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WO2025162491A1 - Procédé de préparation de finerénone et procédé de préparation d'un intermédiaire de finerénone - Google Patents

Procédé de préparation de finerénone et procédé de préparation d'un intermédiaire de finerénone

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Publication number
WO2025162491A1
WO2025162491A1 PCT/CN2025/075836 CN2025075836W WO2025162491A1 WO 2025162491 A1 WO2025162491 A1 WO 2025162491A1 CN 2025075836 W CN2025075836 W CN 2025075836W WO 2025162491 A1 WO2025162491 A1 WO 2025162491A1
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WO
WIPO (PCT)
Prior art keywords
compound
formula
finerenone
salt
group
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/CN2025/075836
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English (en)
Chinese (zh)
Inventor
赵楠
靳家玉
胡文军
李成刚
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Jiangsu Puxin Pharmaceutical Co Ltd
Jiangxi Desano Pharmaceutical Co Ltd
SHANGHAI DESANO PHARMACEUTICALS CO Ltd
Shanghai Desano Chemical Pharmaceutical Co Ltd
Original Assignee
Jiangsu Puxin Pharmaceutical Co Ltd
Jiangxi Desano Pharmaceutical Co Ltd
SHANGHAI DESANO PHARMACEUTICALS CO Ltd
Shanghai Desano Chemical Pharmaceutical Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Jiangsu Puxin Pharmaceutical Co Ltd, Jiangxi Desano Pharmaceutical Co Ltd, SHANGHAI DESANO PHARMACEUTICALS CO Ltd, Shanghai Desano Chemical Pharmaceutical Co Ltd filed Critical Jiangsu Puxin Pharmaceutical Co Ltd
Publication of WO2025162491A1 publication Critical patent/WO2025162491A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/76—Esters of carboxylic acids having a carboxyl group bound to a carbon atom of a six-membered aromatic ring
    • C07C69/78—Benzoic acid esters
    • 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 technical field of pharmaceutical chemistry, and specifically relates to a method for preparing finerenone and its intermediates.
  • Finerenone (trade name Kerendia) is a third-generation non-steroidal mineralocorticoid receptor antagonist developed by Bayer and approved by the FDA in 2021. It is used for patients with chronic kidney disease combined with type 2 diabetes and heart failure to reduce the risk of decreased renal function, renal failure, cardiovascular death, non-fatal heart attack and hospitalization for heart failure. It is a once-a-day oral medication. Finerenone inhibits the binding of aldosterone to the mineralocorticoid receptor, thereby blocking the excessive activation of MR and its mediated sodium reabsorption. The drug has high efficacy and selectivity, and significantly improves the renal and cardiovascular function of patients with chronic kidney disease accompanied by type 2 diabetes.
  • a synthetic route of finerenone is as follows:
  • Patent US2021163474 uses tartrate to split the phenaretone racemate, but the last step of the splitting process will cause a large amount of material waste.
  • Patent CN114605410 adds a catalyst S2O82-/ZrO2/ ⁇ -Al2O3 to the finerenone racemate for transformation, and then uses tartaric acid for splitting. This method has a complex catalyst preparation process and high cost.
  • Patent WO2021074078 uses a resolving agent to resolve the intermediate, but the resulting diastereomeric salts have an ee value of less than 80%, requiring further purification. This process is inefficient, multi-step, and time-consuming, requiring two overnight stirring cycles.
  • carboxyl protecting groups in the above routes are all nitrile ethyl groups, which will produce an equivalent amount of byproduct acrylonitrile during the deprotection process.
  • Acrylonitrile is highly toxic, volatile, and highly flammable, posing a major safety hazard and making it unsuitable for industrial production.
  • Patent CN115340539 addresses the low resolution efficiency and low ee values of intermediates and products in existing processes.
  • the intermediate is resolved to obtain a single-configuration intermediate, which is then deprotected and aminated to obtain finerenone.
