Preparation method of fenerenone raw material

Abstract

The invention discloses a preparation method of a fenerenone raw material. The preparation method comprises the following steps: (1) carrying out condensation reaction on 4-formyl-3-methoxybenzonitrile and 3-oxobutyric acid-2-cyanoethyl ester to obtain a first intermediate; (2) carrying out cyclization reaction on the first intermediate and 4-amino-5-methylpyridone to obtain a second intermediate; (3) ethylating the second intermediate to obtain a third intermediate; (4) performing hydrolysis reaction on the third intermediate to obtain a fourth intermediate; (5) carrying out ammonolysis reaction on the fourth intermediate to obtain a finelrenone raceme; and (6) performing chiral resolution to obtain the fenerenone. According to the invention, a tubular reactor is adopted for cyclization reaction, ethylene glycol diethyl ether is adopted to replace low alcohol as a solvent, and processes such as dynamic kinetic resolution under catalysis of beta zeolite and ammonium iodide are adopted, so that the content of sensitive impurities in the material is greatly reduced, and the quality level of the product is greatly improved; the market competitiveness of the product is improved, the yield of the product is improved, and the production cost of the product is reduced.

Description

Technical Field

[0001] This invention belongs to the field of active pharmaceutical ingredient (API) preparation technology, specifically relating to a method for preparing fenelazone API. Background Technology

[0002] Finerenone, developed by Bayer, is a nonsteroidal selective mineralocorticoid receptor antagonist that blocks the harmful effects of excessive mineralocorticoid receptor activation. In diabetic patients, excessive mineralocorticoid receptor activation is thought to contribute to the progression of chronic kidney disease and cardiovascular damage, potentially driven by metabolic, hemodynamic, or inflammatory and fibrotic factors. On July 14, 2025, Bayer announced that the FDA had approved finerenone for a new indication in the treatment of adult patients with heart failure and a left ventricular ejection fraction (LVEF) ≥40%. With this approval, finerenone becomes the only nonsteroidal aldosterone receptor antagonist (nsMRA) approved in the United States for type 2 diabetes-related chronic kidney disease (CKD) and heart failure with an ejection fraction ≥40% (HFmrEF / HFpEF).

[0003] Chinese patent document CN106795155A discloses a method for preparing (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthidine-3-carboxamide [i.e., phenelzine]. The synthesis route is as follows: .

[0004] The shortcomings of this method are: (1) The second step of cyclization reaction needs to be carried out under high temperature and high pressure for a long time, which is prone to side reactions such as hydrolysis, polymerization and decomposition. In particular, the hydrolysis impurity II produced has very similar physicochemical properties to the cyclization product, which seriously affects the product quality. (2) Since the second step of cyclization reaction is carried out in a low alcohol solvent, the residual low alcohol will generate impurity III with very similar physicochemical properties to the ethylation product in the third step of ethylation reaction, which will further affect the product quality. (3) The third step of ethylation uses concentrated sulfuric acid as a catalyst, which is prone to generating decarboxylation and hydrolysis impurity IV. The fourth step of hydrolysis in sodium hydroxide aqueous solution will also generate cyano hydrolysis impurity V, which will also affect the product quality. (4) The yield of the final step of resolution is low.

[0005] With the expiration of the original patent for fenelazol and the development of new indications, the market demand for fenelazol will further increase, making it urgent to develop a fenelazol preparation process with higher product quality and lower cost. Summary of the Invention

[0006] The purpose of this invention is to solve the above problems and provide a method for preparing fenelazone technical material with less related impurities and higher product purity.

[0007] The technical solution to achieve the objective of this invention is: a method for preparing phenelzine technical material, comprising the following steps: ① The first intermediate is obtained by condensation reaction of 4-formyl-3-methoxybenzyl nitrile and 2-cyanoethyl 3-oxobutyric acid; the reaction formula is as follows: .

[0008] In step ① above, the 3-oxobutyric acid-2-cyanoethyl ester is added dropwise, which can effectively reduce the generation of impurity I and improve product quality.

[0009] The structural formula of impurity I is as follows: .

[0010] ② The first intermediate reacts with 4-amino-5-methylpyridinone via a cyclization reaction to yield the second intermediate; the reaction formula is as follows: .

