A method for preparing racemic mixtures from enantiomeric forms of phenelzine or its intermediates

Abstract

This invention provides a method for preparing a racemic mixture of phenelzine or its intermediates from enantiomers, comprising the steps of: reacting compound Ia under light irradiation in the presence of a base and a photocatalyst to generate compound I. The method of this invention for preparing a racemic mixture of phenelzine or its intermediates is low-cost, environmentally friendly, has high yield, high safety, and is suitable for large-scale industrial production.

Description

Technical Field

[0001] This invention belongs to the field of organic chemical synthesis, and more specifically, relates to a method for preparing racemic mixtures from enantiomers of phenelzine or its intermediates. Background Technology

[0002] In diabetic patients, overactivation of mineralocorticoid receptors is thought to contribute to the progression of chronic kidney disease and cardiovascular damage, which may be driven by factors such as metabolism, hemodynamics, or inflammation and fibrosis. Finerenone (BAY94-8862), a nonsteroidal selective mineralocorticoid receptor antagonist developed by Bayer, has been shown in preclinical studies to block the harmful effects of overactivation of mineralocorticoid receptors. In adult patients with chronic kidney disease associated with type 2 diabetes, it can reduce the risk of persistently declining estimated glomerular filtration rate (eGFR) and end-stage renal disease.

[0003] The prior art WO2008104306 first disclosed the compound structure of fenelone, and its initial synthetic route is described in Discovery of Bay 94-8862: A Nonsteroidal Antagonist of the Mineralocorticoid Receptor for the Treatment of Cardiorenal Diseases, Lars The synthetic route reported in et al., ChemMedChem 2012, 7, 1385, involves separating the racemic finelone obtained from the synthesized finelone using chiral HPLC to obtain a single configuration of finelone. Furthermore, prior art WO2016016287 and WO2017032673 also disclose methods for preparing finelone, both involving separating the racemic finelone obtained from the synthesized finelone using chiral HPLC to obtain a single configuration of finelone. Subsequently, prior art WO2019206909A discloses the use of a tartaric acid derivative as a resolving agent to form a salt with the racemic finelone, and utilizing the solubility difference of the two chiral isomers after salt formation to successfully separate finelone with a chiral purity ee value greater than 97% from the racemic finelone.

[0004]

[0005] In the process of obtaining a single configuration of fenelinone using either chiral HPLC separation or resolving agents, approximately half of the fenelinone enantiomers (byproducts) are generated after product separation. To convert the fenelinone enantiomers into the racemic fenelinone for further separation to obtain fenelinone, the following methods have been reported in the prior art:

[0006] Existing technology WO2017032678 (CN108137587) discloses a method for recovering (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthidine-3-carboxamide. First, the compound is oxidized by a chemical oxidant or by an electrochemical method (aromatization of dihydropyridine), and then racemized by electrochemical reduction. The racemization process is carried out in two stages, the reaction process is cumbersome, and special equipment is required, making it difficult to scale up industrially.

[0007] The prior art CN114555598A discloses a method for preparing a racemic mixture of fenelone or its enantiomers, which includes first oxidizing with oxygen (air), and then irradiating the fenelone enantiomer with ultraviolet light under a nitrogen flow to prepare the racemic mixture of fenelone. Passing oxygen (air) into an organic solvent poses certain risks, and the ultraviolet light source used is energy-intensive, the reaction is slow, and the overall process is cumbersome, which is not conducive to industrial-scale production.

[0008] Existing technology CN115583866A discloses a method for obtaining a racemic phenelzine by reacting a base with the enantiomer at a high temperature of 300 degrees Celsius. However, the high temperature of 300 degrees Celsius requires specialized equipment, which is not conducive to industrial-scale production.

[0009] Currently, existing methods for converting enantiomers of fenelitonee into racemic derivatives are not conducive to industrial scale-up. Therefore, there is an urgent need for a method suitable for large-scale industrial production to prepare racemic derivatives from enantiomers of fenelitonee or its intermediates. Summary of the Invention

[0010] To address the problems in the preparation of racemic mixtures from enantiomers of phenelzine in existing technologies, this invention provides a method for preparing racemic mixtures from enantiomers of phenelzine or its intermediates, the method comprising the following steps:

[0011] Compound Ia reacts under light in the presence of a base and a photocatalyst to produce compound I, as shown in the following reaction formula:

[0012]

[0013] In formulas Ia and I, R1 is a C1-C6 alkoxy, benzyloxy, hydroxyl, or amino group, wherein the C1-C6 alkoxy or benzyloxy group is optionally further substituted by one or more substituents selected from halogen, nitro, cyano, amino, or alkyl groups; R2 is a cyano, fluorine, chlorine, bromine, or iodine group; and R3 is a hydroxyl or C1-C6 alkoxy group.

