Fenerenone intermediate, preparation method thereof and method for preparing fenerenone from intermediate

Abstract

The invention provides a fenerenone intermediate, a preparation method thereof and a method for preparing fenerenone from the intermediate. According to the method disclosed by the invention, the chiral intermediate of the fenerenone is prepared by adopting an efficient asymmetric hydrogenation process, the intermediate does not need a traditional chiral resolution step, the fenerenone can be directly prepared, the enantioselectivity is improved, and the conversion rate is greatly improved; meanwhile, by optimizing the utilization efficiency of the catalyst, the dosage of the catalyst is remarkably reduced. The catalytic efficiency is improved while the cost is reduced, and the process has good amplified production potential.

Description

Technical Field

[0001] This invention belongs to the field of compound synthesis technology, specifically relating to a phenelzine intermediate, its preparation method, and a method for preparing phenelzine from the intermediate. Background Technology

[0002] Finerenone is a novel nonsteroidal mineralocorticoid receptor antagonist (MRA) developed by Bayer. It received FDA approval in July 2021 for the treatment of adult patients with diabetic kidney disease. Finerenone has demonstrated high selectivity, strong affinity, and the absence of metabolites in clinical applications, leading to its recommendation in numerous authoritative guidelines both domestically and internationally, and its inclusion in treatment regimens, thus enhancing its status in the medical field. Furthermore, finerenone has shown potential therapeutic efficacy in treating primary aldosteronism. Based on these advantages, finerenone is expected to possess significant commercial value and industrial potential.

[0003] Finerenone's chemical name is (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-1,4-dihydro-2,8-dimethyl-1,6-naphthidine-3-carboxamide. Its structure is as follows:

[0004]

[0005] Bayer's original patent WO20081043306 (Scheme 1) details the synthesis method and application of phenelzine. The synthesis process uses 4-cyano-2-methoxybenzaldehyde and ethyl 2-cyanoacetoacetate as starting materials, first undergoing a condensation reaction. Subsequently, a cyclization reaction occurs with 4-amino-5-methyl-2-hydroxypyridine. Next, ethylation is carried out in the presence of triethyl orthoformate, followed by hydrolysis with sodium hydroxide. Amination is then carried out in the presence of N,N'-carbonyldiimidazole. Finally, the target compound phenelzine is obtained through a chiral resolution step.

[0006] Furthermore, Chinese patent applications CN116496273A and CN117756801A, based on existing processes, modify the structure of acetoacetate to construct phenelzine intermediates or their racemic mixtures, which are then separated by chiral resolution (including the use of chiral HPLC or chiral resolution reagents). However, the above-mentioned methods for preparing phenelzine using chiral resolution face problems such as low resolution efficiency and high cost, which limit its potential for industrial application.

[0007]

[0008] In the report published in *Angew. Chem. Int. Ed.*, 2020, Vol. 59, p. 23107 (Scheme 2), 4-amino-5-methyl-2-hydroxypyridine was used as the starting material, and an ethyl group was introduced with the aid of expensive silver carbonate. Subsequently, the compound was protected with a p-pentyl group, and lithiation was performed using n-butyllithium to complete the nucleophilic addition process. Following this, phenelzine was successfully synthesized through deprotection and a series of complex reaction steps, including [4+2] cyclization, oxidative aromatization, and asymmetric transfer hydrogenation. However, this synthetic method has some drawbacks: the hazardous reagent n-butyllithium is used in the reaction process, and column chromatography is required to separate and purify the intermediates. Furthermore, this synthetic route requires a large amount of catalyst and faces challenges in scale-up production. These factors result in a high overall synthesis cost, making it unsuitable for industrial production.

[0009] Summary of the Invention

[0010] The technical problem to be solved by this invention is to overcome the shortcomings of the prior art and provide a phenelzine intermediate, a method for preparing the same, and a method for preparing phenelzine from the intermediate. The method for preparing the phenelzine intermediate of this invention effectively overcomes the technical problem of low catalyst conversion efficiency in existing processes, possesses good potential for scale-up production, and is suitable for industrial production.

[0011] To solve the above-mentioned technical problems, the technical solution proposed by this invention is as follows:

[0012] A first aspect of the present invention provides a method for preparing a chiral intermediate of phenelzine, comprising:

[0013] (1) Using the racemic compound shown in formula (±)-1 as the starting material, the intermediate shown in formula (±)-2 is obtained by oxidative aromatization reaction;

[0014]

[0015] (2) The intermediate shown in formula (±)-2 is subjected to an asymmetric transfer hydrogenation reaction to obtain the non-nelitone chiral intermediate shown in formula (-)-1;

[0016]

[0017] Wherein, R is selected from C1-C6 alkyl, C3-C6 alkenylalkyl, C7-C 12Aryl alkyl and C2-C6 alkoxyalkyl, preferably selected from methyl, ethyl, tert-butyl, isobutyl, n-butyl, pterpentyl, allyl, benzyl, 2-methoxyethyl, 2-trimethylsilylethyl, more preferably tert-butyl.

