A method for resolving non-negligible impurities in a non-negligible amount in a non-negligible amount in a non-negligible amount in a non-negligible amount in a non

Abstract

The application discloses a tartaric acid derivative resolving agent and a preparation method thereof, and a finerenone resolving method using the same. The preparation method of the tartaric acid derivative resolving agent is mild in conditions, short in steps and suitable for industrial production. The resolving agent is applied to resolving of racemic finerenone, and an ee value of more than 99% can be achieved by one-time resolving, thereby meeting the API quality requirement.

Description

Technical Field

[0001] This invention belongs to the field of drug synthesis, specifically relating to a tartaric acid derivative resolving agent and its preparation method, and a fenelazol resolving method using the same. Background Technology

[0002] Tartaric acid and its derivatives are widely used chiral selective resolving agents, primarily applied in the resolution of racemic organic amines and basic drugs. Compared to other resolving agents, tartaric acid offers advantages such as structural stability, abundant sources, and low cost. However, its small molecular weight and relatively small steric hindrance result in minimal spatial matching with amines, leading to reduced stereoselectivity. Substitution modification of tartaric acid has become a new research direction. Diacetyl tartaric acid and dibenzoyl tartaric acid are two commonly used resolving agents derived from tartaric acid. Due to the presence of sterically hindered groups, dibenzoyl tartaric acid can be used for the resolution of basic drugs, exhibiting significantly enhanced chiral selectivity compared to tartaric acid.

[0003] Fennellone is a nonsteroidal selective mineralocorticoid receptor antagonist that received marketing approval from the U.S. Food and Drug Administration (FDA) on July 9, 2021, and from the China National Medical Products Administration (NMPA) on June 28, 2022, for the treatment of adult patients with chronic kidney disease (CKD) and type 2 diabetes (T2D).

[0004] CN112041318A discloses a method for preparing phenelzine using benzoyl tartaric acid, and the reaction route is as follows:

[0005] .

[0006] However, the problem with the above method is that its separation efficiency is not high, and the enantiomeric excess (ee value) can only reach 97%-98% at most. Secondary crystallization is required to make the enantiomeric excess (ee value) reach more than 99% in order to meet the API quality requirements.

[0007] Therefore, it is still necessary to develop a more efficient new resolving agent for the resolution of racemic fenelitonee, which can obtain fenelitonee with a high ee value in a single preparation. Summary of the Invention

[0008] In order to overcome the shortcomings of existing production methods and processes, the purpose of this invention is to provide a novel tartaric acid-derived resolving agent and its preparation method, and to apply it to the resolution of racemic fenelone. This resolution method has simple reaction steps, mild conditions, is suitable for industrial production, and can achieve an ee value of more than 99% in a single resolution.

[0009] To achieve the above objectives, the present invention adopts the following technical solution:

[0010] In a first aspect, the present invention provides a tartaric acid derivative resolving agent having a structure shown in formula VI or V-II:

[0011]

[0012] Where Ar is substituted or unsubstituted C6-C 14 Aryl, or substituted or unsubstituted 5- to 8-membered heteroaryl containing 1 to 3 heteroatoms selected from N, O, and S, wherein “substituted” means substituted by 1 to 4 (e.g., 1, 2, 3, 4) substituents selected from: halogen (e.g., F, Cl, Br, I), hydroxyl (-OH), nitro (-NO2), cyano (-CN), C1-C6 alkyl, C1-C6 alkoxy.

[0013] In some implementations, Ar is substituted or unsubstituted C6-C. 10 Aryl, or substituted or unsubstituted 5- to 6-membered heteroaryl groups containing 1 to 3 heteroatoms selected from N, O, and S, preferably substituted or unsubstituted phenyl; wherein “substituted” means substituted by 1 or 2 substituents selected from: halogen (e.g., F, Cl, Br, I), hydroxyl (-OH), nitro (-NO2), cyano (-CN), C1-C4 alkyl (e.g., methyl, ethyl, propyl, or butyl), C1-C4 alkoxy (e.g., methoxy, ethoxy).

[0014] In some embodiments, Ar is phenyl, p-tolyl, p-methoxyphenyl, or p-chlorophenyl.

[0015] In some embodiments, the structure of the tartaric acid derivative resolving agent is selected from the structures shown below:

[0016]

[0017]

[0018]

[0019] .

[0020] In some embodiments, the present invention also provides a solvate of the tartaric acid derivative resolving agent, the structure of which is selected from the following structures:

[0021] ;

[0022] THF represents tetrahydrofuran, and MTBE represents methyl tert-butyl ether.

[0023] Secondly, the present invention provides a method for preparing a tartaric acid derivative resolving agent represented by formula VI or V-II, the reaction route of which is as follows:

[0024] or

[0025]

[0026] Wherein, Ar is defined as described in the first aspect of the present invention;

[0027] The preparation method includes the following steps:

[0028] (1) Compound II or compound I-II reacts with benzyl alcohol to give compound II-I or compound II-II;

[0029] (2) Compound II-I or compound II-II reacts with aryl isocyanate III to give compound IV-I or compound IV-II;

[0030] (3) Compound IV-I or compound IV-II undergoes a catalytic hydrogenation reaction with hydrogen to remove the benzyl group, yielding a tartaric acid derivative resolving agent as shown in formula VI or V-II.

[0031] In some embodiments, step (1) is carried out in a solvent in the presence of a catalyst, wherein the catalyst is one or more selected from p-toluenesulfonic acid, sulfuric acid, and benzenesulfonic acid, preferably p-toluenesulfonic acid; and the solvent is toluene.

[0032] In some embodiments, in step (1), the molar ratio of compound II or compound I-II to benzyl alcohol is 1:2.0~2.5, preferably 1:2.0~2.2; the molar ratio of compound II or compound I-II to catalyst is 1:0.01~0.02; preferably, the reaction is carried out under reflux for 10~20 h.