  • the intermediate diastereomeric salt exhibits a ee value exceeding 98.5%, while the free intermediate exhibits an ee value exceeding 99.5%.
  • the final product, finerenone achieves an ee value exceeding 99.8%.
  • both intermediate configurations form salts with the resolving agent, making the crystallization process unstable.
  • the undesirable R-configuration compound may also precipitate, compromising the resolution.
  • the debenzylation step requires high-pressure hydrogenation under expensive palladium-on-carbon catalysis, requiring specialized, high-pressure-resistant equipment and posing safety risks.
  • impurities are produced, such as excessive reduction impurities and decarboxylation impurities produced at high temperatures, which have a great impact on subsequent purification and product purity.
  • the purpose of the present invention is to provide a method for preparing finerenone which has good resolution effect, stable process, simple operation, low cost and is suitable for industrial production.
  • the resolving agent in step (1) is a compound of formula IIIa, and step (1) comprises:
  • the resolving agent in step (1) is a compound of formula IIIb, and step (1) comprises:
  • Ar is an unsubstituted or substituted C6-C14 aryl group or an unsubstituted or substituted C5-C14 heteroaryl group containing 1-3 groups selected from O, N and S, wherein the substitution refers to substitution with one or more groups selected from the following groups:
  • Ar is unsubstituted or substituted phenyl.
  • Ar has a structure as shown in Formula V:
  • R 1 , R 2 , R 3 , R 4 and R 5 are each independently selected from the group consisting of hydrogen, halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, phenoxy, nitro, cyano and amide.
  • R 1 , R 2 , R 3 , R 4 and R 5 are hydrogen, and one substituent is not hydrogen, preferably R 3 is not hydrogen.
  • the amide group refers to a group having a structure selected from the following group: -NHCOR, -NR'COR, -CONHR, -CONRR', wherein each R and R' are independently methyl, ethyl or phenyl, or N, R, R' and the carbon atom to which they are connected together constitute a 5-7 membered heterocyclic ring containing 1-2 nitrogen atoms.
  • Ar is an unsubstituted or substituted C10-C14 polycyclic aromatic group, such as naphthyl or anthracenyl.
  • Ar is an unsubstituted or substituted C5-C10 heteroaryl group, such as piperidinyl, piperazinyl, or quinolinyl.
  • Ar is selected from the following group:
  • Ar is a monosubstituted phenyl group.
  • Ar is a para-substituted phenyl group.
  • Ar is benzyl, phenyl, nitrophenyl, chlorophenyl, bromophenyl, benzyloxy, or cyanophenyl.
  • Ar is benzyl, phenyl, or benzyloxy.
  • Ar is phenyl or benzyl.
  • Ar is benzyl
  • step 1 the molar ratio of the compound of formula II to the compound of formula IIIa is 1:0.4-1.2, preferably 1:0.5-0.6, and more preferably 1:0.51-0.55.
  • step 1 the molar ratio of the compound of formula II to the compound of formula IIIb is 1:0.4-1.2, preferably 1:0.5-0.6, more preferably 1:0.51-0.55.
  • the resolving agent is a compound of formula IIIa.
  • the salt-forming reaction is carried out in an organic solvent or a mixed solvent of an organic solvent and water, wherein the organic solvent is selected from ethanol, methanol, isopropanol, 1-propanol, 1-pentanol, acetone, 2-butanone, methyl isobutyl ketone, acetic acid, ethyl acetate, isoamyl acetate, dichloromethane, tetrahydrofuran, 2-methyltetrahydrofuran, ethylene glycol dimethyl ether, dioxane, or a combination thereof.
