Method for preparing raceme from enantiomer of fenerenone or intermediate thereof

Abstract

The invention provides a method for preparing raceme from an enantiomer of fennerenone or an intermediate thereof, which comprises the following step: reacting a compound Ia in the presence of alkali and a photocatalyst under illumination to generate a compound I. The compound I is shown in the description. The method for preparing the racemate of the fenerenone or the intermediate of the fenerenone is low in cost, less in environmental pollution, high in yield, high in safety and suitable for industrial large-scale production. # imgabs0 #

Description

Technical Field

[0001] The invention belongs to the field of organic chemical synthesis, and more specifically, relates to a method for preparing a racemate from the enantiomers of finerenone or its intermediates. Background Art

[0002] In patients with diabetes, excessive activation of mineralocorticoid receptors is believed to lead to the progression of chronic kidney disease and cardiovascular damage, which may be driven by metabolic, hemodynamic, or inflammatory and fibrotic factors. Finerenone (BAY94-8862) is a non-steroidal selective mineralocorticoid receptor antagonist developed by Bayer. In preclinical studies, it has been shown to block the harmful effects caused by excessive activation of mineralocorticoid receptors. It is used in adult patients with chronic kidney disease associated with type 2 diabetes to reduce the risk of continued decline in estimated glomerular filtration rate (eGFR) and end-stage renal disease.

[0003] Prior art WO2008104306 first disclosed the compound structure of finerenone, and its initial synthesis route was in Discovery of BAY 94-8862: A Nonsteroidal Antagonist of the Mineralocorticoid Receptor for the Treatment of Cardiorenal Diseases, Lars et.al., ChemMedChem 2012,7,1385, the synthetic route uses chiral HPLC to separate the synthesized finerenone racemate to obtain a single-configuration finerenone. In addition, the prior art WO2016016287 and WO2017032673 also disclose methods for preparing finerenone, both of which involve using chiral HPLC to separate the synthesized finerenone racemate to obtain a single-configuration finerenone. Subsequently, the prior art WO2019206909A discloses the use of tartaric acid derivatives as a resolving agent to form a salt with the racemate, and the difference in solubility of the two chiral isomers after salt formation is used to successfully separate finerenone with a chiral purity ee value greater than 97% from the racemate.

[0004]

[0005] Whether using chiral HPLC separation or using a resolving agent to separate single-configuration finerenone, about half of the finerenone enantiomers (by-products) are produced after product separation. In order to convert the finerenone enantiomers into finerenone racemates and further separate them to obtain finerenone, the prior art reports the following schemes:

[0006] Prior art WO2017032678 (CN108137587) discloses a method for recovering (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide. The compound is first oxidized using a chemical oxidant or an electrochemical method (aromatization of dihydropyridine), and then electrochemically reduced for racemization. The racemization process is carried out in two stages. The reaction process is cumbersome and requires special equipment, which makes it difficult to scale up industrially.

[0007] Prior art CN114555598A discloses a method for preparing a racemate from finerenone or its enantiomers, which includes first passing oxygen (air) for oxidation, and then irradiating the finerenone enantiomers with ultraviolet light under a nitrogen flow to prepare the finerenone racemate. Passing oxygen (air) in an organic solvent is dangerous, and the light source used is ultraviolet light, which has high energy consumption and slow reaction. The overall process steps are complicated, which is not conducive to industrialization and expansion.

[0008] Prior art CN115583866A discloses that a base and a phenarenin enantiomer are reacted at a high temperature of 300 degrees to obtain a phenarenin racemate. The high temperature of 300 degrees requires special equipment, which is not conducive to industrial scale-up.

[0009] At present, the methods disclosed in the prior art for converting enantiomers of finerenone into racemates are not conducive to industrial scale-up. Therefore, there is an urgent need for a method suitable for industrial large-scale production to prepare a racemate from the enantiomers of finerenone or its intermediates. Summary of the invention

[0010] In view of the problems existing in the prior art in preparing a racemate from enantiomers of finerenone, the present invention provides, on one hand, a method for preparing a racemate from enantiomers of finerenone or an intermediate thereof, the method comprising the following steps:

[0011] Compound Ia reacts in the presence of a base and a photocatalyst under light to generate compound I. The reaction formula is as follows:

[0012]

[0013] In Formula Ia and Formula I, R 1 C 1 ~C 6 Alkoxy, benzyloxy, hydroxy or amino, wherein the C 1 ~C 6 The alkoxy group and the benzyloxy group are optionally further substituted by one or more substituents selected from halogen, nitro, cyano, amino, and alkyl. 2 is cyano, fluorine, chlorine, bromine or iodine, R 3 Hydroxyl or C1 ~C 6 Alkoxy,

[0014] The wavelength of light used for illumination is 350-600nm.

[0015] The base is selected from an inorganic base, an organic base, or a combination thereof,

[0016] The photocatalyst is selected from carbazole compounds, phenothiazine compounds, phenazine compounds, aromatic thiophenol compounds, dyes, diaryl disulfide compounds, triarylamine compounds, photoinitiators, complexes of iridium or ruthenium and pyridine compounds, or combinations thereof, wherein the dye is selected from coumarins, acridines, fluoresceins, phthalocyanines, porphyrins, perylene diimides, methylene blues, xanthenes, benzophenones, or combinations thereof.

[0017] In another more preferred embodiment, the wavelength of the light used for the irradiation is 370-550nm.

[0018] In another preferred embodiment, R 1 is methoxy, ethoxy, benzyloxy, isopropoxy, tert-butoxy, butoxy, cyanomethoxy, cyanoethoxy, cyanopropoxy, 2,2,2-trihaloethoxy, hydroxyl or amino, R 2 is cyano, fluorine, chlorine, bromine or iodine, R 3 is hydroxy, methoxy, ethoxy, propoxy, isopropoxy or butoxy.

[0019] In another more preferred embodiment, R 1 is methoxy, ethoxy, benzyloxy, isopropoxy, tert-butoxy, butoxy, cyanomethoxy, cyanoethoxy, cyanopropoxy, 2,2,2-trihaloethoxy, hydroxyl or amino, R 2 is cyano or bromine, R 3 It is a hydroxyl group or an ethoxy group.

[0020] In another preferred embodiment, the photocatalyst is selected from carbazole compounds, phenothiazine compounds, phenazine compounds, aromatic thiophenol compounds or fluorescein compounds.

[0021] In another preferred embodiment, the structural formula of the carbazole compound is Where R 11 , R 12 , R 13 , R 14 , R 15 , R 16 and R 17 are each independently selected from hydrogen, halogen, cyano, nitro, amino, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR 18 、-C(O)R 18Or two adjacent substituents together with the two carbon atoms on the benzene ring to which they are connected form a five- or six-membered ring, where R 18 is selected from alkyl, cycloalkyl, heterocyclic, aryl or heteroaryl. In another more preferred embodiment, in the structural formula of the carbazole compound, R 11 , R 12 , R 13 , R 14 , R 15 Each is independently selected from a group containing carbazole.