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

[0015] The base is selected from inorganic bases, organic bases, or combinations thereof.

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

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

[0018] In another preferred embodiment, R1 is methoxy, ethoxy, benzyloxy, isopropoxy, tert-butoxy, butoxy, cyanomethoxy, cyanoethoxy, cyanopropoxy, 2,2,2-trihaloethoxy, hydroxy, or amino; R2 is cyano, fluorine, chlorine, bromine, or iodine; and R3 is hydroxy, methoxy, ethoxy, propoxy, isopropoxy, or butoxy.

[0019] In another, more preferred example, R 1 For example, methoxy, ethoxy, benzyloxy, isopropoxy, tert-butoxy, butoxy, cyanomethoxy, cyanoethoxy, cyanopropoxy, 2,2,2-trihaloethoxy, hydroxy or amino, R 2 It is either cyano or bromine, R 3 It is either hydroxyl or ethoxy.

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

[0021] In another preferred embodiment, the structural formula of the carbazole compound is as follows: Where R 11 R 12 R 13 R 14 R 15 R 16 and R 17 Each is independently selected from hydrogen, halogen, cyano, nitro, amino, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl, -OR 18 -C(O)R 18 Alternatively, two adjacent substituents, together with the two carbons on the benzene ring they are attached to, can form a five- or six-membered ring, where R 18 Selected from alkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl groups. In another more preferred embodiment, in the structural formula of the carbazole compound, R... 11 R 12 R 13 R14 R 15 Each is independently selected from groups containing carbazole.

[0022] In another preferred embodiment, the structural formula of the phenothiazine compound is as follows: Where R 11 R 12 R 13 R 14 R 15 R 16 and R 17 Each is independently selected from hydrogen, halogen, cyano, nitro, amino, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl, -OR 18 -C(O)R 18 Alternatively, two adjacent substituents, together with the two carbons on the benzene ring they are attached to, can form a five- or six-membered ring, where R 18 Selected from alkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl groups. 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 groups containing phenothiazine.

[0023] In another preferred embodiment, the phenazine compound has the following structural formula: Where R 11 R 12 R 13 R 14 R 15 R 16 and R 17 Each is independently selected from hydrogen, halogen, cyano, nitro, amino, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl, -OR 18 -C(O)R 18 Alternatively, two adjacent substituents, together with the two carbons on the benzene ring they are attached to, can form a five- or six-membered ring, where R 18 It is selected from alkyl, cycloalkyl, heterocyclic, aryl or heteroaryl groups.

[0024] In another preferred embodiment, the aromatic thiophenol compound is benzenethiophenol or a derivative thereof, mercaptopyridine or a derivative thereof.

[0025] In another preferred embodiment, the fluorescein compound is fluorescein or a derivative thereof.

[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 following compounds:

[0031] In another preferred embodiment, the aromatic thiophenol compound is selected from compounds...

[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 combinations thereof.

[0034] In another preferred embodiment, the organic base is selected from diethylamine, triethylamine, dipropylamine, tri-n-propylamine, diisopropylamine, diisopropylethylamine, tetramethylethylenediamine, cyclohexylamine, dimethylaniline, azirmonomorpholine, imidazole, dimethylpiperazine, N-methylpyrrolidine, N-methylpiperidine, pyridine, 4-dimethylaminopyridine, tetramethylguanidine (TMG), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), triethylenediamine (DABCO), 1,5,7-triazidobicyclo(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 combinations 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, N-methylpyrrolidone, 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 0–50°C, more preferably 4–35°C.

[0038] In another preferred embodiment, the present invention provides a method for preparing a racemic mixture from an enantiomer of phenelzine or an intermediate thereof, comprising the following steps:

[0039] Compounds Ib-1 to Ib-7 react under light in the presence of a base and a photocatalyst to generate compounds I-1 to I-7, as shown in the following reaction formulas:

[0040]

[0041]

[0042] The wavelength of the light used for 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, azirmonomorpholine, imidazole, dimethylpiperazine, N-methylpyrrolidine, N-methylpiperidine, pyridine, 4-dimethylaminopyridine, tetramethylguanidine (TMG), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), triethylenediamine (DABCO), 1,5,7-triazidobicyclo(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 combinations thereof.