[0011] The cyclization reaction in step ② above is carried out in a tubular reactor, which can greatly shorten the reaction time and reduce the occurrence of side reactions such as hydrolysis, polymerization, and decomposition caused by prolonged high-temperature reaction. In particular, it can greatly reduce the formation of impurity II and further improve product quality.

[0012] The structural formula of impurity II is as follows: .

[0013] In the tubular reactor, the liquid flow rate is 5–15 mL / min, the back pressure valve pressure is 0.3–0.7 MPa, the reaction temperature is 120–150 °C, and the residence time is 200–300 s.

[0014] In step ② above, ethylene glycol diethyl ether is used instead of lower alcohol as a solvent for the cyclization reaction. This effectively eliminates the possibility that residual lower alcohol may react with the second intermediate in the third ethylation reaction to form impurity III, which has very similar physicochemical properties to the third intermediate, thus further improving product quality.

[0015] The structural formula of impurity III is as follows: .

[0016] Where R represents the corresponding residue of the lower alcohol.

[0017] ③ The second intermediate is ethylated to obtain the third intermediate; the reaction formula is as follows: .

[0018] The ethylation reaction in step ③ above uses p-toluenesulfonic acid as a catalyst. Compared with concentrated sulfuric acid, this can effectively avoid the introduction of water. At the same time, the addition of toluene to the reaction system can shorten the reaction time, thereby reducing the generation of decarboxylation and hydrolysis impurities IV, and further improving product quality.

[0019] The structural formula of impurity IV is as follows: .

[0020] ④ The third intermediate is hydrolyzed to obtain the fourth intermediate; the reaction formula is as follows: .

[0021] The hydrolysis reaction in step ④ above uses lithium hydroxide as a catalyst, which can reduce the formation of impurity V and further improve product quality.

[0022] The structural formula of impurity V is as follows: .

[0023] ⑤ The fourth intermediate is subjected to ammonolysis to yield the racemic phenelzine; the reaction formula is as follows: .

[0024] ⑥ Chiral separation yields phenelzine.

[0025] The chiral resolution reaction in step ⑥ above uses dynamic kinetic resolution catalyzed by β-zeolite and ammonium iodide, which can convert some R configurations into S configurations, greatly improving the product yield.

[0026] Apart from the optimized reaction conditions mentioned above, the remaining reaction conditions are basically the same as those in Chinese patent document CN106795155A.

[0027] The positive effects of this invention are: (1) The first step of the condensation reaction of the present invention is to slowly add 3-oxobutyric acid-2-cyanoethyl ester to the reaction system at the reaction temperature, which can effectively reduce the generation of impurity I and improve product quality.

[0028] (2) The second step of the cyclization reaction of the present invention does not use a conventional batch reactor, but a tubular reactor. This can greatly shorten the reaction time, thereby reducing the occurrence of side reactions such as hydrolysis, polymerization and decomposition caused by long-term high-temperature reaction. In particular, it can greatly reduce the generation of impurity II and further improve product quality.

[0029] (3) In the second step of the cyclization reaction of the present invention, ethylene glycol diethyl ether is used instead of lower alcohol as solvent. This can effectively prevent the possibility that the residual lower alcohol will react with the second intermediate in the third step of the ethylation reaction to form impurity III with the physicochemical properties of the third intermediate, thereby further improving the product quality.

[0030] (4) The third step of the ethylation reaction of the present invention uses p-toluenesulfonic acid as a catalyst, which can effectively avoid the generation of decarboxylation and hydrolysis impurity IV, and further improve the product quality.

[0031] (5) The fourth step of the hydrolysis reaction of the present invention uses a relatively mild lithium hydroxide as a catalyst, which can reduce the generation of cyano hydrolysis impurity V and further improve product quality.

[0032] (6) The sixth step of the present invention, chiral separation, adopts dynamic kinetic separation under the catalysis of β zeolite and ammonium iodide, which can convert some R-configured products into S-configured products, greatly improving the product yield.

[0033] (7) By optimizing the reaction conditions, especially by using a tubular reactor for cyclization reaction, using ethylene glycol diethyl ether to replace lower alcohols as solvents, and using dynamic kinetic separation under the catalysis of β zeolite and ammonium iodide, the present invention has greatly reduced the content of sensitive impurities in the material, thereby greatly improving the quality level of the product, enhancing the market competitiveness of the product, increasing the yield of the product, and reducing the production cost of the product. Attached Figure Description

[0034] Figure 1 The HPLC chromatogram of fenelone prepared in Example 1 is shown.

