Preparation method of fenerenone intermediate

Abstract

The invention discloses a preparation method of a fenerenone intermediate 3, which comprises the following steps: in an organic solvent, carrying out resolution reaction on a fenerenone intermediate 2 and D-diphenyl tartrate to obtain a resolution salt, and then carrying out acid-base reaction on the resolution salt and alkali to obtain the fenerenone intermediate 3. The preparation method provided by the invention has the advantages of short reaction steps, high reaction total yield, simple and safe operation, simple post-treatment steps, high purity of the prepared product, low production cost and suitability for industrial production.

Description

[0001] This application is a divisional application of the invention patent application filed on January 12, 2023, with application number 202310040625.X and invention title "Preparation method of phenelzine intermediate". Technical Field

[0002] This invention relates to a method for preparing fenelone intermediates. Background Technology

[0003] Finelinone, chemically named (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthidine-3-carboxamide, is a nonsteroidal antagonist of the mineralocorticoid receptor and can be used to prevent and / or treat cardiovascular and renal diseases, such as heart failure and chronic kidney disease.

[0004]

[0005] ChemMedChem, 2012, 7, 1385 reported a 10-step reaction to prepare fenelone from vanillin, with an overall yield of only 3.76%.

[0006] WO2008 / 104306 also reported a method for preparing fenelazol, but due to the low overall yield (only 5%), the need for spectral purification of many intermediate colors, and the large consumption of solvents, it is not suitable for commercial production. In WO2008 / 104306, a specially synthesized chiral phase (prepared internally) was used for separation, containing poly(N-methacryloyl-D-leucine-dicyclopropylmethylamide) as a chiral selector. According to Bayer, separation can also be performed on a commercially available phase. This phase, Chiralpak AS-V, is used, with a thickness of 20 μm. The eluent used is a 60:40 mixture of methanol and acetonitrile. In this case, chromatographic analysis can be performed on a conventional chromatographic column, but it is preferred to use techniques known to those skilled in the art, such as SMB (simulated moving bed; G. Paredes, M. Mazotti, Journal of Chromatography A, 1142(2007): 56-68) or Varicol (Computers and Chemical Engineering 27(2003) 1883-1901).

[0007] CN112040318A reports a method for resolving racemic compounds using chiral substituted tartrate esters of general formula (IIIa) or (IIIb) as resolving agents to obtain phenelzine with a resolution of 91.4%. However, the residual resolving agent is difficult to remove after resolution by this method.

[0008] Therefore, there is a need to find an industrially feasible method for preparing fenelone with high overall yield, low production cost, and high product purity. Summary of the Invention

[0009] The technical problem this invention aims to solve is to overcome the shortcomings of existing methods for synthesizing phenelzine, such as long reaction steps, low overall yield, cumbersome post-processing steps, low product purity, complicated resolution steps, high production costs, and unsuitability for industrial production. This invention provides a method for preparing phenelzine intermediates. The preparation of phenelzine using the phenelzine intermediates of this invention features short reaction steps, high overall yield, simple and safe operation, simple post-processing steps, high product purity, low production costs, and suitability for industrial production.

[0010] The present invention provides a method for preparing phenelzine intermediate 3, which includes the following steps: in an organic solvent, phenelzine intermediate 2 is reacted with D-diphenyl tartrate to obtain a resolving salt, and then reacted with a base to obtain the phenelzine intermediate 3.

[0011]

[0012] In this invention, the method for preparing the phenelzine intermediate 3 preferably employs the following reaction conditions:

[0013] In the preparation method of phenelzine intermediate 3, the organic solvent is preferably a halogenated hydrocarbon solvent; the halogenated hydrocarbon solvent is preferably dichloromethane.

[0014] In the preparation method of fenelitone intermediate 3, the volume-to-mass ratio of the organic solvent to the fenelitone intermediate 2 is preferably 1 g / mL to 50 mL, more preferably 20 g / mL to 40 mL, for example 30 mL.

[0015] In the preparation method of fenelitone intermediate 3, the molar ratio of D-diphenyl tartrate to fenelitone intermediate 2 is preferably 0.5 to 3.0, more preferably 0.8 to 1.5, for example 1.1.

[0016] In the preparation method of fenelitone intermediate 3, the temperature of the resolution reaction is preferably 10℃~50℃, more preferably 20℃~40℃, for example 30℃~40℃ or 20℃~25℃.

[0017] In the preparation method of fenelitone intermediate 3, the resolution reaction is preferably carried out for 1 hour to 24 hours, and more preferably for 18 hours to 20 hours.

[0018] In the preparation method of fenelitone intermediate 3, the base can be one or more of sodium phosphate, sodium carbonate, and sodium bicarbonate.

[0019] In the preparation method of fenelitone intermediate 3, the pH of the acid-base reaction is preferably 7-9.

[0020] In the preparation method of fenelitone intermediate 3, the acid-base reaction temperature is preferably 20℃~80℃, for example 50℃~70℃.

[0021] In the preparation method of fenelitone intermediate 3, the acid-base reaction time is preferably 1 hour to 30 hours, and more preferably 5 hours to 15 hours.