[0033] In some embodiments, step (2) is carried out in a solvent in the presence of an alkaline catalyst, wherein the alkaline catalyst is one or more selected from triethylamine, 4-dimethylaminopyridine, pyridine, and diisopropylethylamine, preferably triethylamine or 4-dimethylaminopyridine; and the solvent is one or more selected from ethyl acetate, toluene, tetrahydrofuran, 2-methyltetrahydrofuran, dichloromethane, and acetonitrile, preferably ethyl acetate.

[0034] In some embodiments, in step (2), the molar ratio of compound II-I or compound II-II to aryl isocyanate III is 1:2.0~2.5, preferably 1:2.0~2.2; the molar ratio of compound II-I or compound II-II to the alkaline catalyst is 1:0.01~0.2, preferably 1:0.03~0.07; preferably, the reaction temperature is 10~40℃, preferably 15~30℃; and the reaction time is 1~5h, preferably 2~3h.

[0035] In some embodiments, step (3) is carried out in a solvent in the presence of a catalyst, wherein the catalyst is one or more selected from palladium on carbon, palladium hydroxide on carbon, rhodium on carbon, Raney nickel, preferably palladium on carbon; and the solvent is one or more selected from ethyl acetate, toluene, tetrahydrofuran, 2-methyltetrahydrofuran, isopropyl acetate, preferably one or two of ethyl acetate and tetrahydrofuran.

[0036] In step (3), the mass ratio of compound IV-I or compound IV-II to catalyst is 1:0.04~0.2, preferably 1:0.05~0.1; the reaction temperature is 10~40℃, preferably 10~25℃; and the reaction time is 5~24h, preferably 6~12h.

[0037] In some embodiments, compound VI can also be obtained by stirring, filtering, and drying in a mixed solvent of petroleum ether and methyl tert-butyl ether to give a methyl tert-butyl ether solvate of compound VI. Compound VI can also be obtained by stirring, filtering, and drying in a mixed solvent of petroleum ether and tetrahydrofuran to give a tetrahydrofuran solvate of compound VI.

[0038] Thirdly, the present invention provides a method for resolving phenelzine using the tartaric acid derivative resolving agent described in the first aspect of the present invention, with the following reaction route:

[0039]

[0040] Ar is defined as described in the first aspect of this invention;

[0041] The splitting method includes the following steps:

[0042] (4) Racemic phenelzine reacts with a tartaric acid derivative resolving agent as shown in formula VI to obtain compound VI-I;

[0043] (5) Compound VI-I reacts with an alkaline reagent and dissociates to give phenelzine.

[0044] In some embodiments, in step (4), the reaction is carried out in a solvent, which is one or more selected from methanol, ethanol, water, tetrahydrofuran, 2-methyltetrahydrofuran, and dioxane, preferably a mixed solvent of ethanol and water with a volume ratio of ethanol / water = 1~15:1, and particularly preferably ethanol / water = 2~10:1.

[0045] In some embodiments, in step (4), the molar ratio of racemic phenelzine to the tartaric acid derivative resolving agent shown in Formula VI is 1:0.6~1.6, preferably 1:0.8~1.0; preferably, the reaction temperature is 10~70℃, preferably 15~50℃; and the reaction time is 6~24h, preferably 10~18h.

[0046] In some embodiments, in step (5), the alkalizing agent is one or more selected from sodium phosphate, sodium bicarbonate, disodium hydrogen phosphate, and sodium dihydrogen phosphate, preferably sodium phosphate; preferably, the alkalizing agent adjusts the pH of the reaction system to 8-9.

[0047] In some embodiments, in step (5), the reaction is carried out in a solvent selected from one or more of ethanol, water, tetrahydrofuran, and 2-methyltetrahydrofuran, preferably a mixed solvent of ethanol and water with a volume ratio of ethanol / water = 1:3; preferably, the reaction temperature is 0~40℃, more preferably 0~30℃; the reaction time is 2~6h, more preferably 2~4h.

[0048] In some embodiments, the ee value of the product fenelinone obtained in step (5) is greater than 99.5%.

[0049] Fourthly, the present invention provides a diastereomeric salt of phenelzine having the structure shown in the following formula:

[0050] ;

[0051] Ar is defined as described in the first aspect of this invention.

[0052] More specifically, the diastereomeric salt of phenelzine has a structure selected from the following formula:

[0053] .

[0054] Beneficial effects

[0055] The preparation method of the tartaric acid derivative resolving agent of this invention has mild reaction conditions and is suitable for industrial production. Using the tartaric acid derivative resolving agent of this invention for the resolution of racemic fenelone, a one-time resolution can achieve an ee value of over 99%, meeting API quality requirements. Attached Figure Description

[0056] Figure 1 The DSC spectrum of solvate VI-1-1 in Example 9;

[0057] Figure 2 Thermogravimetric analysis (TGA) spectrum of solvate VI-1-1 in Example 9;

[0058] Figure 3 The DSC spectrum of solvate VI-1-2 in Example 10;

[0059] Figure 4 The thermogravimetric analysis (TGA) spectrum of solvate VI-1-2 in Example 10 is shown. Detailed Implementation

[0060] 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.

[0061] In this document, the terms “comprising,” “including,” “having,” “containing,” or any other 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.”

[0062] 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.

[0063] In pharmaceutical applications, a chiral compound often possesses pharmaceutical value, while its corresponding isomer does not, such as fenelone. High-purity enantiomers are required in pharmaceutical applications, with an ee value exceeding 99%. Currently, enantiomer resolution often only achieves 97-98% ee in a single step, requiring subsequent crystallization purification to further improve purity, but this results in significant yield loss. Improving the purity by even 1% is extremely difficult or significantly increases costs.

[0064] The inventors of this invention have discovered that using a novel tartaric acid-derived resolving agent in the resolution of the racemic mixture of phenelzine can achieve a higher resolution efficiency, obtaining an ee value of over 99% in a single resolution step. This is in contrast to the resolving agent in CN112041318A. The present invention adds an amino group at the junction of the aryl group and tartaric acid, which increases the steric hindrance and electron density of the resolving agent, potentially contributing to the improvement of resolving efficiency. Based on this discovery, the inventors developed the technical solution of this application.