[0046] Another aspect of the present invention provides the use of photocatalysts in the preparation of racemic II using chiral compounds IIa or IIb:

[0047]

[0048] In equations IIa, IIb and I, R 21 R 22 R 23 R 24 R 25 Each is independently selected from hydrogen, halogen, cyano, nitro, amino, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl, -OR 26 -C(O)R 26 Alternatively, two adjacent substituents, together with the two carbons on the benzene ring they are attached to, can form a five- or six-membered ring, where R 26 Selected from alkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl groups.

[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 with pyridine compounds, or combinations thereof. The dye is selected from coumarins, acridines, fluorescein, phthalocyanines, porphyrins, perylene diimides, methylene blue, xanthannaphthalene, benzophenones, or combinations thereof.

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

[0051] In another preferred embodiment, the structural formula of the carbazole compound is as follows: R 11 R 12 R 13 R 14 R 15 R 16 and R 17 Each is independently selected from hydrogen, halogen, cyano, nitro, amino, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl, -OR 18 -C(O)R 18 Alternatively, two adjacent substituents, together with the two carbons on the benzene ring they are attached to, can form a five- or six-membered ring, where R 18 Selected from alkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl groups. 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 groups containing carbazole.

[0052] In another preferred embodiment, the structural formula of the phenothiazine compound is as follows: Where R 11 R 12 R 13 R 14 R 15 R 16 and R 17 Each is independently selected from hydrogen, halogen, cyano, nitro, amino, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl, -OR 18 -C(O)R 18 Alternatively, two adjacent substituents, together with the two carbons on the benzene ring they are attached to, can form a five- or six-membered ring, where R 18Selected from alkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl groups. 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 groups containing phenothiazine.

[0053] In another preferred embodiment, the phenazine compound has the following structural formula: Where R 11 R 12 R 13 R 14 R 15 R 16 and R 17 Each is independently selected from hydrogen, halogen, cyano, nitro, amino, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl, -OR 18 -C(O)R 18 Alternatively, two adjacent substituents, together with the two carbons on the benzene ring they are attached to, can form a five- or six-membered ring, where R 18 It is selected from alkyl, cycloalkyl, heterocyclic, aryl or heteroaryl groups.

[0054] In another preferred embodiment, the aromatic thiophenol compound is benzenethiophenol or a derivative thereof, mercaptopyridine or a derivative thereof.

[0055] In another preferred embodiment, the fluorescein compound is fluorescein or a derivative thereof.

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

[0057]

[0058] Solvent Red 43, or a combination thereof. Attached Figure Description

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

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

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

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

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

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

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

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

[0067] Figure 9 This is the chiral high-performance liquid chromatogram of compound Ib-3 obtained by resolving the racemic compound I-3 in Example 3;

[0068] Figure 10 This is the 1H NMR spectrum of compound Ib-3 obtained by resolving the racemic compound I-3 in Example 3;

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

[0070] Figure 12 This is the mass spectrum of compound Ib-3 obtained by resolving the racemic compound I-3 in Example 3. Detailed Implementation

[0071] To address the problems existing in the methods for converting enantiomers of phenelzine to racemic derivatives disclosed in the prior art, the inventors of this application, through extensive and in-depth research, discovered that by using the photocatalyst mentioned in this invention, in the presence of a base, irradiation with light of a wavelength of 350-600 nm can convert enantiomers of phenelzine or its intermediates to racemic derivatives, thereby further separating phenelzine or its intermediates. Based on this, this invention was completed.

[0072] the term

[0073] Unless otherwise defined, 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 pertains.

[0074] "Halogens" refer to fluorine, chlorine, bromine, and iodine.

[0075] When "alkyl" is used as a group or part of a group, it refers to a group consisting of C1-C2.20 Straight-chain or branched aliphatic hydrocarbon groups. Preferably C1-C. 10 Alkyl groups, more preferably C1-C6 alkyl groups. Examples include 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] C1 to C6 alkoxy groups refer to alkyl-O- groups containing 1 to 6 carbons, where the alkyl group is as defined above. Examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, etc.

[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, such as vinyl, 1-propenyl, 2-propenyl, 1-, 2-, or 3-butenyl. Alkenyl groups can be optionally substituted or unsubstituted.

[0078] "Alynyl" refers to an aliphatic hydrocarbon group containing a single carbon-carbon triple bond, which can be straight-chain or branched. Examples include C2-C10 alkynyl groups, more preferably C2-C6 alkynyl groups, and most preferably C2-C4 alkynyl groups. Examples include ethynyl, 1-propynyl, 2-propynyl, 1-, 2-, or 3-butynyl groups. The alkynyl group can be substituted or unsubstituted.

