Method for preparing finerenone and method for preparing finerenone intermediate

Abstract

The present invention provides a novel finerenone intermediate (a compound as represented by formula I). The use of the intermediate to prepare finerenone can omit palladium-carbon hydrogenation reduction that is not suitable for industrial production, does not require expensive reagents and special devices, and has low energy consumption; the reaction conditions are mild, less impurities are generated, the process is stable, the product purity is high, and the present invention is suitable for large-scale industrial production.

Description

A method for preparing finerenone and its intermediates Technical Field

[0001] The present invention relates to the technical field of pharmaceutical chemistry, and specifically relates to a method for preparing finerenone and its intermediates. Background Art

[0002] 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. Its chemical name is: (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide, and the structural formula is as follows:

[0003] A synthetic route of finerenone is as follows:

[0004] In the methods disclosed in patents US20100136142 and US10059707, a chiral column is used to resolve the finerenone racemate, which is not suitable for industrial production.

[0005] 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.

[0006] Patent CN114605410 adds a catalyst S2O82- / ZrO2 / γ-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.

[0007] 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.

[0008] In addition, the 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.

[0009] Patent CN115340539 addresses the low resolution efficiency and low ee values ​​of intermediates and products in existing processes. By replacing the cyanoethyl protecting group in the above process with a benzyl group, the intermediate is resolved to obtain a single-configuration intermediate, which is then deprotected and aminated to obtain finerenone. Separating the enantiomeric mixture using a tartrate ester, 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%. First, during the resolution step, 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. Second, because the benzyl group is difficult to remove, the debenzylation step requires high-pressure hydrogenation under expensive palladium-on-carbon catalysis, requiring specialized, high-pressure-resistant equipment and posing safety risks. In addition, during the debenzylation process, due to the relatively harsh reaction conditions, a large number of 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.

[0010] In view of this, there is a need in the art to develop a process for preparing finerenone with good resolution effect, stable process, simple operation, low cost and suitability for industrial production. Summary of the Invention

[0011] 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.

[0012] In a first aspect of the present invention, there is provided a method for preparing a compound of formula I, comprising the steps of:

[0013] (1) Using a resolving agent represented by a compound of formula IIIa or a compound of formula IIIb to resolve the racemic compound of formula II, a compound of formula I is obtained.

[0014] In another preferred embodiment, the resolving agent in step (1) is a compound of formula IIIa, and step (1) comprises:

[0015] (1a-1) reacting a racemic compound of formula II with a compound of formula IIIa to form a salt, and separating to obtain a salt represented by the compound of formula IVa;

[0016] (1a-2) The salt of the compound represented by formula IVa obtained in step 1 is treated with a base to obtain the compound represented by formula I.

[0017] In another preferred embodiment, the resolving agent in step (1) is a compound of formula IIIb, and step (1) comprises:

[0018] (1b-1) The racemic compound of formula II is reacted with the compound of formula IIIb to form a salt, and after removing the salt represented by compound IVb, the compound of formula I is obtained.

[0019] Wherein, 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:

[0020] C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, halogen, nitro, cyano, carboxyl, hydroxyl, amide.

[0021] In another preferred embodiment, Ar is unsubstituted or substituted phenyl.

[0022] In another preferred embodiment, Ar has a structure as shown in Formula V:

[0023] Wherein, R1, R2, R3, R4, and R5 are each independently selected from the following group: hydrogen, halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, phenoxy, nitro, cyano, and amide.

[0024] In another preferred embodiment, four substituents among R1, R2, R3, R4 and R5 are hydrogen, and one substituent is not hydrogen, preferably R3 is not hydrogen.

[0025] In another preferred embodiment, 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 form a 5-7 membered heterocyclic ring containing 1-2 nitrogen atoms.

[0026] In another preferred embodiment, Ar is an unsubstituted or substituted C10-C14 polycyclic aromatic group, such as naphthyl or anthracenyl.

[0027] In another preferred embodiment, Ar is an unsubstituted or substituted C5-C10 heteroaryl group, such as piperidinyl, piperazinyl, or quinolinyl.