[0022] In another preferred embodiment, the structural formula of the phenothiazine compound is Where R 11 , R 12 , R 13 , R 14 , R 15 , R 16 and R 17 are each independently selected from hydrogen, halogen, cyano, nitro, amino, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR 18 、-C(O)R 18 Or two adjacent substituents together with the two carbon atoms on the benzene ring to which they are connected form a five- or six-membered ring, where R 18 is selected from alkyl, cycloalkyl, heterocyclic, aryl or heteroaryl. In another more preferred embodiment, in the structural formula of the phenothiazine compound, R 11 , R 12 , R 13 , R 14 , R 15 Each is independently selected from a phenothiazine-containing group.

[0023] In another preferred embodiment, the structural formula of the phenazine compound is Where R 11 , R 12 , R 13 , R 14 , R 15 , R 16 and R 17 are each independently selected from hydrogen, halogen, cyano, nitro, amino, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR 18 、-C(O)R 18 Or two adjacent substituents together with the two carbon atoms on the benzene ring to which they are connected form a five- or six-membered ring, where R 18 is selected from alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl.

[0024] In another preferred embodiment, the aromatic thiophenol compound is thiophenol or its derivatives, mercaptopyridine or its derivatives.

[0025] In another preferred embodiment, the fluorescein compound is fluorescein or its derivatives.

[0026] In another preferred embodiment, the carbazole compound is selected from the following compounds:

[0027]

[0028] In another preferred embodiment, the phenothiazine compound is selected from the following compounds:

[0029]

[0030] In another preferred embodiment, the phenazine compound is selected from the group consisting of:

[0031] In another preferred embodiment, the aromatic thiophenol compound is selected from the group consisting of

[0032] In another preferred embodiment, the fluorescein derivative is selected from Solvent Red 43.

[0033] In another preferred embodiment, the inorganic base is selected from lithium hydroxide, sodium hydroxide, potassium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, or a combination thereof.

[0034] In another preferred embodiment, the organic base is selected from diethylamine, triethylamine, dipropylamine, tri-n-propylamine, diisopropylamine, diisopropylethylamine, tetramethylethylenediamine, cyclohexylamine, dimethylaniline, nitrogen methylmorpholine, imidazole, dimethylpiperazine, N-methylpyrrolidine, N-methylpiperidine, pyridine, 4-dimethylaminopyridine, tetramethylguanidine (TMG), 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU), 1,5-diazidebicyclo [4.3.0] non-5-ene (DBN), triethylenediamine (DABCO), 1,5,7-triazidebicyclo (4.4.0) dec-5-ene (TBD), 7-methyl-1,5,7-triazabicyclo [4.4.0] dec-5-ene (MTBD), 1,8-bis (dimethylaminonaphthalene) (DMAN), or a combination thereof.

[0035] In another preferred embodiment, the solvent used in the reaction is selected from alcohols containing 1 to 4 carbon atoms, dimethyl sulfoxide, acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, N,N-dimethylformamide, N,N-dimethylacetamide, nitrogen methyl pyrrolidone, acetone, butanone, methyl isobutyl ketone, dichloromethane, ethyl acetate, or a mixture thereof with water.

[0036] In another preferred embodiment, the molar ratio of compound Ia base to photocatalyst is 1:(1-20):(0.005-2).

[0037] In another preferred embodiment, the temperature of the photocatalytic reaction is 0 to 50°C, more preferably 4 to 35°C.

[0038] In another preferred embodiment, the present invention provides a method for preparing a racemate from the enantiomers of finerenone or its intermediates, comprising the following steps:

[0039] Compounds Ib-1 to Ib-7 react in the presence of a base and a photocatalyst under light to generate compounds I-1 to I-7. The reaction formula is as follows:

[0040]

[0041]

[0042] The wavelength of the light used for the illumination is 350-600 nm, more preferably 370-550 nm, and the photocatalyst is selected from the following compounds:

[0043]

[0044] Solvent Red 43, or a combination thereof.

[0045] The base is selected from diethylamine, triethylamine, dipropylamine, tri-n-propylamine, diisopropylamine, diisopropylethylamine, tetramethylethylenediamine, cyclohexylamine, dimethylaniline, nitrogen methylmorpholine, imidazole, dimethylpiperazine, N-methylpyrrolidine, N-methylpiperidine, pyridine, 4-dimethylaminopyridine, tetramethylguanidine (TMG), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,5-diazidebicyclo[4.3.0]non-5-ene (DBN), triethylenediamine (DABCO), 1,5,7-triazidebicyclo(4.4.0)dec-5-ene (TBD), 7-methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene (MTBD), 1,8-bis(dimethylaminonaphthalene) (DMAN), or a combination thereof.

[0046] Another aspect of the present invention provides the use of a photocatalyst in preparing a racemate II using a chiral compound IIa or IIb:

[0047]

[0048] In Formula IIa, IIb and Formula I, R 21 , R 22 , R 23 , R 24 , R 25 are each independently selected from hydrogen, halogen, cyano, nitro, amino, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR 26 、-C(O)R26 Or two adjacent substituents together with the two carbon atoms on the benzene ring to which they are connected form a five- or six-membered ring, where R 26 is selected from alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl,

[0049] The photocatalyst is selected from carbazole compounds, phenothiazine compounds, phenazine compounds, aromatic thiophenol compounds, dyes, diaryl disulfide compounds, triarylamine compounds, photoinitiators, complexes of iridium or ruthenium and pyridine compounds, or combinations thereof, wherein the dye is selected from coumarins, acridines, fluoresceins, phthalocyanines, porphyrins, perylene diimides, methylene blue, xanthenes, benzophenones, or combinations thereof, wherein the dye is selected from coumarins, acridines, fluoresceins, phthalocyanines, porphyrins, perylene diimides, methylene blue, xanthenes, benzophenones, or combinations thereof.

[0050] In another preferred embodiment, the photocatalyst is selected from carbazole compounds, phenothiazine compounds, phenazine compounds, aromatic thiophenol compounds or fluorescein compounds.

[0051] In another preferred embodiment, the structural formula of the carbazole compound is R 11 , R 12 , R 13 , R 14 , R 15 , R 16 and R 17 are each independently selected from hydrogen, halogen, cyano, nitro, amino, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR 18 、-C(O)R 18 Or two adjacent substituents together with the two carbon atoms on the benzene ring to which they are connected form a five- or six-membered ring, where R 18 is selected from alkyl, cycloalkyl, heterocyclic, aryl or heteroaryl. In another more preferred embodiment, in the structural formula of the carbazole compound, R 11 , R 12 , R 13 , R 14 , R 15 Each is independently selected from a group containing carbazole.

