320系列LC-MS的光谱仪来测定的，G1329A自动采样器和G1315B DAD检测器应用于分析，ESI源应用于LC-MS光谱仪。
低分辨率质谱(MS)数据通过配备G1311A四元泵和G1316A TCC(柱温保持在30℃)的Agilent 6120系列LC-MS的光谱仪来测定的，G1329A自动采样器和G1315D DAD检测器应用于分析，ESI源应用于LC-MS光谱仪。
以上两种光谱仪都配备了Agilent Zorbax SB-C18柱，规格为2.1×30mm，5μm。注射体积是通过样品浓度来确定；流速为0.6mL/min；HPLC的峰值是通过在210nm和254nm处的UV-Vis波长来记录读取的。流动相为0.1％的甲酸乙腈溶液(相A)和0.1％的甲酸超纯水溶液(相B)。梯度洗脱条件如表1所示：
表1：低分辨率质谱流动相的梯度洗脱条件

化合物纯度、反应产物含量或中控产物含量等数据是通过高效液相色谱(HPLC)法检测得到的。其中，高效液相色谱仪器可为Agilent高效液相色谱，色谱柱可选用Xbridge Phenyl(4.6×150mm,3.5μm)、ZORBAX Extend-C18(4.6×150mm,5μm)或Waters Xbridge phenyl(4.6×150mm,3.5μm)；采用磷酸水溶液(任选地含有磷酸二氢钾)和乙腈作为流动相进行梯度洗脱。
本发明中所述立体异构体采用高效液相色谱法进行检测。其中，高效液相色谱仪器可为Agilent高效液相色谱，色谱柱可选用OJ-RH(4.6×250mm,5μm)、大赛璐CHIRALPAK IC(4.6×250mm,5μm)、菲罗门CHIRAL NY(4.6×250mm,5μm)；采用三氟乙酸-乙腈溶液和正己烷作为流动相进行梯度洗脱。
具体实施方法
本发明实施例公开了制备如式(A)所示吡咯酰胺化合物及其中间体的方法。本领域技术人员可以借鉴本发明内容，适当改进工艺参数来实现。特别需要指出的是，所有类似的替换和改动对本领域技术人员来说是显而易见的，它们都被视为包括在本发明中。本发明的方法已经通过较佳实施例进行了描述，相关人员明显能在不脱离本发明内容、精神和范围内对本文所述的方法进行改动或适当变更与组合，来实现和应用本发明技术。
为了使本领域的技术人员更好地理解本发明，下面结合实施例对本发明进行详细说明。
实施例
实施例1 2-氯-1-(2-羟乙基)-4-甲基-5-(2-(三氟甲基)苯基)-1H-吡咯-3-甲酸(中间体1)的制备
将参照本领域公知的方法制备得到的2-氯-1-(2-羟乙基)-4-甲基-5-(2-(三氟甲基)苯基)-1H-吡咯-3-甲酸乙酯(29.1g,77.44mmol)加到甲醇(90mL)和水(30mL)的混合溶剂中，然后加入氢氧化钾(15.34g,232.32mmol，纯度85％)，加热至回流反应3小时。减压蒸除溶剂，往残余物中加入水(90mL)，用甲基叔丁基醚(90mL)洗涤，水相用2mol/L盐酸溶液调pH＝4，再用乙酸乙酯(150mL×2)萃取，合并有机相，依次用水(100mL)和饱和食盐水(100mL)洗涤，无水硫酸钠干燥，抽滤，滤液减压浓缩，得到淡 黄色固体26.3g，收率97.67％。
实施例2 (S)-2-氯-1-(2-羟乙基)-4-甲基-5-(2-(三氟甲基)苯基)-1H-吡咯-3-甲酸(中间体2)的制备
方法一：
