A chiral preparation method of finerenone

Abstract

The application discloses a chiral preparation method of finerenone, and a reaction route is shown in the specification, and the preparation method comprises the following steps: (1) reacting compound I with a chiral compound II to obtain compound III; (2) reacting the compound III with a compound IV to obtain a compound V; (3) reacting the compound V with an ethylating agent to obtain a compound VI; and (4) removing a protecting group or ammonolysis of the compound VI to obtain a compound VII. Through asymmetric synthesis induced by a chiral compound raw material, more than 95% of a product with a required configuration is obtained, yield is improved, and waste is reduced. The method has mild reaction conditions, low cost and is suitable for industrial production.

Description

Technical Field

[0001] This invention belongs to the field of drug synthesis, specifically relating to a chiral preparation method of fenelone. Background Technology

[0002] Finerenone is a nonsteroidal selective mineralocorticoid receptor antagonist used to treat adult patients with chronic kidney disease (CKD) and type 2 diabetes (T2D).

[0003] Existing patents report the following preparation routes for phenelzine:

[0004] Route 1:

[0005]

[0006] CN107849043B reported Route 1, which uses 4-formyl-3-methoxybenzonitrile as a raw material to prepare fenelone, but the cost is high due to the use of chiral column chromatography for separation.

[0007] Route 2:

[0008]

[0009] CN114667284A reported Route 2, which uses tartrate ester resolving agents to separate intermediates and final products. The separation recovery rate is not high (not exceeding 50%), and multiple crystallizations are required to obtain the required enantiomeric chirality. The separation method generates a large amount of waste and is not environmentally friendly. Summary of the Invention

[0010] To overcome the shortcomings of existing production methods and processes, the purpose of this invention is to provide a chiral preparation method for phenelzine, which features mild reaction conditions, low cost, and suitability for industrial production. This invention utilizes asymmetric synthesis induced by chiral compound raw materials to obtain a product containing over 95% of the desired configuration, thereby improving yield and reducing waste.

[0011] To achieve the above objectives, the present invention adopts the following technical solution:

[0012] This invention provides a chiral method for the preparation of phenelzine, the reaction route of which is as follows:

[0013]

[0014] The preparation method includes the following steps:

[0015] (1) Compound I reacts with chiral compound II to give compound III;

[0016] (2) Compound III and compound IV react to give compound V;

[0017] (3) Compound V reacts with an ethylating agent to give compound VI;

[0018] (4) Compound VI is deprotected or ammonolyzed to obtain compound VII;

[0019] Where R represents

[0020] R1 and R2 are independently hydrogen or chiral prosthetic groups, and at least one of R1 and R2 is a chiral prosthetic group; or R1 and R2 together with the nitrogen atom attached to them constitute a nitrogen-containing heterocyclic chiral prosthetic group; R3 is a chiral prosthetic group;

[0021] The chiral cofactor is selected from the following groups having a chiral structure: substituted or unsubstituted C1-C 10 Alkyl, substituted or unsubstituted C3-C 20 Alicyclic group, substituted or unsubstituted, containing 1-4 (e.g., 1, 2, 3, or 4) heteroatoms selected from N, P, S, or O, 4-20 membered heterocyclic group, substituted or unsubstituted, C6-C 20 Aryl, substituted or unsubstituted 5-20 membered heteroaryl groups containing 1-4 (e.g. 1, 2, 3 or 4) heteroatoms selected from N, P, S or O;

[0022] The nitrogen-containing heterocyclic chiral prosthetic group is selected from the following groups having a chiral structure: substituted or unsubstituted nitrogen-containing 4-20-membered heterocyclic groups, substituted or unsubstituted nitrogen-containing 5-20-membered heteroaryl groups, wherein the heterocyclic group and the heteroaryl group optionally also contain 1-4 (e.g. 1, 2, 3, 4) heteroatoms selected from N, P, S or O.

[0023] The substitution refers to being replaced by one or more substituents selected from group A below;

[0024] Group A substituents: halogen, hydroxyl (-OH), carboxyl (-COOH), amino (-NH2), mercapto (-SH), oxo (=O), C1-C6 alkyl, C2-C6 olefin, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 alkylthio, C1-C6 alkyl-O-C1-C6 alkyl, C1-C6 alkyl-S-C1-C6 alkyl, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)(C1-C6 alkyl), C1-C6 acyloxy, C1-C6 amide, C1-C6 alkoxy-C1-C6 acyl, C3-C 20 Alicyclic groups, 4-20 membered heterocyclic groups, C6-C 20 Aryl, 5-20 heteroaryl, C3-C 20Alicyclic C1-C6 alkyl, 4-20 membered heterocyclic C1-C6 alkyl, C6-C 20 Aryl C1-C6 alkyl, 5-20 heteroaryl C1-C6 alkyl;

[0025] Among them, C3-C in group A substituents 20 Alicyclic groups, 4-20 membered heterocyclic groups, C6-C 20 Aryl, 5-20 heteroaryl, C3-C 20 Alicyclic C1-C6 alkyl, 4-20 membered heterocyclic C1-C6 alkyl, C6-C 20 The aryl C1-C6 alkyl and 5-20 heteroaryl C1-C6 alkyl may optionally be substituted by one or more substituents selected from group B below;

[0026] Group B substituents: halogen, hydroxyl (-OH), carboxyl (-COOH), amino (-NH2), mercapto (-SH), oxo (=O), C1-C6 alkyl, C2-C6 olefin, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 alkylthio, -NH (C1-C6 alkyl), -N (C1-C6 alkyl)(C1-C6 alkyl), C1-C6 acyloxy, C1-C6 amide, C3-C 20 Alicyclic groups, 4-20 membered heterocyclic groups, C6-C 20 Aryl, 5-20 heteroaryl.

[0027] In a specific embodiment, the chiral cofactor is selected from the following groups having a chiral structure: substituted or unsubstituted C1-C4 alkyl groups, substituted or unsubstituted C3-C4 alkyl groups. 10 Alicyclic groups, substituted or unsubstituted heterocyclic groups containing 1-3 heteroatoms selected from N, P, S or O, 4-10 membered heterocyclic groups, substituted or unsubstituted C6-C 10 Aryl, substituted or unsubstituted 5-10 membered heteroaryl groups containing 1-3 heteroatoms selected from N, P, S or O;

[0028] The nitrogen-containing heterocyclic chiral prosthetic group is selected from the following groups having a chiral structure: substituted or unsubstituted nitrogen-containing 4-10-membered heterocyclic groups, substituted or unsubstituted nitrogen-containing 5-10-membered heteroaryl groups, wherein the heterocyclic group and the heteroaryl group optionally also contain 1-3 (e.g., 1, 2, 3) heteroatoms selected from N, P, S or O.