[0065] The following embodiments are merely examples illustrating implementations of the present invention and do not constitute any limitation on the present invention. Those skilled in the art will understand that modifications made without departing from the spirit and concept of the present invention fall within the protection scope of the present invention. Unless otherwise specified, the reagents and instruments used in the following embodiments are commercially available products.

[0066] Example 1

[0067]

[0068] (1) (2) R ,3 R Preparation of dibenzyl succinate (compound II-I)

[0069] L-tartaric acid (compound II) (22.5 g, 150 mmol), toluene (300 mL), benzyl alcohol (35.6 g, 330 mmol), and p-toluenesulfonic acid monohydrate (TsOH·H₂O) (0.428 g, 2.25 mmol) were added sequentially to a three-necked flask equipped with a water separator and a reflux condenser. The reaction mixture was stirred under reflux for 16 h until all water was separated. The reaction solution was cooled to approximately 30 ± 5°C, filtered, and the solid was washed with a small amount of toluene. The filtrate was concentrated to remove most of the toluene, diluted with petroleum ether / ethyl acetate (10V / 1V) to induce crystallization, filtered, and the solid was collected and dried under reduced pressure to give 40.3 g of compound II-I, with a yield of 81.4%. 1 H NMR (400 MHz, DMSO-) d 6) δ 7.29-7.41 (m, 10H), 5.69 (d, J= 8.0 Hz, 2H), 5.16 (s, 4H), 4.53 (d, J= 8.0 Hz, 2H).

[0070] (2) (2) R ,3 R Preparation of dibenzyl 2,3-bis(((4-chlorophenyl)carbamoyl)oxo)succinate (compound IV-I-1)

[0071] Compound II-I (10 g, 30 mmol) was added to ethyl acetate (110 mL), followed by compound III-1 (9.6 g, 63 mmol) and 4-dimethylaminopyridine (183 mg, 1.5 mmol). The mixture was stirred at room temperature for 2 hours. Dilute hydrochloric acid (15 mL, 0.1 mol / L) was added to the reaction mixture, and the mixture was stirred at room temperature for another 0.5 h. The mixture was filtered, washed successively with 20 mL of water and 20 mL of petroleum ether, and dried under reduced pressure to give 15.2 g of compound IV-I-1, in 80% yield. 1 H NMR (400 MHz, DMSO- d 6)δ 10.16 (s, 2H), 7.18-7.52 (m, 18H), 5.84 (s, 2H), 5.33 (d, J= 12.0 Hz, 2H), 5.15 (d, J= 12.0 Hz, 2H).

[0072] (3) (2) R ,3 R Preparation of 2,3-bis(((4-chlorophenyl)carbamoyl)oxo)succinic acid (compound VI-1)

[0073] Compound IV-I-1 (15.2 g, 23.8 mmol) was added to tetrahydrofuran (100 mL), followed by 5% wet palladium on carbon (1 g, 7 wt%). The mixture was stirred at room temperature under hydrogen atmosphere for 10 hours. The mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. Ethanol was added to remove the precipitate, and the product was washed with petroleum ether (5V) and dried under reduced pressure to give compound VI-1 10.6 g, with a yield of 97%. 1 H NMR (400 MHz, DMSO-) d 6) δ 13.75 (s, 2H), 10.14 (s, 2H), 7.55 (d, J= 8.0 Hz, 4H), 7.37 (d, J= 8.0 Hz, 4H), 5.59 (s, 2H).

[0074]

[0075] (4) Preparation of the diastereomeric salt VI-I-1 of 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthidine-3-carboxamide

[0076] Racemic 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthidine-3-carboxamide (rac-fenelone) (11.3 g, 30 mmol) and compound VI-1 (13.7 g, 30 mmol) were suspended in a mixture of 420 mL ethanol and 140 mL water, and the mixture was heated to 35 °C and stirred for 2 hours. The mixture was then stirred overnight at room temperature, filtered, and the filter cake was washed twice with a mixture of 20 mL ethanol / water (3 v: 1 v). The mixture was dried under reduced pressure to give 11.7 g of compound VI-I-1.

[0077] 1 H NMR (400 MHz, DMSO- d 6) δ:13.3-14.2 (brs, 2H),10.21 (s, 2H),7.69 (s,1H),7.59 (d, J= 8.0 Hz, 4H),7.55(s,1H),7.41 (d, J= 8.0 Hz, 4H),7.36 (d, J =1.5 Hz, 1H), 7.27 (dd, J = 8.0, 1.5 Hz, 1H), 7.15 (d, J= 8.0 Hz, 1H), 6.88-6.50(bs, 2H),5.61 (s, 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 = 7.0 Hz, 3H).

[0078] (5) S Preparation of 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthidine-3-carboxamide (fenelidine)

[0079] 11.7 g of compound VI-I-1 was suspended in 100 mL of a mixture of water / ethanol (3 v: 1 v) and cooled to 0 °C. Then, 20% sodium phosphate aqueous solution was added gradually (over 1 hour), and the pH was adjusted to pH 8-9. The mixture was stirred for another 2 hours at this temperature. The mixture was extracted twice with 100 mL of dichloromethane / methanol (10 v: 1 v), washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and dried under reduced pressure to give 5.2 g of fenelone. The two-step yield was 46%, with an ee of 99.8%. 1 H NMR (400 MHz, DMSO- d 6) δ:7.69 (s,1H),7.55(s,1H),7.36 (d, J = 1.5 Hz, 1H), 7.27 (dd, J = 8.0, 1.5 Hz, 1H), 7.15 (d, J = 8.0 Hz, 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 = 7.0 Hz, 3H).

[0080] Example 2

[0081]

[0082] (1) (2) R ,3 R Preparation of dibenzyl succinate (compound II-I)

[0083] Same as step (1) in Example 1.