[0079] "Cycloalkyl" refers to a saturated or partially saturated monocyclic, fused, bridged, or spirocyclic carbon ring. Preferably, it is C3-C. 12 Cycloalkyl groups, more preferably C3-C8 cycloalkyl groups, and most preferably C3-C6 cycloalkyl groups. Examples of monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cyclohepttrienyl, cyclooctyl, etc., with cyclopropyl and cyclohexenyl being preferred. The cycloalkyl group may be optionally substituted or unsubstituted.

[0080] "Heterocyclic group" refers to a non-aromatic heterocyclic group in which one or more cyclic atoms are heteroatoms, such as oxygen, nitrogen, or sulfur atoms, including monocyclic, polycyclic, fused, bridged, and spirocyclic rings. Preferably, it is a 4- to 11-membered heterocycle, which may contain 1, 2, or 3 atoms selected from nitrogen, oxygen, and sulfur. Examples of "heterocyclic groups" include, but are not limited to, morpholino, oxobutyl, thiomorpholino, tetrahydropyrano, piperidino, pyrrolidinyl, and piperazine. The heterocyclic group can be substituted or unsubstituted.

[0081] "Aryl" refers to a carbocyclic aromatic system containing one or two rings, which may be fused together. The term "aryl" includes monocyclic or bicyclic aryl groups, such as phenyl, naphthyl, and tetrahydronaphthyl aromatic groups. Aryl groups can 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, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiopheneyl, oxazolyl, isoxazolyl, oxadiazolyl, imidazolyl, pyrroleyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, benzothiopheneyl, benzimidazolyl, carbazoleyl (…). * indicates a linking site), phenothiazine group ( * indicates a linking site), indolyl, isoyindolyl, quinolinyl, indazole, benzisothiazolyl, benzoxazolyl, benzoxazolyl, etc. Heteroaryl groups can be substituted or unsubstituted.

[0083] "Substitution" means that one or more hydrogen atoms in a group are independently replaced by a corresponding number of substituents. Unless otherwise specified, "substitution" or "substituted" means that the group can be replaced by one or more substituents selected from the following: alkyl, alkenyl, haloalkyl, alkynyl, alkoxy, alkylthio, carbonyl, carboxyl, carboxylic acid ester, amino, halogen, sulfhydryl, hydroxyl, nitro, cyano, cycloalkyl, heterocyclic, aryl, benzyl, heteroaryl, cycloalkoxy, heterocyclic alkoxy, cycloalkylthio, heterocyclic alkylthio, etc.

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

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

[0086] Any light source emitting light in the 370-550nm range can be used in this invention. For example, a mercury lamp emitting light in this wavelength range.

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

[0088] The basic principle of the method for preparing racemic derivatives of phenelzine or its intermediates from enantiomers using photocatalysts in this invention is that the reaction involves two stages: an oxidation stage and a reduction stage. These two processes are intertwined to achieve the racemization of the enantiomers.

[0089]

[0090] Oxidation stage: Under light irradiation, the photocatalyst absorbs light energy from PC. n+ Transition to excited state *pc n+ It possesses both strong oxidation and reduction capabilities (a characteristic of photocatalysis; the excited state *pcn+ is a transition state that can participate in both oxidation and reduction reactions, depending on the substrate); chiral dihydropyridine derivatives exhibit strong oxidative properties, donating electrons, while the photocatalyst exhibits oxidizing properties and gains electrons; after two consecutive single-electron oxidations and deprotonation, the chiral dihydropyridine derivative is oxidized to form an aromatized intermediate, changing from a chiral enantiomer to an achiral pyridine intermediate; the photocatalyst gains one electron to form a reduced state of the photocatalyst PC. (n-1)+ .

[0091] Reduction stage: Due to the strong electron-deficient nature of the chiral pyridine intermediate, the photocatalyst PC formed in the oxidation stage is in a reduced state. (n-1)+ Exhibiting strong reducing properties, after two consecutive single-electron reductions and protonation, the aromatized pyridine intermediate is reduced to a racemic chiral dihydropyridine derivative. The reduced photocatalyst loses an electron and recovers to the ground-state photocatalyst PC. n+ Actually, *PC n+ It can also participate in the restoration phase, resulting in the formation of PC. (n+1)+ It can also participate in the oxidation stage. Therefore, this is an intertwined process.

[0092] Through the two intertwined processes of oxidation and reduction described above, enantiomers of phenelzine or its intermediates are converted into racemic mixtures.