  • the organic solvent is selected from ethanol, methanol, isopropanol, 1-propanol, 1-pentanol, acetone, 2-butanone, methyl isobutyl ketone, acetic acid, ethyl acetate, isoamyl acetate, dichloromethane, tetrahydrofuran, 2-methyltetrahydrofuran, ethylene glyco
  • the salt-forming reaction independently has one or more of the following characteristics:
  • the concentration of the compound of formula II in the solvent is 0.1-0.3 mmol/mL, preferably 0.10-0.15 mmol/mL;
  • the salt-forming reaction is carried out at 40-100° C., preferably 60-80° C.;
  • reaction time of the salt-forming reaction is 1-4 h, preferably 2 h.
  • the separation in step 1a-1 is filtration separation or centrifugal separation, preferably filtration separation.
  • the separation comprises: cooling the reaction system to 20-90°C (preferably 30-60°C or 40-50°C) for precipitation, and separating by filtration.
  • the base is an inorganic base or an organic base.
  • the inorganic base is selected from ammonia water, potassium hydroxide, sodium hydroxide, lithium hydroxide, potassium phosphate, sodium phosphate, ammonium phosphate, ammonium carbonate, lithium carbonate, potassium carbonate, sodium carbonate, ammonium bicarbonate, sodium bicarbonate or potassium bicarbonate, preferably potassium hydroxide, sodium hydroxide, potassium phosphate or sodium phosphate;
  • the organic base is selected from triethylamine, imidazole, N-methylimidazole, pyridine or DBU.
  • the base in step 1a-2, can be used in an anhydrous form or in the form of a hydrate thereof.
  • the alkali treatment step of step 1a-2 is carried out in water, an organic solvent, or a mixed solvent of an organic solvent and water, wherein the organic solvent is selected from ethanol, methanol, isopropanol, 1-propanol, 1-pentanol, acetone, 2-butanone, methyl isobutyl ketone, acetic acid, ethyl acetate, isoamyl acetate, dichloromethane, tetrahydrofuran, 2-methyltetrahydrofuran, ethylene glycol dimethyl ether, dioxane, or a combination thereof.
  • the organic solvent is selected from ethanol, methanol, isopropanol, 1-propanol, 1-pentanol, acetone, 2-butanone, methyl isobutyl ketone, acetic acid, ethyl acetate, isoamyl acetate, dichloromethane, tetrahydrofuran, 2-methylte
  • step 1a-2 the alkali treatment is carried out in an aqueous alkali solution.
  • step 1a-2 the pH of the alkali treatment step is 7-12, preferably 7.5-10, preferably 7.5-8.5.
  • the alkali treatment further has one or more of the following characteristics:
  • reaction time of the alkali treatment is 0.5-4 h, preferably 2 h.
  • step 1b-1 includes the steps of: cooling the reaction solution of the salt-forming reaction to crystallize (e.g., 30-90°C, or 50-65°C), filtering, concentrating the filtrate to remove the reaction solvent, then separating the liquid between water and an organic solvent, removing the organic solvent after obtaining the organic phase, and then crystallizing in a crystallization solvent to obtain a compound of formula I.
  • the organic solvent is selected from acetone, 2-butanone, methyl isobutyl ketone, acetic acid, ethyl acetate, isoamyl acetate, n-heptane, dichloromethane, tetrahydrofuran, 2-methyltetrahydrofuran, ethylene glycol dimethyl ether, dioxane, or a combination thereof.
  • the crystallization solvent is selected from: acetone, 2-butanone, methyl isobutyl ketone, ethyl acetate, n-heptane, dichloromethane, tetrahydrofuran, 2-methyltetrahydrofuran, ethylene glycol dimethyl ether or dioxane or a combination thereof.
  • the crystallization comprises refluxing and stirring in a crystallization solvent and then cooling (eg, 10-25° C.) for crystallization.
  • the method further comprises the following steps:
  • step s3 when the p-methoxybenzyl group is removed using an acid, an acid addition salt corresponding to the compound of formula I-1 is obtained and is directly used in the next reaction.
  • step s3 trifluoroacetic acid is used to remove the p-methoxybenzyl group.