[0084] (2) (2) R ,3R Preparation of dibenzyl 2,3-bis((((4-methylphenyl)carbamoyl)oxo)succinate (compound IV-I-2)

[0085] Compound II-I (10 g, 30 mmol) was added to ethyl acetate (110 mL), followed by compound III-2 (8.3 g, 63 mmol) and triethylamine (152 mg, 1.5 mmol). The mixture was stirred at room temperature for 2 hours. Dilute hydrochloric acid (15 mL, 0.1 mol / L) was added to the reaction mixture, and the mixture was stirred at room temperature for another 0.5 h. The mixture was filtered, washed successively with 20 mL of water and 20 mL of petroleum ether, and dried under reduced pressure to give 15.3 g of compound IV-I-2, in 85% yield. 1 H NMR (400 MHz, DMSO- d 6) δ 10.14(s, 2H), 7.18-7.45(m, 18H), 5.80(s, 2H), 5.31(d, J= 12.0 Hz, 2H), 5.14(d, J=12.0 Hz, 2H), 2.31 (s, 6H).

[0086] (3) (2) R ,3 R Preparation of 2,3-bis(((4-methylphenyl)carbamoyl)oxo)succinic acid (compound VI-2)

[0087] Compound IV-I-2 (15.3 g, 25.6 mmol) was added to tetrahydrofuran (100 mL), followed by 5% wet palladium on carbon (1 g, 7 wt%). The mixture was stirred at room temperature under hydrogen atmosphere for 10 hours. The mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. Ethanol was added to remove the precipitate, and the product was washed with petroleum ether (5V) and dried under reduced pressure to give compound VI-2 10.4 g, with a yield of 97%. 1 H NMR (400MHz, DMSO- d 6) δ 13.71(s, 2H), 10.12(s, 2H), 7.45 (d, J= 8.0 Hz, 4H), 7.34(d,J= 8.0 Hz, 4H), 5.52(s, 2H), 2.31 (s, 6H).

[0088]

[0089] (4) Preparation of the diastereomeric salt VI-I-2 of 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthidine-3-carboxamide

[0090] Racemic 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthidine-3-carboxamide (rac-fenelone) (11.3 g, 30 mmol) and compound VI-2 (12.5 g, 30 mmol) were suspended in a mixture of 420 mL ethanol and 140 mL water, and the mixture was heated to 35 °C and stirred for 2 hours. The mixture was then stirred overnight at room temperature, filtered, and the filter cake was washed twice with a mixture of 20 mL ethanol / water (3 v: 1 v). The mixture was dried under reduced pressure to give 10.7 g of compound VI-I-2.

[0091] 1 H NMR (400 MHz, DMSO- d 6) δ:13.2-13.8 (brs, 2H),10.12(s, 2H),7.69 (s,1H),7.55(s,1H),7.47 (d, J= 8.0 Hz, 4H),7.36 (d, J = 1.5 Hz, 1H),7.32(d, J= 8.0Hz, 4H),7.27 (dd, J = 8.0, 1.5 Hz, 1H), 7.15 (d, J = 8.0 Hz, 1H), 6.88-6.50 (bs,2H),5.51(s, 2H),5.37 (s,1H),4.08-3.95 (m, 2H), 3.82 (s,3H), 2.31 (s, 6H),2.18(s,3H),2.12 (s,3H),1.05 (t, J = 7.0 Hz, 3H).

[0092] (5) S Preparation of 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthidine-3-carboxamide (fenelidine)

[0093] 10.7 g of compound VI-I-2 was suspended in 100 mL of a mixture of water / ethanol (3 v:1 v) and cooled to 0 °C. Then, 20% sodium phosphate aqueous solution was added gradually (over 1 hour), and the pH was adjusted to pH 8-9. The mixture was stirred for another 2 hours at this temperature. The mixture was extracted twice with 100 mL of dichloromethane / methanol (10 v:1 v), washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and dried under reduced pressure to give 5.0 g of fenelone. The two-step yield was 44%, 99.6% ee.

[0094] Example 3

[0095]

[0096] (1) (2) R ,3 R Preparation of dibenzyl succinate (compound II-I)

[0097] Same as step (1) in Example 1.

[0098] (2) (2) R ,3 R Preparation of dibenzyl 2,3-bis((phenylcarbamoyl)oxo)succinate (compound IV-I-3)

[0099] Compound II-I (10 g, 30 mmol) was added to toluene (110 mL), followed by compound III-3 (7.5 g, 63 mmol) and 4-dimethylaminopyridine (183 mg, 1.5 mmol). The mixture was stirred at 30 °C for 2 h. Dilute hydrochloric acid (15 mL, 0.1 mol / L) was added to the reaction mixture, and the mixture was stirred at room temperature for 0.5 h. The mixture was filtered, washed successively with 20 mL of water and 20 mL of petroleum ether, and dried under reduced pressure to give 14.8 g of compound IV-I-3, in 87% yield. 1 H NMR (400 MHz, DMSO- d 6) δ10.14 (s, 2H), 7.18-7.50 (m, 20H), 5.83 (s, 2H), 5.28 (d, J= 12.0 Hz, 2H), 5.14 (d, J= 12.0 Hz, 2H).

[0100] (3) (2) R ,3 R Preparation of 2,3-bis((phenylcarbamoyl)oxo)succinic acid (compound VI-3)

[0101] Compound IV-I-3 (13.5 g, 23.8 mmol) was added to a mixed solvent of tetrahydrofuran (100 mL) and ethyl acetate (50 mL), followed by the addition of 5% wetted palladium on carbon (1 g, 7 wt%). The mixture was stirred at room temperature under hydrogen atmosphere for 10 hours. The mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. Ethanol was added to remove the precipitate, and the product was washed with petroleum ether (5V) and dried under reduced pressure to obtain compound VI-3 8.9 g, with a yield of 96%. 1 H NMR (400 MHz, DMSO- d6) δ 13.42 (s, 2H), 10.11 (s, 2H), 7.18-7.50 (m, 10H), 5.56 (s, 2H).