[0028] In another preferred embodiment, Ar is selected from the following group:

[0029] Where * represents a connection point.

[0030] In another preferred embodiment, Ar is a monosubstituted phenyl group.

[0031] In another preferred embodiment, Ar is a para-substituted phenyl group.

[0032] In another preferred embodiment, Ar is benzyl, phenyl, nitrophenyl, chlorophenyl, bromophenyl, benzyloxy, or cyanophenyl.

[0033] In another preferred embodiment, Ar is benzyl, phenyl, or benzyloxy.

[0034] In another preferred embodiment, Ar is phenyl or benzyl.

[0035] In another preferred embodiment, Ar is benzyl.

[0036] In another preferred embodiment, in 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.

[0037] In another preferred embodiment, in 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.

[0038] In another preferred embodiment, in step 1, the resolving agent is a compound of formula IIIa.

[0039] In another preferred embodiment, in steps 1a-1 and 1b-1, 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.

[0040] In another preferred embodiment, in steps 1a-1 and 1b-1, the salt-forming reaction independently has one or more of the following characteristics:

[0041] (a) 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;

[0042] (b) the salt-forming reaction is carried out at 40-100° C., preferably 60-80° C.;

[0043] (c) The reaction time of the salt-forming reaction is 1-4 h, preferably 2 h.

[0044] In another preferred embodiment, the separation in step 1a-1 is filtration separation or centrifugal separation, preferably filtration separation.

[0045] In another preferred embodiment, in step 1a-1, 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.

[0046] In another preferred embodiment, in step 1a-2, 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.

[0047] In another preferred embodiment, in step 1a-2, the base can be used in an anhydrous form or in the form of a hydrate thereof.

[0048] In another preferred embodiment, 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.

[0049] In another preferred embodiment, in step 1a-2, the alkali treatment is carried out in an aqueous alkali solution.

[0050] In another preferred embodiment, in step 1a-2, the pH of the alkali treatment step is 7-12, preferably 7.5-10, preferably 7.5-8.5.

[0051] In another preferred embodiment, in step 1a-2, the alkali treatment further has one or more of the following characteristics:

[0052] (a) the concentration of the salt represented by the compound of formula IVa in the solvent is 0.05-0.20 mmol / mL;

[0053] (b) the alkali treatment is carried out at a temperature of 5-30° C.;

[0054] (c) The reaction time of the alkali treatment is 0.5-4 h, preferably 2 h.

[0055] In another preferred embodiment, 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.

[0056] In another preferred embodiment, 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.

[0057] In another preferred embodiment, 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.

[0058] In another preferred embodiment, the crystallization comprises refluxing and stirring in a crystallization solvent and then cooling (eg, 10-25° C.) for crystallization.

[0059] In another preferred embodiment, the method further comprises the following steps:

[0060] i) reacting compound II-1 with compound II-2 to obtain compound II-3;

[0061] ii) reacting compound II-3 with compound II-4 to obtain compound II-5;

[0062] iii) reacting compound II-5 with triethyl orthoformate to obtain a compound of formula II;

[0063] The reaction formula is as follows:

[0064] In a second aspect of the present invention, there is provided a method for preparing finerenone, the method comprising the steps of:

[0065] (s1) providing a compound of formula II;

[0066] (s2) using the compound of formula II as a raw material and performing separation to prepare the compound of formula I, wherein the method for preparing the compound of formula I is as described in the first aspect of the present invention;

[0067] (s3) removing the p-methoxybenzyl group from the compound of formula I to obtain a compound of formula I-1; removing the p-methoxybenzyl group using an acid selected from the group consisting of trifluoroacetic acid, methanesulfonic acid, sulfuric acid, hydrochloric acid, p-toluenesulfonic acid, and trifluoromethanesulfonic acid;

[0068] (s4) the compound of formula I-1 is aminated to obtain finerenone;

[0069] The reaction formula is as follows:

[0070] In another preferred embodiment, in 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.