[0035] Figure 2 The image shows the ESI-MS spectrum of fenelone obtained in Example 1. Detailed Implementation

[0036] (Example 1) This example demonstrates the preparation method of the second intermediate of phenelzine, as detailed below: ① Add 600 mL of dichloromethane, 72.5 g of 4-formyl-3-methoxybenzyl nitrile (0.45 mol), 3.75 g of piperidine, and 2.6 g of acetic acid to the reaction flask. Add 74.5 g of 3-oxobutyric acid-2-cyanoethyl ester (0.48 mol) dropwise at a controlled temperature of 20–25 °C over approximately 1 hour. Then, stir at a controlled temperature of 20–25 °C for 30 minutes, and then slowly raise the temperature to reflux for 3–4 hours until the reaction is complete.

[0037] After the reaction was completed, the mixture was cooled to room temperature, and the reaction solution was washed twice with water (250 mL × 2). The organic phase was distilled to recover dichloromethane, and then 30 mL of toluene was added for vacuum distillation to remove all dichloromethane, yielding the first intermediate oily substance, which was directly transferred to the next reaction step without further treatment.

[0038] ② Add 330 mL of ethylene glycol diethyl ether to the reaction flask, then add the first intermediate oil obtained in step ①, followed by 55.8 g of 4-amino-5-methylpyridinone (0.45 mol) and 5 mL of DMAc. Stir until dissolved, then send the reaction solution into the inlet of the reaction section of the tubular reactor via a metering pump. The metering pump controls the liquid flow rate at 10 mL / min, the back pressure valve pressure at 0.5 MPa, the reaction temperature at 130–135 °C, and the residence time at 240 s. Introduce the reaction solution into a 1 L reaction flask equipped with a condenser and maintain it at 50–60 °C for later use.

[0039] After the reaction was completed, the reaction solution was cooled to 0°C in an ice-salt bath, and a large amount of solid precipitated out. After stirring for 3 hours, the mixture was filtered, and the wet product was slurried with 200 mL of methyl tert-butyl ether. After filtration, the filter cake was dried under vacuum to obtain 167.4 g of the second intermediate, a light yellow solid. The yield of the two-step reaction was 92.1%, the HPLC purity was 99.51%, and impurity II was not detected.

[0040] (Comparison Example 1) This comparative example also describes the preparation method of the second intermediate of phenelzine, as follows: ① Add 600 mL of dichloromethane, 72.5 g of 4-formyl-3-methoxybenzyl nitrile (0.45 mol), 3.75 g of piperidine, 2.6 g of acetic acid, and 74.5 g of 2-cyanoethyl 3-oxobutyrate (0.48 mol) to the reaction flask. First, maintain the temperature at 20-25℃ and stir for 30 min. Then, slowly increase the temperature to reflux and react for 3-4 h until the reaction is complete.

[0041] After the reaction was completed, the mixture was cooled to room temperature, and the reaction solution was washed twice with water (250 mL × 2). The organic phase was distilled to recover dichloromethane, and then 30 mL of toluene was added for vacuum distillation to remove all dichloromethane, yielding the first intermediate oily substance, which was directly transferred to the next reaction step without further treatment.

[0042] ② Add 330 mL of 2-butanol to the reaction flask, then add the first intermediate oil obtained in step ①, followed by 55.8 g of 4-amino-5-methylpyridinone (0.45 mol), stir, and gradually heat to remove residual dichloromethane, then gradually raise the temperature to about 98 °C and react under reflux for 20 h until the reaction is complete.

[0043] After the reaction was completed, heating was stopped and the mixture was gradually cooled to 0°C, a solid precipitated, stirred for 4 hours, filtered, and the filter cake was dried under vacuum to obtain 151.1 g of the second intermediate, a light yellow solid. The yield of the two-step reaction was 83.1%, the HPLC purity was 98.32%, and the impurity II content was 0.21%.