[0018] In the preparation method of the present invention, the racemic compound shown in formula (±)-1 is used as the starting material, and the nonelinone chiral intermediate shown in formula (-)-1 is prepared by sequentially undergoing oxidative aromatization reaction and asymmetric transfer hydrogenation reaction. This intermediate does not require the traditional chiral resolution step, improves enantioselectivity, and significantly increases the conversion rate.

[0019] In some embodiments of the present invention, step (1) is carried out in the presence of an oxidizing agent. In the oxidizing aromatization reaction of the present invention, the addition of an oxidizing agent can carry out a dehydrogenation reaction, thereby oxidizing the racemic compound shown in formula (±)-1 to the intermediate shown in formula (±)-2.

[0020] Oxidants suitable for use in this invention include, but are not limited to, concentrated nitric acid, elemental iodine, hydrogen peroxide, peroxytert-butanol, sodium hypochlorite, 2,3-dichloro-5,6-dicyanobenzoquinone, and manganese dioxide.

[0021] In this invention, in step (1), the molar ratio of the racemic compound represented by formula (±)-1 to the oxidant is 1:(1~2).

[0022] In some embodiments of the present invention, the oxidative aromatization reaction is carried out in the presence of a first solvent. Choosing a suitable first solvent not only provides good solubility for the racemic compound represented by formula (±)-1, but also stabilizes the oxidizing agent and allows for appropriate adjustment of the reaction rate.

[0023] The first solvent suitable for use in this invention includes, but is not limited to, dichloromethane, chloroform, 1,2-dichloroethane, ethyl acetate, methanol, ethanol, isopropanol, n-butanol, tert-butanol, methyl tert-butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, toluene, acetonitrile, and 1,4-dioxane.

[0024] In this invention, the mass ratio of the racemic compound represented by formula (±)-1 to the volume ratio of the first solvent is 1g:(5~20)mL, for example, 1g:5mL, 1g:8mL, 1g:10mL, 1g:12mL, 1g:15mL, 1g:20mL or a range thereof.

[0025] In some embodiments of the present invention, the reaction conditions for the oxidative aromatization reaction in step (1) include: a reaction temperature of 0-100°C, preferably 30-80°C; and a reaction time of 1-8h, preferably 1.5-6h.

[0026] In the asymmetric transfer hydrogenation reaction of this invention, the catalyst has a dual function: 1) the hydroxyl group attached to the phosphorus atom can provide a proton or hydrogen bond; 2) the phosphorus-oxygen double bond can provide a lone pair of electrons. The intermediate shown in formula (±)-2 is linked to the reducing agent through weak interactions, thereby achieving the transfer of hydrogen from the reducing agent to the intermediate shown in formula (±)-2. Most importantly, it provides a chiral environment, easily inducing stereoselectivity in the reaction. Adding additives can increase the enantiomeric excess (ee) value of the non-nelitone chiral intermediate shown in formula (-)-1. The added reducing agent not only acts as a hydrogen donor but also has a certain aromatization driving force, making it easier for the intermediate shown in formula (±)-2 to be reduced to the non-nelitone chiral intermediate shown in formula (-)-1.

[0027] In some embodiments of the present invention, in step (2), the asymmetric transfer hydrogenation reaction is carried out in the presence of a catalyst, an additive, and a reducing agent; the catalyst is an aryl phosphate; preferably, the catalyst is selected from (S)-3,3'-bis(9-anthrayl)-1,1'-binaphthol phosphate, (S)-3,3'-bis(9-anthrayl)-5,5',6,6',7,7',8,8'-octahydro-1,1'-binaphthol phosphate, (S)-2,6-bis(9-phenanthyl)-8,9,10,11,12,13,14,15-octahydro-1,1'-binaphthol phosphate, (S)- 3,3'-Di-9-phenanthroline-1,1'-binaphthol phosphate, (11bS)-2,6-di-1-pyrene-4-hydroxy-4-oxide dinaphtho[2,1-d:1',2'-f][1,3,2]dioxophosphazene, (11bS)-4-hydroxy-2,6-di(pyrene-1-yl)-8,9,10,11,12,13,14,15-octahydrodinaphtho[2,1-d:1',2'-f][1,3,2]dioxophosphazene 4-oxide, (8aS)-18-hydroxy-8,9-diphenyldiphenanthroline[4,3-d:3',4'-f][ [1,3,2] Dioxaphosphonium-heptanyl-18-oxide, (12S)-2-hydroxy-9,10-diphenyldinaphthol [1,2-D:2',1'-F][1,3,2] Dioxaphosphonium-2-oxide, (S)-2,2'-diphenyl-3,3'-biphenanthrene-4,4'-dimethylphosphate, (11aS)-10,11,12,13-tetrahydro-5-hydroxy-3,7-bis(biphenyl-4-yl)-diindrone [7,1-DE:1',7'-FG][1,3,2] Dioxaphosphonium-octacyclic-5-oxide, (S)-5,5',6,6',7,7',8,8 '-Octahydrobinaphthol phosphate, (S)-3,3'-bis(triphenylsilyl)binaphthol phosphate; (S)-3,3'-diphenyl-1,1'-binaphthol phosphate or (S)-3,3'-bis[3,5-bis(trifluoromethyl)phenyl]-1,1'-binaphthol phosphate; more preferably, the catalyst is selected from (S)-3,3'-bis(9-anthrayl)-1,1'-binaphthol phosphate or (11bS)-2,6-di-1-pyrene-4-hydroxy-4-oxide dinaphtho[2,1-d:1',2'-f][1,3,2]dioxophosphorus heterocyclic heptene; and / or, the additive is selected from Molecular sieves Molecular sieve or Molecular sieve; and / or, the reducing agent is selected from at least one of 2,6-dimethyl-1,4-dihydro-3,5-pyridinedicarboxylate, diethyl 2,6-dimethyl-1,4-dihydro-3,5-pyridinedicarboxylate, di-tert-butyl 2,6-dimethyl-1,4-dihydro-3,5-pyridinedicarboxylate, and 2,6-dimethyl-1,4-dihydro-3,5-pyridinediamide. The asymmetric transfer hydrogenation reaction optimizes the catalyst dosage, achieving a significant reduction in catalyst usage, thus reducing raw material costs and potential pollution risks, and possessing good potential for process scale-up.