[0052] In another preferred embodiment, the structural formula of the phenothiazine compound is Where R 11 , R 12 , R 13 , R 14 , R 15 , R 16 and R 17are each independently selected from hydrogen, halogen, cyano, nitro, amino, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR 18 、-C(O)R 18 Or two adjacent substituents together with the two carbon atoms on the benzene ring to which they are connected form a five- or six-membered ring, where R 18 is selected from alkyl, cycloalkyl, heterocyclic, aryl or heteroaryl. In another more preferred embodiment, in the structural formula of the phenothiazine compound, R 11 , R 12 , R 13 , R 14 , R 15 Each is independently selected from a phenothiazine-containing group.

[0053] In another preferred embodiment, the structural formula of the phenazine compound is Where R 11 , R 12 , R 13 , R 14 , R 15 , R 16 and R 17 are each independently selected from hydrogen, halogen, cyano, nitro, amino, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR 18 、-C(O)R 18 Or two adjacent substituents together with the two carbon atoms on the benzene ring to which they are connected form a five- or six-membered ring, where R 18 is selected from alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl.

[0054] In another preferred embodiment, the aromatic thiophenol compound is thiophenol or its derivatives, mercaptopyridine or its derivatives.

[0055] In another preferred embodiment, the fluorescein compound is fluorescein or its derivatives.

[0056] In another preferred embodiment, the photocatalyst is selected from the following compounds:

[0057]

[0058] Solvent Red 43, or a combination thereof. BRIEF DESCRIPTION OF THE DRAWINGS

[0059] Figure 1 is the HPLC chart of the racemic compound I-1 obtained in Example 1;

[0060] Figure 2 is the HPLC chart of compound Ib-1 obtained by resolving the racemic compound I-1 in Example 1;

[0061] Figure 3 is a chiral high performance liquid chromatogram of compound Ib-1 obtained by resolving the racemic compound I-1 in Example 1;

[0062] Figure 4 is the H NMR spectrum of compound Ib-1 obtained by resolving the racemic compound I-1 in Example 1;

[0063] Figure 5 is the NMR carbon spectrum of compound Ib-1 obtained by resolving the racemic compound I-1 in Example 1;

[0064] Figure 6 is the mass spectrum of compound Ib-1 obtained by resolving the racemic compound I-1 in Example 1;

[0065] Figure 7 is the HPLC chart of the racemic compound I-3 obtained in Example 3;

[0066] Figure 8 is the HPLC chart of compound Ib-3 obtained by resolving the racemic compound I-3 in Example 3;

[0067] Fig. 9 This is a chiral HPLC chromatogram of compound Ib-3 obtained by resolving the racemic compound I-3 in Example 3;

[0068] Fig.10 is the H NMR spectrum of compound Ib-3 obtained by resolving the racemic compound I-3 in Example 3;

[0069] Fig.11 is the NMR carbon spectrum of compound Ib-3 obtained by resolving the racemic compound I-3 in Example 3;

[0070] Fig.12 This is the mass spectrum of compound Ib-3 obtained by resolving the racemic compound I-3 in Example 3. DETAILED DESCRIPTION

[0071] In view of the problems existing in the methods for converting enantiomers of finerenone into racemates disclosed in the prior art, the inventors of the present application have conducted extensive and in-depth research and found that the enantiomers of finerenone or its intermediates can be converted into racemates by irradiating light with a wavelength of 350-600 nm in the presence of a base using the photocatalyst mentioned in the present invention, thereby further separating and obtaining finerenone or its intermediates. On this basis, the present invention was completed.

[0072] the term

[0073] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

[0074] "Halogen" refers to fluorine, chlorine, bromine and iodine.

[0075] "Alkyl" as a group or part of a group refers to a group comprising C 1 -C 20 A straight chain or branched aliphatic hydrocarbon group. Preferably C 1 -C 10 Alkyl, more preferably C 1 -C 6 Alkyl. For example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, etc. The alkyl group may be substituted or unsubstituted.

[0076] C 1 ~C 6 Alkoxy refers to an alkyl-O-group containing 1 to 6 carbon atoms, wherein alkyl is as defined above, for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, and the like.

[0077] "Alkenyl" refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond, for example, ethenyl, 1-propenyl, 2-propenyl, 1-, 2- or 3-butenyl, etc. Alkenyl groups may be optionally substituted or unsubstituted.

[0078] "Alkynyl" refers to an aliphatic hydrocarbon group containing a carbon-carbon triple bond, which may be straight chain or branched. For example, C2-C10 alkynyl, more preferably C2-C6 alkynyl, most preferably C2-C4 alkynyl. For example, ethynyl, 1-propynyl, 2-propynyl, 1-, 2- or 3-butynyl, etc. Alkynyl may be substituted or unsubstituted.

[0079] "Cycloalkyl" refers to a saturated or partially saturated monocyclic, fused, bridged, or spirocyclic carbon ring. 3 -C 12 Cycloalkyl, more preferably C 3 -C 8 Cycloalkyl, most preferably C 3 -C 6Cycloalkyl. Examples of monocyclic cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, etc., preferably cyclopropyl and cyclohexenyl. Cycloalkyl may be optionally substituted or unsubstituted.

[0080] "Heterocyclic group" refers to a non-aromatic heterocyclic group, in which one or more atoms forming the ring are heteroatoms, such as oxygen, nitrogen, sulfur atoms, etc., including monocyclic, polycyclic, condensed, bridged and spirocyclic rings. Preferably, a 4-11-membered heterocyclic ring may contain 1, 2 or 3 atoms selected from nitrogen, oxygen and sulfur. Examples of "heterocyclic group" include, but are not limited to, morpholinyl, oxetanyl, thiomorpholinyl, tetrahydropyranyl, piperidinyl, pyrrolidinyl, piperazinyl, etc. The heterocyclic group may be substituted or unsubstituted.

[0081] "Aryl" refers to a carbocyclic aromatic system containing one or two rings, wherein the rings may be linked together in a fused manner. The term "aryl" includes monocyclic or bicyclic aromatic groups, such as phenyl, naphthyl, and tetrahydronaphthyl aromatic groups. Aryl groups may be substituted or unsubstituted.

[0082] "Heteroaryl" refers to an aromatic 5- to 6-membered monocyclic or 8- to 10-membered bicyclic ring which may contain 1 to 4 atoms selected from nitrogen, oxygen and sulfur. Examples of "heteroaryl" include, but are not limited to, furanyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, thienyl, oxazolyl, isoxazolyl, oxadiazolyl, imidazolyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, benzothienyl, benzimidazolyl, carbazolyl ( * indicates the attachment site), phenothiazine group ( * indicates a linking site), indolyl, isoindolyl, quinolyl, indazolyl, benzisothiazolyl, benzoxazolyl, benzisoxazolyl, etc. The heteroaryl group may be substituted or unsubstituted.