[0044] (Example 2) This example demonstrates the preparation method of the third intermediate of phenelzine, as detailed below: Under nitrogen protection, 600 mL of NMP, 180 mL of toluene, and 142.5 g of the second intermediate (0.35 mol) prepared in Example 1 were added to the reaction flask. The mixture was heated and refluxed to remove water for 1 h. Then, the temperature was lowered to 70–80 °C, and 200 g of triethyl orthoacetate and 2.0 g of p-toluenesulfonic acid were added. The mixture was stirred and heated to 110 °C for 1 h. The reaction was carried out under controlled conditions until complete.

[0045] After the reaction was completed, the reaction system was cooled to 40-50℃, and 650mL of water was slowly added dropwise over 1 hour. The mixture was then cooled to 0-5℃ in an ice-water bath to crystallize. The crystals were filtered, and the filter cake was washed twice with water (90mL x 2). The mixture was then dried under vacuum at 50℃ to obtain 146.5g of the third intermediate, a light yellow solid, with a yield of 96.1% and an HPLC purity of 99.62%. Impurities III and IV were not detected.

[0046] (Comparative Example 2) This comparative example also describes the preparation method of the third intermediate of phenelzine, as follows: Under nitrogen protection, 800 mL of NMP and 142.5 g of the second intermediate (0.35 mol) prepared in Comparative Example 1 were first added to the reaction flask, followed by 200 g of triethyl orthoacetate and 10 g of concentrated sulfuric acid. The mixture was stirred and heated to 110 °C for 2 h, and the reaction was carried out under controlled conditions until complete.

[0047] After the reaction was completed, the reaction system was cooled to 40-50℃, and 350mL of water was slowly added dropwise over 1 hour. Then, the mixture was cooled to 0-5℃ in an ice-water bath to crystallize. The crystals were filtered, and the filter cake was washed twice with water (90mL x 2). The mixture was then dried under vacuum at 50℃ to obtain 141.5g of a third intermediate, a light yellow solid with a yield of 92.8%, an HPLC purity of 98.51%, impurity III content of 0.21%, and impurity IV content of 0.72%.

[0048] (Example 3) This example demonstrates the preparation method of the fourth intermediate of phenelzine, as detailed below: 800 mL of tetrahydrofuran, 400 mL of water, and 140 g of the third intermediate (0.32 mol) prepared in Example 2 were added sequentially to the reaction flask. The mixture was stirred to dissolve and cooled to 0–5 °C in an ice-water bath. A lithium hydroxide aqueous solution (prepared by dissolving 15.5 g of lithium hydroxide in 300 mL of water) was added dropwise and the mixture was kept at 0 °C with stirring for 1–2 h.

[0049] After the reaction was completed, the sample was extracted twice with MTBE (300 mL × 2), and then once with 300 mL of ethyl acetate. After standing and separating the layers, the pH of the aqueous phase was adjusted to neutral with dilute hydrochloric acid (prepared by adding 25 g of concentrated hydrochloric acid to 100 mL of water). Then, an aqueous solution of ammonium chloride (prepared by adding 130 g of ammonium chloride to 350 mL of water) was added, and the mixture was stirred for 2 h. The mixture was then filtered, and the filter cake was washed twice with water (75 mL × 2). The mixture was then filtered to dryness and dried under vacuum at 40 °C to obtain 120.2 g of the fourth intermediate, a light-colored powder. The yield was 97.9%, the HPLC purity was 99.87%, and impurity V was not detected.

[0050] (Comparative Example 3) This comparative example also describes the preparation method of the fourth intermediate of phenelzine, as follows: 800 mL of tetrahydrofuran, 400 mL of water, and 140 g of the third intermediate (0.32 mol) prepared in Comparative Example 2 were added sequentially to the reaction flask. The mixture was stirred to dissolve and cooled to 0–5 °C in an ice-water bath. A sodium hydroxide aqueous solution (prepared by mixing 26.6 g of sodium hydroxide with 300 mL of water) was added dropwise and the mixture was kept at 0 °C with stirring for 1–2 h.