[0028] In this invention, in step (2), the molar ratio of the intermediate shown in formula (±)-2 to the catalyst is 1:(0.001~0.05); the mass ratio of the intermediate shown in formula (±)-2 to the additive is 1:(3~5); and the molar ratio of the intermediate shown in formula (±)-2 to the reducing agent is 1:(1~2).

[0029] In some embodiments of the present invention, the asymmetric transfer hydrogenation reaction is carried out in the presence of a second solvent. Suitable second solvents for use in the present invention include, but are not limited to, dichloromethane, chloroform, 1,2-dichloroethane, ethyl acetate, methanol, ethanol, isopropanol, n-butanol, tert-butanol, methyl tert-butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, toluene, acetonitrile, and 1,4-dioxane.

[0030] In this invention, the mass ratio of the intermediate shown in Formula (±)-2 to the volume ratio of the second solvent is 1g:(10~30)mL, for example, 1g:10mL, 1g:15mL, 1g:20mL, 1g:25mL, 1g:30mL or a range thereof.

[0031] In some embodiments of the present invention, the reaction conditions for the asymmetric transfer hydrogenation reaction in step (2) include: a reaction temperature of 60-130°C, preferably 100-120°C; and a reaction time of 30-72 h, preferably 48-55 h.

[0032] A second aspect of the present invention provides the use of the fenelitonee chiral intermediate prepared by the above-described method in the preparation of fenelitonee.

[0033] A third aspect of the present invention provides a method for preparing phenelzine, comprising: hydrolyzing a chiral intermediate of formula (-)-1 to obtain an intermediate of formula (-)-3; and subjecting the intermediate of formula (-)-3 to an amidation reaction to obtain phenelzine;

[0034]

[0035] Wherein, R is selected from C1-C6 alkyl, C3-C6 alkenylalkyl, C7-C12 Aryl alkyl and C2-C6 alkoxyalkyl, preferably selected from methyl, ethyl, tert-butyl, isobutyl, n-butyl, pteropentyl, allyl, benzyl, 2-methoxyethyl, 2-trimethylsilylethyl.

[0036] In some embodiments of the present invention, R is tert-butyl, and the chiral intermediate shown in formula (-)-1 is hydrolyzed in the presence of an acidic reagent to obtain the intermediate shown in formula (-)-3; the acidic reagent is selected from hydrochloric acid, hydrobromic acid, trifluoromethanesulfonic acid, trifluoroacetic acid, acetic acid, formic acid, citric acid, cerium trichloride, aluminum trichloride, ferric trichloride, titanium tetrachloride, and zinc dichloride.

[0037] In this invention, in the hydrolysis reaction, the molar ratio of the chiral intermediate represented by formula (-)-1 to the acidic reagent is 1:(5-15).

[0038] In some embodiments of the present invention, the hydrolysis reaction is carried out in the presence of a third solvent, which may include, but is not limited to, dichloromethane, chloroform, 1,2-dichloroethane, ethyl acetate, methanol, ethanol, isopropanol, n-butanol, tert-butanol, methyl tert-butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, toluene, acetonitrile, and 1,4-dioxane.

[0039] In this invention, the mass ratio of the chiral intermediate represented by formula (-)-1 to the volume ratio of the third solvent is 1g:(4-10)mL, for example, 1g:4mL, 1g:5mL, 1g:6mL, 1g:7mL, 1g:8mL, 1g:9mL, 1g:10mL or a range thereof.

[0040] In some embodiments of the present invention, the reaction conditions for the hydrolysis reaction include: a reaction temperature of 0-50°C, preferably 20-30°C; and a reaction time of 1-6 h, preferably 2-4 h.

[0041] In some embodiments of the present invention, the amidation reaction is carried out in the presence of a condensation reagent and an ammonia reagent; the condensation reagent is selected from N,N'-carbonyldiimidazole, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, N,N'-dicyclohexylcarbodiimide, or N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluorophosphate urea; the ammonia reagent is selected from ammonia water, a methanol solution of ammonia, an ethanol solution of ammonia, an isopropanol solution of ammonia, ammonia gas, or hexamethyldisilazane.