[0083] "Substitution" means that one or more hydrogen atoms in a group are replaced independently by a corresponding number of substituents. Unless otherwise specified, "substitution" or "substituted" means that a group may be substituted by one or more groups selected from the following groups: alkyl, alkenyl, haloalkyl, alkynyl, alkoxy, alkylthio, carbonyl, carboxyl, carboxylate, amino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocyclyl, aryl, benzyl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio and the like.

[0084] The "finerenone intermediate" refers to a compound whose carbon 4 (carbon 4 of 1,4-dihydropyridine) configuration is the same as that of finerenone and which can be further reacted to obtain finerenone.

[0085] Unless otherwise stated, in the description of this specification, the term "room temperature" or "normal temperature" refers to a temperature of 4 to 40°C, preferably, 25±5°C.

[0086] Any light source device that emits 370-550nm light can be used in the present invention, for example, a mercury lamp that emits wavelengths in this band.

[0087] In 2008, the MacMillan group (Merging Photoredox Catalysis with Organocatalysis: The Direct Asymmetric Alkylation of Aldehydes, David A. Nicewicz, et al, Science, Vol 322, Page 77-80) reported for the first time an organic chemical reaction via photocatalysis. This type of photocatalytic reaction has the advantages of low cost, low cost, easy availability, no environmental pollution, and few by-products, and has been widely used in organic chemical synthesis reactions.

[0088] The basic principle of the method for preparing a racemate from the enantiomer of finerenone or its intermediate by using a photocatalyst is that the reaction involves two stages, namely an oxidation stage and a reduction stage, and the two processes are intertwined to achieve the racemization of the enantiomer.

[0089]

[0090] Oxidation stage: When the photocatalyst is exposed to light, it absorbs light energy and converts it into n+ Transition to excited state *pc n+ , it has strong oxidation and reduction ability at the same time (the characteristics of photocatalysis, the excited state *pcn+ is the reaction transition state and can participate in both oxidation and reduction reactions, depending on the substrate); chiral dihydropyridine derivatives have strong prototoxicity, giving electrons, and the photocatalyst exhibits oxidative properties to obtain electrons; after two consecutive single-electron oxidations and deprotonation, the chiral dihydropyridine derivatives are oxidized to form an aromatized intermediate state, from a chiral enantiomer to a pyridine intermediate without chirality; the photocatalyst obtains an electron to form a reduced state of the photocatalyst pc (n-1)+ .

[0091] Reduction stage: Since the achiral pyridine intermediate has a strong electron-deficient property, the photocatalyst reduced state PC formed in the oxidation stage (n-1)+ It has strong reducibility. After two consecutive single-electron reductions and protonations, the aromatized pyridine intermediate is reduced to generate racemic chiral dihydropyridine derivatives. The reduced photocatalyst loses an electron and returns to the ground state photocatalyst pc. n+ . In fact, *PC n+It can also participate in the reduction phase, and the PC formed (n+1)+ It can also participate in the oxidation phase. So, it's an intertwined process.

[0092] Through the above two intertwined processes of oxidation and reduction, a racemate is obtained from the enantiomer of finerenone or its intermediate.

[0093] The method for preparing a racemate from an enantiomer of the present invention has the following advantages:

[0094] 1. According to the method of the present invention, compound Ia, a base and a photocatalyst can react rapidly in a solvent under light to obtain a racemate I, and the product can be obtained by simple post-treatment; the reaction conditions are mild, the light source used is easily available and has low energy loss, less environmental pollution, a simple process, and easy industrialization.

[0095] 2. The method of the present invention has high product yield and good purity.

[0096] 3. The method of the present invention uses alkali and solvents that are conventional bulk chemicals, which are low in cost and easily available, and the photocatalyst can be reused after recovery.

[0097] The present invention is further illustrated below in conjunction with examples, but the present invention is not limited to these examples. The experimental methods used in the following examples are conventional methods unless otherwise specified. The materials, reagents, etc. used in the following examples, unless otherwise specified, can all be obtained from commercial sources.

[0098] The structural formulas of the photocatalysts 1 to 8 mentioned in the following examples are as follows:

[0099]

[0100]

[0101] The preparation of photocatalyst 1 refers to the contents recorded on page 7 in the appendix of the document Journal of the American Chemical Society (2021), 143(9), 3613-3627.

[0102] The preparation of photocatalyst 2 refers to the content recorded on page 4 of Org.Lett.2022,24,31,5817–5824.

[0103] The preparation of photocatalyst 3 refers to the content described on page 4 of Eur. J. Org. Chem. 2023, 26, e202300081 (1 of 6).

[0104] The preparation method of photocatalyst 4 refers to the preparation method of catalyst 2, the only difference is that the raw material 2-bromo-9,10-anthracenedione is used.

[0105] The preparation method of photocatalyst 5 refers to the preparation method of catalyst 2, the only difference is that the raw material 3-bromo-9H-xanthene-9-one is used.

[0106] The preparation of photocatalyst 6 refers to the contents described on page 10 of the appendix of Nature Catalysis volume (2018), 1,794-804.

[0107] Photocatalyst 7 is prepared according to a method disclosed in the prior art, and the reference for the preparation process is Science (2016), 352 (6289), 1082-1086, page 16 of the appendix.

[0108] The preparation of photocatalyst 8 refers to the contents described in Chinese Chemical Letters (2020), 31(7), 1899-1902, page 3, paragraph 5.

[0109] In the following implementation, "nitrogen protection" can be achieved by replacing the air in the reactor with nitrogen after adding the reaction materials to the reactor, or by purging the container with nitrogen before adding the reaction materials to the reactor, and then replacing the air in the reactor with nitrogen after adding the reaction materials to the container.

[0110] Example 1

[0111] 1.1 Separation to obtain enantiomer compound Ia-1

[0112]

[0113] Referring to the prior art CN114555598A Example 1, the racemic compound 1-1 was split to prepare phenareninone (compound Ib-1) and phenareninone enantiomer (compound Ia-1)

[0114] 1.2 Preparation of racemic compound I-1 from enantiomer compound Ia-1

[0115]

[0116] 20L acetone, 804.6g of base DBU, 500g of compound Ia-1 and 27.2g of photocatalyst 3 were added to the reactor in sequence at room temperature. Under nitrogen protection, the photocatalytic reaction was carried out for 5 hours under the action of light of 420 nm wavelength at room temperature, and stirring was performed during the photocatalytic reaction. HPLC detection was performed until the ratio of p-phenarene:phenarene enantiomers (compound Ib-1: compound Ia-1) was ≥47:53, the reaction was stopped, and the reaction solution was concentrated to about 1 / 7 of the original volume under reduced pressure, 3L of water was added thereto, solids were precipitated, filtered, and the filter cake was dried to obtain a crude compound I-1. The crude product was crystallized by ethanol reflux beating, filtered, and dried to obtain 403.2g of racemic compound I-1, with a yield of about 80.6% and an HPLC purity of 99.8% (see the spectrum). Figure 1 ), the photocatalyst 3 in the mother liquor after crystallization can be recovered and reused.