[0051] After the reaction was completed, the sample was extracted twice with MTBE (300 mL × 2), and then once with 300 mL of ethyl acetate. After standing and separating the layers, the pH of the aqueous phase was adjusted to neutral with dilute hydrochloric acid (prepared by adding 25 g of concentrated hydrochloric acid to 100 mL of water). Then, an aqueous solution of ammonium chloride (prepared by adding 130 g of ammonium chloride to 350 mL of water) was added, and the mixture was stirred for 2 h. The mixture was then filtered, and the filter cake was washed twice with water (75 mL × 2). The mixture was then filtered to dryness and dried under vacuum at 40 °C to obtain 117.7 g of the fourth intermediate, a light-colored powder. The yield was 95.8%, the HPLC purity was 99.80%, and the impurity V content was 0.18%.

[0052] (Example 4) This example demonstrates the preparation method of fenelazol, as detailed below: ① Add 480 mL of tetrahydrofuran, 100 g of the fourth intermediate (0.26 mol) prepared in Example 3, and 60 g of carbonyl diimidazole to a reaction flask. Stir at 20 °C and add 3.2 g of 4-dimethylaminopyridine to release gas. Then gradually raise the temperature to 50 °C and stir for 2 h. Add 185 g of hexamethyldisilazane at 50 °C. Finally, raise the temperature to reflux and react for 20 h. The reaction is completed under controlled conditions.

[0053] After the reaction was completed, the reaction solution was cooled to 5°C, and tetrahydrofuran aqueous solution (prepared by adding 80 mL tetrahydrofuran + 48 mL water) was added. The mixture was stirred and cooled to 0°C, and a solid precipitated. The solid was filtered, and the filter cake was dried under vacuum at 70°C to obtain 94.7 g of fenelone racemic solid, a light yellow solid, with a yield of 95.0% and an HPLC purity of 99.92%.

[0054] ② In a reaction flask, add 480 mL of dichloromethane, 92 g of the racemic phenelzine obtained in step ① (0.24 mol), and 92.8 g of D-(+)-dibenzoyl tartaric acid (0.26 mol). Stir and heat to reflux for 2 h. Then add 120 g of water, 8 g of β-zeolite, and 2 g of ammonium iodide. Reflux and stir for another 4 h. Then cool to 20 °C and keep warm and stir for 10 h. The solid precipitates out and is filtered to obtain 130.6 g (dry weight) of the double salt as a crystalline powder, with a yield of 72.1%.

[0055] Add 480 mL of ethanol-water (3:1) to the reaction flask, then add the above double salt, stir, cool to 0 °C, add dropwise a 30 wt% sodium phosphate aqueous solution, adjust the pH to 7.2, continue stirring for 4 h, precipitate solid, filter, wash, and vacuum dry to obtain 63.7 g of fenelone, a white crystalline powder, with a free yield of 96%, an ee value of 99.7%, and an HPLC purity of 99.91%.

[0056] (Comparative Example 4) This comparative example also describes the preparation method of fenelazol, as follows: ① Add 480 mL of tetrahydrofuran, 100 g of the fourth intermediate (0.26 mol) prepared in Comparative Example 3, and 60 g of carbonyl diimidazole to a reaction flask. Stir at 20 °C and add 3.2 g of 4-dimethylaminopyridine, releasing gas. Then gradually raise the temperature to 50 °C, stir for 2 h, and add 185 g of hexamethyldisilazane at 50 °C. Finally, raise the temperature to reflux and react for 20 h until the reaction is complete.

[0057] After the reaction was completed, the reaction solution was cooled to 5°C, and tetrahydrofuran aqueous solution (prepared by adding 80 mL tetrahydrofuran + 48 mL water) was added. The mixture was stirred and cooled to 0°C, and a solid precipitated. The solid was filtered, and the filter cake was dried under vacuum at 70°C to obtain 93.0 g of fenelone racemic solid, a light yellow solid with a yield of 93.2% and an HPLC purity of 99.85%.

[0058] ② In a reaction flask, add 480 mL of dichloromethane, 92 g of the racemic phenelzine obtained in step ① (0.24 mol), and 92.8 g of D-(+)-dibenzoyl tartaric acid (0.26 mol), stir and heat to reflux for 4 h, then cool to 20 °C, keep warm and stir for 10 h, precipitate solid, filter, and obtain 82.9 g (dry weight) of double salt, crystalline powder, with a yield of 45.8%.