[0042] In this invention, in the amidation reaction, the molar ratio of the intermediate shown in Formula (-)-3 to the condensation reagent is 1:(1.2 to 1.5); the molar ratio of the intermediate shown in Formula (-)-3 to the ammonia reagent is 1:(4 to 6).

[0043] In some embodiments of the present invention, the amidation reaction is carried out in the presence of a fourth solvent, which may include, but is not limited to, dichloromethane, chloroform, 1,2-dichloroethane, ethyl acetate, methanol, ethanol, isopropanol, n-butanol, tert-butanol, methyl tert-butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, toluene, acetonitrile, and 1,4-dioxane.

[0044] In this invention, the mass ratio of the intermediate shown in Formula (-)-3 to the volume ratio of the fourth solvent is 1g:(15-20)mL, for example, 1g:15mL, 1g:16mL, 1g:17mL, 1g:18mL, 1g:19mL, 1g:20mL or a range thereof.

[0045] In some embodiments of the present invention, the reaction conditions for the amidation reaction include: a reaction temperature of 0-80°C, preferably 5-60°C; and a reaction time of 15-36 h, preferably 20-28 h.

[0046] The technical solution provided by this invention has the following beneficial effects:

[0047] This invention utilizes a highly efficient asymmetric hydrogenation process to convert intermediates containing amide groups in existing technologies into intermediates containing ester groups, improving enantioselectivity and significantly increasing conversion rate. Finelerone can be obtained without the traditional chiral resolution step, which helps improve the purity of finelerone. Simultaneously, the catalyst dosage is optimized, achieving a significant reduction to less than 0.5%, thus reducing raw material costs and potential pollution risks, and possessing good potential for process scale-up. This preparation route is simple to operate, facilitating more efficient and precise control of the chemical reaction process, and helping to reduce production costs. Attached Figure Description

[0048] The invention will now be described in more detail with reference to embodiments and the accompanying drawings.

[0049] Figure 1 This invention shows the intermediate (R = tert-butyl) represented by formula (±)-2. 1 H-NMR spectrum;

[0050] Figure 2 This invention shows the chiral intermediate (R = tert-butyl) of formula (-)-1. 1 H-NMR spectrum;

[0051] Figure 3 This invention shows the intermediate (R = methyl) represented by formula (±)-2. 1 H-NMR spectrum;

[0052] Figure 4 This invention shows the chiral intermediate (R = methyl) of formula (-)-1. 1 H-NMR spectrum;

[0053] Figure 5 The intermediate shown in Formula (-)-3 of the present invention is illustrated. 1 H-NMR spectrum;

[0054] Figure 6 The invention demonstrates the feninone prepared by means of this invention. 1 H-NMR spectrum;

[0055] Figure 7 The HPLC chromatogram of the chiral intermediate (R = tert-butyl) represented by formula (-)-1 of this invention is shown:

[0056] Figure 8 The HPLC chromatogram of the chiral intermediate (R = methyl) represented by formula (-)-1 of this invention is shown:

[0057] Figure 9 The HPLC chromatogram of fenelone prepared by the present invention is shown. Detailed Implementation

[0058] To make the present invention easier to understand, the present invention will be described in detail below with reference to embodiments and accompanying drawings. These embodiments are for illustrative purposes only and should not be considered as limiting the scope of the present invention. Unless otherwise specified, specific conditions in the embodiments are performed under conventional conditions or conditions recommended by the manufacturer. Unless otherwise specified, the materials used in the embodiments are commercially available products or conventional products that can be synthesized by known methods.

[0059] The endpoints and any values ​​of the ranges disclosed herein are not limited to the precise ranges or values, and these ranges or values ​​should be understood to include values ​​close to these ranges or values. For numerical ranges, the endpoint values ​​of the various ranges, the endpoint values ​​of the various ranges and individual point values, and individual point values ​​can be combined with each other to obtain one or more new numerical ranges, which should be considered as specifically disclosed herein.

[0060] The data in this embodiment of the invention is obtained through the following method:

[0061] 1. 1 H-NMR spectra were measured on a Bruker AVANCE 400MHz NMR spectrometer after the sample was dissolved in deuterated chloroform (the solvent residue peak of deuterated chloroform is 7.26 ppm) or deuterated dimethyl sulfoxide (the solvent residue peak of deuterated dimethyl sulfoxide is 2.50 ppm).

[0062] 2. The chiral purity of the chiral intermediate (R = tert-butyl, methyl) shown in formula (-)-1 was determined by HPLC (normal phase) using an (AD-H) column.

[0063] 3. The chiral purity of fenelitonee was determined by HPLC (reversed phase) using an IC column.

[0064] In this invention, the ee value is an indicator used to describe the excess of enantiomers in a compound sample. It measures the degree of excess of one enantiomer relative to another. It is usually expressed as a percentage; the calculation formula is ee = ([S] - [R] / [S] + [R]) * 100%, where [R] + [S] = 1.