[0022] The method for preparing felinone intermediate 3 of the present invention further includes a method for preparing felinone intermediate 2, which includes the following steps: in an organic solvent, felinone intermediate 1 is subjected to a cyclization reaction with 4-amino-5-methyl-2-hydroxypyridine to obtain the felinone intermediate 2.

[0023] .

[0024] The preparation of phenelzine intermediate 2 can be carried out under conventional conditions for this type of cyclization reaction in the art. The following reaction conditions are preferred in this invention:

[0025] In the preparation method of fenelitone intermediate 2, the organic solvent is preferably an alcohol solvent; the alcohol solvent is preferably 2-butanol (sec-butanol) and / or 1-butanol (n-butanol).

[0026] In the preparation method of fenelitone intermediate 2, the volume-to-mass ratio of the organic solvent to the fenelitone intermediate 1 is preferably 1 mL / g to 30 mL / g; more preferably 1 mL / g to 5 mL / g, for example 2 mL / g.

[0027] In the preparation method of felinone intermediate 2, the mass ratio of felinone intermediate 1 to 4-amino-5-methyl-2-hydroxypyridine is preferably 1.0 to 5.0, more preferably 2.0 to 3.0, for example 2.6.

[0028] In the preparation method of fenelitone intermediate 2, the cyclization reaction temperature is preferably 80℃~150℃, more preferably 90℃~140℃, for example 120℃.

[0029] In the preparation method of fenelitone intermediate 2, the cyclization reaction time is monitored using conventional detection methods in the art (e.g., HPLC, NMR or TLC). Generally, the reaction endpoint is defined as the disappearance of fenelitone intermediate 1, preferably 1 hour to 24 hours, more preferably 10 hours to 20 hours, for example 16 hours.

[0030] The preferred method for preparing phenelzine intermediate 2 involves the following post-processing steps: after the reaction, cooling, crystallization, and slurrying are performed to obtain phenelzine intermediate 2. The cooling is preferably performed at 40°C to 50°C. The crystallization temperature is preferably 0 to 10°C. The crystallization time is preferably 1 to 10 hours, for example, 2 to 3 hours. The slurrying process preferably uses an aqueous citric acid solution. The concentration of the aqueous citric acid solution is preferably 1% to 10%, for example, 5%, where the concentration refers to the percentage of citric acid by mass relative to the total mass of the aqueous citric acid solution.

[0031] The method for preparing phenelzine intermediate 3 of the present invention further includes a method for preparing phenelzine intermediate 1, which includes the following steps: in an organic solvent, in the presence of an acid and a catalyst, 4-bromo-2-methoxybenzaldehyde and ethyl 2-cyanoacetoacetate are subjected to a condensation reaction to obtain the phenelzine intermediate 1.

[0032]

[0033] The preparation of phenelzine intermediate 1 can be carried out using conventional methods for this type of condensation reaction in the art. The present invention particularly prefers the following reaction conditions:

[0034] In the preparation method of fenelitone intermediate 1, the organic solvent is preferably an alcohol solvent; the alcohol solvent is preferably isopropanol.

[0035] In the preparation method of fenelone intermediate 1, the volume-to-mass ratio of the organic solvent to the 4-bromo-2-methoxybenzaldehyde is preferably 1.0 mL / g to 30.0 mL / g, more preferably 2.0 mL / g to 10.0 mL / g, for example 3.3 mL / g.

[0036] In the preparation method of felinone intermediate 1, the mass ratio of ethyl 2-cyanoacetoacetate to 4-bromo-2-methoxybenzaldehyde is preferably 1.0 to 5.0, more preferably 1.0 to 2.0, for example 1.0.

[0037] In the preparation method of fenelone intermediate 1, the acid is preferably an organic acid; the organic acid is preferably acetic acid.

[0038] In the preparation method of fenelone intermediate 1, the molar ratio of the acid to the 4-bromo-2-methoxybenzaldehyde is preferably 0.01 to 1, more preferably 0.10 to 0.30, for example 0.15.

[0039] In the preparation method of phenelzine intermediate 1, the catalyst is preferably piperidine.

[0040] In the preparation method of fenelone intermediate 1, the molar ratio of the catalyst to the 4-bromo-2-methoxybenzaldehyde is preferably 0.01 to 1, more preferably 0.10 to 0.30, for example 0.15.

[0041] In the preparation method of fenelitone intermediate 1, the condensation reaction temperature is preferably 10℃~60℃, more preferably 20℃~50℃, for example 30℃~40℃.

[0042] In the preparation method of fenelitone intermediate 1, the time of the condensation reaction can be monitored by conventional detection methods in the art (e.g., HPLC, TLC or NMR). Generally, the reaction endpoint is when the 4-bromo-2-methoxybenzaldehyde disappears. In this invention, 1 hour to 24 hours is preferred, for example, 3 hours to 4 hours.

[0043] The preferred method for preparing phenelzine intermediate 1 includes the following post-processing steps: after the reaction is complete, crystallization, filtration, and washing are performed to obtain phenelzine intermediate 1. The crystallization temperature is preferably 10°C to 20°C. The crystallization time is preferably 1 hour to 24 hours, for example, 16 hours. The washing is preferably performed using an alcohol solvent; methanol is the preferred alcohol solvent.