称量奎宁(7.28g,22.43mmol)于反应瓶中，向其中加入N,N-二甲基乙酰胺(6.5mL)、乙酸乙酯(65mL)和水(3.9mL)，加热至60℃。将2-氯-1-(2-羟乙基)-4-甲基-5-(2-(三氟甲基)苯基)-1H-吡咯-3-甲酸(中间体1)(13.00g,37.39mmol)加到N,N-二甲基乙酰胺(6.5mL)和乙酸乙酯(48mL)中，加热溶清后滴加至前述奎宁溶液中。关闭加热，冷却至室温，抽滤，用乙酸乙酯(13mL×2)淋洗，滤饼真空干燥。将滤饼加到乙酸乙酯(80mL)和水(60mL)的混合溶剂中，搅拌下加入2mol/L盐酸溶液(18.7mL)，10分钟后分离水相，有机相依次用水(50mL)和饱和食盐水(40mL)洗涤，无水硫酸钠干燥，抽滤，滤液减压浓缩，得到淡黄色固体6.35g，ee值96.04％，纯度99.65％，收率48.84％。
方法二：
向奎宁(83.97g,172.55mmol)中加入N,N-二甲基乙酰胺(75mL)、乙酸乙酯(1050mL)和水(45mL)，完毕后将体系加热至65℃。将2-氯-1-(2-羟乙基)-4-甲基-5-(2-(三氟甲基)苯基)-1H-吡咯-3-甲酸(中间体1)(150.0g,287.59mmol)加入到N,N-二甲基乙酰胺(75mL)和乙酸乙酯(255mL)中，溶清后滴加到奎宁反应液中，滴加完毕，65℃保温搅拌1小时后降至室温。抽滤，滤饼用乙酸乙酯(50mL×2)淋洗，收集滤饼，45℃真空干燥11小时，得白色固体(131.96g)。向所得白色固体中加入4M盐酸溶液至pH≤3，室温搅拌5小时。抽滤，滤饼用水(500mL)洗涤，收集滤饼，60℃下真空干燥17小时，得目标产物为白色固体(64.83g,43.22％)。
中间体2的鉴定：
MS(ESI,pos.ion)m/z:314.2(M+1)；
1H 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).
实施例3 (S)-1-(2-(苄氧基)乙基)-2-氯-4-甲基-5-(2-(三氟甲基)苯基)-1H-吡咯-3-甲酸苄基酯(中间体3)的制备
方法一：
氮气保护下，将中间体2(100g,287.59mmol)和苄基溴(147.56g,862.77mmol)溶于N,N-二甲基乙酰胺(2L)中，加入叔戊醇钠(95.02g,862.77mmol)后加热至40℃反应过夜。反应液倒入水(4000mL)中，然后用MTBE(800mL×3)萃取，合并有机相，用饱和食盐水(600mL×2)洗涤，减压浓缩除去溶剂，得淡黄色透明油状物(151g,99.45％)。
方法二：
向反应瓶中加入中间体2(8.25g,23.73mmol)、苄基溴(12.18g,71.19mmol)、N,N-二甲基乙酰胺(83mL)和叔戊醇钠(7.84g,71.19mmol)，完毕后氮气置换3次，然后在氮气保护下加热至50±5℃反应4小时。反应液中加入水(250mL)稀释，用甲基叔丁基醚(75mL×2)萃取，有机相用20％食盐水洗涤(200mL×2)，减压浓缩得目标产物为淡黄色透明油状物(12.52g,99.95％)。
实施例4 (S)-1-(2-(苄氧基)乙基)-2-氯-4-甲基-5-(2-(三氟甲基)苯基)-1H-吡咯-3-甲酸(中间体4)的制备
向中间体3(70g,132.59mmol)中加入乙醇(240mL)、氢氧化钾(35.01g,530.36mmol,纯度85％)和水(60mL)，完毕后加热至70℃反应6小时。降温至45℃，加入水(240mL)稀释反应液，减压旋蒸除去乙醇。烧杯中加入甲基叔丁基醚(400mL)和庚烷(200mL)，将两种溶剂混匀备用。向减蒸残留物中加入约一半上述混匀溶剂，搅拌5分钟后静置分去上层有机相，保留水相。水相中再加入另一半上述混匀溶剂，搅拌5分钟后静置分去上层有机相，保留水相。向保留的水相中加入稀盐酸(2M，购自成都科隆)调节pH≤3，乙酸乙酯萃取(500mL)，有机相分别用水(200mL)、饱和食盐水(200mL)洗涤，有机相减压浓缩，得目标产物为棕黄色油状物(58.03g,99.96％)。MS(ESI,pos.ion)m/z:438.1(M+1)。