[0029] The substitution refers to being replaced by one or more substituents selected from group A below;

[0030] Group A substituents: halogen, hydroxyl (-OH), carboxyl (-COOH), amino (-NH2), mercapto (-SH), oxo (=O), C1-C4 alkyl, C2-C4 olefin, C2-C4 alkynyl, C1-C4 alkoxy, C1-C4 alkylthio, C1-C4 alkyl-O-C1-C4 alkyl, C1-C4 alkyl-S-C1-C4 alkyl, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)(C1-C4 alkyl), C1-C4 acyloxy, C1-C4 amide, C1-C4 alkoxy-C1-C4 acyl, C3-C 10 Alicyclic group, 4-10 membered heterocyclic group, C6-C 10 Aryl, 5-10 heteroaryl, C3-C 10 Alicyclic C1-C4 alkyl, 4-10 membered heterocyclic C1-C4 alkyl, C6-C 10 Aryl C1-C4 alkyl, 5-10 heteroaryl C1-C4 alkyl;

[0031] Among them, C3-C in group A substituents 10 Alicyclic group, 4-10 membered heterocyclic group, C6-C 10 Aryl, 5-10 heteroaryl, C3-C 10 Alicyclic C1-C4 alkyl, 4-10 membered heterocyclic C1-C4 alkyl, C6-C 10 The aryl C1-C4 alkyl and 5-10 heteroaryl C1-C4 alkyl may optionally be substituted by one or more substituents selected from group B below;

[0032] Group B substituents: halogen, hydroxyl (-OH), carboxyl (-COOH), amino (-NH2), mercapto (-SH), oxo (=O), C1-C4 alkyl, C2-C4 olefin, C2-C4 alkynyl, C1-C4 alkoxy, C1-C4 alkylthio, -NH (C1-C6 alkyl), -N (C1-C6 alkyl), C1-C6 acyloxy, C1-C6 amide, C3-C 10 Alicyclic group, 4-10 membered heterocyclic group, C6-C 10 Aryl, 5-10 heteroaryl.

[0033] In a specific embodiment, the chiral cofactor is selected from the following groups having a chiral structure: substituted C1-C2 alkyl groups, substituted C3-C4 alkyl groups, etc. 10 Alicyclic group, substituted 4-10 membered heterocyclic group containing one or two heteroatoms selected from N, S or O; preferably substituted methyl, substituted ethyl, substituted cyclohexyl, borneol, isoborneol, substituted oxazolyl, substituted pyrrolidinyl, (1R,2S)-(+)-2,10-camphorsulfonamide, (1S,2R)-(-)-2,10-camphorsulfonamide;

[0034] The nitrogen-containing heterocyclic chiral prosthetic group is selected from the following groups having a chiral structure: substituted nitrogen-containing 4-10 membered heterocyclic groups, wherein the heterocyclic group optionally also contains one heteroatom selected from N, S or O; preferably substituted oxazolyl, substituted pyrrolidinyl, (1R,2S)-(+)-2,10-camphorsulfonamide, (1S,2R)-(-)-2,10-camphorsulfonamide;

[0035] The substitution refers to being replaced by one or more substituents selected from group A below;

[0036] Group A substituents: halogen, hydroxyl (-OH), carboxyl (-COOH), amino (-NH2), mercapto (-SH), oxo (=O), methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, methoxymethyl, ethoxycarbonyl, quinolinyl, 1-aza-bicyclo[2.2.2]octyl, phenyl, benzyl;

[0037] In this group, the quinolinyl, 1-aza-bicyclo[2.2.2]octyl, phenyl, and benzyl groups in group A are optionally replaced by one or more substituents selected from group B below;

[0038] Group B substituents: halogen, hydroxyl (-OH), carboxyl (-COOH), amino (-NH2), mercapto (-SH), oxo (=O), methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, vinyl, phenyl.

[0039] In a specific implementation, R is selected from:

[0040]

[0041] Wherein, Bn represents benzyl, Ph represents phenyl, and Me represents methyl.

[0042] In some embodiments, step (1) is carried out in a solvent in the presence of a catalyst, wherein the catalyst is an organic acid and an organic base; preferably, the organic acid is one or more selected from formic acid, acetic acid, propionic acid, and citric acid; the organic base is one or more selected from piperidine, pyridine, N,N-diisopropylethylamine, triethylamine, and 4-methylaminopyridine; preferably, the catalyst is piperidine and acetic acid; the solvent is one or more selected from dichloromethane, methanol, ethanol, propylene glycol, isopropanol, tetrahydrofuran, acetonitrile, and toluene, preferably dichloromethane, propylene glycol, or isopropanol.

[0043] In some embodiments, in step (1), the molar ratio of compound I to compound II is 1:0.3 to 1.5, preferably 1:0.9 to 1.0.

[0044] In some embodiments, in step (1), the molar ratio of compound I, organic acid, and organic base is 1:0.05-0.15:0.05-0.15, preferably 1:0.1:0.1.

[0045] In some embodiments, in step (1), the reaction temperature is 25-90°C, preferably 40-80°C; and the reaction time is 2-50 h, preferably 10-30 h.

[0046] In some embodiments, step (2) is carried out in a solvent selected from one or more of isopropanol, n-butanol, 2-butanol, n-pentanol, ethylene glycol monomethyl ether, N-methylpyrrolidone, N,N-dimethylacetamide, chlorobenzene, butyl acetate, benzyl alcohol, sulfolane, and dimethyl sulfoxide, preferably n-butanol, 2-butanol, ethylene glycol monomethyl ether, N-methylpyrrolidone, or dimethyl sulfoxide.

[0047] In some embodiments, in step (2), the molar ratio of compound III to compound IV is 1:0.7 to 1.5, preferably 1:1.1.

[0048] In some embodiments, in step (2), the reaction temperature is 90-150°C, preferably 110-130°C; and the reaction time is 20-90h, preferably 20-80h.

[0049] In some embodiments, step (3) is carried out in a solvent in the presence of a catalyst, wherein the catalyst is an acid, preferably one or more selected from concentrated sulfuric acid, trifluoromethanesulfonic acid, p-toluenesulfonic acid, and methanesulfonic acid, more preferably concentrated sulfuric acid; the solvent is selected from N,N-dimethylacetamide and N-methylpyrrolidone; the ethylating agent is one or more selected from chloroethane, bromoethane, iodoethane, diethyl carbonate, diethyl sulfate, ethyl orthoate, and ethyl sulfonate; the ethyl orthoate includes triethyl orthoformate, triethyl orthoacetate, triethyl orthopropionate, triethyl orthobutyrate, and tetraethyl orthocarbonate; the ethyl sulfonate includes ethyl p-toluenesulfonate, ethyl benzenesulfonate, and ethyl methanesulfonate; preferably, the ethylating agent is triethyl orthoformate or triethyl orthoacetate.

[0050] In some embodiments, in step (3), the molar ratio of compound V, catalyst, and ethylating agent is 1:0.1 to 0.8:3.5 to 7.5, preferably 1:0.45:5.5.