[0044] The present invention also provides a method for preparing phenelzine intermediate 4, which includes the following steps: after obtaining phenelzine intermediate 3 according to the above method, phenelzine intermediate 3 is subjected to a nucleophilic substitution reaction with triethyl orthoformate in an organic solvent in the presence of acid to obtain phenelzine intermediate 4.

[0045] .

[0046] The preparation of phenelzine intermediate 4 can be carried out using conventional conditions for this type of nucleophilic substitution reaction in the art. In this invention, the following reaction conditions are particularly preferred:

[0047] In the preparation method of felindone intermediate 4, the organic solvent is preferably an amide solvent; the amide solvent is preferably N,N-dimethylacetamide and / or N,N-dimethylformamide.

[0048] In the preparation method of fenelitone intermediate 4, the volume-to-mass ratio of the organic solvent to the fenelitone intermediate 3 is preferably 1 mL / g to 100 mL / g, more preferably 2 mL / g to 10 mL / g, for example 5.7 mL / g.

[0049] In the preparation method of fenelitone intermediate 4, the mass ratio of triethyl orthoformate to fenelitone intermediate 3 is preferably 1 to 5, more preferably 1.1 to 2.0, for example 1.4.

[0050] In the preparation method of fenelone intermediate 4, the acid is preferably an inorganic acid, and the inorganic acid is preferably concentrated sulfuric acid. The concentrated sulfuric acid can be a commercially available concentrated sulfuric acid reagent. The concentration of the concentrated sulfuric acid can be 98%, where concentration refers to the percentage of the mass of sulfuric acid in the total mass of the concentrated sulfuric acid aqueous solution.

[0051] In the preparation method of fenelitone intermediate 4, the molar ratio of the acid to the fenelitone intermediate 3 is preferably 0.10 to 0.50, more preferably 0.20 to 0.45, for example 0.38.

[0052] In the preparation method of fenelitone intermediate 4, the temperature of the nucleophilic substitution reaction is preferably 100℃~150℃, more preferably 110℃~140℃, for example 115℃~125℃.

[0053] In the preparation method of phenelzine intermediate 4, the time of the nucleophilic substitution reaction is monitored by conventional detection methods in the art (e.g., TLC, HPLC or NMR). Generally, the reaction endpoint is when the phenelzine intermediate 3 disappears. The time of the nucleophilic substitution reaction is preferably 1 hour to 10 hours, for example, 2 hours to 3 hours.

[0054] The preferred method for preparing phenelzine intermediate 4 includes the following post-processing steps: after the reaction is complete, the mixture is cooled, water is added, and crystallization occurs to obtain phenelzine intermediate 4. The cooling temperature can be reduced to 50°C–60°C. Crystallization is preferably carried out by adding seed crystals and stirring; the crystallization temperature is preferably 0–10°C; and the crystallization time is preferably 2–3 hours.

[0055] The present invention also provides a method for synthesizing phenelzine intermediate 5, which includes the following steps: after obtaining phenelzine intermediate 4 according to the above method, phenelzine intermediate 4 is then hydrolyzed in a solvent to obtain phenelzine intermediate 5.

[0056]

[0057] The preparation of phenelzine intermediate 5 can be carried out under conventional conditions for this type of hydrolysis reaction in the art, and the following reaction conditions are particularly preferred in this invention:

[0058] In the preparation method of fenelitone intermediate 5, the organic solvent is preferably an ether solvent; the ether solvent is preferably tetrahydrofuran (THF).

[0059] In the preparation method of fenelitone intermediate 5, the volume-to-mass ratio of the organic solvent to the fenelitone intermediate 4 is preferably 1 mL / g to 100 mL / g, more preferably 2 mL / g to 10 mL / g, for example 5.3 mL / g.

[0060] In the preparation method of fenelone intermediate 5, the base is preferably an inorganic base, and the inorganic base is preferably sodium hydroxide. The sodium hydroxide can be used in the form of an aqueous solution. The concentration of the sodium hydroxide aqueous solution can be 1% to 50%, for example, 7.3%, where the percentage refers to the mass of sodium hydroxide relative to the total mass of the sodium hydroxide aqueous solution.

[0061] In the preparation method of fenelitone intermediate 5, the molar ratio of the base to the fenelitone intermediate 4 is preferably 1 to 5, more preferably 1.1 to 3.0, for example 2.0.

[0062] In the preparation method of fenelitone intermediate 5, the hydrolysis reaction temperature is preferably -10℃ to 20℃, more preferably -5℃ to 10℃, for example -5℃ to 5℃.

[0063] In the preparation method of fenelitone intermediate 5, the hydrolysis reaction time is monitored by conventional detection methods in the art (e.g., TLC, HPLC or NMR). Generally, the reaction endpoint is when the fenelitone intermediate 4 disappears. The hydrolysis reaction time is preferably 1 hour to 10 hours, for example, 4 hours to 5 hours.

[0064] The preferred method for preparing phenelzine intermediate 5 includes the following post-processing steps: after the reaction, extraction, pH adjustment to approximately 3, filtration, and washing are performed to obtain phenelzine intermediate 5. Toluene is preferably used for extraction. Hydrochloric acid can be used for pH adjustment; the concentration of the hydrochloric acid can be 5%–15%, for example, 10%, where the percentage refers to the mass of hydrogen chloride relative to the total mass of the hydrochloric acid aqueous solution. Washing is preferably performed sequentially with water and toluene; the number of washes is preferably 1–3 times, for example, 2 times.