  • the molar ratio of the compound of formula I to the reagent for removing the p-methoxybenzyl group is 1:0.5-5.0, preferably 1:2.0-4.0, and more preferably 1:3.0.
  • step s3 the reaction is carried out in an organic solvent, wherein the organic solvent is selected from ethanol, methanol, isopropanol, 1-propanol, 1-pentanol, acetone, 2-butanone, methyl isobutyl ketone, acetic acid, ethyl acetate, isoamyl acetate, dichloromethane, tetrahydrofuran, 2-methyltetrahydrofuran, ethylene glycol dimethyl ether or dioxane, or a combination thereof.
  • the organic solvent is selected from ethanol, methanol, isopropanol, 1-propanol, 1-pentanol, acetone, 2-butanone, methyl isobutyl ketone, acetic acid, ethyl acetate, isoamyl acetate, dichloromethane, tetrahydrofuran, 2-methyltetrahydrofuran, ethylene glycol dimethyl ether or dioxan
  • step s3 the reaction further has one or more of the following characteristics:
  • the concentration of the compound of formula I in the organic solvent is 0.1-0.5 mmol/mL, preferably 0.30-0.40 mmol/mL;
  • reaction is carried out at 5-40°C, preferably 10-20°C;
  • reaction time of the reaction is 1-4h, preferably 2h;
  • the reaction further comprises: adding an organic solvent for crystallization after the reaction is completed, wherein the organic solvent is selected from: n-heptane, dichloromethane, methyl tert-ether, toluene, or a combination thereof.
  • step s4 the amination is carried out under conventional acid-amine condensation reaction conditions.
  • step s4 the amination is carried out in the presence of a condensing agent, a catalyst, and a nitrogen source, wherein the condensing agent is selected from condensing agents commonly used in acid-amine condensation reactions, such as: 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI), N,N'-carbonyldiimidazole (CDI), N,N-dicyclohexylcarbodiimide (DCC), CBMIT, N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (HATU), 1-propylphosphoric anhydride (T3P), N,N'-diisopropylcarbodiimide (DIC), or a chloroformate represented by formula VI,
  • EDCI 1-ethyl-(3-dimethylaminopropyl)carbod
  • R6 is a C1-C10 alkyl group.
  • the ammonia source is selected from the group consisting of ammonia gas, ammonia water, ammonium chloride, ammonium bicarbonate, ammonium carbonate, hexamethyldisilazane, ammonium acetate, ammonium formate, formamide, and ammonium carbamate.
  • the catalyst is selected from the group consisting of: 4-(dimethylamino)pyridine, pyridine, N,N-diisopropylethylamine, triethylamine, or 1,8-diazobisspiro[5.4.0]undec-7-ene (DBU).
  • step (s1) the method further comprises the following steps:
  • the wavy line represents a racemic structure.
  • a diastereomeric salt or a pharmaceutically acceptable salt thereof is provided, as shown in the following formula:
  • the diastereomeric salt is IVa.
  • the ee (enantiomeric excess) value of the diastereomeric salt is ⁇ 98%, ⁇ 99%, ⁇ 99.5% or ⁇ 99.8%.
  • a finerenone intermediate is provided, wherein the intermediate is a compound of formula II or an isomer thereof or a pharmaceutically acceptable salt thereof.
  • the intermediate is a racemic compound of formula II.
  • the intermediate is the (S)-isomer of the compound of formula II, i.e., the compound of formula I
  • the ee value of the intermediate is ⁇ 98%, ⁇ 99%, ⁇ 99.5% or ⁇ 99.8%.
  • FIG1 is a peak table of the HPLC spectrum of the compound I-1 sample prepared in Example 5.
  • FIG2 is a peak table of the HPLC spectrum of the compound I-1 sample prepared in Comparative Example 1.
  • the inventors unexpectedly discovered a method for preparing finerenone suitable for industrial production. Specifically, the inventors discovered a new finerenone intermediate.