[0117] The racemate was separated by the method disclosed in Examples 1a-1c of the prior art CN114555598A, using dibenzoyl-D-tartaric acid as a resolving agent to obtain 192.7 g of compound Ib-1 (fenerenone), with a separation yield of about 47.8% and a HPLC purity of 99.9% (see the spectrum). Figure 2 ), ee value is 100% (see spectrum Figure 3 ). The H NMR spectrum of compound Ib-1 is shown in Figure 4 The NMR carbon spectrum of compound Ib-1 is shown in Figure 5 The mass spectrum of compound Ib-1 is shown in Figure 6 , where mass spectrum information: m / z = 379.2 (M+H) + .

[0118] Example 2.

[0119] 2.1 Separation to obtain enantiomer compound Ia-2

[0120]

[0121] Compound I-2 was prepared with reference to the prior art CN107849043A Examples 1-5.

[0122] With reference to the prior art CN114555598A, Example 1, the racemic compound I-2 was resolved to obtain a phenarenin intermediate (compound Ib-2) and an enantiomer of the phenarenin intermediate (compound Ia-2).

[0123] 2.2 Preparation of racemic compound I-2 from enantiomer compound Ia-2

[0124] At room temperature, 200 mL of DMAc, 25.6 g of base DABCO, 20 g of compound Ia-2 and 1.3 g of photocatalyst 2 were added to the reaction bottle in sequence. Under nitrogen protection, the photocatalytic reaction was carried out for 3 hours at room temperature under the action of light with a wavelength of 440 nm. Stirring was performed during the photocatalytic reaction. HPLC detected that the ratio of compound Ib-2: compound Ia-2 was ≥47:53, and the reaction was stopped. The reaction solution was concentrated to about 100 ml under reduced pressure, 100 mL of water was added thereto, solids were precipitated, filtered, and the filter cake was dried to obtain a crude compound I-2. The crude product was refluxed with ethanol for crystallization, filtered, and dried to obtain 16.5 g of racemate I-2, with a yield of about 82.5% and an HPLC purity of 98.2%. Mass spectrum information: m / z=351.1 (M+H) + .

[0125] Example 3.

[0126] 3.1 Separation to obtain enantiomer compound Ia-3

[0127]

[0128] Compound I-3 was prepared by the method disclosed in Examples 1 and 2 of the prior art CN115340539A, and the racemic compound I-3 was resolved according to Examples 3 and 15 to obtain the finerenone intermediate (Compound Ib-3). The mother liquor and washing solution of Example 3 were combined, and the pH was adjusted to 7-7.5 using an aqueous sodium phosphate solution (mass concentration of about 9%), and the mixture was concentrated under reduced pressure until the organic solvent was substantially distilled off, and the mixture was cooled to about 5°C, stirred overnight, filtered and washed with water, and the filter cake was vacuum dried at 45°C overnight to obtain the enantiomeric compound Ia-3.

[0129] 3.2 Preparation of racemic compound I-3 from enantiomer compound Ia-3

[0130]

[0131] 1000 mL of acetonitrile, 19.6 g of base TMG, 20 g of compound Ib-3 (wherein compound Ib-3: compound Ia-3 is 99:1) and 1.52 g of photocatalyst, solvent red 43 were added to the reaction bottle in sequence at room temperature. Under nitrogen protection, the photocatalytic reaction was carried out under the action of light of 420 nm wavelength at room temperature for 1.5 hours, and stirring was performed during the photocatalytic reaction. HPLC detected that the ratio of enantiomers (compound Ib-3: compound Ia-3) was ≥47:53, and the reaction was stopped. The reaction solution was concentrated to about 100 ml under reduced pressure, 100 mL of water was added thereto, and a solid was precipitated. After filtering and drying, a solid crude product of compound I-3 was obtained. The crude product was slurried with methanol (150 ml) to obtain 17.9 g of compound I-3, with a yield of about 89.5% and a HPLC purity of 99.8% (see the spectrum). Figure 7).

[0132] Compound I-3 was prepared by the method disclosed in the prior art CN115340539A (Examples 3 and 15) using a resolving agent to obtain 8.4 g of pure compound Ib-3 (fenerenone intermediate), with a resolution yield of about 47% and a HPLC purity of 99.8% (see the spectrum). Figure 8 ), ee is 99.0% (see the spectrum Fig. 9 ). The H NMR spectrum of compound Ib-3 is shown in Fig.10 The NMR carbon spectrum of compound Ib-3 is shown in Fig.11 The mass spectrum of compound Ib-3 is shown in Fig.12 , where mass spectrum information: m / z = 470.3 (M+H) +

[0133] Example 4

[0134] 4.1 Separation to obtain enantiomer compound Ia-4

[0135]

[0136] Compound I-4 was prepared by the method disclosed in Example 1 of the prior art CN115340539A, and the racemic compound I-4 was resolved according to Examples 3 and 15 to obtain the finerenone intermediate (Compound Ib-4). The mother liquor and washing solution of Example 3 were combined, and the pH was adjusted to 7-7.5 using an aqueous sodium phosphate solution (mass concentration of about 9%), and the mixture was concentrated under reduced pressure until the organic solvent was substantially distilled off, and the mixture was cooled to about 5°C, stirred overnight, filtered and washed with water, and the filter cake was vacuum dried at 45°C overnight to obtain the enantiomer compound Ia-4.

[0137] 4.2 Preparation of racemic compound I-4 from enantiomer compound Ia-4

[0138]

[0139] At room temperature, 800 mL of dichloromethane, 25.2 g of base TBD, 20 g of compound Ia-4 and 1.7 g of photocatalyst 6 were added to the reaction bottle in sequence. Under nitrogen protection, the photocatalytic reaction was carried out under the action of light of 390 nm wavelength at room temperature for 1 hour. Stirring was performed during the photocatalytic reaction. HPLC detected that the ratio of enantiomers (compound Ib-4: compound Ia-4) was ≥47:53, and the reaction was stopped. The reaction solution was concentrated under reduced pressure until no liquid flowed out, 100 mL of water was added thereto, solid was precipitated, filtered, and dried to obtain a solid crude product of compound I-4. The crude product was slurried with methanol, filtered and the filter cake was dried to obtain racemic compound I-4, 17.4 g, with a yield of about 86.1% and an HPLC purity of 99.0%. Mass spectrum information: m / z=442.2 (M+H) + .