[0102]

[0103] (4) Preparation of the diastereomeric salt VI-I-3 of 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthidine-3-carboxamide

[0104] Racemic 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthidine-3-carboxamide (rac-fenelone) (11.3 g, 30 mmol) and compound VI-3 (11.6 g, 30 mmol) were suspended in a mixture of 420 mL ethanol and 140 mL water, and the mixture was heated to 35 °C and stirred for 2 hours. The mixture was then stirred overnight at room temperature, filtered, and the filter cake was washed twice with a mixture of 20 mL ethanol / water (3 v: 1 v). The mixture was dried under reduced pressure to give 10.7 g of compound VI-I-3. 1 H NMR (400 MHz, DMSO- d 6) δ:13.1-13.8 (brs, 2H),10.16 (s, 2H),7.69 (s,1H),7.55(s,1H),7.18-7.50 (m, 12H),7.15 (d, J = 8.0 Hz, 1H), 6.88-6.50 (brs, 2H),5.58 (s, 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 = 7.0 Hz, 3H).

[0105] (5) S Preparation of 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthidine-3-carboxamide (fenelidine)

[0106] 10.7 g of compound VI-I-3 was suspended in 100 mL of a mixture of water / ethanol (3 v: 1 v) and cooled to 0 °C. Then, 20% sodium phosphate aqueous solution was added gradually (over 1 hour), and the pH was adjusted to pH 8-9. The mixture was stirred for another 2 hours at this temperature. The mixture was extracted twice with 100 mL of dichloromethane / methanol (10 v: 1 v), washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and dried under reduced pressure to give 4.9 g of fenelone. The two-step yield was 43%, with an ee of 99.7%.

[0107] Example 4

[0108]

[0109] (1) (2) R ,3 R Preparation of dibenzyl succinate (compound II-I)

[0110] Same as step (1) in Example 1.

[0111] (2) (2) R ,3 R Preparation of dibenzyl 2,3-bis(((4-methoxyphenyl)carbamoyl)oxo)succinate (compound IV-I-4)

[0112] Compound II-I (10 g, 30 mmol) was added to ethyl acetate (110 mL), followed by compound III-4 (9.4 g, 63 mmol) and triethylamine (152 mg, 1.5 mmol). The mixture was stirred at room temperature for 2 hours. Dilute hydrochloric acid (15 mL, 0.1 mol / L) was added to the reaction mixture, and the mixture was stirred at room temperature for another 0.5 h. The mixture was filtered, washed successively with 20 mL of water and 20 mL of petroleum ether, and dried under reduced pressure to give 16.2 g of compound IV-I-4, in 86% yield. 1 H NMR (400 MHz, DMSO- d 6) δ 10.14(s, 2H), 7.10-7.45 (m, 18H), 5.84 (s, 2H), 5.32 (d, J= 12.0 Hz, 2H), 5.13 (d,J= 12.0 Hz, 2H), 3.85 (s, 6H).

[0113] (3) (2) R ,3 R Preparation of 2,3-bis(((4-methoxyphenyl)carbamoyl)oxo)succinic acid (compound VI-4)

[0114] Compound IV-I-4 (16.1 g, 25.6 mmol) was added to tetrahydrofuran (150 mL), followed by 5% wet palladium on carbon (1 g, 7 wt%). The mixture was stirred at room temperature under hydrogen atmosphere for 10 hours. The mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. Ethanol was added to remove the precipitate, and the product was washed with petroleum ether (5V) and dried under reduced pressure to give compound VI-4 10.9 g, with a yield of 95%. 1 H NMR (400MHz, DMSO- d 6) δ 13.70 (s, 2H), 10.14 (s, 2H), 7.42 (d, J= 8.0 Hz, 4H), 7.27 (d, J= 8.0 Hz, 4H), 5.51 (s, 2H), 3.86 (s, 6H).

[0115]

[0116] (4) Preparation of the diastereomeric salt VI-I-4 of 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthidine-3-carboxamide

[0117] Racemic 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthidine-3-carboxamide (rac-fenelone) (11.3 g, 30 mmol) and compound VI-4 (13.4 g, 30 mmol) were suspended in a mixture of 420 mL ethanol and 140 mL water, and the mixture was heated to 35 °C and stirred for 2 hours. The mixture was then stirred overnight at room temperature, filtered, and the filter cake was washed twice with a mixture of 20 mL ethanol / water (3 v: 1 v). The mixture was dried under reduced pressure to give 11.9 g of compound VI-I-4.

[0118] 1 H NMR (400 MHz, DMSO- d 6) δ:13.0-13.9 (brs, 2H),10.15 (s, 2H),7.69 (s,1H),7.55(s,1H),7.42 (d, J= 8.0 Hz, 4H),7.36 (d, J = 1.5 Hz, 1H),7.22-7.28 (m,5H),7.15 (d, J= 8.0 Hz, 1H), 6.88-6.50 (bs, 2H),5.51 (s, 2H),5.37 (s,1H),4.08-3.95 (m, 2H),3.88 (s, 6H) 3.82 (s,3H), 2.18 (s,3H),2.12 (s,3H),1.05 (t, J = 7.0 Hz, 3H).

[0119] (5) S Preparation of 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthidine-3-carboxamide (fenelidine)

[0120] 11.9 g of compound VI-I-4 was suspended in 120 mL of a mixture of water / ethanol (3 v: 1 v) and cooled to 0 °C. Then, 20% sodium phosphate aqueous solution was added gradually (over 1 hour), and the pH was adjusted to pH 8-9. The mixture was stirred for another 2 hours at this temperature. The mixture was extracted twice with 100 mL of dichloromethane / methanol (10 v: 1 v), washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and dried under reduced pressure to give 5.3 g of fenelone. The two-step yield was 46%, with an ee of 99.6%.