[0051] In some embodiments, in step (3), the reaction temperature is 100-150°C, preferably 105-125°C; and the reaction time is 0.5-4h, preferably 1-2h.

[0052] In some embodiments, in step (4), the deprotecting group of compound VI is removed in an alcohol solvent in the presence of a catalyst by reacting with hydrogen.

[0053] Preferably, the alcohol solvent is one or more selected from methanol, ethanol, n-propanol, isopropanol, tert-butanol, tert-amyl alcohol, n-butanol, ethylene glycol or propylene glycol, and more preferably methanol;

[0054] Preferably, the catalyst is one or more selected from Pd / C, Pd(OH)2 / C, and Pt / C, and more preferably Pd / C;

[0055] In step (4), the ammonolysis of compound VI is carried out in an ammonia solution;

[0056] Preferably, the solvent of the ammonia solution is one or more selected from water, methanol, ethanol, n-propanol, isopropanol, tert-butanol, tert-amyl alcohol, n-butanol, ethylene glycol, propylene glycol, tetrahydrofuran, 2-methyltetrahydrofuran, and dioxane, more preferably methanol;

[0057] Preferably, the concentration of NH3 in the ammonia solution is 3–12 M.

[0058] In some embodiments, in step (4), the reaction temperature is 20-100°C, preferably 20-60°C; and the reaction time is 10-50h, preferably 20-30h.

[0059] Terminology Explanation

[0060] As used herein, “heteroatom” refers to N, O, S, P atoms, particularly N, O, or S, each of which may be substituted or unsubstituted, including their oxidized forms. Examples of heteroatoms include, but are not limited to, -O-, -N=, -NR-, -S-, -S(O)-, and -S(O)2-, where R is hydrogen or a substituent as described above.

[0061] As used in this article, "C1-C" 10 "Alkyl" refers to a fully saturated, straight-chain or branched monovalent hydrocarbon group containing 1-20 carbon atoms, preferably C1-C6, C1-C4, or C1-C3 alkyl. Representative examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 3-methylhexyl, 2,2-dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl, and n-decyl. This definition applies whether the term "alkyl" appears alone or as part of other groups such as haloalkyl or alkoxy groups.

[0062] As used in this article, "C3-C" 20"Alicyclic group" refers to a fully saturated or partially unsaturated aliphatic ring containing 1-20 carbon atoms, including monocyclic, bicyclic (including fused rings), or spirocyclic rings. When it is a fully saturated aliphatic ring, it is a cycloalkyl group. Preferably, it is C3-C. 16 Alicyclic group, C3-C 10 Alicyclic groups, C3-C7 alicyclic groups, C3-C6 alicyclic groups, C3-C5 alicyclic groups, and C3-C4 alicyclic groups. Exemplary monocyclic alicyclic groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, and cyclohexenyl; exemplary bicyclic alicyclic groups include borneol, isoborneol, tetrahydronaphthyl, decahydronaphthyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.1]heptenyl, 6,6-dimethylbicyclo[3.1.1]heptyl, 2,6,6-trimethylbicyclo[3.1.1]heptyl, and bicyclo[2.2.2]octyl; exemplary tricyclic alicyclic groups include adamantyl, etc. Whether the term "alicyclic group" appears alone or as other groups such as C3-C4, the meaning of the term is not explicitly stated. 20 This definition applies to the presence of alicyclic C1-C6 alkyl groups, etc.

[0063] As used herein, “4-20 membered heterocyclic group” refers to a 4-20 membered non-aromatic ring, which is partially or fully saturated and contains 1-4, preferably 1-3, or 1-2 ring heteroatoms selected from N, P, S, or O, with the remaining ring atoms being carbon. It includes monocyclic, bicyclic (including fused rings), or spirocyclic rings, and includes “heterocyclic alkyl” and “partially saturated heterocycles”. Preferably, the heterocyclic group is a 4-16 membered heterocyclic group, a 4-10 membered heterocyclic group, a 4-8 membered heterocyclic group, a 4-7 membered heterocyclic group, a 4-6 membered heterocyclic group, or a 4-5 membered heterocyclic group. Exemplary monocyclic heterocyclic groups include, but are not limited to, ethylene oxide, aziridinyl, aziridine, oxazolidinyl, aziridine, aziridine (pyrrolidinyl), tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydrothiophenyl 1,1-dioxide, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, isothiazolyl, pyrrolidinyl-2-one, imidazolylone, piperidinyl (hexahydropyridine), N-methylpiperidinyl, tetrahydropyranyl, oxazinyl, 1,3-oxazinyl, and hexahydropyrimidine. The following groups are included: 1,4-dioxa-8-aza-spiro[4.5]decane-8-yl, morpholino, thiomorpholino, thiomorpholino-S-monoxide, thiomorpholino-S,S-dioxide, octahydropyrrolo[3,2-b]pyrrole, 1-aza-bicyclo[2.2.2]octyl, (1R,2S)-(+)-2,10-camphorsulfonamide, (1S,2R)-(-)-2,10-camphorsulfonamide, etc. This definition applies whether the term "heterocyclic group" appears alone or as part of other groups such as 4-20 membered heterocyclic C1-C6 alkyl groups.

[0064] As used in this article, "C6-C" 20 "Aryl" refers to an aromatic group consisting of one or more fused rings having 6-20 carbon atoms, preferably C6-C. 14 Aryl, C6-C 12 Aryl, C6-C 10 Aryl groups include monocyclic aryl groups (e.g., phenyl); or fused bicyclic systems, where one ring is an aromatic ring and the other is an aromatic ring (e.g., in naphthalene, biphenyl) or a non-aromatic ring (e.g., in dihydroindene, tetrahydronaphthalene). Non-limiting examples of aryl groups include phenyl, biphenyl, naphthyl, tetrahydronaphthyl, indene, dihydroindene, or anthracene, etc. Whether the term "aryl" appears alone or as other groups such as C6-C... 20 This definition applies to the presence of any of the aryl C1-C6 alkyl groups.

[0065] As used herein, "5-20-membered heteroaryl" refers to an aromatic ring system containing 1-4, preferably 1-3, cyclic heteroatoms selected from N, P, O, or S, comprising 5-20, preferably 5-14, preferably 5-10, more preferably 5-7, or 5-6-membered rings, including monocyclic, bicyclic, or fused polycyclic rings, with the remaining ring atoms being carbon atoms. Examples of heteroaryl groups include, but are not limited to: pyrrole, furanyl, thiophene, pyrazolyl, imidazolyl, triazolyl, thiazolyl, isothiazolyl, oxazolyl, pyridinyl, pyranyl, pyrazinyl, pyridazinyl, pyrimidinyl, oxazinyl, oxadiazinyl, quinolinyl, isoquinolinyl, borazinyl, quinazolinyl, quinoxalinyl, benzoxazinyl, 2H-chromene, benzopyranyl, benzothiophene, indole, inzolyl, benzene The following groups are included: pyrazole, benzimidazolyl, imidazopyridyl, benzoxazolyl, benzothiazolyl, 7-azaindolyl, 6-azaindolyl, 5-azaindolyl, 4-azaindolyl, 1H-benzo[d][1,2,3]triazolyl, [1,2,4]triazolo[1,5-a]pyridyl, [1,2,4]triazolo[4,3-a]pyridine, pyrazolo[1,5-a]pyridine, etc. This definition applies whether the term "heteroaryl" appears alone or as part of other groups such as 5-20-membered heteroaryl C1-C6 alkyl groups.