[0071] In another preferred embodiment, in step s3, trifluoroacetic acid is used to remove the p-methoxybenzyl group.

[0072] In another preferred embodiment, in step s3, 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.

[0073] In another preferred embodiment, in 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. Preferably, dichloromethane, methanol, acetic acid, or a combination thereof.

[0074] In another preferred embodiment, in step s3, the reaction further has one or more of the following characteristics:

[0075] (a) 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;

[0076] (b) the reaction is carried out at 5-40°C, preferably 10-20°C;

[0077] (c) the reaction time of the reaction is 1-4h, preferably 2h;

[0078] (d) 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.

[0079] In another preferred embodiment, in step s4, the amination is carried out under conventional acid-amine condensation reaction conditions.

[0080] In another preferred embodiment, in 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,

[0081] Wherein, R6 is a C1-C10 alkyl group.

[0082] 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.

[0083] 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).

[0084] In another preferred embodiment, in step (s1), the method further comprises the following steps:

[0085] i) reacting compound II-1 with compound II-2 to obtain compound II-3;

[0086] ii) reacting compound II-3 with compound II-4 to obtain compound II-5;

[0087] iii) reacting compound II-5 with triethyl orthoformate to obtain a compound of formula II;

[0088] The reaction formula is as follows:

[0089] The wavy line represents a racemic structure.

[0090] In the third aspect of the present invention, a diastereomeric salt or a pharmaceutically acceptable salt thereof is provided, as shown in the following formula:

[0091] wherein Ar is as defined in the first aspect of the present invention.

[0092] In another preferred embodiment, the diastereomeric salt is IVa.

[0093] In another preferred embodiment, the ee (enantiomeric excess) value of the diastereomeric salt is ≥98%, ≥99%, ≥99.5% or ≥99.8%.

[0094] In the fourth aspect of the present invention, a finerenone intermediate is provided, wherein the intermediate is a compound of formula II or an isomer thereof or a pharmaceutically acceptable salt thereof.

[0095] In another preferred embodiment, the intermediate is a racemic compound of formula II.

[0096] In another preferred embodiment, the intermediate is the (S)-isomer of the compound of formula II, i.e., the compound of formula I

[0097] In another preferred embodiment, the ee value of the intermediate is ≥98%, ≥99%, ≥99.5% or ≥99.8%.

[0098] In the fifth aspect of the present invention, there is provided a use of the diastereomeric salt or pharmaceutically acceptable salt thereof according to the third aspect of the present invention, and the compound of formula II or its enantiomer or pharmaceutically acceptable salt thereof according to the fourth aspect of the present invention as an intermediate in the preparation of finerenone.

[0099] It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features described in detail below (such as in the embodiments) can be combined with each other to form new or preferred technical solutions. Due to space limitations, they will not be listed here one by one. BRIEF DESCRIPTION OF THE DRAWINGS

[0100] FIG1 is a peak table of the HPLC spectrum of the compound I-1 sample prepared in Example 5.

[0101] FIG2 is a peak table of the HPLC spectrum of the compound I-1 sample prepared in Comparative Example 1. DETAILED DESCRIPTION

[0102] After extensive and in-depth research, the inventors unexpectedly discovered a method for preparing finerenone suitable for industrial production. Specifically, the inventors discovered a new finerenone intermediate. By replacing the nitrile ethyl / benzyl group in existing processes with a specific p-methoxybenzyl group, not only can a high-ee intermediate be obtained, but 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. Furthermore, 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.

[0103] definition

[0104] The following are definitions of terms used in this specification. Unless otherwise indicated, the initial definitions of groups or terms provided herein apply to the groups or terms used in this specification alone or as part of other groups.

[0105] As used herein, 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."

[0106] The prefix "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. For example, "C1-6 alkyl" means that the alkyl group has 1 to 6 carbon atoms.

[0107] The term "halogen" or "halo" refers to fluorine, chlorine, bromine, or iodine.

[0108] The term "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). Examples of "alkyl" 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.

[0109] The terms "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. As used herein, 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. Typically, 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.