[0065] Example 1: Preparation of intermediate shown in formula (±)-2 from racemic compound shown in formula (±)-1

[0066] Example 1-1

[0067]

[0068] The racemic compound (R = tert-butyl) (43.5 g, 0.1 mol) shown in Formula (±)-1 was added to a 500 mL round-bottom flask equipped with a stir bar, along with isopropanol (250 mL) and concentrated nitric acid (10.3 mL, 0.15 mol). The reaction flask was then placed in an oil bath at 75 °C for 1.5 hours. After the reaction was complete, a large amount of white solid was observed to precipitate in the solution. After filtration, the filter cake was washed with isopropanol to obtain the intermediate (R = tert-butyl) (37.8 g, yield 87.3%) shown in Formula (±)-2. 1 HNMR (400MHz, CDCl3) δ8.01(s,1H),7.32(dd,J=7.6,1.4Hz,1H),7.18(d,J=7.6Hz,1H),7.13(d,J=1.4 Hz,1H),4.15-3.99(m,2H),3.71(s,3H),2.77(s,3H),2.57(s,3H),1.22(s,9H),0.77(t,J=7.1Hz,3H).

[0069] Examples 1-2

[0070]

[0071] The racemic compound (R = methyl) (39.3 g, 0.1 mol) shown in Formula (±)-1 was added to a 500 mL round-bottom flask equipped with a stir bar, along with isopropanol (250 mL) and concentrated nitric acid (10.3 mL, 0.15 mol). The reaction flask was then placed in an oil bath at 75 °C for 1.5 hours. After the reaction was complete, a large amount of white solid was observed to precipitate in the solution. After filtration, the filter cake was washed with isopropanol to obtain the intermediate (R = methyl) (33.7 g, yield 86.2%) shown in Formula (±)-2. 1 H NMR (400MHz, CDCl3) δ8.03 (s, 1H), 7.30 (dd, J = 7.6, 1.4Hz, 1H), 7.17-7.11 (m, 2H), 4.16- 3.98(m,2H),3.71(s,3H),3.54(s,3H),2.75(s,3H),2.58(s,3H),0.78(t,J=7.1Hz,3H).

[0072] Example 2: Preparation of the chiral intermediate of phenelzine (-)-1 from the intermediate shown in formula (±)-2

[0073]

[0074] Example 2-1

[0075] The intermediate (R = tert-butyl) shown in formula (±)-2 (21.7 g, 50 mmol) was added to a 500 mL round-bottom flask equipped with a stir bar, along with 2-methyltetrahydrofuran (250 mL). Molecular sieve (65.1 g), diethyl 2,6-dimethyl-1,4-dihydro-3,5-pyridinedicarboxylate (19.0 g, 75 mmol, 1.5 equiv.), and (S)-3,3'-bis(9-anthrayl)-1,1'-binaphthol phosphate (52.6 mg, 0.075 mmol, 0.0015 equiv.) were used. The reaction flask was then refluxed in an oil bath at 110 °C for 48 hours. After the reaction was complete, the solid was filtered off, the filter cake was washed with ethyl acetate, the filtrate was evaporated to dryness, and column chromatography was performed to obtain the chiral intermediate of phenelzine (R = tert-butyl) of formula (-)-1 (18.3 g, yield 84%, ee value 92%). 1¹H NMR (400MHz, CDCl₃) δ 7.61 (s, 1H), 7.37 (d, J = 7.8 Hz, 1H), 7.13 (dd, J = 7.8, 1.6 Hz, 1H), 7.00 (s, 1H), 5.78 (s, 1H), 5.40 (s, 1H), 4.20–4.08 (m, 2H), 3.73 (s, 3H), 2.38 (s, 3H), 2.12 (s, 3H), 1.36 (s, 9H), 1.21 (d, J = 6.8 Hz, 3H). ee values ​​were determined by HPLC using an AD-H column and an isopropanol:n-hexane (96:4) mobile phase.

[0076] Example 2-2

[0077] The intermediate (R = tert-butyl) shown in formula (±)-2 (21.7 g, 50 mmol) was added to a 500 mL round-bottom flask equipped with a stir bar, along with 2-methyltetrahydrofuran (250 mL). Molecular sieve (65.1 g), diethyl 2,6-dimethyl-1,4-dihydro-3,5-pyridinedicarboxylate (19.0 g, 75 mmol, 1.5 equiv.), and (11bS)-2,6-di-1-pyrene-4-hydroxy-4-oxide dinaphtho[2,1-d:1',2'-f][1,3,2]dioxophosphoric heptanene (56.2 mg, 0.075 mmol, 0.0015 equiv.) were used. The reaction flask was then refluxed in an oil bath at 110 °C for 48 hours. After the reaction was complete, the solid was filtered off, the filter cake was washed with ethyl acetate, the filtrate was evaporated to dryness, and column chromatography was performed to obtain the chiral intermediate of phenelzine (R = tert-butyl) of formula (-)-1 (17.3 g, yield 80%, ee value 92%). The ee value was determined by HPLC using an AD-H column and an isopropanol:n-hexane (96:4) as the mobile phase.