[0140] Example 5

[0141] 5.1 Separation to obtain enantiomer compound Ia-5

[0142]

[0143] Compound I-5 was prepared by the method disclosed in Examples 1-5 of the prior art CN106795155A, and the racemic compound I-5 was resolved according to the contents disclosed in Examples 1a and 1b of CN114698375A to obtain the finerenone intermediate (Compound Ib-5). The mother liquor and washing solution of Example 1a were combined, and the pH was adjusted to 7-7.5 using an aqueous sodium phosphate solution (mass concentration of about 9%), and the mixture was concentrated under reduced pressure until the organic solvent was substantially distilled off, and the mixture was cooled to about 5°C, stirred overnight, filtered and washed with water, and the filter cake was vacuum dried at 45°C overnight to obtain the enantiomeric compound Ia-5.

[0144] 5.2 Preparation of racemic compound I-5 from enantiomer compound Ia-5

[0145]

[0146] 800 mL of butanone, 28.3 g of base MTBD, 20 g of compound Ia-5 and 0.6 g of photocatalyst 7 were added to the reaction bottle in sequence at room temperature. Under nitrogen protection, the photocatalytic reaction was carried out for 2 hours under the action of light of 420 nm wavelength at room temperature. Stirring was performed during the photocatalytic reaction. When the ratio of enantiomers (compound Ib-5: compound Ia-5) was ≥47:53 by HPLC detection, the reaction was stopped, and the reaction solution was concentrated to about 100 ml under reduced pressure. 100 mL of water was added thereto, solid was precipitated, filtered, and dried to obtain a crude solid product of compound II-6. The crude product was slurried with methanol to obtain 18 g of solid, with a yield of about 88.8% and a HPLC purity of 98.7%. Mass spectrum information: m / z=433.2 (M+H) + .

[0147] Example 6

[0148] 6.1 Separation to obtain enantiomer compound Ia-6

[0149]

[0150] Compound I-6 was prepared by the method disclosed in Example 1-2 of the prior art CN116041347A, and the racemic compound I-6 was resolved according to the method disclosed in Example 3 of the prior art to obtain the finerenone intermediate (Compound Ib-6). The mother liquor and the washing solution after the salt filtration of Example 3 were combined, and the pH was adjusted to 7-7.5 with an aqueous sodium phosphate solution (mass concentration of about 9%), and the mixture was concentrated under reduced pressure until the organic solvent was basically distilled off, and the mixture was cooled to about 5°C, stirred overnight, filtered and washed with water, and the filter cake was vacuum dried at 45°C overnight to obtain the enantiomeric compound Ia-6.

[0151] 6.2 Preparation of racemic compound I-6 from enantiomer compound Ia-6

[0152]

[0153] At room temperature, 300 mL of tetrahydrofuran, 35.3 g of base DMAN, 20 g of compound Ib-6 and 1.5 g of photocatalyst 8 were added to the reaction bottle in sequence. Under nitrogen protection, the photocatalytic reaction was carried out for 3 hours at room temperature under the action of light with a wavelength of 440 nm. Stirring was performed during the photocatalytic reaction. HPLC detected that the ratio of enantiomers (compound Ib-6: compound Ia-6) was ≥47:53, and the reaction was stopped. The reaction solution was concentrated to about 100 ml under reduced pressure, 100 ml of water was added thereto, solids were precipitated, filtered, and dried to obtain a solid crude product of compound I-6. The crude product was slurried with ethanol, filtered and the filter cake was dried to obtain 16.5 g of racemic compound I-6, with a yield of about 81.5% and an HPLC purity of 98.8%. Mass spectrum information: m / z=487.1 (M+H) + .

[0154] Example 7

[0155] 7.1 Separation to obtain enantiomer compound Ia-7

[0156]

[0157] Compound I-7 was prepared by the method disclosed in Example 1-3 of the prior art CN116715663A, and the racemic compound I-7 was resolved according to the methods disclosed in Examples 4-1 and 5-1 of the prior art to obtain the finerenone intermediate (Compound Ib-9). The mother liquor and washing solution after filtering the salt in Example 4-1 were combined, and the pH was adjusted to 7-7.5 using an aqueous sodium phosphate solution (mass concentration of about 9%), and the mixture was concentrated under reduced pressure until the organic solvent was basically distilled off, and the mixture was cooled to about 5°C, stirred overnight, filtered and washed with water, and the filter cake was vacuum dried at 45°C overnight to obtain the enantiomer compound Ia-7.

[0158] 7.2 Preparation of racemate I-7 from enantiomeric compound Ia-7

[0159]

[0160] At room temperature, 300 mL of acetonitrile, 22.8 g of base (tetramethylethylenediamine), 20 g of compound Ia-9 and 0.26 g of photocatalyst, o-carboxybenzenethiol, were added to the reaction bottle in sequence. Under nitrogen protection, the photocatalytic reaction was carried out for 3 hours at room temperature under the action of light of 400 nm wavelength, and stirring was performed during the photocatalytic reaction. HPLC detected that the ratio of enantiomers (compound Ib-7: compound Ia-7) was ≥47:53, and the reaction was stopped. The reaction solution was concentrated to about 100 ml under reduced pressure, 100 ml of water was added thereto, solid was precipitated, filtered, and dried to obtain a solid crude product of compound I-7. The crude product was slurried with methanol, filtered and the filter cake was dried to obtain 17.5 g of racemic compound I-7, with a yield of about 86.2% and an HPLC purity of 98.5%. Mass spectrum information: m / z=510 (M+H) + .

[0161] Example 8

[0162] 8.1 Separation to obtain enantiomer compound Ia-8

[0163]

[0164] Compound I-8 was prepared by the method disclosed in Examples 1-3 of the prior art CN115340540A, and the racemic compound I-8 was resolved according to the methods disclosed in Examples 4 and 15 of the prior art to obtain the finerenone intermediate (Compound Ib-8). The mother liquor and the washing solution after filtering the salt in Example 4 were combined, and the pH was adjusted to 7-7.5 using an aqueous sodium phosphate solution (mass concentration of about 9%), and the mixture was concentrated under reduced pressure until the organic solvent was basically distilled off, and the mixture was cooled to about 5°C, stirred overnight, filtered and washed with water, and the filter cake was vacuum dried at 45°C overnight to obtain enantiomer Ia-8.