实施例5 (S)-1-(2-(苄氧基)乙基)-4-甲基-5-(2-(三氟甲基)苯基)-1H-吡咯-3-甲酸(中间体5)的制备
示例1：
将中间体4(12.0g,27.41mmol)、二水甲酸钠(4.28g,41.12mmol)、钯碳(1.20g,1.12mmol,纯度10％)溶于乙醇(120mL)、甲苯(60mL)和水(12mL)的混合溶剂中，升温至65℃反应3.5小时。反应液经硅藻土抽滤，滤饼用乙醇洗涤。滤液减压浓缩除去溶剂，残余物经乙醇(40mL)溶解，用2.5mol/L盐酸调至pH＝2，将溶液滴加至冰水(400mL)中，自然升温至室温并搅拌过夜。抽滤，收集滤饼，60℃真空干燥，得目标产物为类白色固体(9.6g,86.83％)。HPLC：96.81％，MS(ESI,pos.ion)m/z:404.2(M+1)。
1H NMR(400MHz,DMSO-d6)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).
示例2-5：
参照示例1的方法，对制备中间体5的方法条件进行试验，其中，反应温度为60℃，甲酸钠用量为1.5当量(即，甲酸钠的摩尔量是中间体4的摩尔量的1.5倍)，钯碳的用量为10％(以原料中间体4的质量百分比计算)；实验结果如下表所示。
表A
说明：上表中，混合溶剂的比例是指体积比；中控产物含量是指反应结束后、后处理前的反应体系中的产物含量，该含量是从反应体系中取样并经HPLC检测所得的产物的峰面积比值。
以中间体5为原料，按照现有技术公开的类似方法可制备得到式(A)化合物。
在本说明书的描述中，参考术语“一个实施例”、“一些实施例”、“示例”、“具体示例”、或“一些示例” 等的描述意指结合该实施例或示例描述的具体特征、结构、材料或者特点包含于本发明的至少一个实施例或示例中。在本说明书中，对上述术语的示意性表述不必须针对的是相同的实施例或示例。
尽管上面已经示出和描述了本发明的实施例，可以理解的是，上述实施例是示例性的，不能理解为对本发明的限制，本领域的普通技术人员在本发明的范围内可以对上述实施例进行变化、修改、替换和变型。

Claims (14)

  1. 式(I)所示化合物，
    其中，R1为OH、NH2、C2-4烷氧基或苄氧基，所述C2-4烷氧基和苄氧基分别任选地被1、2、3或4个独立地选自卤素、C1-4烷基、C1-4卤代烷基、C1-4烷氧基和C1-4卤代烷氧基的取代基取代。
  2. 一种化合物，其具有如下其中之一的结构，
  3. 制备式(II)所示化合物的方法，
    其中，所述方法包括：
    步骤c)式(I-B)所示化合物在合适条件下在溶剂中脱氯得到式(II)所示化合物，
  4. 根据权利要求3所述的方法，其中，所述溶剂为甲醇、乙醇、异丙醇、叔丁醇、或它们与其他溶剂任意组成的混合溶剂，其中所述其他溶剂为四氢呋喃、DMF、乙酸乙酯、甲基叔丁基醚、乙二醇二甲醚、乙二醇单甲醚、甲苯、水或它们的任意组合；
    任选地，所述溶剂为甲醇、乙醇、乙醇/甲苯、乙醇/水、乙醇/甲苯/水、乙醇/四氢呋喃、或乙醇/四氢呋喃/水。
  5. 根据权利要求3或4所述的方法，其中，所述步骤c)的反应是在过渡金属催化剂的存在下进行；任选地，所述过渡金属催化剂为钯碳催化剂、醋酸钯催化剂或镍催化剂。