[0110] The term "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. As used 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 membered heteroaryl), 5 to 12 ring atoms (i.e., 5-10 ...12 ring atoms (i.e., 5-10 membered heteroaryl), ), or 5 to 6 ring atoms (i.e., 5-6 membered heteroaryl). 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. Examples of "heteroaryl" 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.

[0111] The term "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.

[0112] Compound of formula II and preparation method thereof

[0113] 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.

[0114] A preferred method for preparing a compound of formula II comprises the steps of:

[0115] i) reacting compound II-1 with compound II-2 to obtain compound II-3;

[0116] ii) reacting compound II-3 with compound II-4 to obtain compound II-5;

[0117] iii) reacting compound II-5 with triethyl orthoformate to obtain a compound of formula II;

[0118] The reaction formula is as follows:

[0119] Compounds of formula I and preparation methods thereof

[0120] The present invention also provides a method for preparing a compound of formula I from a compound of formula II, comprising the steps of:

[0121] (1) Using a resolving agent represented by a compound of formula IIIa or a compound of formula IIIb to resolve the racemic compound of formula II, a compound of formula I is obtained.

[0122] In another preferred embodiment, the resolving agent in step (1) is a compound of formula IIIa, and step (1) comprises:

[0123] (1a-1) reacting a racemic compound of formula II with a compound of formula IIIa to form a salt, and separating to obtain a salt represented by the compound of formula IVa;

[0124] (1a-2) The salt of the compound represented by formula IVa obtained in step 1 is treated with a base to obtain the compound represented by formula I.

[0125] In another preferred embodiment, the resolving agent in step (1) is a compound of formula IIIb, and step (1) comprises:

[0126] (1b-1) The racemic compound of formula II is reacted with the compound of formula IIIb to form a salt, and after removing the salt represented by compound IVb, the compound of formula I is obtained.

[0127] Wherein, 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.

[0128] In another preferred embodiment, Ar is selected from the following group:

[0129] Where * represents a connection point.

[0130] Preferably, in 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. In other words, 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.

[0131] Preferably, in 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. In other words, 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.

[0132] In another preferred embodiment, in step 1, the resolving agent is a compound of formula IIIa. In particular, 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. Therefore, when the molar ratio of the compound of formula IIIa to the racemic compound of formula II is about 0.5 (such as 0.5-0.6), 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. Surprisingly, when the amount of the resolving agent of the compound of formula IIIa is reduced by about half, a high yield of the resolved salt of the S-configuration compound of formula II can be obtained, and the product ee value (≥99.5%) is higher than when a sufficient amount of the resolving agent is used.

[0133] In fact, when the ee value of the compound of formula II does not meet the required requirement (such as ee value ≤ 90%, ee value ≤ 50% or ee value 0), the method of the present invention can be used for further separation.

[0134] Diastereomeric resolution salts

[0135] The present invention also provides a diastereomeric salt or a pharmaceutically acceptable salt thereof, as shown in the following formula:

[0136] wherein Ar is as defined in the first aspect of the present invention.

[0137] In another preferred embodiment, the diastereomeric salt is IVa.

[0138] In another preferred embodiment, the ee (enantiomeric excess) value of the diastereomeric salt is ≥98%, ≥99%, ≥99.5% or ≥99.8%.

[0139] The present invention also provides the (S)-isomer of the compound of formula II, i.e., the compound of formula I

[0140] In another preferred embodiment, the ee value of the intermediate is ≥98%, ≥99%, ≥99.5% or ≥99.8%.