[0066] As used herein, "C2-C6 olefinic group" refers to a straight-chain or branched monovalent hydrocarbon group containing 2-6 carbon atoms and at least one double bond, preferably a C2-C4 olefinic group. Representative examples include, but are not limited to, vinyl, propenyl, isopropenyl, butenyl, isobutenyl, pentenyl, isopentenyl, hexenyl, etc.

[0067] As used herein, "C2-C6 alkyne group" refers to a straight-chain or branched monovalent hydrocarbon group containing 2-6 carbon atoms and at least one triple bond, preferably a C2-C4 alkyne group. Representative examples include, but are not limited to, ethynyl, propynyl, isopropynyl, butynyl, isobutynyl, penynyl, isopentenynyl, hexynyl, etc.

[0068] As used herein, “C1-C6 alkoxy” refers to a C1-C6 alkyl group as defined herein, i.e., an alkyl-O- group, preferably a C1-C4 alkoxy or a C1-C3 alkoxy group, with representative examples including but not limited to methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, pentoxy, hexoxy, etc.

[0069] As used herein, “C1-C6 alkylthio” refers to a C1-C6 alkyl group as defined herein, i.e., an alkyl-S-group, preferably a C1-C4 alkylthio or C1-C3 alkylthio, with representative examples including but not limited to methylthio, ethylthio, propylthio, 2-propylthio, butylthio, tert-butylthio, pentylthio, hexylthio, etc.

[0070] As used herein, "halogen" refers to fluorine, chlorine, bromine, and iodine. Preferred halogens as substituents are fluorine and chlorine.

[0071] Beneficial effects

[0072] This invention utilizes asymmetric synthesis induced by chiral compound raw materials to obtain a product containing over 95% of the desired configuration, thereby improving yield and reducing waste. The chiral preparation method of fenelone of this invention features mild reaction conditions, low cost, and suitability for industrial production. Detailed Implementation

[0073] The present invention will now be described in detail. Before proceeding with the description, it should be understood that the terminology used in this specification and the appended claims should not be construed as limited to its general or dictionary meaning, but rather should be interpreted according to the meaning and concept corresponding to the technical aspects of the invention, based on the principle that the inventors are allowed to appropriately define the terms for the best interpretation. Therefore, the description presented herein is merely a preferred example for illustrative purposes and is not intended to limit the scope of the invention. It should be understood that other equivalents or modifications can be obtained from it without departing from the spirit and scope of the invention.

[0074] In this document, the terms “comprising,” “including,” “having,” “containing,” or any similar terms are open-ended conjunctions intended to cover non-exclusive inclusions. For example, a composition or article containing a plurality of elements is not limited to those listed herein, but may also include other elements not explicitly listed but typically inherent to the composition or article. Furthermore, unless explicitly stated to the contrary, the term “or” is inclusive, not exclusive. For example, the condition “A or B” is satisfied in any of the following cases: A is true (or exists) and B is false (or does not exist); A is false (or does not exist) and B is true (or exists); A and B are both true (or exist). Moreover, in this document, the terms “comprising,” “including,” “having,” and “containing” should be interpreted as specifically disclosed and simultaneously cover closed or semi-closed conjunctions such as “composed of” and “substantially composed of.”

[0075] In this document, all features or conditions defined in the form of numerical ranges or percentage ranges are for the sake of brevity and convenience only. Accordingly, descriptions of numerical ranges or percentage ranges should be considered as covering and specifically disclosing all possible secondary ranges and individual values ​​within those ranges, particularly integer values. For example, a range description of "1 to 8" should be considered as specifically disclosing all secondary ranges such as 1 to 7, 2 to 8, 2 to 6, 3 to 6, 4 to 8, 3 to 8, etc., particularly secondary ranges defined by all integer values, and should be considered as specifically disclosing individual values ​​within those ranges such as 1, 2, 3, 4, 5, 6, 7, 8, etc. Unless otherwise specified, the foregoing interpretation applies to all content throughout this invention, regardless of its scope.

[0076] If a quantity or other numerical value or parameter is expressed as a range, a preferred range, or a series of upper and lower limits, it should be understood that this document has specifically disclosed all ranges consisting of any upper or preferred value of that range and the lower or preferred value of that range, regardless of whether such ranges are separately disclosed. Furthermore, when a range of numerical values ​​is mentioned herein, unless otherwise stated, the range shall include its endpoints and all integers and fractions within the range.

[0077] In this document, numerical values ​​are to be understood as having a precision with significant digits, provided that the purpose of the invention can be achieved. For example, the number 40.0 should be understood to cover the range from 39.50 to 40.49.

[0078] Example 1

[0079]

[0080] (1) Preparation of compound III-1

[0081] Compound I-1 (6.2 g, 38.3 mmol, 1.0 eq), compound II-1 (9.0 g, 34.6 mmol, 0.9 eq), piperidine (324 mg, 3.83 mmol, 0.1 eq), and glacial acetic acid (230 mg, 3.83 mmol, 0.1 eq) were sequentially added to isopropanol (32 mL, 5.2 V). The mixture was heated to 60 °C and stirred for 16 hours. After the reaction was completed, the reaction solution was poured into EA / H2O, extracted, and separated into layers. The organic layer was dried, concentrated, and purified by column chromatography (DCM / MeOH = 30:1) to obtain compound III-1 (11.2 g, 80% yield). 1HNMR (400MHz, DMSO-d6) δ7.74 (s, 1H), 7.45 (d, J=8.0Hz, 1H), 7.21-7.35 (m, 6H), 7.15 (s, 1H) , 4.74(brs, 1H), 4.12-4.31(m, 2H), 3.92(s, 3H), 3.48(brs, 1H), 2.72(brs, 1H), 2.53(s, 3H).