[0093] The method for preparing racemates from enantiomers according to the present invention has the following advantages:

[0094] 1. The method of the present invention allows for the rapid reaction of compound Ia, base, and photocatalyst in a solvent under light irradiation to obtain racemic I, and the product can be obtained through simple post-processing; the reaction conditions are mild, the light source used is readily available and has low energy consumption, resulting in less environmental pollution, and the process is simple and easy to industrialize.

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

[0096] 3. The method of the present invention uses traditional bulk chemicals for both the alkali and the solvent, which are low in cost and readily available. The photocatalyst can be recycled and reused.

[0097] The present invention is further illustrated below with reference to the embodiments, but the present invention is not limited to these embodiments. Unless otherwise specified, the experimental methods used in the following embodiments are conventional methods. Unless otherwise specified, the materials and reagents used in the following embodiments are commercially available.

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

[0099]

[0100]

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

[0102] The preparation of photocatalyst 2 is described on page 4 of Org. Lett. 2022, 24, 31, 5817–5824.

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

[0104] The preparation of photocatalyst 4 is based on the same method as that of catalyst 2, except that the raw material 2-bromo-9,10-anthradinone is used.

[0105] The preparation of photocatalyst 5 is based on the same method as that of catalyst 2, except that the raw material used is 3-bromo-9H-xanthon-9-one.

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

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

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

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

[0110] Example 1

[0111] 1.1 Resolution yielded enantiomeric compound Ia-1

[0112]

[0113] Referring to existing technology CN114555598A, Example 1 describes the preparation of phenelzine (compound Ib-1) and its enantiomer (compound Ia-1) by resolving racemic compound 1-1.

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

[0115]

[0116] At room temperature, 20 L of acetone, 804.6 g of base DBU, 500 g of compound Ia-1, and 27.2 g of photocatalyst 3 were added sequentially to a reaction vessel. Under nitrogen protection, the photocatalytic reaction was carried out at room temperature under light at a wavelength of 420 nm for 5 hours. The reaction was stirred during the process. HPLC analysis showed that the enantiomer ratio of phenelzine to phenelzine (compound Ib-1:compound Ia-1) was ≥47:53. The reaction was then stopped, and the reaction solution was concentrated under reduced pressure to approximately 1 / 7 of its original volume. 3 L of water was added, and a solid precipitated. The solid was filtered, and the filter cake was dried to obtain crude compound I-1. This crude product was refluxed with ethanol to crystallize, filtered, and dried to obtain 403.2 g of racemic compound I-1, with a yield of approximately 80.6% and an HPLC purity of 99.8% (spectrum shown). Figure 1The photocatalyst 3 in the mother liquor after crystallization can be recycled and reused.

[0117] The racemic mixture was resolved using the method disclosed in Examples 1a-1c of CN114555598A, with benzoyl-D-tartaric acid as the resolving agent, yielding 192.7 g of compound Ib-1 (phenelzine), with a resolution of approximately 47.8% and an HPLC purity of 99.9% (see chromatogram). Figure 2 The ee value is 100% (see spectrum). Figure 3 The 1H NMR spectrum of compound Ib-1 is shown below. Figure 4 The carbon NMR spectrum of compound Ib-1 is shown below. Figure 5 The mass spectrum of compound Ib-1 is shown in [image]. Figure 6 The mass spectrometry information is as follows: m / z = 379.2 (M+H). + .

[0118] Example 2.

[0119] 2.1 Resolution yielded enantiomeric compound Ia-2

[0120]

[0121] Compound I-2 was prepared according to examples 1-5 of the prior art CN107849043A.

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

[0123] 2.2 Preparation of racemic compound I-2 from enantiomer 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 sequentially to a reaction flask. Under nitrogen protection, the photocatalytic reaction was carried out at room temperature under light at a wavelength of 440 nm for 3 hours, with stirring during the reaction. The reaction was stopped when the ratio of compound Ib-2 to compound Ia-2 reached ≥47:53 according to HPLC. The reaction solution was concentrated under reduced pressure to approximately 100 mL, and 100 mL of water was added, causing a solid to precipitate. The solid was filtered, and the filter cake was dried to obtain crude compound I-2. This crude product was refluxed with ethanol to crystallize, filtered, and dried to obtain 16.5 g of racemic I-2, with a yield of approximately 82.5% and an HPLC purity of 98.2%. Mass spectrometry information: m / z = 351.1 (M+H). + .

[0125] Example 3.