[0141] Preparation method of finerenone

[0142] The present invention also provides a novel method for preparing finerenone, which comprises the following steps:

[0143] (s1) providing a compound of formula II;

[0144] (s2) using the compound of formula II as a raw material and performing separation to prepare the compound of formula I, wherein the method for preparing the compound of formula I is as described in the first aspect of the present invention;

[0145] (s3) removing the p-methoxybenzyl group from the compound of formula I to obtain a compound of formula I-1; removing the p-methoxybenzyl group using an acid selected from the group consisting of trifluoroacetic acid, methanesulfonic acid, sulfuric acid, hydrochloric acid, p-toluenesulfonic acid, and trifluoromethanesulfonic acid;

[0146] (s4) the compound of formula I-1 is aminated to obtain finerenone;

[0147] The reaction formula is as follows:

[0148] The compound of formula II of the present invention uses a specific p-methoxybenzyl protecting group. Experiments have found that the protecting group can be removed at room temperature under acidic conditions. Compared with the prior art that requires palladium-carbon hydrogenation reduction to remove the benzyl protecting group, the present invention not only does not require expensive reagents and special equipment, but also has low energy consumption. In addition, 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.

[0149] Advantages of the present invention include:

[0150] 1. 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;

[0151] 2. 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;

[0152] 3. The amount of splitting agent used is reduced, which not only reduces costs but also improves splitting effect and process stability;

[0153] 4. When finerenone is prepared using this method, 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%.

[0154] The present invention will be further described below in conjunction with specific examples. It should be understood that these examples are intended to illustrate the present invention and are not intended to limit the scope of the invention. The experimental methods in the following examples, for which no specific conditions are specified, are generally based on conventional conditions or the conditions recommended by the manufacturer. Unless otherwise stated, percentages and parts are by weight.

[0155] Example 1

[0156] Preparation of Compound II

[0157] Compound II-1 (150.0 g, 0.93 mol) was dissolved in isopropanol (750 mL), and acetic acid (1.68 g, 0.028 mol), piperidine (2.38 g, 0.028 mol) and compound II-2 (227.35 g, 1.02 mol) were added and reacted at 50°C. After the reaction, the temperature was lowered to 15°C, stirred for 0.5 h, filtered, and the filter cake was dried under reduced pressure at 45°C to obtain 319.30 g of compound II-3 with a molar yield of 93.89%.

[0158] Compound II-3 (320 g, 0.88 mol) and compound II-4 (119.59 g, 0.96 mol) were dissolved in DMF (1280 mL), heated to 120°C, and kept warm for 8 h. The reaction system was concentrated under reduced pressure until almost no fraction was obtained, cooled to 60°C, and ethanol (1600 mL) was added and refluxed for 0.5 h. The temperature was then lowered to 20°C and stirred for 2 h. The mixture was filtered and the filter cake was dried under reduced pressure at 50°C to obtain 345.89 g of compound II-5 with a molar yield of 83.76%.

[0159] Compound II-5 (200.0 g, 0.42 mol) was dissolved in DMF (500 mL), the temperature was raised to 115°C, triethyl orthoformate (138.30 g) and concentrated sulfuric acid (10.20 g, diluted with 100 mL DMF) were added, and the reaction was carried out at 115°C. After the reaction, 600 mL of water was added, and the mixture was cooled to room temperature and stirred for more than 0.5 h. The mixture was filtered and the filter cake was dried under reduced pressure at 45°C to obtain 188.27 g of compound II with a molar yield of 88.85%.

[0160] Example 2

[0161] Preparation of compound Iva-1

[0162] Compound II (5.00 g, 10.0 mmol) and compound IIIa-1 (1.97 g, 5.5 mmol) were added to a mixed solvent of acetic acid (25 mL) and ethyl acetate (50 mL), heated to 65°C for reaction, then cooled to 50°C for crystallization for 2 hours, cooled to 25°C for filtration, and the filter cake was rinsed with ethyl acetate. The filter cake was dried under reduced pressure at 45°C to obtain 4.20 g of compound Iva-1 (97.83% of the theoretical value) with an ee value of 99.5%.

[0163] Example 3

[0164] Preparation of Compound I

[0165] Water (100 mL) was added to compound Iva-1 (10.0 g, 11.7 mmol), stirred for 0.5 h, and 20% aqueous sodium hydroxide solution was added dropwise to adjust the pH value of the aqueous phase to 9. The mixture was stirred for 2 h, filtered, rinsed once with water (20 mL), and the filter cake was dried to obtain 5.49 g of compound I with a molar yield of 94.28%, an ee value of 99.8%, and a purity of 99.7%.