[0065] The present invention also provides a method for preparing phenelzine intermediate 6, which includes the following steps: after obtaining phenelzine intermediate 5 according to the above method, phenelzine intermediate 5 is then subjected to a condensation reaction with hexamethyldiazylsilane in an organic solvent in the presence of a catalyst and a condensing agent to obtain the phenelzine intermediate 6.

[0066]

[0067] The preparation method of the phenelzine intermediate 6 can employ conventional methods and conditions for this type of condensation reaction in the art. The present invention particularly prefers the following reaction conditions:

[0068] In the preparation method of fenelitone intermediate 6, the organic solvent is preferably an ether solvent; the ether solvent is preferably tetrahydrofuran (THF).

[0069] In the preparation method of fenelitone intermediate 6, the volume-to-mass ratio of the organic solvent to the fenelitone intermediate 5 is preferably 1 mL / g to 30 mL / g, more preferably 2 mL / g to 10 mL / g, for example 5.2 mL / g.

[0070] In the preparation method of fenelone intermediate 6, the catalyst is preferably 4-dimethylaminopyridine (DMAP).

[0071] In the preparation method of fenelitone intermediate 6, the molar ratio of the catalyst to the fenelitone intermediate 5 is preferably 0.01 to 2, more preferably 0.05 to 0.2, for example 0.1.

[0072] In the preparation method of felindone intermediate 6, the condensing agent is preferably N,N′-carbonyldiimidazole (CDI).

[0073] In the preparation method of fenelitone intermediate 6, the molar ratio of the condensing agent to the fenelitone intermediate 5 is preferably 1.0 to 5.0, more preferably 1.1 to 2.0, for example 1.4.

[0074] In the preparation method of phenelzine intermediate 6, the molar ratio of hexamethyldisilazane to phenelzine intermediate 5 is preferably 1.0 to 10.0, more preferably 2.0 to 6.0, for example 4.4.

[0075] In the preparation method of fenelitone intermediate 6, the condensation reaction temperature is preferably 20°C to 100°C, more preferably 65°C to 75°C, for example 70°C.

[0076] In the preparation method of fenelitone intermediate 6, the time of the condensation reaction is monitored by conventional detection methods in the art (e.g., TLC, HPLC or NMR). Generally, the reaction endpoint is when the fenelitone intermediate 5 disappears. The condensation reaction time is preferably 5 hours to 25 hours, more preferably 10 hours to 20 hours, for example 16 hours.

[0077] The preferred method for preparing phenelzine intermediate 6 includes the following post-processing steps: after the reaction is complete, add a tetrahydrofuran aqueous solution, reflux, cool, filter, and wash to obtain the phenelzine intermediate 6. The volume ratio of tetrahydrofuran to water in the tetrahydrofuran aqueous solution is preferably 0.5–5, for example, 1.4. The reflux temperature is preferably 70°C–80°C. The cooling temperature is preferably reduced to approximately 0°C. The cooling rate is preferably 14°C / hour–27°C / hour. The washing is preferably performed sequentially with tetrahydrofuran and water; the number of washes is preferably 1–3 times, for example, 2 times.

[0078] The present invention also provides a method for preparing phenelzine, which includes the following steps: after obtaining phenelzine intermediate 6 according to the above method, phenelzine intermediate 6 is subjected to a nucleophilic substitution reaction with zinc cyanide in an organic solvent in the presence of a catalyst to obtain phenelzine.

[0079]

[0080] The method for preparing phenelzine can employ conventional methods and conditions for this type of nucleophilic substitution reaction in the art. The present invention particularly prefers the following reaction conditions:

[0081] In the preparation method of fenelone, the organic solvent is preferably an amide solvent; the amide solvent is preferably N,N-dimethylformamide (DMF).

[0082] In the preparation method of fenelitone, the volume-to-mass ratio of the organic solvent to the fenelitone intermediate 6 is preferably 1 mL / g to 30 mL / g, more preferably 2 mL / g to 20 mL / g, for example 10 mL / g.

[0083] In the preparation method of fenelitone, the molar ratio of zinc cyanide to fenelitone intermediate 6 is preferably 0.5 to 3, more preferably 1.0 to 2.0, for example 1.5.

[0084] In the preparation method of fenelone, the catalyst is preferably 1,1'-bis(diphenylphosphine)ferrocene and / or Pd2(dba). 3， Tetraphenylphosphine-palladium.

[0085] In the preparation method of fenelitone, the molar ratio of the catalyst to the fenelitone intermediate 6 is preferably 0.001 to 1.0, more preferably 0.05 to 0.2, for example 0.10.

[0086] In the preparation method of fenelone, the temperature of the nucleophilic substitution reaction is preferably 60℃~150℃, more preferably 90℃~140℃, for example 100℃.

[0087] In the preparation method of fenelitone, the time of the nucleophilic substitution reaction can be monitored by conventional detection methods in the art (e.g., HPLC, TLC or NMR). Generally, the reaction endpoint is when the fenelitone intermediate 6 disappears. In this invention, 1 hour to 30 hours is preferred, and 5 hours to 25 hours is even more preferred, for example, 15 hours to 20 hours.