[0082] (2) Preparation of compound V-1

[0083] Compound III-1 (2 g, 4.94 mmol, 1.0 eq) and compound IV-1 (670 mg, 5.4 mmol, 1.1 eq) were added to DMSO (15 mL), and the mixture was heated to 120 °C and stirred for 72 hours. LC / MS showed an isomer ratio of 95:5. After the reaction, the reaction solution was cooled to room temperature and poured into DCM / H₂O (100 mL / 30 mL). Extraction and separation were performed, the organic layer was dried, concentrated, and purified by column chromatography (DCM / MeOH = 10:1) to give compound V-1 (1.79 g, yield 71%). 1 HNMR (400MHz, CDCl3) δ7.26-7.35(m, 3H), 7.13-7.24(m, 3H), 7.02-7.09(m, 2H), 6.75-6.83(m, 1H), 5.75and 5.67(s, 1H), 5.49(s, 1H), 4.39(brs, 1H), 4.11-4.26(m, 2H), 3.89and 3.83 (s, 3H), 3.42 (d, J=12.0Hz, 1H), 2.71-2.86 (m, 1H), 2.01 (s, 3H), 1.99 (s, 3H).

[0084] (3) Preparation of compound VI-1

[0085] Compound V-1 (1.0 g, 1.96 mmol, 1.0 eq), triethyl orthoacetate (1.75 g, 10.8 mmol, 5.5 eq), and concentrated sulfuric acid (86 mg, 0.87 mmol, 0.45 eq) were sequentially added to N,N-dimethylacetamide (6 mL). The mixture was heated to 115 °C and stirred for 1.5 h. After the reaction was complete, the reaction solution was added to water (15 mL), and the pH was adjusted to neutral with saturated sodium bicarbonate aqueous solution. The mixture was then extracted with dichloromethane (30 mL × 2). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and purified by column chromatography (DCM / MeOH = 10:1) to give compound VI-1 (0.84 g, yield 81%). 1HNMR (400MHz, CDCl3) δ7.98and8.03(s,1H),7.63(s,1H),7.13-7.46(m,6H),6.95(d,J=8.0Hz,1H),5.44and 5.67(s,1H),4.15-4.68(m,3H),3.95-4.15(m,2H),3.84and 3.91(s,3H),2.59-2.64(m,3H),2.18(s,3H),2.00and 2.03(s,3H),0.93and 1.00(t, J=8.0Hz, 3H).

[0086] (4) Preparation of compound VII

[0087] Compound VI-1 (500 mg, 0.93 mmol) was added to 7 MNH3 / MeOH (5 mL), and the mixture was heated to 50 °C and stirred overnight. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the concentrate was slurried and stirred with methyl tert-butyl ether to obtain compound VII (i.e., phenelzine, 300 mg, white solid, yield 85%, 99% ee). 1 H NMR (400MHz, DMSO-d6) δ: 7.69 (s, 1H), 7.55 (s, 1H), 7.36 (d, J=1.5Hz, 1H), 7.27 (dd, J=8.0, 1.5Hz, 1H), 7.15 (d, J=8.0Hz , 1H), 6.88-6.50 (bs, 2H), 5.37 (s, 1H), 4.08-3.95 (m, 2H), 3.82 (s, 3H), 2.18 (s, 3H), 2.12 (s, 3H), 1.05 (t, J=7.0Hz, 3H).

[0088] Example 2

[0089]

[0090] (1) Preparation of compound III-2

[0091] Compound I-1 (1.0 g, 6.2 mmol, 1.0 eq), compound II-2 (1.24 g, 6.2 mmol, 1.0 eq), piperidine (53 mg, 0.62 mmol, 0.1 eq), and glacial acetic acid (37 mg, 0.62 mmol, 0.1 eq) were sequentially added to isopropanol (10 mL), and the mixture was heated to 60 °C and stirred for 24 hours. After the reaction was completed, the reaction solution was poured into EA / H2O, extracted, and separated into layers. The organic layer was dried, concentrated, and purified by column chromatography (DCM / MeOH = 30:1) to obtain a yellow oily substance, namely compound III-2 (1.33 g, yield 62%). 1H NMR (500MHz, DMSO-d6) δ8.40 (s, 1H), 8.28 (d, J = 1.1Hz, 1H), 7.57 (d, J = 2.1Hz, 1H), 7.44-7.33 ( m, 3H), 7.33-7.20 (m, 4H), 4.83-4.74 (m, 1H), 2.35 (s, 3H), 2.33 (s, 3H), 1.48 (d, J=6.8Hz, 3H).

[0092] (2) Preparation of compound V-2

[0093] Compound III-2 (1085 mg, 3.12 mmol, 1.0 eq) and compound IV-1 (426 mg, 3.43 mmol, 1.1 eq) were added to DMSO (20 mL), and the mixture was heated to 120 °C and stirred for 24 hours. LC / MS showed an isomer ratio of 89:11. After the reaction was complete, the reaction solution was cooled to room temperature and poured into DCM / H2O (100 mL / 30 mL). The layers were extracted and separated. The organic layer was dried, concentrated, and purified by column chromatography (DCM / MeOH = 10:1) to obtain a yellow oily substance, namely compound V-2 (993 mg, yield 70%). 1 H NMR (500MHz, DMSO-d6) δ11.24(s, 1H), 9.19and 9.13(s, 1H), 8.40and 8.37 (s, 1H), 7.94 (dd, J=7.5, 1.0Hz, 1H), 7.54 (dd, J=7.5, 2.1Hz, 1H), 7.41-7.34 (m, 3H), 7.33-7.21 (m, 4H), 5.36and 5.28 (s, 1H), 4.87-4.77 (m, 1H), 3.74 (s, 3H), 2.24 (d, J = 0.7Hz, 3H), 2.09 and 2.07 (d, J = 0.7Hz, 3H), 1.48 (d, J = 6.8Hz, 3H).

[0094] (3) Preparation of compound VI-2

[0095] Compound V-2 (800 mg, 1.76 mmol, 1.0 eq), triethyl orthoformate (1.43 g, 9.68 mmol, 5.5 eq), and concentrated sulfuric acid (78 mg, 0.79 mmol, 0.45 eq) were sequentially added to N,N-dimethylacetamide (6 mL), and the mixture was heated to 115 °C and stirred for 2 hours. After the reaction was complete, the reaction solution was added to water (15 mL), the pH was adjusted to neutral with saturated sodium bicarbonate aqueous solution, and the mixture was extracted with dichloromethane (30 mL × 2). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and purified by column chromatography (DCM / MeOH = 10:1) to give a yellow oily substance, namely compound VI-2 (700 mg, yield 82%). 1 H NMR (500MHz, DMSO-d6) δ8.88and 8.70(s, 1H), 8.40and 8.37(s, 1H), 7.62-7.50(m, 2H), 7.43-7.32(m, 4H), 7.33-7.20(m, 3H), 5.49and 5.38 (s, 1H), 4.85-4.78 (m, 1H), 4.31 (dq, J=12.0, 6.0Hz, 1H), 4.11 (dq, J=12.2, 6.1Hz, 1H), 3.74 (s, 3H), 2.30 (d, J=1.1Hz, 3H), 2.02and 2.00 (s, 3H), 1.48 (d, J = 6.8Hz, 3H), 1.36 (t, J = 6.0Hz, 3H).