  • the p-methoxybenzyl group of the present invention is also easier to remove, eliminating the need for palladium-on-carbon hydrogenation reduction, and removing the protecting group using trifluoroacetic acid at room temperature and pressure.
  • the inventors discovered that, in the resolution step, reducing the amount of the resolving agent to approximately 0.5 equivalents allows the resolving agent to selectively form a salt with a single configuration of the compound of Formula II, thereby facilitating separation from the enantiomorphic compound (non-salt form), resulting in better resolution and significantly reducing resolution reagent and production costs.
  • This method is simple to operate, operates under mild conditions, and requires no special reagents, equipment, or expensive reagents. Finerenone prepared using this method has a purity exceeding 99.9% and an ee value of 100%, making it very suitable for industrial production. Based on this, the inventors completed the present invention.
  • the terms “comprising” or “including” may be open, semi-closed, or closed. In other words, the terms also include “consisting essentially of” or “consisting of.”
  • Cu-v indicates that the following group has u to v carbon atoms, such as “C1-6” can be C1, C2, C3, C4, C5 or C6.
  • C1-6 alkyl means that the alkyl group has 1 to 6 carbon atoms.
  • halogen refers to fluorine, chlorine, bromine, or iodine.
  • alkyl refers to a straight or branched unsubstituted hydrocarbon group having 1 to 10 carbon atoms (i.e., C1-10 alkyl), preferably 1 to 6 carbon atoms (i.e., C1-6 alkyl), and more preferably 1 to 3 carbon atoms (i.e., C1-3 alkyl).
  • alkyl examples include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, and 3-methylpentyl, and the like.
  • aromatic ring and aryl refer to aromatic carbocyclic groups having a single ring (e.g., monocyclic) or multiple rings (e.g., bicyclic or tricyclic), including fused systems.
  • aryl has 6 to 14 ring carbon atoms (i.e., C6-14 aryl), 6 to 12 carbon ring atoms (i.e., C6-12 aryl) or 6 to 10 carbon ring atoms (i.e., C6-10 aryl).
  • Aryl includes bicyclic groups that include fused to a saturated or partially unsaturated aromatic ring, or an aromatic carbocyclic or heterocyclic ring in the group.
  • aryl groups include, but are not limited to, the following groups: benzene, naphthalene, anthracene, biphenyl, 1,2-dihydronaphthalene, 1,2,3,4-tetrahydronaphthyl, etc.
  • Aryl types include structures of aryl rings fused to cycloalkyl, heterocycloalkyl, and heteroaryl rings.
  • heteroaryl or “heteroaromatic ring” refers to a heteroaromatic system containing one or more heteroatoms selected from oxygen, nitrogen, sulfur, silicon, boron and phosphorus, including monocyclic, bicyclic or polycyclic fused systems.
  • the heteroaryl group can be optionally substituted with one or more substituents described herein.
  • the heteroaryl group can have 5 to 14 ring atoms (i.e., 5-14 membered heteroaryl), 5 to 12 ring atoms (i.e., 5-12 membered heteroaryl), 5 to 10 ring atoms (i.e., 5-10 membered heteroaryl), 5 to 8 ring atoms (i.e., 3-8 membered heteroaryl), 5 to 12 ring atoms (i.e., 5-12 membered heteroaryl), 5 to 10 ring atoms (i.e., 5-10 membered heteroaryl), 5 to 8 ring atoms (i.e., 3-8 membered heteroaryl), 5 to 14 ring atoms (i.e., 5-14 membered heteroaryl), 5 to 12 ring atoms (i.e., 5-12 membered heteroaryl), 5 to 10 ring atoms (i.e., 5-10 membered heteroaryl), 5 to 8 ring atoms (i.e., 3-8 member
  • a heteroaryl group can have 1 to 5 heteroatoms, 1 to 4 heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms, or 1 ring heteroatom, wherein the ring heteroatoms are independently selected from oxygen, nitrogen, sulfur, silicon, boron, and phosphorus.