[0088] The preferred method for preparing fenelone includes the following post-processing steps: after the reaction is complete, cooling, extraction, washing, and drying are performed to obtain crude fenelone. The crude fenelone is preferably recrystallized to obtain fenelone. The solvent used for recrystallization is preferably an alcohol solvent; the preferred alcohol solvent is ethanol.

[0089] The preferred synthetic route for preparing fenelazolone according to the present invention is as follows:

[0090]

[0091] The present invention also provides a method for preparing phenelzine intermediate 1, which includes the following steps: in an organic solvent, in the presence of an acid and a catalyst, 4-bromo-2-methoxybenzaldehyde and ethyl 2-cyanoacetoacetate are subjected to a condensation reaction to obtain the phenelzine intermediate 1.

[0092]

[0093] The reaction conditions are the same as described above.

[0094] The present invention also provides a method for preparing phenelzine intermediate 2, which includes the following steps: in an organic solvent, phenelzine intermediate 1 is subjected to a cyclization reaction with 4-amino-5-methyl-2-hydroxypyridine to obtain the phenelzine intermediate 2.

[0095]

[0096] The reaction conditions are the same as described above.

[0097] The present invention also provides a method for preparing phenelzine intermediate 4, which includes the following steps: in an organic solvent, in the presence of an acid, phenelzine intermediate 3 is subjected to a nucleophilic substitution reaction with triethyl orthoformate to obtain phenelzine intermediate 4.

[0098]

[0099] The reaction conditions are the same as described above.

[0100] The present invention also provides a method for preparing phenelzine intermediate 5, which includes the following steps: hydrolyzing phenelzine intermediate 4 in a solvent to obtain phenelzine intermediate 5.

[0101]

[0102] The reaction conditions are the same as described above.

[0103] The present invention also provides a method for preparing phenelzine intermediate 6, which includes the following steps: in an organic solvent, in the presence of a catalyst and a condensing agent, phenelzine intermediate 5 is subjected to a condensation reaction with hexamethyldiazylsilane to obtain the phenelzine intermediate 6.

[0104]

[0105] The reaction conditions are the same as described above.

[0106] The present invention also provides a method for preparing phenelzine, which includes the following steps: in an organic solvent and in the presence of a catalyst, phenelzine intermediate 6 is subjected to a nucleophilic substitution reaction with zinc cyanide to obtain phenelzine;

[0107]

[0108] The reaction conditions are the same as described above.

[0109] Unless otherwise specified, all raw materials or reagents described in this invention are commercially available.

[0110] In this invention, room temperature refers to ambient temperature, which is 10℃ to 35℃.

[0111] The positive and progressive effects of this invention are as follows: the preparation of fenelone using the intermediate of this invention has a short reaction step, high overall reaction yield, simple and safe operation, simple post-processing steps, high product purity, low production cost, and is suitable for industrial production. Detailed Implementation

[0112] The present invention is further illustrated below by way of embodiments, but the invention is not limited to the scope of the embodiments described herein. Experimental methods in the following embodiments that do not specify specific conditions were performed according to conventional methods and conditions, or as selected according to the product instructions.

[0113] Example 1 Preparation of phenelzine intermediate 1

[0114] Add 150 g of 0.698 mol of p-4-bromo-2-methoxybenzaldehyde, 500 ml of isopropanol, 9.1 g of piperidine (0.107 mol), and 6.4 g of acetic acid (0.107 mol) to a reaction flask. Stir until homogeneous, heat to 30-40 °C, and add dropwise a solution of 146 g of ethyl 2-cyanoacetoacetate in 50 ml of isopropanol. After the addition is complete, react at 30-40 °C for 3-4 hours, then cool to 10-20 °C and stir for 16 hours. Filter, wash the filter cake with 100 ml of methanol, and dry to obtain 170 g of solid (fenelone intermediate 1). HPLC purity: 92.50%, yield: 82.1%.

[0115] Example 2 Preparation of phenelzine intermediate 2

[0116] 150g of phenelzine intermediate 1, 57g of 4-amino-5-methyl-2-hydroxypyridine, and 300ml of 2-butanol were added to an autoclave. The reaction was carried out at 120℃ for 16 hours, then cooled to 40-50℃, and then gradually cooled to 0-10℃. The mixture was stirred for 2-3 hours, filtered, and the filter cake was slurried with 600ml of 5% citric acid aqueous solution (the percentage refers to the mass of citric acid to the total mass of the citric acid aqueous solution). The mixture was filtered again, and the filter cake was washed with 300ml of water and dried to obtain 148.5g of solid (phenelzine intermediate 2). The HPLC purity was 98.08%, and the yield was 73.1%.