[0078]

[0079] Example 2-3

[0080] The intermediate (R = methyl) shown in formula (±)-2 (19.6 g, 50 mmol) was added to a 500 mL round-bottom flask equipped with a stir bar, along with 2-methyltetrahydrofuran (250 mL). Molecular sieve (65.1 g), diethyl 2,6-dimethyl-1,4-dihydro-3,5-pyridinedicarboxylate (19.0 g, 75 mmol, 1.5 equiv.), and (S)-3,3'-bis(9-anthrayl)-1,1'-binaphthol phosphate (52.6 mg, 0.075 mmol, 0.0015 equiv.) were used. The reaction flask was then refluxed in an oil bath at 110 °C for 48 hours. After the reaction was complete, the solid was filtered off, the filter cake was washed with ethyl acetate, the filtrate was evaporated to dryness, and column chromatography was performed to give the chiral intermediate of phenelzine (R = methyl) of formula (-)-1 (16.9 g, yield 86%, ee value 86%). 1 ¹H NMR (400MHz, CDCl₃) δ 7.63 (s, 1H), 7.33 (d, J = 7.8 Hz, 1H), 7.12 (dd, J = 7.8, 1.5 Hz, 1H), 7.00 (d, J = 1.6 Hz, 1H), 5.90 (s, 1H), 5.47 (s, 1H), 4.20–4.05 (m, 2H), 3.77 (s, 3H), 3.58 (s, 3H), 2.42 (s, 3H), 2.13 (d, J = 0.9 Hz, 3H), 1.19 (t, J = 7.1 Hz, 3H). ee values ​​were determined by HPLC using an AD-H column and an isopropanol:n-hexane (96:4) mobile phase.

[0081] Example 3: Preparation of fenelazol from the chiral intermediate shown in formula (-)-1

[0082] (1) Prepare the intermediate shown in formula (-)-3 from the chiral intermediate (R = tert-butyl) shown in formula (-)-1.

[0083]

[0084] The chiral intermediate (R = tert-butyl) (4.4 g, 10 mmol) shown in Formula (-)-1 was added to a 100 mL round-bottom flask equipped with a stir bar, along with dichloromethane (21 mL) and trifluoroacetic acid (7.6 mL, 100 mmol, 10 equiv.). The reaction flask was then placed at room temperature for 3 hours. After the reaction was complete, the solvent was evaporated, and the mixture was slurried with petroleum ether to obtain the intermediate shown in Formula (-)-3 (2.8 g, 71% yield). 1 H NMR(400MHz,DMSO-d6)δ11.46(s,1H),8.14(s,1H),7.57(s,1H),7.31(s,1H),7.27-7.24(m,2H) ,5.33(s,1H),4.05-4.00(m,2H),3.73(s,3H),2.37(s,3H),2.14(s,3H),1.11(t,J=7.0Hz,3H).

[0085] (2) Preparation of fenelone from the intermediate shown in formula (-)-3

[0086]

[0087] The intermediate shown in formula (-)-3 (2.8 g, 7.4 mmol) was added to a 250 mL round-bottom flask equipped with a stir bar, along with 1,1-carbonyldiimidazole (1.8 g, 11.1 mmol, 1.5 equiv.) and tetrahydrofuran (50 mL). Then, 4-dimethylaminopyridine (90.4 mg, 0.7 mmol, 0.1 equiv.) was added at room temperature, and the mixture was stirred for 1 h. The temperature was then raised to 50 °C, and stirring was continued for 2.5 h. Hexamethyldisilazane (6.5 mL, 31.1 mmol, 4.2 equiv.) was added to the reaction mixture, and the mixture was heated under reflux for 22 h. The mixture was then cooled to 5°C, and a mixture of 25 mL tetrahydrofuran and 25 mL purified water was slowly added. The mixture was then refluxed for 1 h, cooled to room temperature, extracted with ethyl acetate, and the organic phase was dried over anhydrous Na2SO4. The product was then evaporated to dryness, and the crude product was subjected to column chromatography to obtain a white solid product, fenelone (2.6 g, yield 93%, 90% ee). 1 ¹H NMR (400MHz, DMSO-d⁶) δ 7.69 (s, 1H), 7.55 (s, 1H), 7.37 (d, J = 1.6 Hz, 1H), 7.30–7.24 (m, 1H), 7.15 (d, J = 7.9 Hz, 1H), 6.72 (d, J = 28.4 Hz, 2H), 5.38 (s, 1H), 4.01 (qd, J = 7.1, 2.6 Hz, 2H), 3.83 (s, 3H), 2.19 (s, 3H), 2.12 (s, 3H), 1.05 (t, J = 7.0 Hz, 3H). ee values ​​were determined by HPLC using an IC column and a mobile phase of acetonitrile:water containing 0.1% diethylamine (50:50).