[0096] (4) Preparation of compound VII

[0097] Compound VI-2 (450 mg, 0.93 mmol) was added to methanol (5 mL), followed by Pd / C (45 mg, 5% Pd / C containing 50% water). Hydrogen gas was bubbled through to 1.0 MPa, and the reaction was carried out at room temperature for 24 hours. After the reaction was complete, the reaction solution was filtered, the filtrate was concentrated, and the concentrate was stirred with methyl tert-butyl ether (5 mL) for 1 hour. The mixture was then filtered, the filter cake was washed with methyl tert-butyl ether, and dried to give compound VII (i.e., phenelzine, 288 mg, white solid, yield 82%, 98% ee).

[0098] Example 3

[0099]

[0100] (1) Preparation of compound III-3

[0101] Compound I-1 (1.0 g, 6.2 mmol, 1.0 eq), compound II-3 (1.49 g, 6.2 mmol, 1.0 eq), piperidine (53 mg, 0.62 mmol, 0.1 eq), and glacial acetic acid (37 mg, 0.62 mmol, 0.1 eq) were sequentially added to isopropanol (10 mL), and the mixture was heated to 60 °C and stirred for 24 hours. After the reaction was completed, the reaction solution was poured into EA / H2O, extracted, and separated into layers. The organic layer was dried, concentrated, and purified by column chromatography (DCM / MeOH = 30:1) to obtain a yellow oily substance, namely compound III-3 (1.2 g, yield 51%). 1 HNMR (400MHz, CDCl3) δ7.78 (s, 1H), 7.53 (d, J=8.0Hz, 1H), 7.20 (d, J=8.0Hz, 1H), 7.14 (s, 1H), 4.80 (dt, J=12.0, 4.0Hz, 1H), 3.92 (s, 3H), 2.43 (s, 3 H), 1.60-1.71 (m, 4H), 1.22-1.32 (m, 2H), 1.01-1.12 (m, 1H), 0.91 (d, J=8. 0Hz, 3H), 0.82-0.89 (m, 2H), 0.78 (d, J=8.0Hz, 3H), 0.70 (d, J=4.0Hz, 3H).

[0102] (2) Preparation of compound V-3

[0103] Compound III-3 (1080 mg, 2.81 mmol, 1.0 eq) and compound IV-1 (384 mg, 3.09 mmol, 1.1 eq) were added to DMSO (20 mL), and the mixture was heated to 120 °C and stirred for 24 hours. LC / MS analysis showed an isomer ratio of 88:12. After the reaction was complete, the reaction solution was cooled to room temperature and poured into DCM / H₂O (100 mL / 30 mL). Extraction and separation were performed, the organic layer was dried, concentrated, and purified by column chromatography (DCM / MeOH = 10:1) to obtain a yellow oily substance, compound V-3 (800 mg, yield 58%). 1 H NMR (400MHz, CDCl3) δ11.97 (s, 1H), 7.45 (dd, J=20.0, 8.0Hz, 1H), 7.09-7.15 (m, 1H), 6.99 (s, 1H), 6.77 (s, 1H), 5.87and 5.79 (s, 1H), 5.39and 5.35(s, 1H), 4.57-4.79(m, 1H), 3.76and 3.77(s, 3H), 2.43and 2.37(s, 3H), 2.02and 2.00(s, 3H), 0.50-1.90(m, 18H).

[0104] (3) Preparation of compound VI-3

[0105] Compound V-3 (600 mg, 1.23 mmol, 1.0 eq), triethyl orthoformate (1.0 g, 6.76 mmol, 5.5 eq), and concentrated sulfuric acid (54 mg, 0.55 mmol, 0.45 eq) were sequentially added to N,N-dimethylacetamide (6 mL), and the mixture was heated to 115 °C and stirred for 2 hours. After the reaction was complete, the reaction solution was added to water (15 mL), the pH was adjusted to neutral with saturated sodium bicarbonate aqueous solution, and the mixture was extracted with dichloromethane (30 mL × 2). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and purified by column chromatography (DCM / MeOH = 10:1) to give a yellow oily substance, namely compound VI-3 (500 mg, yield 78%). 1 HNMR (400MHz, CDCl3) δ7.63 (s, 1H), 7.33-7.38 (m, 1H), 7.12 (d, J=8.0Hz, 1H), 6.99 (s, 1H), 5.87and 5.83 (s, 1H), 5.48and 5.41(s, 1H), 4.59-4.76(m, 1H), 4.08-4.23(m, 2H), 3.78and 3.76(s, 3H), 2.45and 2.42(s, 3H), 2.13and 2.10(s, 3H), 0.54-1.92(m, 21H).

[0106] (4) Preparation of compound VII

[0107] Compound VI-3 (500 mg, 0.96 mmol) was added to 7 M NH3 / MeOH (5 mL), and the mixture was heated to 50 °C and stirred overnight. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the concentrate was slurried and stirred with methyl tert-butyl ether to obtain compound VII (i.e., phenelzine, 280 mg, white solid, yield 77%, 95% ee).

[0108] Example 4

[0109]

[0110] (1) Preparation of compound III-4

[0111] Compound I-1 (1.0 g, 6.2 mmol, 1.0 eq), compound II-4 (1.64 g, 6.2 mmol, 1.0 eq), piperidine (53 mg, 0.62 mmol, 0.1 eq), and glacial acetic acid (37 mg, 0.62 mmol, 0.1 eq) were sequentially added to isopropanol (10 mL), and the mixture was heated to 60 °C and stirred for 24 hours. After the reaction was completed, the reaction solution was poured into EA / H2O, extracted, and separated into layers. The organic layer was dried, concentrated, and purified by column chromatography (DCM / MeOH = 30:1) to obtain a yellow oily substance, namely compound III-4 (1.5 g, yield 59%). 1 H NMR (500MHz, DMSO-d6) δ8.24-8.19 (m, 1H), 7.54-7.45 (m, 2H), 7.33 (h, J=1.9Hz, 3H), 7.29-7.22 (m, 3H), 6. 44 (d, J=0.9Hz, 1H), 4.10 (ddt, J=26.0, 12.3, 6.2Hz, 2H), 3.87 (s, 3H), 2.30 (s, 3H), 1.22 (t, J=6.0Hz, 3H).