[0126] 3.1 Resolution yielded enantiomeric compound Ia-3

[0127]

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

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

[0130]

[0131] At room temperature, 1000 mL of acetonitrile, 19.6 g of alkali TMG, 20 g of compound Ib-3 (with a ratio of Ib-3 to Ia-3 of 99:1), and 1.52 g of photocatalyst were added sequentially to a reaction flask. Solvent Red 43 was used. Under nitrogen protection, the photocatalytic reaction was carried out at room temperature under light at a wavelength of 420 nm for 1.5 hours. The reaction was stirred during the process. HPLC analysis showed that the enantiomeric ratio (compound Ib-3: Ia-3) was ≥47:53. The reaction was then stopped, and the reaction solution was concentrated under reduced pressure to approximately 100 mL. 100 mL of water was added, precipitating a solid. This solid was filtered, dried, and the crude compound I-3 was obtained. The crude product was then slurried with methanol (150 mL) to yield 17.9 g of compound I-3, with a yield of approximately 89.5% and an HPLC purity of 99.8% (see chromatogram). Figure 7 ).

[0132] Compound I-3 was resolved using the method disclosed in prior art CN115340539A (Examples 3 and 15) with a resolving agent to obtain 8.4 g of pure compound Ib-3 (fenelone intermediate), with a resolution of approximately 47% and an HPLC purity of 99.8% (see chromatogram). Figure 8 ), ee is 99.0% (see graph) Figure 9 The 1H NMR spectrum of compound Ib-3 is shown below. Figure 10 The carbon NMR spectrum of compound Ib-3 is shown below. Figure 11 The mass spectrum of compound Ib-3 is shown in [image]. Figure 12 The mass spectrometry information is as follows: m / z = 470.3 (M+H). +

[0133] Example 4

[0134] 4.1 Resolution yielded the enantiomer compound Ia-4

[0135]

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

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

[0138]

[0139] At room temperature, 800 mL of dichloromethane, 25.2 g of alkali TBD, 20 g of compound Ia-4, and 1.7 g of photocatalyst 6 were added sequentially to a reaction flask. Under nitrogen protection, the photocatalytic reaction was carried out at room temperature under light at a wavelength of 390 nm for 1 hour. The reaction was stirred during the process. HPLC analysis showed that the enantiomeric ratio (compound Ib-4:compound Ia-4) was ≥47:53. The reaction was then stopped, and the reaction solution was concentrated under reduced pressure until no liquid flowed out. 100 mL of water was added, precipitating a solid. This solid was filtered, dried, and the crude compound I-4 was obtained. The crude product was slurried with methanol, filtered, and the filter cake was dried to obtain 17.4 g of racemic compound I-4, with a yield of approximately 86.1% and an HPLC purity of 99.0%. Mass spectrometry information: m / z = 442.2 (M+H). + .

[0140] Example 5

[0141] 5.1 Resolution yielded enantiomer compound Ia-5

[0142]

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

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

[0145]

[0146] At room temperature, 800 mL of butanone, 28.3 g of MTBD, 20 g of compound Ia-5, and 0.6 g of photocatalyst 7 were added sequentially to a reaction flask. Under nitrogen protection, the photocatalytic reaction was carried out at room temperature under light at a wavelength of 420 nm for 2 hours. The reaction was stirred during the process. HPLC analysis showed that the enantiomeric ratio (compound Ib-5:compound Ia-5) was ≥47:53. The reaction was then stopped, and the reaction solution was concentrated under reduced pressure to approximately 100 mL. 100 mL of water was added, causing a solid to precipitate. This solid was filtered, dried, and yielded crude compound II-6. This crude product was then slurried with methanol to obtain 18 g of solid, with a yield of approximately 88.8% and an HPLC purity of 98.7%. Mass spectrometry information: m / z = 433.2 (M+H). + .

[0147] Example 6

[0148] 6.1 Resolution yielded the enantiomer compound Ia-6

[0149]

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

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

[0152]

[0153] At room temperature, 300 mL of tetrahydrofuran, 35.3 g of the base DMAN, 20 g of compound Ib-6, and 1.5 g of photocatalyst 8 were added sequentially to a reaction flask. Under nitrogen protection, the photocatalytic reaction was carried out at room temperature under light at a wavelength of 440 nm for 3 hours, with stirring during the reaction. The reaction was stopped when the enantiomeric ratio (compound Ib-6:compound Ia-6) was ≥47:53, as detected by HPLC. The reaction solution was concentrated under reduced pressure to approximately 100 mL, and 100 mL of water was added, precipitating a solid. This solid was filtered, dried, and the crude compound I-6 was obtained. 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 approximately 81.5% and an HPLC purity of 98.8%. Mass spectrometry information: m / z = 487.1 (M+H). + .