[0117] Example 3 Preparation of phenelzine intermediate 3

[0118] Add 35g of phenelzine intermediate 2 (0.076mol), dichloromethane solution (1050mL), and 31g of D-diphenyl tartrate to the reaction flask. 0.086 mol), the reaction solution was heated to 30-40℃ and stirred for 2-4 hours, then cooled to 20-25℃ and stirred for 16 hours, filtered, and dried to obtain 31.5 g of the decomposed salt. Add the sample to a bottle, add 60 ml of ethanol and 250 ml of water, heat to 50°C, add 100 ml of 9.1% sodium phosphate aqueous solution dropwise (the percentage refers to the mass of sodium phosphate to the total mass of the sodium phosphate aqueous solution), adjust the pH to 7-8, stir at 50°C for 1-2 hours, then gradually cool to 20-25°C, stir overnight, filter, wash with 25 ml of 25% ethanol, dry to obtain 14.1 g of solid, add 120 ml of ethanol and 60 ml of water, heat to 70°C and stir for 30 minutes, add 7 g of 1.6% sodium phosphate to the reaction solution, adjust the pH to about 9, stir at 70°C overnight after the addition is complete, cool to 40°C, concentrate until almost no distillate, add 180 ml of water, stir at room temperature for 1-2 hours, filter, dry the filter cake to obtain 13.3 g of solid (fenelone intermediate 3). HPLC purity 98.9%, chiral purity 99.5%, yield 38.0%.

[0119] Example 4 Preparation of phenelzine intermediate 4

[0120] Add 140 g of phenelzine intermediate 3 (0.305 mol) and 800 ml of N,N-dimethylacetamide to a reaction flask. Heat to 100 °C and stir for 10-20 minutes. Add 191 g of triethyl orthoformate and 11.5 g of concentrated sulfuric acid (0.115 mol). Heat to 115-125 °C and stir for 2-3 hours. Cool to 50-60 °C, add 800 ml of water dropwise, add seed crystals to induce crystallization, add another 800 ml of water, cool to 0-10 °C and stir for 2-3 hours. Filter, wash the filter cake with 150 ml of water, and dry to obtain 143.9 g of powder (phenelzine intermediate 4). HPLC purity: 97.30%, chiral purity: 99.8%, yield: 93.9%.

[0121] Example 5 Preparation of phenelzine intermediate 5

[0122] Add 175.5 g (0.361 mol) of phenelzine intermediate 4, 936 mL of THF, and 468 mL of water to a reaction flask. Cool to -5 to 5°C and add dropwise a solution of sodium hydroxide (28.9 g, 0.7225 mol) in 365 mL of water. After the addition is complete, keep the mixture at this temperature for 4 to 5 hours. Add toluene (390 mL) and sodium acetate (30 g) to the reaction solution and stir for 30 minutes. Separate the mixture and extract the aqueous phase once with toluene (390 mL). Retain the aqueous phase and adjust the pH to approximately 3 with 10% hydrochloric acid. Stir for 1 hour, filter, and wash the filter cake with water (300 mL × 2) and toluene (50 mL × 2). Collect the filter cake and dry it at 50°C to obtain 165.3 g of phenelzine intermediate 5, with an HPLC purity of 96.08%, a chiral purity of 99.9%, and a yield of 99%.

[0123] Example 6 Preparation of phenelzine intermediate 6

[0124] Fennedone intermediate 5 (43.3 g, 0.10 mol), N,N′-carbonyldiimidazole (CDI, 22.7 g, 0.14 mol) were dissolved in THF (227 ml), and 4-dimethylaminopyridine (DMAP, 1.22 g, 0.01 mol) was added. The mixture was reacted at 20-25°C for 1-2 hours, then heated to about 50°C and reacted for 2-3 hours. Hexamethyldisilazane (HMDS, 70.4 g, 0.44 mol) was added to the reaction solution, and the mixture was slowly heated to about 70°C and reacted for 16 hours. THF (45 ml) was added to the reaction solution, and the temperature was lowered to 0-5°C. A mixture of THF (28 ml) and water (20 ml) was then slowly added dropwise to the reaction solution. After the addition was complete, the mixture was heated to 70-80°C and refluxed for 1-2 hours. The temperature was then gradually lowered to about 0°C (3-5 hours), and the mixture was stirred for another 1-2 hours. The mixture was filtered, washed twice with THF (50 ml) and twice with water (80 ml), and the filter cake was collected and dried at 70°C overnight to obtain 40.6 g of white solid powder (fenelone intermediate 6), with HPLC purity of 100%, chiral purity of 100%, and yield of 94.1%.

[0125] Example 7 Preparation of fenelazol

[0126] Finelenone intermediate 6 (30 g, 0.0694 mol) and zinc cyanide (12.2 g, 0.104 mol) were added to N,N-dimethylformamide (DMF, 300 mL), followed by tetrakis(triphenylphosphine)palladium (8.02 g, 0.00694 mol) to a reaction flask. The mixture was purged with nitrogen three times, heated to 100 °C, and stirred for 15-20 hours until the reaction was complete. The temperature was then lowered to 20-25 °C, and water (50 mL) and dichloromethane (DCM, 150 mL) were added to the reaction mixture. The mixture was stirred for 30 min, separated, and the aqueous phase was extracted three times with DCM (150 mL). The combined organic phases were washed three times with saturated brine (100 mL), dried over anhydrous sodium sulfate, concentrated, and recrystallized from ethanol to obtain 20 g of finelenone with an HPLC purity of 99%, a chiral purity of 100%, and a yield of 76%.