[0112] (2) Preparation of compound V-4

[0113] Compound III-4 (1145 mg, 2.81 mmol, 1.0 eq) and compound IV-1 (384 mg, 3.09 mmol, 1.1 eq.) were added to DMSO (20 mL), and the mixture was heated to 120 °C and stirred for 24 hours. LC / MS showed an isomer ratio of 85:15. After the reaction, the reaction solution was cooled to room temperature and poured into DCM / H₂O (100 mL / 30 mL). Extraction and separation were performed, the organic layer was dried, concentrated, and purified by column chromatography (DCM / MeOH = 10:1) to obtain a yellow oily substance, compound V-4 (800 mg, yield 55%). 1 H NMR (500MHz, DMSO-d6) δ11.24 (s, 1H), 9.19and 9.17(s, 1H), 7.63-7.53(m, 2H), 7.45-7.37(m, 2H), 7.35-7.23(m, 5H), 6.50( d, J=1.4Hz, 1H), 5.61 (t, J=1.1Hz, 1H), 4.51 (dq, J=12.1, 6.0Hz, 1H), 3.74and 3.72 (s, 3H), 3.27 (dq, J=12.1, 6.0Hz, 1H), 2.28 (d, J=1.07, 3H), 2.10and 2.08 (s, 3H), 1.22 (t, J=6.1Hz, 3H).

[0114] (3) Preparation of compound VI-4

[0115] Compound V-4 (600 mg, 1.17 mmol, 1.0 eq), triethyl orthoformate (954 mg, 6.44 mmol, 5.5 eq), and concentrated sulfuric acid (52 mg, 0.53 mmol, 0.45 eq) were sequentially added to N,N-dimethylacetamide (6 mL), and the mixture was heated to 115 °C and stirred for 2 hours. After the reaction was complete, the reaction solution was added to water (15 mL), the pH was adjusted to neutral with saturated sodium bicarbonate aqueous solution, and the mixture was extracted with dichloromethane (30 mL × 2). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and purified by column chromatography (DCM / MeOH = 10:1) to give a yellow oily substance, namely compound VI-4 (500 mg, yield 79%). 1 H NMR (500MHz, DMSO-d6) δ8.88 (s, 1H), 7.77 (dd, J=7.5, 1.1Hz, 1H), 7.61-7.49 (m , 4H), 7.39-7.26 (m, 3H), 6.80 (d, J = 2.1Hz, 1H), 6.50 (d, J = 1.3Hz, 1H), 5.28and 5.26 (s, 1H), 4.33-4.25 (m, 2H), 4.05 (dq, J=12.1, 6.0Hz, 1H), 3.85-3.65 (m, 4H), 2.30 (d, J=1.1Hz, 3H), 2.03and 2.00(s, 3H), 1.36(t, J=6.0Hz, 3H), 1.22(t, J=6.0Hz, 3H).

[0116] (4) Preparation of compound VII

[0117] Compound VI-4 (500 mg, 0.92 mmol) was added to 7 MNH3 / MeOH (5 mL), and the mixture was heated to 50 °C and stirred overnight. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the concentrate was slurried and stirred with methyl tert-butyl ether to obtain compound VII (i.e., phenelzine, 270 mg, white solid, yield 78%, 95% ee).

[0118] Example 5

[0119]

[0120] (1) Preparation of compound III-5

[0121] Compound I-1 (1.0 g, 6.2 mmol, 1.0 eq), compound II-5 (1.48 g, 6.2 mmol, 1.0 eq), piperidine (53 mg, 0.62 mmol, 0.1 eq), and glacial acetic acid (37 mg, 0.62 mmol, 0.1 eq) were sequentially added to isopropanol (10 mL), and the mixture was heated to 60 °C and stirred for 24 hours. After the reaction was completed, the reaction solution was poured into EA / H2O, extracted, and separated into layers. The organic layer was dried, concentrated, and purified by column chromatography (DCM / MeOH = 30:1) to obtain a yellow oily substance, namely compound III-5 (1.2 g, yield 51%). 1 H NMR (500MHz, DMSO-d6) δ8.21 (d, J=0.9Hz, 1H), 7.55-7.41 (m, 2H), 7.32 (d, J=1.9Hz, 1H), 4.40 (t, J=7.0Hz, 1H), 3.87 (s, 3H), 2.26(s, 3H), 2.04-1.90(m, 1H), 1.66-1.50(m, 2H), 1.39-1.28(m, 1H), 1.22-0.97(m, 3H), 0.77(s, 6H), 0.59(s, 3H).

[0122] (2) Preparation of compound V-5

[0123] Compound III-5 (1080 mg, 2.83 mmol, 1.0 eq) and compound IV-1 (386 mg, 3.11 mmol, 1.1 eq) were added to DMSO (20 mL), and the mixture was heated to 120 °C and stirred for 24 hours. LC / MS showed an isomer ratio of 90:10. After the reaction was complete, the reaction solution was cooled to room temperature and poured into DCM / H₂O (100 mL / 30 mL). Extraction and separation were performed, the organic layer was dried, concentrated, and purified by column chromatography (DCM / MeOH = 10:1) to obtain a yellow oily substance, compound V-5 (800 mg, yield 56%). 1H NMR (500MHz, DMSO-d6) δ11.24 (s, 1H), 9.19and 9.16 (s, 1H), 7.43-7.30 (m, 3H), 7.27 (d, J=1.3Hz, 1H), 5.40and 5.38 (s, 1H), 4.44 (t, J = 7.0Hz, 1H), 3.74 (s, 3H), 2.28 (d, J = 1.0Hz, 3H), 2.10and 2.08(s, 3H), 2.03(dt, J=12.7, 6.8Hz, 1H), 1.67-1.52(m, 2H), 1.39(dt, J= 12.9, 6.9Hz, 1H), 1.21-1.05(m, 2H), 0.98-0.90(m, 1H), 0.90-0.71(m, 9H).

[0124] (3) Preparation of compound VI-5

[0125] Compound V-5 (620 mg, 1.23 mmol, 1.0 eq), triethyl orthoformate (1.0 g, 6.76 mmol, 5.5 eq), and concentrated sulfuric acid (54 mg, 0.55 mmol, 0.45 eq) were sequentially added to N,N-dimethylacetamide (6 mL), and the mixture was heated to 115 °C and stirred for 2 hours. After the reaction was complete, the reaction solution was added to water (15 mL), the pH was adjusted to neutral with saturated sodium bicarbonate aqueous solution, and the mixture was extracted with dichloromethane (30 mL × 2). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and purified by column chromatography (DCM / MeOH = 10:1) to give a yellow oily substance, namely compound VI-5 (500 mg, yield 77%). 1 H NMR (500MHz, DMSO-d6) δ8.88 (s, 1H), 7.64 (dd, J=7.6, 1.0Hz, 1H), 7.57 (s, 1H), 7.52 (dd, J=7.4, 1.9Hz, 1H), 6.49 (d, J=2.0Hz, 1H), 5.24 (s, 1H), 4.42 ( t, J=7.0Hz, 1H), 4.30 (dq, J=12.0, 6.0Hz, 1H), 4.14 (dq, J=12.1, 6.1Hz, 1H) , 3.74 (s, 3H), 2.30 (d, J = 1.1Hz, 3H), 2.03 (dd, J = 13.2, 6.7Hz, 1H), 1.99and 1.96 (s, 3H), 1.66-1.55 (m, 2H), 1.47-1.33 (m, 4H), 1.23 (ddt, J=36.7, 13.0, 6.7Hz, 3H), 0.86-0.66 (m, 9H).