[0059] Add 480 mL of ethanol-water (3:1) to the reaction flask, then add the above double salt, stir, cool to 0 °C, add dropwise a 30 wt% sodium phosphate aqueous solution, adjust the pH to 7.2, continue stirring for 4 h, precipitate solid, filter, wash, and vacuum dry to obtain 40.5 g of fenelone, a white crystalline powder, with a free yield of 96%, ee value of 99.2%, and HPLC purity of 99.23%.

[0060] (Example 1) This embodiment describes a method for preparing fenelazol, which includes the following steps: ① Add 2.4 L of dichloroethane, 290 g of 4-formyl-3-methoxybenzyl nitrile (1.8 mol), 15 g of piperidine, and 10.5 g of acetic acid to the reaction flask. Add 298 g of 3-oxobutyric acid-2-cyanoethyl ester (1.92 mol) dropwise at a controlled temperature of 20-25℃ over approximately 2 hours. Then, maintain the temperature at 20-25℃ and stir for 30 minutes. Finally, slowly raise the temperature to 38-42℃ and react for 3-4 hours, controlling the reaction until complete.

[0061] After the reaction was completed, the mixture was cooled to room temperature, and the reaction solution was washed twice with water (1L×2). The organic phase was distilled to recover dichloroethane, and then 120mL of toluene was added for vacuum distillation to remove all dichloroethane, yielding the first intermediate oily substance, which was directly transferred to the next reaction step without further treatment.

[0062] ② Add 1.3L of ethylene glycol diethyl ether to the reaction flask, then add the first intermediate oil obtained in step ①, followed by 223.2g of 4-amino-5-methylpyridinone (1.8mol) and 20mL of DMF. Stir until dissolved, then send the reaction solution into the inlet of the reaction section of the tubular reactor via a metering pump. The metering pump controls the liquid flow rate at 10mL / min, the back pressure valve pressure at 0.5MPa, the reaction temperature at 130~135℃, and the residence time at 240s. The reaction solution is then introduced into a 3L reaction flask equipped with a condenser and kept at 50~60℃ for later use.

[0063] After the reaction was completed, the reaction solution was cooled to 0°C in an ice-salt bath, and a large amount of solid precipitated out. The mixture was stirred for 3 hours, filtered, and the wet product was slurried with 800 mL of methyl tert-butyl ether. After filtration, the filter cake was dried under vacuum to obtain 677 g of the second intermediate, a light yellow solid. The yield of the two-step reaction was 93.1%, the HPLC purity was 99.61%, and impurity II was not detected.

[0064] ③ Under nitrogen protection, add 2.2 L of DMAc, 720 mL of toluene, and 570 g of the second intermediate (1.4 mol) obtained in step ② to the reaction flask. Heat and reflux to remove water for 1 h, then cool to 70-80 °C, add 800 g of triethyl orthoacetate and 8.0 g of p-toluenesulfonic acid, stir and heat to 110 °C for 2 h, and control the reaction to complete.

[0065] After the reaction was completed, the reaction system was cooled to 40-50℃, and 2L of water was slowly added dropwise over 1 hour. Then, the mixture was cooled to 0-5℃ in an ice-water bath to crystallize. The crystals were filtered, and the filter cake was washed twice with water (350mL×2). The filter cake was then dried under vacuum at 50℃ to obtain 587.3g of the third intermediate, a light yellow solid, with a yield of 96.4% and an HPLC purity of 99.65%. Impurities III and IV were not detected.

[0066] ④ Add 3.2L of tetrahydrofuran, 1.2L of water and 560g of the third intermediate (1.29mol) obtained in step ③ to the reaction flask in sequence, stir to dissolve, cool to 0-5℃ in an ice-water bath, and uniformly add lithium hydroxide aqueous solution (62g of lithium hydroxide dissolved in 1200mL of water), and keep the mixture at 0℃ with stirring for 1-2h.

[0067] After the reaction was completed, the sample was extracted twice with MTBE (1.2 L × 2), and then once with 1.2 L of ethyl acetate. After standing and separating the layers, the pH of the aqueous phase was adjusted to neutral with dilute hydrochloric acid (prepared by 100 g concentrated hydrochloric acid + 400 mL water). An aqueous solution of ammonium chloride (prepared by 520 g ammonium chloride + 1.4 L water) was added, and the mixture was stirred for 2 h. The mixture was then filtered, and the filter cake was washed twice with water (300 mL × 2). The mixture was then filtered to dryness and dried under vacuum at 40 °C to obtain 480.9 g of the fourth intermediate, a light-colored powder. The yield was 97.9%, the HPLC purity was 99.20%, and impurity V was not detected.