[0165] 8.2 Preparation of racemic compound I-8 from enantiomer compound Ia-8

[0166]

[0167] At room temperature, 300 mL of tetrahydrofuran, 35.3 g of triethylamine, 20 g of compound Ia-8 and 1.1 g of photocatalyst 3 were added to the reaction bottle in sequence. Under nitrogen protection, the photocatalytic reaction was carried out for 2.5 hours at room temperature under the action of light with a wavelength of 420 nm. Stirring was performed during the photocatalytic reaction. HPLC detected that the ratio of enantiomers (compound Ib-8: compound Ia-8) was ≥47:53, and the reaction was stopped. The reaction solution was concentrated to about 100 ml under reduced pressure, 100 ml of water was added thereto, solid was precipitated, filtered, and dried to obtain a crude solid product of compound I-8. The crude product was slurried with ethanol, filtered, and the filter cake was dried to obtain 16.5 g of racemic compound I-6, with a yield of about 81.5% and an HPLC purity of 98.8%. Mass spectrum information: m / z=487.1 (M+H) + .

[0168] Example 9

[0169] Preparation of racemate using phenaretone

[0170]

[0171] 800 mL of tetrahydrofuran, 26.3 g of base DBN, 20 g of compound Ib-1 (phenarezone) and 0.86 g of photocatalyst 1 were added to the reaction bottle in sequence at room temperature. Under nitrogen protection, the photocatalytic reaction was carried out for 2 hours under the action of light with a wavelength of 420 nm at room temperature. Stirring was performed during the photocatalytic reaction. When the ratio of enantiomers (compound Ia-1: compound Ib-1) was ≥47:53 by HPLC detection, the reaction was stopped, the reaction solution was concentrated to about 100 ml under reduced pressure, 100 ml of water was added thereto, a solid was precipitated, filtered, and dried to obtain a solid crude product of compound II-2. The crude product was crystallized by reflux beating with ethanol, filtered, and dried to obtain 17.4 g of racemic compound I-1, with a yield of about 87% and an HPLC purity of 99%. Mass spectrum information: m / z=379.2 (M+H) + .

[0172] Comparative Example 1

[0173] Referring to the method of Example 4a in the prior art CN114555598A (the right holder is the original Bayer): 2.12g of S-phenarene (compound Ia-1) was dissolved in 250mL of acetonitrile and 5.13g of DBU (6 equivalents) was added. The reaction bottle was irradiated with a 200w 365nm light source, first filled with synthesis gas (30% oxygen) for 30 minutes, and then kept under a constant nitrogen flow for 1h. After 1 hour, synthetic air (30% oxygen) was introduced for one hour, and then adjusted to a constant nitrogen flow for 1h. Stirring was performed during the photocatalytic reaction, and the chiral ratio of S-phenarene and its enantiomer was sampled and detected to be 95.9:4.1 (Figure 13). The reaction was very slow using Bayer's experimental conditions.

[0174] Comparative Example 2

[0175] The materials were the same as those in Comparative Example 1: 2.12 g of S-phenarenin (Compound Ia-1) was dissolved in 250 mL of acetonitrile and 5.13 g of DBU (6 equivalents) was added. The system was protected by nitrogen and irradiated with a light source having a wavelength of 420 nm under a constant nitrogen flow. The chiral ratio of S-phenarenin and its enantiomer was 100:0 after sampling for 1 hour, and no reaction was observed. Photocatalyst 3 was added to the system, protected by nitrogen, and irradiated with a light source having a wavelength of 420 nm of 200 W. The chiral ratio of S-phenarenin and its enantiomer was 51.8:48.2 after sampling for 60 minutes (Figure 14).

[0176] By comparing Examples 1 to 8 and Comparative Examples 1 to 2, it can be seen that the method of the present invention for preparing a racemic form by irradiating the enantiomers of finerenone or its intermediates in the presence of a photocatalyst has low experimental equipment requirements (light with a wavelength of 350-600 nanometers is easy to obtain and has low energy consumption), high safety (no need to pass air, oxygen or other combustion-supporting gases into the organic solvent), fast reaction, and is suitable for industrial large-scale production.

[0177] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, rather than to limit it. Although the present invention has been described in detail with reference to the aforementioned embodiments, those skilled in the art should understand that they can still modify the technical solutions described in the aforementioned embodiments, or make equivalent replacements for some of the technical features therein. However, these modifications or replacements do not cause the essence of the corresponding technical solutions to deviate from the technical solution scope of the embodiments of the present invention.

Claims

1. A method for preparing a racemate from the enantiomers of finerenone or its intermediates, characterized in that: The method comprises the following steps: Compound Ia reacts in the presence of a base and a photocatalyst under light to generate compound I. The reaction formula is as follows: In Formula Ia and Formula I, R1 is C1-C6 alkoxy, benzyloxy, hydroxyl or amino, wherein the C1-C6 alkoxy and benzyloxy are optionally further substituted by one or more substituents selected from halogen, nitro, cyano, amino, alkyl, R2 is cyano, fluorine, chlorine, bromine or iodine, R3 is hydroxyl or C1-C6 alkoxy, The wavelength of the light used for illumination is 350-600nm, preferably 370-550nm, The base is selected from an inorganic base, an organic base, or a combination thereof, The photocatalyst is selected from carbazole compounds, phenothiazine compounds, phenazine compounds, aromatic thiophenol compounds, dyes, diaryl disulfide compounds, triarylamine compounds, photoinitiators, complexes of iridium or ruthenium and pyridine compounds, or combinations thereof, wherein the dye is selected from coumarins, acridines, fluoresceins, phthalocyanines, porphyrins, perylene diimides, methylene blues, xanthenes, benzophenones, or combinations thereof.

2. The method according to claim 1, characterized in that R1 is methoxy, ethoxy, benzyloxy, isopropoxy, tert-butoxy, butoxy, cyanomethoxy, cyanoethoxy, cyanopropoxy, 2,2,2-trihaloethoxy, hydroxyl or amino, R2 is cyano, fluorine, chlorine, bromine or iodine, and R3 is hydroxyl, methoxy, ethoxy, propoxy, isopropoxy or butoxy.

3. The method according to claim 1 or 2, characterized in that: R 1 is methoxy, ethoxy, benzyloxy, isopropoxy, tert-butoxy, butoxy, cyanomethoxy, cyanoethoxy, cyanopropoxy, 2,2,2-trihaloethoxy, hydroxyl or amino, R 2 is cyano or bromine, R 3 is hydroxyl or ethoxy, and / or The photocatalyst is selected from carbazole compounds, phenothiazine compounds, phenazine compounds, aromatic thiophenol compounds or fluorescein compounds.