[0154] Example 7

[0155] 7.1 Resolution yielded the enantiomer compound Ia-7

[0156]

[0157] Compound I-7 was prepared using the method disclosed in Examples 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 phenelzine intermediate (compound Ib-9). The mother liquor and washing solution after filtration of the salt from Example 4-1 were combined, and the pH was adjusted to 7-7.5 using an aqueous sodium phosphate solution (approximately 9% by mass). The mixture was concentrated under reduced pressure until the organic solvent was substantially distilled off. The mixture was cooled to approximately 5°C, stirred overnight, filtered, washed with water, and the filter cake was dried under vacuum at 45°C overnight to obtain the enantiomeric compound Ia-7.

[0158] 7.2 Preparation of racemic 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 and o-carboxythiophenol were added sequentially to a reaction flask. Under nitrogen protection, the photocatalytic reaction was carried out at room temperature under light at a wavelength of 400 nm for 3 hours. The reaction was stirred during the process. HPLC analysis showed that the enantiomeric ratio (compound Ib-7:compound Ia-7) was ≥47:53. The reaction was then stopped, and the reaction solution was concentrated under reduced pressure to approximately 100 mL. 100 mL of water was added, causing a solid to precipitate. This solid was filtered, dried, and the crude compound I-7 was obtained. 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 approximately 86.2% and an HPLC purity of 98.5%. Mass spectrometry information: m / z = 510 (M+H). + .

[0161] Example 8

[0162] 8.1 Resolution yielded the enantiomer compound Ia-8

[0163]

[0164] Compound I-8 was prepared using 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 phenelzine intermediate (compound Ib-8). The mother liquor and washing solution after filtration of the salt from Example 4 were combined, and the pH was adjusted to 7-7.5 using an aqueous sodium phosphate solution (approximately 9% by mass). The mixture was concentrated under reduced pressure until the organic solvent was substantially distilled off. The mixture was cooled to approximately 5°C, stirred overnight, filtered, washed with water, and the filter cake was dried under vacuum at 45°C overnight to obtain enantiomer Ia-8.

[0165] 8.2 Preparation of racemic compound I-8 from enantiomer 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 sequentially to a reaction flask. Under nitrogen protection, the photocatalytic reaction was carried out at room temperature under light at a wavelength of 420 nm for 2.5 hours. The reaction was stirred during the process. HPLC analysis showed that the enantiomeric ratio (compound Ib-8:compound Ia-8) was ≥47:53. The reaction was then stopped, and the reaction solution was concentrated under reduced pressure to approximately 100 mL. 100 mL of water was added, causing a solid to precipitate. This solid was filtered, dried, and the crude compound I-8 was obtained. 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 approximately 81.5% and an HPLC purity of 98.8%. Mass spectrometry information: m / z = 487.1 (M+H).+ .

[0168] Example 9

[0169] Preparation of racemic mixtures using phenadione

[0170]

[0171] At room temperature, 800 mL of tetrahydrofuran, 26.3 g of base DBN, 20 g of compound Ib-1 (phenelzine), and 0.86 g of photocatalyst 1 were added sequentially to a reaction flask. Under nitrogen protection, the photocatalytic reaction was carried out at room temperature under light at a wavelength of 420 nm for 2 hours, with stirring during the reaction. The reaction was stopped when the enantiomeric ratio (compound Ia-1:compound Ib-1) was ≥47:53, as detected by HPLC. The reaction solution was concentrated under reduced pressure to approximately 100 mL, and 100 mL of water was added, precipitating a solid. After filtration and drying, compound II-2 was obtained as a crude solid. The crude solid was crystallized by reflux with ethanol, filtered, and dried to obtain 17.4 g of the racemic compound I-1, with a yield of approximately 87% and an HPLC purity of 99%. Mass spectrometry information: m / z = 379.2 (M+H) + .

[0172] Comparative Example 1

[0173] Following the method described in Example 4a of prior art CN114555598A (rights holder: Bayer), 2.12 g of S-fenelone (compound Ia-1) was dissolved in 250 mL of acetonitrile, and 5.13 g of DBU (6 equivalents) was added. The reaction flask was irradiated with a 200 W 365 nm light source. First, syngas (30% oxygen) was introduced for 30 minutes, followed by irradiation under a constant nitrogen flow for 1 hour. After 1 hour, syngas (30% oxygen) was introduced for another hour, and then the nitrogen flow was adjusted again for 1 hour. The reaction was stirred during the photocatalytic reaction, and the chiral ratio of S-fenelone to its enantiomer was measured to be 95.9:4.1. The reaction was slow under Bayer's experimental conditions.