[0088] It should be noted that the embodiments described above are only for explaining the present invention and do not constitute any limitation on the present invention. The present invention has been described with reference to typical embodiments, but it should be understood that the words used therein are descriptive and explanatory terms, not limiting terms. Modifications can be made to the present invention within the scope of the claims, and revisions can be made to the present invention without departing from the scope and spirit of the present invention. Although the present invention described herein relates to specific methods, materials, and embodiments, it does not mean that the present invention is limited to the specific examples disclosed herein; on the contrary, the present invention can be extended to all other methods and applications with the same function.

Claims

1. A method for preparing a non-naliramine chiral intermediate, comprising: (1) taking a racemic compound represented by formula (±)-1 as a starting material, and performing an oxidative aromatization reaction to obtain an intermediate represented by formula (±)-2; (2) performing an asymmetric transfer hydrogenation reaction on the intermediate represented by formula (±)-2 to obtain a non-naliramine chiral intermediate represented by formula (-)-1; the oxidative aromatization reaction in step (1) is performed in the presence of an oxidizing agent selected from at least one of concentrated nitric acid, elemental iodine, hydrogen peroxide, tert-butyl hydroperoxide, sodium hypochlorite, 2,3-dichloro-5,6-dicyano-benzoquinone, and manganese dioxide; and / or, the oxidative aromatization reaction is performed in the presence of a first solvent selected from at least one of dichloromethane, chloroform, 1,2-dichloroethane, ethyl acetate, methanol, ethanol, isopropanol, n-butanol, tert-butanol, methyl tert-butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, toluene, acetonitrile, and 1,4-dioxane; in step (1), the molar ratio of the racemic compound represented by formula (±)-1 to the oxidizing agent is 1: (1-2) ; and the mass ratio of the racemic compound represented by formula (±)-1 to the volume of the first solvent is 1 g: (5-20) mL; and / or, the reaction conditions of the oxidative aromatization reaction in step (1) include: a reaction temperature of 0-100℃, preferably 30-80℃; and a reaction time of 1-8h, preferably 1.5-6h; the asymmetric transfer hydrogenation reaction in step (2) is performed in the presence of a catalyst, an additive, and a reducing agent. ​ ​ wherein R is selected from the group consisting of C1-C6 alkyl, C3-C6 alkenylalkyl, C7-C 12 C2-C6 alkenyl, C3-C6 alkynyl, C3-C6 cycloalkyl, C4-C10 cycloalkylalkyl, C6-C10 aryl, C7-C12 aralkyl, and C2-C6 alkoxyalkyl, preferably one selected from the group consisting of methyl, ethyl, t-butyl, i-butyl, n-butyl, t-amyl, allyl, benzyl, 2-methoxyethyl, 2-trimethylsilyl ethyl, more preferably t-butyl.

2. The method of preparing a chiral intermediate of finerenone according to claim 1, characterized in that, ​ ​ 3. The method of preparation of the chiral intermediate of non-neglitinide according to claim 2, wherein, ​ ​ 4. The process for the preparation of chiral intermediates of finerenone according to any one of claims 1 to 3, characterized in that, ​ the catalyst is an aryl phosphate; preferably, the catalyst is selected from (S)-3,3'-bis(9-anthryl)-1,1'-binaphthyl phosphate, (S)-3,3'-bis(9-anthryl)-5,5',6,6',7,7',8,8'-octahydro-1,1'-binaphthyl phosphate, (S)-2,6-bis(9-phenanthryl)-8,9,10,11,12,13,14,15-octahydro-1,1'-binaphthyl phosphate, (S)-3,3'-di-9-phenanthryl-1,1'-binaphthyl phosphate, (11bS)-2,6-di-1- pyrenyl-4-hydroxy-4-oxidodiaphtho[2,1-d:1',2'-f][1,3,2]dioxaphosphepin, (11bS)-4-hydroxy-2,6-bis(pyren-1-yl)-8,9,10,11,12,13,14,15-octahydrodaphno[2,1-d:1',2'-f][1,3,2]dioxaphosphepin 4-oxide, (8aS)-18-hydroxy-8,9-diphenyldiphenanthro[4,3-d:3',4'-f][1,3,2]dioxaphosphepin 18-oxide, (12S)-2-hydroxy-9,10-diphenylnaphtho[1,2-d:2',1'-f][1,3,2]dioxaphosphepin 2-oxide, (S)-2,2'-diphenyl-3,3'-binaphthyl-4,4'-diyl phosphate, (11aS)-10,11,12,13-tetrahydro-5-hydroxy-3,7-bis(biphenyl-4-yl)-diindeno[7,1-DE:1',7'-FG][1,3,2]dioxaphosphepin-5-oxide, (S)-5,5',6,6',7,7',8,8'-octahydrobinaphthyl phosphate, (S)-3,3'-bis(triphenylsilyl)binaphthyl phosphate, (S)-3,3'-diphenyl-1,1'-binaphthyl phosphate, or (S)-3,3'-bis[3,5-di(trifluoromethyl)phenyl]-1,1'-binaphthyl phosphate; more preferably, the catalyst is selected from (S)-3,3'-bis(9-anthryl)-1,1'-binaphthyl phosphate or (11bS)-2,6-di-1-pyrenyl-4-hydroxy-4-oxidodiaphtho[2,1-d:1',2'-f][1,3,2]dioxaphosphepin; and / or the additive is selected from molecular sieve, molecular sieve or molecular sieve; and / or the reducing agent is selected from at least one of 2,6-dimethyl-1,4-dihydro-3,5- pyridinedicarboxylic acid dimethyl ester, 2,6-dimethyl-1,4-dihydro-3,5-pyridinedicarboxylic acid diethyl ester, 2,6-dimethyl-1,4-dihydro-3,5-pyridinedicarboxylic acid di-tert-butyl ester, 2,6-dimethyl-1,4-dihydro-3,5-pyridinediamide.