[0121] Example 5

[0122]

[0123] (1) (2) S ,3 S Preparation of dibenzyl succinate (compound II-II)

[0124] D-tartaric acid (compound I-II) (22.5 g, 150 mmol), toluene (310 mL), benzyl alcohol (35.6 g, 330 mmol), and p-toluenesulfonic acid monohydrate (TsOH·H2O) (0.428 g, 2.25 mmol) were added sequentially to a three-necked flask equipped with a water separator and a reflux condenser. The reaction mixture was refluxed and stirred for 16 h until all water was separated. The reaction solution was cooled to approximately 30 ± 5°C, filtered, and the solid was washed with a small amount of toluene. The filtrate was concentrated to remove most of the toluene, diluted with petroleum ether / ethyl acetate (10V / 1V) to induce crystallization, filtered, and the solid was collected and dried under reduced pressure to give 41 g of compound II-II, with a yield of 83%. 1 HNMR (400 MHz, DMSO- d6) δ 7.29-7.45 (m, 10H), 5.67 (d, J= 8.0 Hz, 2H), 5.16 (s, 4H), 4.53 (d, J= 8.0 Hz, 2H).

[0125] (2) (2) S ,3 S Preparation of dibenzyl 2,3-bis(((4-chlorophenyl)carbamoyl)oxo)succinate (compound IV-II-1)

[0126] Compound II-II (10 g, 30 mmol) was added to ethyl acetate (110 mL), followed by compound III-1 (9.6 g, 63 mmol) and 4-dimethylaminopyridine (183 mg, 1.5 mmol). The mixture was stirred at room temperature for 2 hours. Dilute hydrochloric acid (15 mL, 0.1 mol / L) was added to the reaction mixture, and the mixture was stirred at room temperature for another 0.5 h. The mixture was filtered, washed successively with 20 mL of water and 20 mL of petroleum ether, and dried under reduced pressure to give 15.4 g of compound IV-II-1, in 83% yield. 1 H NMR (400 MHz, DMSO- d 6)δ 10.17 (s, 2H), 7.17-7.51 (m, 18H), 5.84 (s, 2H), 5.33 (d, J= 12.0 Hz, 2H), 5.15 (d, J= 12.0 Hz, 2H).

[0127] (3) (2) S ,3 S Preparation of 2,3-bis(((4-chlorophenyl)carbamoyl)oxo)succinic acid (compound V-II-1)

[0128] Compound IV-II-1 (18.2 g, 28.6 mmol) was added to tetrahydrofuran (120 mL), followed by 5% wet palladium on carbon (1.2 g, 7 wt%). The mixture was stirred at room temperature under hydrogen atmosphere for 12 hours. The mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. Ethanol was added to remove the precipitate, and the product was washed with petroleum ether (5V) and dried under reduced pressure to give 12.5 g of compound V-II-1, with a yield of 96%. 1 H NMR (400 MHz, DMSO-) d 6) δ 13.76 (s, 2H), 10.14 (s, 2H), 7.55 (d, J= 8.0 Hz, 4H), 7.36 (d, J= 8.0 Hz, 4H), 5.58 (s, 2H).

[0129]

[0130] (4) Preparation of diastereomeric salt VI-II-1 of 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthidine-3-carboxamide

[0131] Racemic 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthidine-3-carboxamide (rac-fenelone) (11.3 g, 30 mmol) and compound V-II-1 (13.7 g, 30 mmol) were suspended in a mixture of 420 mL ethanol and 140 mL water, and the mixture was heated to 35 °C and stirred for 2 hours. The mixture was then stirred overnight at room temperature, filtered, and the filter cake was washed twice with a mixture of 20 mL ethanol / water (3 v: 1 v). The mixture was dried under reduced pressure to give 12.2 g of compound VI-II-1.

[0132] 1 H NMR (400 MHz, DMSO- d 6) δ:13.3-14.4 (brs, 2H),10.24 (s, 2H),7.71 (s,1H),7.57 (d, J= 8.0 Hz, 4H),7.55(s,1H),7.41 (d, J= 8.0 Hz, 4H),7.34 (d, J =1.5 Hz, 1H), 7.28 (dd, J = 8.0, 1.5 Hz, 1H), 7.15 (d, J = 8.0 Hz, 1H), 6.87-6.50(bs, 2H),5.61 (s, 2H),5.37 (s,1H),4.07-3.94 (m, 2H), 3.83 (s,3H), 2.18 (s,3H),2.12 (s,3H),1.05 (t, J = 7.0 Hz, 3H).

[0133] (5) R Preparation of 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthidine-3-carboxamide

[0134] 12.2 g of compound VI-II-1 was suspended in 100 mL of a mixture of water / ethanol (3 v: 1 v) and cooled to 0 °C. Then, 20% sodium phosphate aqueous solution was added gradually (over 1 hour), and the pH was adjusted to pH 8-9. The mixture was stirred for another 2 hours at this temperature. The product was extracted twice with 100 mL of dichloromethane / methanol (10 v: 1 v), washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and dried under reduced pressure to give 5.3 g of the product. The two-step yield was 47%, 99.9% ee. 1 H NMR (400 MHz, DMSO- d 6) δ:7.69 (s,1H),7.55(s,1H),7.36 (d, J = 1.5 Hz, 1H), 7.27 (dd, J = 8.0, 1.5 Hz, 1H), 7.15 (d, J = 8.0 Hz, 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 = 7.0 Hz, 3H).

[0135] Example 6

[0136]

[0137] (1) (2) S ,3 S Preparation of dibenzyl succinate (compound II-II)

[0138] Same as step (1) in Example 5.