[0068] ⑤ Add 1.8 L of tetrahydrofuran, 400 g of the fourth intermediate (1.05 mol) obtained in step ④ and 305 g of dicyclohexylcarbodiimide to the reaction flask. Stir at 20 °C and add 16 g of 4-dimethylaminopyridine. Then gradually raise the temperature to 50 °C and stir for 2 h. Add 740 g of hexamethyldisilazane at 50 °C. Finally, raise the temperature to reflux and react for 20 h. The reaction is completed under central control.

[0069] After the reaction was completed, the reaction solution was cooled to 5°C, and tetrahydrofuran aqueous solution (320 mL tetrahydrofuran and 200 mL water) was added. The mixture was stirred and cooled to 0°C, and a solid precipitated. The solid was filtered, and the filter cake was dried under vacuum at 70°C to obtain 379.8 g of fenelone racemic solid, which was a light yellow solid with a yield of 95.2% and an HPLC purity of 99.91%.

[0070] ⑥ In a reaction flask, add 1.9 L of dichloromethane, 368 g of the racemic phenelzine obtained in step ⑤ (0.97 mol), and 371.2 g of D-(+)-dibenzoyl tartaric acid (1.04 mol). Stir and heat to reflux for 2 h. Then add 480 g of water, 32 g of β-zeolite, and 8 g of ammonium iodide. Reflux and stir for 4 h. Cool to 20 °C and keep warm and stir for 10 h. The solid precipitates. Filter to obtain 550.5 g (dry weight) of the double salt, crystalline powder, with a yield of 75.2%.

[0071] Add 1920 mL of ethanol-water (volume ratio 3:1) to the reaction flask, then add the above-mentioned double salt, stir, cool to 0°C, add dropwise a 30 wt% sodium phosphate aqueous solution to adjust the pH to 7.2, continue stirring for 4 h, precipitate a solid, filter, wash, and vacuum dry to obtain 265.7 g of fenelone, a white crystalline powder, with a free yield of 96%, an ee value of 99.8%, and an HPLC purity of 99.97 (see [link to reaction flask]). Figure 1 ESI-MS spectra are shown below. Figure 2 ,Depend on Figure 2 It can be seen that its molecular weight is 378 (M+H).

Claims

1. A method for preparing fenelazol technical grade drug, comprising the following steps: ①The first intermediate is obtained by condensation reaction of 4-formyl-3-methoxybenzyl nitrile and 2-cyanoethyl 3-oxobutyric acid; ② The first intermediate reacts with 4-amino-5-methylpyridinone via a cyclization reaction to yield the second intermediate; ③ The second intermediate is ethylated to obtain the third intermediate; ④ The third intermediate is hydrolyzed to obtain the fourth intermediate; ⑤ The fourth intermediate was subjected to ammonolysis to obtain the racemic phenelzine; ⑥ Chiral resolution yields phenelzine; characterized in that: the chiral resolution in step ⑥ is carried out in the presence of β-zeolite and ammonium iodide.

2. The method for preparing phenelzine technical material according to claim 1, characterized in that: The cyclization reaction in step ② above is carried out in a tubular reactor.

3. The method for preparing phenelzine technical material according to claim 2, characterized in that: In the tubular reactor, the liquid flow rate is 5–15 mL / min, the back pressure valve pressure is 0.3–0.7 MPa, the reaction temperature is 120–150 °C, and the residence time is 200–300 s.

4. The method for preparing phenelzine technical material according to claim 1, characterized in that: The cyclization reaction in step ② above is carried out in ethylene glycol diethyl ether solvent.

5. The method for preparing fenelazol technical material according to any one of claims 1 to 4, characterized in that: The ethylation reaction in step ③ above uses p-toluenesulfonic acid as a catalyst.

6. The method for preparing fenelazol technical material according to any one of claims 1 to 4, characterized in that: The catalyst used in step ④ above for the hydrolysis reaction is lithium hydroxide.

7. The method for preparing fenelazol technical material according to any one of claims 1 to 4, characterized in that: In step ① above, the 3-oxobutyric acid-2-cyanoethyl ester is added dropwise.

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