5. The method of preparation of the chiral intermediate of finerenone according to claim 4, characterized in that, The asymmetric transfer hydrogenation reaction is carried out in the presence of a second solvent selected from at least one of dichloromethane, chloroform, 1,2-dichloroethane, ethyl acetate, methanol, ethanol, isopropanol, n-butanol, t-butanol, methyl t-butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, toluene, acetonitrile, 1,4-dioxane.

6. The method of preparing a chiral intermediate of finerenone according to claim 5, characterized in that, In step (2), the molar ratio of the intermediate of formula (±)-2 to the catalyst is 1:(0.001-0.05); the mass ratio of the intermediate of formula (±)-2 to the additive is 1:(3-5); the molar ratio of the intermediate of formula (±)-2 to the reducing agent is 1:(1-2); and the mass of the intermediate of formula (±)-2 to the volume of the second solvent is 1g:(10-30)mL. In step (2), the asymmetric transfer hydrogenation reaction is carried out under the following reaction conditions: the reaction temperature is 60-130°C, preferably 100-120°C; and the reaction time is 30-72h, preferably 48-55h.

7. Use of a chiral intermediate of finerenone prepared by the preparation method according to any one of claims 1-6 in the preparation of finerenone.

8. A preparation method of finerenone, comprising: hydrolysis of a chiral intermediate of formula (-)-1 to obtain an intermediate of formula (-)-3; amide reaction of the intermediate of formula (-)-3 to obtain finerenone; wherein R is selected from the group consisting of C1-C6 alkyl, C3-C6 alkenylalkyl, C7-C 12 C2-C6 alkenyl, C3-C6 alkynyl, C3-C6 cycloalkyl, C4-C10 cycloalkenyl, C6-C10 aryl, C7-C12 aralkyl, and C2-C6 alkoxyalkyl, preferably one selected from the group consisting of methyl, ethyl, t-butyl, i-butyl, n-butyl, t-amyl, allyl, benzyl, 2-methoxyethyl, 2-trimethylsilyl ethyl.

9. The method of preparing non-negligible according to claim 8, characterized in that, R is t-butyl, and the chiral intermediate of formula (-)-1 is hydrolyzed in the presence of an acidic reagent to obtain the intermediate of formula (-)-3; the acidic reagent is selected from hydrochloric acid, hydrobromic acid, triflic acid, trifluoroacetic acid, acetic acid, formic acid, citric acid, cerium trichloride, aluminum trichloride, iron trichloride, titanium tetrachloride, and zinc dichloride; In step (2), the asymmetric transfer hydrogenation reaction is carried out under the following reaction conditions: the reaction temperature is 60-130°C, preferably 100-120°C; and the reaction time is 30-72h, preferably 48-55h. Preferably, in the hydrolysis reaction, the molar ratio of the chiral intermediate of formula (-)-1 to the acidic reagent is 1:(5-15); and the mass of the chiral intermediate of formula (-)-1 to the volume of the third solvent is 1g:(4-10)mL. In step (2), the asymmetric transfer hydrogenation reaction is carried out under the following reaction conditions: the reaction temperature is 60-130°C, preferably 100-120°C; and the reaction time is 30-72h, preferably 48-55h.

10. The method of preparing non-nelfϊnavir according to claim 9, wherein, The amide reaction is carried out in the presence of a condensing reagent and an ammonia reagent; the condensing reagent is selected from N,N'-carbonyldiimidazole, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, N,N'-dicyclohexylcarbodiimide, or N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)urea hexafluorophosphate; and the ammonia reagent is selected from aqueous ammonia, a methanolic solution of ammonia, an ethanolic solution of ammonia, an isopropanolic solution of ammonia, ammonia gas, or hexamethyldisilazane. and / or, the amidation reaction is carried out in the presence of a fourth solvent selected from at least one of dichloromethane, chloroform, 1,2-dichloroethane, ethyl acetate, methanol, ethanol, isopropanol, n-butanol, t-butanol, methyl t-butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, toluene, acetonitrile, 1,4-dioxane; Preferably, in the amidation reaction, the molar ratio of the intermediate represented by (-)-3 to the condensation reagent is 1:(1.2-1.5); the molar ratio of the intermediate represented by (-)-3 to the ammonia reagent is 1:(4-6); the mass ratio of the intermediate represented by formula (-)-3 to the volume of the fourth solvent is 1g:(15-20)mL. and / or, the reaction conditions of the amidation reaction include: the reaction temperature is 0-80℃, preferably 5-60℃; the reaction time is 15-36h, preferably 20-28h.

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