[0174] Comparative Example 2

[0175] The same feeding method as Comparative Example 1 was used: 2.12 g of S-fenelone (compound Ia-1) was dissolved in 250 mL of acetonitrile and 5.13 g of DBU (6 equivalents) was added. Under nitrogen protection and constant nitrogen flow, the mixture was irradiated with a light source of 420 nm wavelength. After 1 hour, the chiral ratio of S-fenelone to its enantiomer was 100:0, indicating no reaction. Photocatalyst 3 was added to the above system, and under nitrogen protection, the mixture was irradiated with a light source of 420 nm wavelength at 200 W. After 60 minutes, the chiral ratio of S-fenelone to its enantiomer was 51.8:48.2.

[0176] By comparing Examples 1 to 8 and Comparative Examples 1 to 2, it can be seen that the method of preparing racemic derivatives from enantiomers of phenelzine or its intermediates by irradiation in the presence of a photocatalyst has the advantages of low experimental equipment requirements (light with wavelengths of 350-600 nm is readily available and energy consumption is low), high safety (no need to introduce combustion-supporting gases such as air or oxygen into the organic solvent), fast reaction, and suitability for large-scale industrial production.

[0177] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, and not to limit them; although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art should understand that modifications can still be made to the technical solutions described in the foregoing embodiments, or equivalent substitutions can be made to some of the technical features; and these modifications or substitutions do not cause the essence of the corresponding technical solutions to deviate from the scope of the technical solutions of the embodiments of the present invention.

Claims

1. A process for preparing a racemate from an enantiomer of non- naflixone or an intermediate thereof, characterized in that, The method comprises the following steps: The compound Ia is reacted in the presence of a base and a photocatalyst under irradiation to form the compound I, and 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 irradiation is 350-600 nm, The base is selected from diethylamine, triethylamine, dipropylamine, tri-n-propylamine, diisopropylamine, diisopropylethylamine, tetramethylethylenediamine, cyclohexylamine, dimethylaniline, azamethylmorpholine, imidazole, dimethylpiperazine, N-methylpyrrolidine, N-methylpiperidine, pyridine, 4-dimethylaminopyridine, tetramethylguanidine, 1,8-diazabicyclo[5.4.0]undec-7-ene, 1,5-diazobicyclo[4.3.0]non-5-ene, triethylenediamine, 1,5,7-triazabicyclo(4.4.0)dec-5-ene, 7-methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene, 1,8-bisdimethylaminonaphthalene, or a combination thereof, The photocatalyst is selected from the following compounds: , , , , , , solvent red 43, or a combination thereof.

2. The method of claim 1, wherein, The wavelength of the light used for irradiation is 370-550 nm.

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

4. The method of claim 3, wherein, The temperature of the photocatalytic reaction is 4-35°C.

5. The method of claim 1, wherein The compound Ia is compound Ia-1, the compound I is compound I-1, and the compound Ia-1 is reacted in the presence of the base and the photocatalyst under irradiation to form the compound I-1, and the reaction formula is as follows: or The compound Ia is compound Ia-2, the compound I is compound I-2, and the compound Ia-2 is reacted in the presence of the base and the photocatalyst under irradiation to form the compound I-2, and the reaction formula is as follows: or The compound Ia is compound Ia-3, the compound I is compound I-3, and the compound Ia-3 is reacted in the presence of the base and the photocatalyst under irradiation to form the compound I-3, and the reaction formula is as follows: or The compound Ia is compound Ia-4, the compound I is compound I-4, and the compound Ia-4 is reacted in the presence of the base and the photocatalyst under irradiation to form the compound I-4, and the reaction formula is as follows: or The compound Ia is compound Ia-5, the compound I is compound I-5, and the compound Ia-5 is reacted in the presence of the base and the photocatalyst under irradiation to form the compound I-5, and the reaction formula is as follows: or Compound Ia is compound Ia-6, compound I is compound I-6, compound Ia-6 is reacted in the presence of the base and the photocatalyst under irradiation to generate compound I-6, and the reaction formula is as follows: or Compound Ia is compound Ia-7, compound I is compound I-7, compound Ia-7 is reacted in the presence of the base and the photocatalyst under irradiation to generate compound I-7, and the reaction formula is as follows: or Compound Ia is compound Ia-8, compound I is compound I-8, compound Ia-8 is reacted in the presence of the base and the photocatalyst under irradiation to generate compound I-8, and the reaction formula is as follows: 。 6. The method of claim 5, wherein, The wavelength of the light used for irradiation is 370-550 nm.

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