  • heteroaryl examples include, but are not limited to, pyrrolyl, pyridyl, pyrazolyl, imidazolyl, pyrazinyl, imidazopyridyl, benzofuranyl, pyrimidinyl, triazolyl, tetrazolyl, furanyl, thienyl, thiazolyl, quinolyl, isoquinolyl, indolyl, and the like.
  • substituted refers to the replacement of one or more hydrogen atoms in a specific group by any substituent mentioned in the present specification. Unless otherwise specified, “substituted” means that one or more (e.g., 2, 3, or 4) hydrogen atoms in the group are optionally independently replaced by a group selected from the group consisting of C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, halogen, nitro, cyano, carboxyl, hydroxyl, and amide.
  • the present invention provides a racemic compound of formula II and a preparation method thereof.
  • Using the racemic compound as a key intermediate for preparing finerenone has the advantages of mild reaction conditions, improved yield and product purity, and is very suitable for the industrial production of finerenone.
  • a preferred method for preparing a compound of formula II comprises the steps of:
  • the present invention also provides a method for preparing a compound of formula I from a compound of formula II, comprising the steps of:
  • the resolving agent in step (1) is a compound of formula IIIa, and step (1) comprises:
  • the resolving agent in step (1) is a compound of formula IIIb, and step (1) comprises:
  • Ar is an unsubstituted or substituted C6-C14 aryl group or an unsubstituted or substituted C5-C14 heteroaryl group containing 1-3 groups selected from O, N and S, wherein the substitution refers to substitution by one or more groups selected from the following groups: C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, halogen, nitro, cyano, carboxyl, hydroxyl, amide.
  • Ar is selected from the following group:
  • the molar ratio of the compound of formula II to the compound of formula IIIa is 1:0.4-1.2, preferably 1:0.5-0.6, and more preferably 1:0.51-0.55.
  • the molar ratio of the compound of formula II (the compound of formula I) to the compound of formula IIIa is 1:1-1.2, more preferably 1:1-1.1.
  • the molar ratio of the compound of formula II to the compound of formula IIIb is 1:0.4-1.2, preferably 1:0.5-0.6, more preferably 1:0.51-0.55.
  • the molar ratio of the compound of formula II with R configuration to the compound of formula IIIb is 1:1-1.2, more preferably 1:1-1.1.
  • the resolving agent in step 1, is a compound of formula IIIa.
  • the compound of formula IIIa when the resolving agent is a compound of formula IIIa, the compound of formula IIIa can selectively preferentially form a salt with the desired S-configuration compound of formula II, and is not easy to form a salt with the R-configuration compound of formula II.
  • the S-configuration compound of formula II can be converted into a salt and separated by crystallization and filtration; at this time, the R-configuration compound of formula II has not yet formed a salt and is not easy to crystallize, and is retained in the filtrate, thereby easily separating from the crystals obtained by crystallization, and avoiding the co-crystallization of the resolved salts of the two configurations of the compound of formula II.
  • the method of the present invention can be used for further separation.
  • the present invention also provides a diastereomeric salt or a pharmaceutically acceptable salt thereof, as shown in the following formula:
  • the diastereomeric salt is IVa.
  • the ee (enantiomeric excess) value of the diastereomeric salt is ⁇ 98%, ⁇ 99%, ⁇ 99.5% or ⁇ 99.8%.
  • the present invention also provides the (S)-isomer of the compound of formula II, i.e., the compound of formula I
  • the ee value of the intermediate is ⁇ 98%, ⁇ 99%, ⁇ 99.5% or ⁇ 99.8%.
  • the present invention also provides a novel method for preparing finerenone, which comprises the following steps:
  • the compound of formula II of the present invention uses a specific p-methoxybenzyl protecting group.
  • the protecting group can be removed at room temperature under acidic conditions.
  • the present invention not only does not require expensive reagents and special equipment, but also has low energy consumption.