Claims

1. A method for preparing phenelzine intermediate 3, characterized in that... The process includes the following steps: In an organic solvent, phenelzine intermediate 2 is reacted with diphenyl D-tartrate to obtain a resolving salt, which is then reacted with a base to obtain phenelzine intermediate 3; the organic solvent is dichloromethane; and the base is one or more of sodium phosphate, sodium carbonate, and sodium bicarbonate. The preparation method of phenelzine intermediate 2 includes the following steps: in an organic solvent, phenelzine intermediate 1 is subjected to a cyclization reaction with 4-amino-5-methyl-2-hydroxypyridine to obtain phenelzine intermediate 2; wherein the organic solvent is 2-butanol and / or 1-butanol. A method for preparing phenelzine intermediate 1 includes the following steps: 4-bromo-2-methoxybenzaldehyde and ethyl 2-cyanoacetoacetate are subjected to a condensation reaction in an organic solvent in the presence of an acid and a catalyst to obtain phenelzine intermediate 1; the organic solvent is isopropanol; the acid is acetic acid; and the catalyst is piperidine. 。 2. The method for preparing phenelzine intermediate 3 as described in claim 1, characterized in that: In the preparation method of fenelitone intermediate 3, the volume-to-mass ratio of the organic solvent to the fenelitone intermediate 2 is 1 mL / g to 50 mL / g. And / or, In the preparation method of phenelzine intermediate 3, the molar ratio of D-diphenyl tartrate to phenelzine intermediate 2 is 0.5 to 3.

0. And / or, In the preparation method of fenelone intermediate 3, the temperature of the resolution reaction is 10℃~50℃; And / or, In the preparation method of fenelitonee intermediate 3, the resolution reaction time is 1 hour to 24 hours; And / or, In the preparation method of fenelitone intermediate 3, the pH of the acid-base reaction is 7-9; And / or, In the preparation method of fenelone intermediate 3, the acid-base reaction temperature is 20℃~80℃; And / or, In the preparation method of fenelitone intermediate 3, the acid-base reaction time is 1 hour to 30 hours.

3. The method for preparing phenelzine intermediate 3 as described in claim 2, characterized in that: In the preparation method of phenelzine intermediate 3, the volume-to-mass ratio of the organic solvent to the phenelzine intermediate 2 is 20 mL / g to 40 mL / g. And / or, In the preparation method of phenelzine intermediate 3, the molar ratio of D-diphenyl tartrate to phenelzine intermediate 2 is 0.8 to 1.

5. And / or, In the preparation method of fenelone intermediate 3, the temperature of the resolution reaction is 20℃~40℃; And / or, In the preparation method of fenelitonee intermediate 3, the resolution reaction time is 18 to 20 hours; And / or, In the preparation method of fenelone intermediate 3, the base is sodium phosphate; And / or, In the preparation method of fenelone intermediate 3, the acid-base reaction temperature is 50℃~70℃; And / or, In the preparation method of fenelitone intermediate 3, the acid-base reaction time is 5 to 15 hours.

4. The method for preparing phenelzine intermediate 3 as described in claim 1, characterized in that: In the preparation method of phenelzine intermediate 2, the volume-to-mass ratio of the organic solvent to phenelzine intermediate 1 is 1 mL / g to 30 mL / g. And / or, In the preparation method of fenelitonee intermediate 2, the mass ratio of fenelitonee intermediate 1 to 4-amino-5-methyl-2-hydroxypyridine is 1.0 to 5.

0. And / or, In the preparation method of phenelzine intermediate 2, the cyclization reaction temperature is 80℃~150℃; And / or, In the preparation method of phenelzine intermediate 2, the cyclization reaction time is 1 hour to 24 hours; And / or, The preparation method of phenelzine intermediate 2 adopts the following post-processing steps: after the reaction is completed, the temperature is lowered, crystallization is performed, and the mixture is slurryed to obtain phenelzine intermediate 2.

5. The method for preparing phenelzine intermediate 3 as described in claim 4, characterized in that: In the preparation method of phenelzine intermediate 2, the volume-to-mass ratio of the organic solvent to phenelzine intermediate 1 is 1 mL / g to 5 mL / g. And / or, In the preparation method of fenelitonee intermediate 2, the mass ratio of fenelitonee intermediate 1 to 4-amino-5-methyl-2-hydroxypyridine is 2.0 to 3.

0. And / or, In the preparation method of phenelzine intermediate 2, the cyclization reaction temperature is 90℃~140℃; And / or, In the preparation method of phenelzine intermediate 2, the cyclization reaction time is 10 to 20 hours; And / or, In the post-processing steps of the method for preparing fenelitone intermediate 2, the cooling is performed to a temperature of 40°C to 50°C. And / or, In the post-processing steps of the method for preparing phenelzine intermediate 2, the crystallization temperature is 0–10°C. And / or, In the post-processing steps of the method for preparing fenelitone intermediate 2, the crystallization time is 1 hour to 10 hours. And / or, In the post-processing steps of the method for preparing fenelitone intermediate 2, the pulping is performed using an aqueous solution of citric acid.

6. The method for preparing phenelzine intermediate 3 as described in claim 1, characterized in that: In the preparation method of phenelzine intermediate 1, the volume-to-mass ratio of the organic solvent to the 4-bromo-2-methoxybenzaldehyde is 1.0 mL / g to 30.0 mL / g; And / or, In the preparation method of phenelzine intermediate 1, the mass ratio of ethyl 2-cyanoacetoacetate to 4-bromo-2-methoxybenzaldehyde is 1.0 to 5.