  6. 根据权利要求3-5任意一项所述的方法，其中，所述步骤c)的反应是在甲酸铵、甲酸钠、磷酸氢 二钠、酸、三乙胺或氢气的存在下进行。
  7. 根据权利要求3-6任意一项所述的方法，其中，所述步骤c)的反应是在加热条件下进行的；任选地，所述步骤c)的加热条件是加热至45℃-75℃、55℃-70℃或60℃-65℃。
  8. 根据权利要求3-7任意一项所述的方法，其还包括式(I-B)所示化合物的制备方法，其中，所述式(I-B)所示化合物的制备方法包括：
    步骤a)式(I-1)所示化合物与苄基保护基试剂反应得到式(I-A)所示化合物，
    步骤b)式(I-A)所示化合物在合适条件下脱去苄基保护基得到式(I-B)所示化合物；
  9. 根据权利要求8所述的方法，其中，所述步骤a)中的苄基保护基试剂为卤代苄基，优选地为苄基溴；
    任选地，所述步骤a)是在叔戊醇钠的存在下进行的；
    任选地，所述步骤a)的反应溶剂是N,N-二甲基乙酰胺；
    任选地，所述步骤a)的反应温度是25℃至60℃、或35℃-55℃、或45℃-55℃。
  10. 根据权利要求8或9所述的方法，其中，所述步骤b)的反应是在碱的作用下进行的，所述碱为碳酸钠、碳酸钾、碳酸铯、磷酸钾、氢氧化锂、氢氧化钾或氢氧化钠；
    任选地，所述步骤b)的反应是在溶剂中进行，所述溶剂为丙酮、乙腈、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、DMSO、甲醇、乙醇、THF、甲基叔丁基醚、水或它们的任意组合；
    任选地，所述步骤b)的反应是在加热条件下进行的，所述加热条件是指加热至60℃至80℃或65℃至75℃。
  11. 根据权利要求8-10任意一项所述的方法，其还包含式(I-1)所示化合物的制备方法，其中，所述式(I-1)所示化合物的制备方法包括：
    1a)式(I-0)所示化合物与光活性胺反应得到相应的式(I-1)化合物的光活性胺的盐，和
    1b)步骤1a)所得的盐反应得到式(I-1)所示化合物；
  12. 根据权利要求11所述的方法，其中，所述光活性胺为具有奎宁骨架的光学活性胺；任选地，所述具有奎宁骨架的光学活性胺为奎宁、氢化奎宁、奎尼丁、辛可宁或辛可尼丁。
  13. 根据权利要求11或12所述的方法，其中，所述步骤1b)的反应为水解反应；
    任选地，所述步骤1b)的反应是在酸性条件下进行的；任选地，所述酸性条件是盐酸、硫酸、氢溴酸或柠檬酸存在的条件；
    任选地，所述步骤1b)的反应溶剂为N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、乙腈、四氢呋喃、乙醇、丙酮、乙酸异丙酯、乙酸乙酯、甲基叔丁基醚、水、二甲氧基乙烷或它们的任意组合。
  14. 根据权利要求11-13任意一项所述的方法，其中，所述步骤1a)的反应溶剂为N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、乙腈、四氢呋喃、乙醇、丙酮、乙酸异丙酯、乙酸乙酯、甲基叔丁基醚、水、二甲氧基乙烷或它们的任意组合；
    任选地，所述步骤1a)的反应温度是室温至100℃；优选地，所述步骤1a)的反应温度是50℃-80℃或55℃-65℃。
PCT/CN2024/105063 2023-07-12 2024-07-12 制备吡咯甲酸化合物的方法 Pending WO2025011627A1 (zh)

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