[0139] (2) (2) S ,3 S Preparation of dibenzyl 2,3-bis(((4-methylphenyl)carbamoyl)oxo)succinate (compound IV-II-2)

[0140] Compound II-II (20 g, 60 mmol) was added to ethyl acetate (250 mL), followed by compound III-2 (16.6 g, 126 mmol) and triethylamine (304 mg, 3 mmol). The mixture was stirred at room temperature for 2 hours. Dilute hydrochloric acid (30 mL, 0.1 mol / L) was added to the reaction mixture, and the mixture was stirred at room temperature for another 0.5 h. The mixture was filtered, washed successively with 40 mL of water and 40 mL of petroleum ether, and dried under reduced pressure to give 31.5 g of compound IV-II-2, in 86% yield.1 H NMR (400 MHz, DMSO- d 6) δ 10.14(s, 2H), 7.18-7.45(m, 18H), 5.80(s, 2H), 5.31(d, J= 12.0 Hz, 2H), 5.15(d, J=12.0 Hz, 2H), 2.31 (s, 6H).

[0141] (3) (2) S ,3 S Preparation of 2,3-bis(((4-methylphenyl)carbamoyl)oxo)succinic acid (compound V-II-2)

[0142] Compound IV-II-2 (15.3 g, 25.6 mmol) was added to tetrahydrofuran (120 mL), followed by 5% wet palladium on carbon (1 g, 7 wt%). The mixture was stirred at room temperature under hydrogen atmosphere for 10 hours. The mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. Ethanol was added to remove the precipitate, and the product was washed with petroleum ether (5V) and dried under reduced pressure to give 10.5 g of compound V-II-2, with a yield of 97%. 1 H NMR (400MHz, DMSO- d 6) δ 13.74(s, 2H), 10.12(s, 2H), 7.45 (d, J= 8.0 Hz, 4H), 7.34(d,J= 8.0 Hz, 4H), 5.52(s, 2H), 2.31 (s, 6H).

[0143] Example 7

[0144]

[0145] (1) (2) S ,3 S Preparation of dibenzyl succinate (compound II-II)

[0146] Same as step (1) in Example 5.

[0147] (2) (2) S ,3 S Preparation of dibenzyl 2,3-bis((phenylcarbamoyl)oxo)succinate (compound IV-II-3)

[0148] Compound II-II (10 g, 30 mmol) was added to toluene (120 mL), followed by compound III-3 (7.5 g, 63 mmol) and 4-dimethylaminopyridine (183 mg, 1.5 mmol). The mixture was stirred at 30 °C for 2 h. Dilute hydrochloric acid (15 mL, 0.1 mol / L) was added to the reaction mixture, and the mixture was stirred at room temperature for 0.5 h. The mixture was filtered, washed successively with 20 mL of water and 20 mL of petroleum ether, and dried under reduced pressure to give 14.1 g of compound IV-II-3, in 83% yield. 1 H NMR (400 MHz, DMSO- d 6) δ10.16 (s, 2H), 7.17-7.50 (m, 20H), 5.83 (s, 2H), 5.28 (d, J= 12.0 Hz, 2H), 5.14 (d, J= 12.0 Hz, 2H).

[0149] (3) (2) S ,3 S Preparation of 2,3-bis((phenylcarbamoyl)oxo)succinic acid (compound V-II-3)

[0150] Compound IV-II-3 (13.5 g, 23.8 mmol) was added to a mixed solvent of tetrahydrofuran (100 mL) and ethyl acetate (50 mL), followed by the addition of 5% wetted palladium on carbon (1 g, 7 wt%). The mixture was stirred at room temperature under hydrogen atmosphere for 10 hours. The mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. Ethanol was added to remove the precipitate, and the product was washed with petroleum ether (5V) and dried under reduced pressure to obtain compound V-II-3 8.7 g, with a yield of 95%. 1 H NMR (400 MHz, DMSO- d 6) δ 13.42 (s, 2H), 10.11 (s, 2H), 7.18-7.50 (m, 10H), 5.56 (s, 2H).

[0151] Example 8

[0152]

[0153] (1) (2) S ,3 S Preparation of dibenzyl succinate (compound II-II)

[0154] Same as step (1) in Example 5.

[0155] (2) (2) S ,3 SPreparation of dibenzyl 2,3-bis(((4-methoxyphenyl)carbamoyl)oxo)succinate (compound IV-II-4)

[0156] Compound II-II (10 g, 30 mmol) was added to ethyl acetate (110 mL), followed by compound III-4 (9.4 g, 63 mmol) and triethylamine (152 mg, 1.5 mmol). The mixture was stirred at room temperature for 2 hours. Dilute hydrochloric acid (15 mL, 0.1 mol / L) was added to the reaction mixture, and the mixture was stirred at room temperature for another 0.5 h. The mixture was filtered, washed successively with 20 mL of water and 20 mL of petroleum ether, and dried under reduced pressure to give 16.0 g of compound IV-II-4, in 85% yield. 1 H NMR (400 MHz, DMSO- d 6) δ 10.11(s, 2H), 7.10-7.45 (m, 18H), 5.84 (s, 2H), 5.32 (d, J= 12.0 Hz, 2H), 5.13 (d,J= 12.0 Hz, 2H), 3.84 (s, 6H).

[0157] (3) (2) S ,3 S Preparation of 2,3-bis(((4-methoxyphenyl)carbamoyl)oxo)succinic acid (compound V-II-4)

[0158] Compound IV-II-4 (16.1 g, 25.6 mmol) was added to tetrahydrofuran (150 mL), followed by 5% wet palladium on carbon (1 g, 7 wt%). The mixture was stirred at room temperature under hydrogen atmosphere for 10 hours. The mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. Ethanol was added to remove the precipitate, and the product was washed with petroleum ether (5V) and dried under reduced pressure to give 10.6 g of compound V-II-4, with a yield of 92%. 1 H NMR (400 MHz, DMSO-) d 6) δ 13.70 (s, 2H), 10.14 (s, 2H), 7.41 (d, J= 8.0 Hz, 4H), 7.27 (d, J= 8.0 Hz, 4H), 5.51 (s, 2H), 3.85 (s, 6H).