0. And / or, In the preparation method of phenelzine intermediate 1, the molar ratio of the acid to the 4-bromo-2-methoxybenzaldehyde is 0.01 to 1. And / or, In the method for preparing nelitone intermediate 1, the molar ratio of the catalyst to the 4-bromo-2-methoxybenzaldehyde is 0.01 to 1. And / or, In the preparation method of fenelone intermediate 1, the temperature of the condensation reaction is 10℃~60℃; And / or, In the preparation method of phenelzine intermediate 1, the condensation reaction time is 1 hour to 24 hours; And / or, The preparation method of phenelzine intermediate 1 includes the following post-processing steps: after the reaction is completed, crystallization, filtration, and washing are performed to obtain the phenelzine intermediate 1.

7. The method for preparing phenelzine intermediate 3 as described in claim 6, characterized in that: In the preparation method of phenelzine intermediate 1, the volume-to-mass ratio of the organic solvent to the 4-bromo-2-methoxybenzaldehyde is 2.0 mL / g to 10.0 mL / g. And / or, In the preparation method of phenelzine intermediate 1, the mass ratio of ethyl 2-cyanoacetoacetate to 4-bromo-2-methoxybenzaldehyde is 1.0 to 2.

0. And / or, In the method for preparing phenelzine intermediate 1, the molar ratio of the acid to the 4-bromo-2-methoxybenzaldehyde is 0.10 to 0.

30. And / or, In the method for preparing phenelzine intermediate 1, the molar ratio of the catalyst to the 4-bromo-2-methoxybenzaldehyde is 0.10 to 0.

30. And / or, In the preparation method of fenelone intermediate 1, the temperature of the condensation reaction is 20℃~50℃; And / or, In the preparation method of fenelone intermediate 1, the condensation reaction time is 3 to 4 hours; And / or, In the post-processing steps of the method for preparing fenelone intermediate 1, the crystallization temperature is 10℃~20℃. And / or, In the post-processing steps of the method for preparing fenelitone intermediate 1, the crystallization time is 1 hour to 24 hours. And / or, The washing process in the post-processing steps of the preparation method of fenelitone intermediate 1 uses an alcohol solvent.

8. A method for preparing phenelzine intermediate 4, characterized in that... The process includes the following steps: after preparing phenelzine intermediate 3 according to the method described in any one of claims 1 to 7, phenelzine intermediate 3 is then subjected to a nucleophilic substitution reaction with triethyl orthoformate in an organic solvent in the presence of an acid to obtain phenelzine intermediate 4; wherein the organic solvent is N,N-dimethylacetamide and / or N,N-dimethylformamide; and the acid is concentrated sulfuric acid. 。 9. The method for preparing phenelzine intermediate 4 as described in claim 8, characterized in that: In the preparation method of phenelzine intermediate 4, the volume-to-mass ratio of the organic solvent to the phenelzine intermediate 3 is 1 mL / g to 100 mL / g. And / or, In the preparation method of fenelitone intermediate 4, the mass ratio of triethyl orthoformate to fenelitone intermediate 3 is 1 to 5. And / or, In the preparation method of phenelzine intermediate 4, the molar ratio of the acid to the phenelzine intermediate 3 is 0.10 to 0.

50. And / or, In the preparation method of fenelone intermediate 4, the temperature of the nucleophilic substitution reaction is 100℃~150℃; And / or, In the preparation method of phenelzine intermediate 4, the nucleophilic substitution reaction time is 1 hour to 10 hours; And / or, The preparation method of phenelzine intermediate 4 includes the following post-processing steps: after the reaction is completed, the temperature is lowered, water is added, and crystallization is performed to obtain the phenelzine intermediate 4.

10. The method for preparing phenelzine intermediate 4 as described in claim 9, characterized in that: In the preparation method of phenelzine intermediate 4, the volume-to-mass ratio of the organic solvent to the phenelzine intermediate 3 is 2 mL / g to 10 mL / g. And / or, In the preparation method of phenelzine intermediate 4, the mass ratio of triethyl orthoformate to phenelzine intermediate 3 is 1.1 to 2.

0. And / or, In the preparation method of phenelzine intermediate 4, the molar ratio of the acid to phenelzine intermediate 3 is 0.20 to 0.

45. And / or, In the preparation method of fenelone intermediate 4, the temperature of the nucleophilic substitution reaction is 110℃~140℃; And / or, In the preparation method of fenelone intermediate 4, the nucleophilic substitution reaction takes 2 to 3 hours; And / or, In the post-processing steps of the preparation method of fenelitone intermediate 4, the cooling temperature is reduced to 50℃~60℃. And / or, The preparation method of fenelitone intermediate 4 includes a post-processing step in which crystallization is achieved by adding seed crystals and stirring to induce crystallization. And / or, In the post-processing steps of the preparation method of fenelitone intermediate 4, the crystallization temperature is 0-10°C. And / or, In the post-processing steps of the method for preparing fenelitone intermediate 4, the crystallization time is 2 to 3 hours.

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