  • the reaction conditions are mild, impurities are less generated, the process is stable, and the product purity is high (purity ⁇ 98%, or even ⁇ 99%), making it very suitable for large-scale industrial production.
  • the present invention adopts a specific p-methoxybenzyl group as a protecting group, so that the deprotection step avoids palladium carbon hydrogenation reduction which is not suitable for industrial production, does not require expensive reagents and special equipment, and has low energy consumption;
  • the deprotection step can be carried out under mild reaction conditions at room temperature and normal pressure, resulting in less impurities, higher product purity and controllable quality;
  • the ee value of the intermediate compound I can reach above 99.8%, and the ee value of the final product finerenone can reach above 99.9%.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

La présente invention concerne un nouvel intermédiaire de finerénone (un composé tel que représenté par la formule I). L'utilisation de l'intermédiaire pour préparer la finerénone permet d'éviter d'avoir recours à une réduction d'hydrogénation palladium-carbone qui n'est pas appropriée pour une production industrielle, ne nécessite pas de réactifs coûteux et de dispositifs spéciaux, et présente une faible consommation d'énergie; les conditions réactionnelles sont douces, moins d'impuretés sont générées, le procédé est stable, la pureté du produit est élevée, et la présente invention est appropriée pour une production industrielle à grande échelle.
PCT/CN2025/075836 2024-01-30 2025-02-05 Procédé de préparation de finerénone et procédé de préparation d'un intermédiaire de finerénone Pending WO2025162491A1 (fr)

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WO2025081981A1 (fr) * 2023-10-20 2025-04-24 山东诚创蓝海医药科技有限公司 Intermédiaire de finérénone, son procédé de préparation et procédé de préparation de finérénone
CN118047774A (zh) * 2024-01-30 2024-05-17 上海迪赛诺化学制药有限公司 一种制备非奈利酮及其中间体的方法

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN115340539A (zh) * 2022-01-19 2022-11-15 奥锐特药业股份有限公司 制备非奈利酮及其中间体的方法
CN115340540A (zh) * 2022-01-20 2022-11-15 奥锐特药业股份有限公司 制备非奈利酮及其中间体的方法
CN116804011A (zh) * 2023-07-05 2023-09-26 江苏德源药业股份有限公司 通过外消旋体拆分制备非奈利酮中间体的方法
WO2024075139A1 (fr) * 2022-10-06 2024-04-11 Maithri Drugs Private Limited Procédé de préparation de finérénone et de ses intermédiaires
CN118047774A (zh) * 2024-01-30 2024-05-17 上海迪赛诺化学制药有限公司 一种制备非奈利酮及其中间体的方法
CN119143755A (zh) * 2024-09-12 2024-12-17 奥锐特药业股份有限公司 一种由非奈利酮或其中间体的对映体制备外消旋体的方法

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN115340539A (zh) * 2022-01-19 2022-11-15 奥锐特药业股份有限公司 制备非奈利酮及其中间体的方法
WO2023138336A1 (fr) * 2022-01-19 2023-07-27 奥锐特药业股份有限公司 Procédé de préparation de finérénone et d'un intermédiaire de celle-ci
CN115340540A (zh) * 2022-01-20 2022-11-15 奥锐特药业股份有限公司 制备非奈利酮及其中间体的方法
WO2024075139A1 (fr) * 2022-10-06 2024-04-11 Maithri Drugs Private Limited Procédé de préparation de finérénone et de ses intermédiaires
CN116804011A (zh) * 2023-07-05 2023-09-26 江苏德源药业股份有限公司 通过外消旋体拆分制备非奈利酮中间体的方法
CN118047774A (zh) * 2024-01-30 2024-05-17 上海迪赛诺化学制药有限公司 一种制备非奈利酮及其中间体的方法
CN119143755A (zh) * 2024-09-12 2024-12-17 奥锐特药业股份有限公司 一种由非奈利酮或其中间体的对映体制备外消旋体的方法

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