[0159] Example 9

[0160]

[0161] (2 R ,3 RPreparation of methyl tert-butyl ether solvate of 2,3-bis((((4-chlorophenyl)carbamoyl)oxo)succinic acid (compound VI-1-1)

[0162] Compound VI-1 (4.57 g, 10 mmol) was added to methyl tert-butyl ether (10 mL) and stirred. Petroleum ether (100 mL) was slowly added, and a solid slowly precipitated. The mixture was stirred for 1 h, filtered, and the solid was dried under reduced pressure to give compound VI-1-15.5 g, with a yield of 95%. 1 H NMR (400 MHz, DMSO- d 6) δ 13.74 (s, 2H), 10.13 (s, 2H), 7.53(d, J= 8.0 Hz, 4H), 7.35 (d, J= 8.0 Hz, 4H), 5.58 (s, 2H), 3.08(s, 4.6H), 1.11(s, 14.5H). [MH] - =455.1.

[0163] The solvate VI-1-1 was analyzed by differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA). The DSC and TGA spectra are shown in [see attached images]. Figure 1 , Figure 2 It can be observed that the solvate VI-1-1 is relatively stable below 100℃, with no significant weight reduction. It begins to decompose and remove the solvent at around 120℃; the compound begins to decompose at around 180-190℃.

[0164] Example 10

[0165]

[0166] (2 R ,3 R Preparation of tetrahydrofuran solvate of 2,3-bis((((4-chlorophenyl)carbamoyl)oxo)succinic acid (compound VI-1-2)

[0167] Compound VI-1 (4.57 g, 10 mmol) was added to tetrahydrofuran (4 mL) and stirred. Petroleum ether (100 mL) was slowly added, and a solid slowly precipitated. The mixture was stirred for 1 h, filtered, and the solid was dried under reduced pressure to give compound VI-1-2 5.1 g, with a yield of 90%. 1 H NMR (400 MHz, DMSO- d6) δ 13.74 (s, 2H), 10.12 (s, 2H), 7.53 (d, J= 8.0 Hz, 4H), 7.36 (d, J= 8.0 Hz, 4H), 5.58 (s, 2H), 3.60(d, J= 8.0 Hz, 6H),1.76(t, J= 5.6 Hz, 6H). [MH] - =455.1.

[0168] The solvate VI-1-2 was analyzed by differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA). The results of the DSC and TGA analyses are shown in the attached images. Figure 3 , Figure 4 It can be observed that the solvate VI-1-2 is relatively stable below 100℃, with no significant weight reduction. It begins to decompose and remove the solvent at around 103℃; the compound begins to decompose at around 180-190℃.

[0169] The above description is merely a specific embodiment of the present invention, but the scope of protection of the present invention is not limited thereto. Any variations or substitutions that can be easily conceived by those skilled in the art within the technical scope disclosed in the present invention should be included within the scope of protection of the present invention. Therefore, the scope of protection of the present invention should be determined by the scope of the claims.

Claims

1. A method for resolving phenelzine using a tartaric acid derivative resolving agent, the reaction route of which is as follows: The splitting method includes the following steps: (4) The racemic phenelzine reacts with the tartaric acid derivative resolving agent shown in formula VI to obtain compound VI-I; (5) Compound VI-I reacts with an alkaline reagent to dissociate into phenelzine; in the tartaric acid derivative resolving agent of formula VI, Ar is phenyl, p-tolyl, p-methoxyphenyl or p-chlorophenyl.

2. The phenelzine resolution method according to claim 1, characterized in that, The structure of the tartaric acid derivative resolving agent is selected from the structure shown below: 。 3. The phenelzine resolution method according to claim 1, characterized in that, The tartaric acid derivative resolving agent is a solvate, selected from the structures shown below: ； THF represents tetrahydrofuran, and MTBE represents methyl tert-butyl ether.

4. The phenelzine resolution method according to claim 1, characterized in that, In step (4), the reaction is carried out in a solvent selected from one or more of methanol, ethanol, water, tetrahydrofuran, 2-methyltetrahydrofuran, and dioxane; and / or In step (4), the molar ratio of the racemic phenelzine to the tartaric acid derivative resolving agent shown in Formula VI is 1:0.6~1.6; the reaction temperature is 10~70℃; the reaction time is 6~24h; and / or In step (5), the alkalizing agent is selected from one or more of sodium phosphate, sodium bicarbonate, disodium hydrogen phosphate, and sodium dihydrogen phosphate; the alkalizing agent adjusts the pH of the reaction system to 8-9; and / or In step (5), the reaction is carried out in a solvent selected from one or more of ethanol, water, tetrahydrofuran, and 2-methyltetrahydrofuran; the reaction temperature is 0~40℃; and the reaction time is 2~6h.

5. The phenelzine resolution method according to claim 4, characterized in that, In step (4), the solvent is ethanol and water, and the volume ratio is ethanol / water = 1~15:

1.

6. The phenelzine resolution method according to claim 4, characterized in that, In step (5), the solvent is ethanol and water, and the volume ratio is ethanol / water = 1:

3.

7. The phenelzine resolution method according to claim 4, characterized in that, In step (4), the reaction is carried out in a solvent, which is a mixture of ethanol and water with a volume ratio of ethanol / water = 2~10:1; and / or In step (4), the molar ratio of the racemic phenelzine to the tartaric acid derivative resolving agent shown in Formula VI is 1:0.8~1.0; the reaction temperature is 15~50℃; the reaction time is 10~18h; and / or In step (5), the alkalizing agent is sodium phosphate; the alkalizing agent adjusts the pH of the reaction system to 8-9; and / or In step (5), the reaction is carried out in a solvent, which is a mixture of ethanol and water; the reaction temperature is 0~30℃; and the reaction time is 2~4h.

8. A diastereomeric salt of phenelzine having the structure shown in the following formula: ； in, Ar is defined as described in claim 1.

9. The diastereomeric salt of phenelzine according to claim 8, characterized in that, The diastereomeric salts of phenelzine have structures selected from those shown in the following formula: 。

Images