[0166] Example 4

[0167] Preparation of Compound I

[0168] Compound II (5.00 g, 10.0 mmol) and compound IIIb-1 (2.12 g, 5.5 mmol) were added to isoamyl acetate (90 mL), the temperature was raised to 100 ° C for reaction, then the temperature was lowered to 80 ° C for crystallization for 2 hours, the temperature was lowered to 60 ° C for filtration, the filtrate was concentrated under reduced pressure until no fraction was distilled out, water (50 mL) and dichloromethane (50 mL) were added, stirred for 0.5 h, separated, the organic phase was washed once with water (50 mL), the organic phase was concentrated under reduced pressure until no fraction was distilled out, ethyl acetate (30 mL) was added, refluxed and stirred for 2 h, cooled to 20 ° C for crystallization for 2 h, filtered, and the filter cake was dried to obtain 4.49 g of compound I with a molar yield of 89.80%, an ee value of 99.2%, and a purity of 99.5%.

[0169] Example 5

[0170] Preparation of compound I-1

[0171] Compound I (5.0 g, 10.0 mmol) was dissolved in dichloromethane (30 mL), and trifluoroacetic acid (3.42 g, 30.0 mmol) was added. The mixture was stirred at 15°C for 2 h. The HPLC purity of the reaction solution was measured, and the content of the target compound I-1 was 98.0%. The HPLC spectrum is shown in Figure 1; 20 mL of water was added, stirred for 1 h, and the liquid was separated. The organic phase was taken, cooled to about 5°C, and n-heptane (90 mL) was added dropwise. After the addition was completed, stirring was continued for 2 h to crystallize; the mixture was filtered, and the filter cake was rinsed once with a mixed solvent of dichloromethane and n-heptane (1:3) (5 mL). The filter cake was dried to obtain 3.72 g of compound I-1 with a molar yield of 97.96%, an ee value of 99.6%, and a purity of 99.1%.

[0172] Example 6

[0173] Preparation of Finerenone

[0174] Compound I-1 (10 g, 26.4 mmol) and N,N'-carbonyldiimidazole (5.1 g, 31.5 mmol) were dissolved in acetonitrile (50 mL) and reacted at 0-10 degrees for 1 h; 4-dimethylaminopyridine (0.32 g, 2.62 mmol) and 25% ammonia water (73.90 g, 527.1 mmol) were added, the temperature was raised to reflux, the reaction was continued for 2 h, the temperature was lowered to 45 ° C, water (100 mL) was added dropwise, the temperature was lowered to room temperature after the addition was completed, the filter cake was rinsed twice with water (10 mL each time); anhydrous ethanol (40 mL) was added to the filter cake, the mixture was refluxed for 0.5 h, the temperature was lowered to 0-5 ° C, the filter cake was dried to obtain 8.95 g of the product with a molar yield of 89.72%, a purity of 99.9%, and an ee value of 100%.

[0175] Comparative Example 1

[0176] Preparation of compound I-1 (using palladium-carbon catalysis)

[0177] Compound I (5.0 g, 10.0 mmol) was dissolved in tetrahydrofuran (50 mL), 5% palladium carbon (0.29 g) was added, the atmosphere was replaced with argon three times, hydrogen three times, the hydrogen pressure was 0.5 MPa, and the reaction was carried out at room temperature for 3 h. The HPLC purity of the reaction liquid was measured, and the content of the target compound I-1 was 89.6%. The HPLC spectrum is shown in Figure 2; the palladium carbon was filtered, and the filtrate was concentrated under reduced pressure until no fraction was distilled out; dichloromethane (30 mL) and water (20 mL) were added to the concentrate, stirred for 1 h, separated, and the organic phase was taken, cooled to about 5°C, and n-heptane (90 mL) was added dropwise. After the addition was completed, stirring was continued for 2 h to crystallize; filtered, and the filter cake was rinsed once with a mixed solvent of dichloromethane and n-heptane (1:3) (5 mL). The filter cake was dried to obtain 3.63 g of compound I-1 with a molar yield of 95.59%, an ee value of 99.4%, and a purity of 92.8%.