4. The method according to claim 3, characterized in that The structural formula of the carbazole compound is Where R 11 , R 12 , R 13 , R 14 , R 15 , R 16 and R 17 are each independently selected from hydrogen, halogen, cyano, nitro, amino, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR 18 、-C(O)R 18 Or two adjacent substituents together with the two carbon atoms on the benzene ring to which they are connected form a five- or six-membered ring, where R 18 is selected from alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, and / or The structural formula of the phenothiazine compound is Where R 11 , R 12 , R 13 , R 14 , R 15 , R 16 and R 17 are each independently selected from hydrogen, halogen, cyano, nitro, amino, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR 18 、-C(O)R 18 Or two adjacent substituents together with the two carbon atoms on the benzene ring to which they are attached form a five- or six-membered ring, where R 18 is selected from alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, and / or The structural formula of the phenazine compound is Where R 11 , R 12 , R 13 , R 14 , R 15 , R 16 and R 17 are each independently selected from hydrogen, halogen, cyano, nitro, amino, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR 18 、-C(O)R 18 Or two adjacent substituents together with the two carbon atoms on the benzene ring to which they are attached form a five- or six-membered ring, where R 18 is selected from alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, and / or The aromatic thiophenol compound is thiophenol or its derivatives, mercaptopyridine or its derivatives, and / or The fluorescein compound is fluorescein or its derivatives.

5. The method according to claim 4, characterized in that The carbazole compound is selected from the following compounds: and / or The phenothiazine compound is selected from the following compounds: and / or The phenazine compound is selected from the group consisting of: and / or The aromatic thiophenol compound is selected from the group consisting of compounds and / or The fluorescein derivative is selected from Solvent Red 43.

6. The method according to claim 1, characterized in that The inorganic base is selected from lithium hydroxide, sodium hydroxide, potassium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, or a combination thereof, and / or The organic base is selected from diethylamine, triethylamine, dipropylamine, tri-n-propylamine, diisopropylamine, diisopropylethylamine, tetramethylethylenediamine, cyclohexylamine, dimethylaniline, nitrogen methylmorpholine, imidazole, dimethylpiperazine, N-methylpyrrolidine, N-methylpiperidine, pyridine, 4-dimethylaminopyridine, tetramethylguanidine, 1,8-diazabicyclo[5.4.0]undec-7-ene, 1,5-diazidebicyclo[4.3.0]non-5-ene, triethylenediamine, 1,5,7-triazidebicyclo(4.4.0)dec-5-ene, 7-methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene, 1,8-bis(dimethylaminonaphthalene), or a combination thereof.

7. The method according to claim 1, characterized in that The solvent used in the reaction is selected from alcohols containing 1 to 4 carbon atoms, dimethyl sulfoxide, acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, N,N-dimethylformamide, N,N-dimethylacetamide, nitrogen methyl pyrrolidone, acetone, butanone, methyl isobutyl ketone, dichloromethane, ethyl acetate, or a mixture thereof with water, and / or The molar ratio of compound Ia, base and photocatalyst is 1:(1-20):(0.005-2), and / or The temperature of the photocatalytic reaction is 0-100°C, more preferably 4-35°C.

8. A method for preparing a racemate from the enantiomers of finerenone or its intermediates, characterized in that: The method comprises the following steps: Compounds Ia-1 to Ia-7 react in the presence of a base and a photocatalyst under light to generate compounds I-1 to I-7. The reaction formula is as follows: The wavelength of the light used for illumination is 350-600nm, preferably 370-550nm, and the photocatalyst is selected from the following compounds: Solvent Red 43, or a combination thereof, The base is selected from diethylamine, triethylamine, dipropylamine, tri-n-propylamine, diisopropylamine, diisopropylethylamine, tetramethylethylenediamine, cyclohexylamine, dimethylaniline, nitrogen methylmorpholine, imidazole, dimethylpiperazine, N-methylpyrrolidine, N-methylpiperidine, pyridine, 4-dimethylaminopyridine, tetramethylguanidine, 1,8-diazabicyclo[5.4.0]undec-7-ene, 1,5-diazidebicyclo[4.3.0]non-5-ene, triethylenediamine, 1,5,7-triazidebicyclo(4.4.0)dec-5-ene, 7-methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene, 1,8-bis(dimethylaminonaphthalene), or a combination thereof.

9. Use of photocatalyst in the preparation of racemate II using chiral compound IIa or IIb: In Formula IIa, IIb and Formula I, R 21 , R 22 , R 23 , R 24 , R 25 are each independently selected from hydrogen, halogen, cyano, nitro, amino, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR 26 、-C(O)R 26 Or two adjacent substituents together with the two carbon atoms on the benzene ring to which they are connected form a five- or six-membered ring, where R 26 is selected from alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, The photocatalyst is selected from carbazole compounds, phenothiazine compounds, phenazine compounds, aromatic thiophenol compounds, dyes, diaryl disulfide compounds, triarylamine compounds, photoinitiators, complexes of iridium or ruthenium and pyridine compounds, or combinations thereof, wherein the dye is selected from coumarins, acridines, fluoresceins, phthalocyanines, porphyrins, perylene diimides, methylene blue, xanthenes, benzophenones, or combinations thereof, wherein the dye is selected from coumarins, acridines, fluoresceins, phthalocyanines, porphyrins, perylene diimides, methylene blue, xanthenes, benzophenones, or combinations thereof.

10. The use according to claim 9, characterized in that The photocatalyst is selected from carbazole compounds, phenothiazine compounds, phenazine compounds, aromatic thiophenol compounds or fluorescein compounds, More preferably, the structural formula of the carbazole compound is Where R 11 , R 12 , R 13 , R 14 , R 15 , R 16 and R 17 are each independently selected from hydrogen, halogen, cyano, nitro, amino, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR 18 、-C(O)R 18 Or two adjacent substituents together with the two carbon atoms on the benzene ring to which they are attached form a five- or six-membered ring, where R 18 is selected from alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, More preferably, the structural formula of the phenothiazine compound is Where R 11 , R 12 , R 13 , R 14 , R 15 , R 16 and R 17 are each independently selected from hydrogen, halogen, cyano, nitro, amino, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR 18 、-C(O)R 18 Or two adjacent substituents together with the two carbon atoms on the benzene ring to which they are attached form a five- or six-membered ring, where R 18 is selected from alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, More preferably, the structural formula of the phenazine compound is Where R 11 , R 12 , R 13 , R 14 , R 15 , R 16 and R 17 are each independently selected from hydrogen, halogen, cyano, nitro, amino, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR 18 、-C(O)R 18 Or two adjacent substituents together with the two carbon atoms on the benzene ring to which they are attached form a five- or six-membered ring, where R 18 is selected from alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, More preferably, the aromatic thiophenol compound is thiophenol or its derivatives, mercaptopyridine or its derivatives, and More preferably, the fluorescein compound is fluorescein or its derivatives.

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