[0126] (4) Preparation of compound VII

[0127] Compound VI-5 (510 mg, 0.96 mmol) was added to 7 M NH3 / MeOH (5 mL), and the mixture was heated to 50 °C and stirred overnight. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the concentrate was slurried with methyl tert-butyl ether to give compound VII (fenelone, 290 mg, white solid, yield 80%, 98% ee).

[0128] The above embodiments are merely illustrative of the technical solutions of the present invention and are not intended to limit it. 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 be made to the technical solutions described in the foregoing embodiments, or equivalent substitutions can be made to some or all of the technical features therein, without departing from the spirit and substance defined by the claims of the present invention; and such modifications or substitutions are still within the scope defined by the claims of the present invention.

Claims

1. A chiral method for preparing fenelone, the reaction route of which is as follows: The preparation method includes the following steps: (1) Compound I reacts with chiral compound II to give compound III; (2) Compound III and compound IV react to give compound V; (3) Compound V reacts with an ethylating agent to give compound VI; (4) Compound VI is deprotected or ammonolyzed to obtain compound VII; Where R represents , , , or Wherein, Bn represents benzyl, Ph represents phenyl, and Et represents ethyl.

2. The chiral preparation method of phenelzine according to claim 1, characterized in that: Step (1) is carried out in a solvent in the presence of a catalyst, wherein the catalyst is an organic acid and an organic base; and / or, the solvent is one or more selected from dichloromethane, methanol, ethanol, propylene glycol, isopropanol, tetrahydrofuran, acetonitrile, and toluene.

3. The chiral preparation method of phenelzine according to claim 2, characterized in that: The organic acid is selected from one or more of formic acid, acetic acid, propionic acid, and citric acid; The organic base is selected from one or more of piperidine, pyridine, N,N-diisopropylethylamine, triethylamine, and 4-methylaminopyridine.

4. The chiral preparation method of phenelzine according to claim 3, characterized in that: The catalyst is piperidine and acetic acid, and the solvent is dichloromethane, propylene glycol or isopropanol.

5. The chiral preparation method of phenelzine according to claim 2, characterized in that: The molar ratio of compound I, organic acid, and organic base is 1:0.05~0.15:0.05~0.

15.

6. The chiral preparation method of phenelzine according to claim 2, characterized in that: The molar ratio of compound I, organic acid, and organic base is 1:0.1:0.

1.

7. The chiral preparation method of phenelzine according to any one of claims 1-6, characterized in that: In step (1), the molar ratio of compound I to compound II is 1:0.3~1.5; and / or The reaction temperature is 25~90 ℃; the reaction time is 2~50 h.

8. The chiral preparation method of phenelzine according to claim 7, characterized in that: The molar ratio of compound I to compound II is 1:0.9~1.0; and / or The reaction temperature is 40~80 ℃; the reaction time is 10~30 h.

9. The chiral preparation method of phenelzine according to any one of claims 1-6, characterized in that: Step (2) is carried out in a solvent, wherein the solvent is one or more selected from isopropanol, n-butanol, 2-butanol, n-pentanol, ethylene glycol monomethyl ether, N-methylpyrrolidone, N,N-dimethylacetamide, chlorobenzene, butyl acetate, benzyl alcohol, sulfolane, and dimethyl sulfoxide; and / or In step (2), the molar ratio of compound III to compound IV is 1:0.7~1.5; and / or The reaction temperature is 90~150 ℃; the reaction time is 20~90 h.

10. The chiral preparation method of phenelzine according to claim 9, characterized in that: The solvent is n-butanol, 2-butanol, ethylene glycol monomethyl ether, N-methylpyrrolidone, or dimethyl sulfoxide; and / or The molar ratio of compound III to compound IV is 1:1.1; and / or The reaction temperature is 110~130 ℃; the reaction time is 20~80 h.

11. The chiral preparation method of phenelzine according to any one of claims 1-6, characterized in that: Step (3) is carried out in a solvent in the presence of a catalyst; The catalyst is an acid; The solvent is selected from N,N-dimethylacetamide and N-methylpyrrolidone; and / or The ethylating agent is selected from one or more of chloroethane, bromoethane, iodoethane, diethyl carbonate, diethyl sulfate, ethyl orthoate ethylating agents, and ethyl sulfonate ethylating agents; the ethyl orthoate ethylating agents include triethyl orthoformate, triethyl orthoacetate, triethyl orthopropionate, triethyl orthobutyrate, and tetraethyl orthocarbonate; the ethyl sulfonate ethylating agents include ethyl p-toluenesulfonate, ethyl benzenesulfonate, and ethyl methanesulfonate.

12. The chiral preparation method of phenelzine according to claim 11, characterized in that: The acid is one or more selected from concentrated sulfuric acid, trifluoromethanesulfonic acid, p-toluenesulfonic acid, and methanesulfonic acid; and / or The ethylating agent is triethyl orthoformate or triethyl orthoacetate.

13. The chiral preparation method of phenelzine according to claim 12, characterized in that: The acid is concentrated sulfuric acid.

14. The chiral preparation method of phenelzine according to claim 11, characterized in that: The molar ratio of compound V, catalyst, and ethylating agent is 1:0.1~0.8:3.5~7.5; and / or The reaction temperature is 100~150 ℃; the reaction time is 0.5~4 h.

15. The chiral preparation method of phenelzine according to claim 14, characterized in that: The molar ratio of compound V, catalyst, and ethylating agent is 1:0.45:5.5; and / or The reaction temperature is 105~125 ℃; the reaction time is 1~2 h.

16. The chiral preparation method of phenelzine according to any one of claims 1-6, characterized in that: In step (4), the deprotecting group of compound VI is removed in an alcohol solvent in the presence of a catalyst by reacting with hydrogen. The alcohol solvent is selected from one or more of methanol, ethanol, n-propanol, isopropanol, tert-butanol, tert-amyl alcohol, n-butanol, ethylene glycol, or propylene glycol; The catalyst is selected from one or more of Pd / C, Pd(OH)2 / C, and Pt / C; In step (4), the ammonolysis of compound VI is carried out in an ammonia solution; The solvent of the ammonia solution is selected from one or more of the following: water, methanol, ethanol, n-propanol, isopropanol, tert-butanol, tert-amyl alcohol, n-butanol, ethylene glycol, propylene glycol, tetrahydrofuran, 2-methyltetrahydrofuran, and dioxane. The concentration of NH3 in the ammonia solution is 3~12M; and / or The reaction temperature in step (4) is 20~100℃; the reaction time is 10~50h.

17. The chiral preparation method of phenelzine according to claim 16, characterized in that: The alcohol solvent is methanol; The catalyst is Pd / C; The solvent for the ammonia solution is methanol; and / or The reaction temperature in step (4) is 20~60℃; the reaction time is 20~30h.

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