[0178] Comparative Example 2

[0179] Preparation of compound I-1 (using benzyl-protected compound V as raw material)

[0180] Dissolve compound V (5.0 g, 10.6 mmol) in dichloromethane (30 mL), add 3 equivalents of the acid listed in the table below, and stir at 15°C to react. After 2 hours, observe the reaction on a plate:

[0181] Comparative Example 3

[0182] Preparation of compound Iva-1 (using 1.1 equivalents of resolving agent)

[0183] Compound II (5.00 g, 10.0 mmol) and compound IIIa-1 (3.94 g, 11.0 mmol) were added to a mixed solvent of acetic acid (25 mL) and ethyl acetate (50 mL), and the temperature was raised to 65°C for reaction. The temperature was then lowered to 50°C for crystallization for 2 hours, and the temperature was lowered to 25°C for filtration. The filter cake was rinsed with ethyl acetate and dried under reduced pressure at 45°C to obtain 4.48 g of compound Iva-1 (104.35% of the theoretical value) with an ee value of 97.5%.

[0184] All documents mentioned in this application are incorporated herein by reference, just as if each document were incorporated herein by reference individually. It should also be understood that after reading the above teachings of the present invention, those skilled in the art may make various changes or modifications to the present invention, and that such equivalents also fall within the scope of the claims appended hereto.

Claims

1. A method for preparing a compound of formula I, comprising the steps of: (1) using a resolving agent represented by a compound of formula IIIa or a compound of formula IIIb to resolve a racemic compound of formula II to obtain a compound of formula I; in, The resolving agent in step (1) is a compound of formula IIIa, and step (1) comprises: (1a-1) reacting a racemic compound of formula II with a compound of formula IIIa to form a salt, and separating to obtain a salt represented by the compound of formula IVa; (1a-2) treating the salt represented by the compound of formula IVa obtained in step 1 with a base to obtain the compound of formula I; or The resolving agent in step (1) is a compound of formula IIIb, and step (1) comprises: (1b-1) reacting the racemic compound of formula II with the compound of formula IIIb to form a salt, and removing the salt represented by compound IVb to obtain the compound of formula I; Wherein, 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.

2. The method according to claim 1, wherein Ar has the structure shown in Formula V: Wherein, R1, R2, R3, R4, and R5 are each independently selected from the following group: hydrogen, halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, phenoxy, nitro, cyano, and amide.

3. The method according to claim 1, wherein Ar is selected from the group consisting of: Where * represents a connection point.

4. The method according to claim 1, wherein In 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, more preferably 1:0.51-0.

55.

5. The method according to claim 1, wherein In 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.

6. The method according to claim 4, wherein In step 1, the resolving agent is a compound of formula IIIa.

7. A method for preparing finerenone, comprising the steps of: (s1) providing a compound of formula II; (s2) using the compound of formula II as a raw material, and preparing the compound of formula I by splitting, wherein the method for preparing the compound of formula I is as described in claim 1; (s3) The compound of formula I is subjected to removal of the p-methoxybenzyl group to obtain a compound of formula I-1; wherein, Using an acid to remove the p-methoxybenzyl group, wherein the acid is selected from the group consisting of trifluoroacetic acid, methanesulfonic acid, sulfuric acid, hydrochloric acid, p-toluenesulfonic acid, and trifluoromethanesulfonic acid; (s4) the compound of formula I-1 is aminated to obtain finerenone; The reaction formula is as follows:

8. A diastereomeric salt or a pharmaceutically acceptable salt thereof, represented by the following formula: in, Ar is as defined in claim 1.

9. A finerenone intermediate, which is the following compound or a pharmaceutically acceptable salt thereof in, Formula II is a racemate.

10. Use of the diastereomeric salt or pharmaceutically acceptable salt thereof according to claim 8, or the compound of formula II or its enantiomer or pharmaceutically acceptable salt thereof according to claim 9 as an intermediate in the preparation of finerenone.

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