Preparation method of mianserin sulfate

Abstract

The invention belongs to the technical field of medicine synthesis processes, and particularly relates to a preparation method of high-yield and high-purity mianserin sulfate. The method comprises the following steps: by taking toluene as a system solvent of a'one-pot 'reaction, and N-methylethanolamine and phenyl ethylene oxide as starting materials, sequentially carrying out condensation and chlorination, carrying out condensation reaction with 2-aminobenzyl alcohol under an alkaline condition, carrying out intramolecular dehydration reaction on a reaction product, and refining to obtain mianserin sulfate. According to the method, the reaction operation is simplified, the reaction yield is remarkably increased, impurities in the used solvent system are easy to remove, the process atom economy is good, the output of three wastes is small, and the method is green and environment-friendly.

Description

Technical Field

[0001] This invention relates to the field of medicinal chemistry, specifically to a method for preparing high-purity, high-yield micarin sulfate. Background Technology

[0002] Mianserin's chemical name is (14bRS)-2-methyl-1,2,3,4,10,14b-hexahydrodibenzo-[c,f]pyrazino[1,2-a]azapyridine, and its structural formula is as follows:

[0003] .

[0004] Mianserin is a norepinephrine and specific 5-HT receptor antagonist that blocks norepinephrine alpha. ２ It can increase the concentration of NE and 5-HT in the synaptic cleft by both autoreceptors and heteroreceptors, thus playing an antidepressant, anti-anxiety, and sleep-promoting role. It can also selectively block 5-HT2 and 5-HT3 receptors, reducing the side effects of sexual dysfunction and nausea and vomiting. At the same time, it blocks H1 receptors, thus having a sedative effect.

[0005] The main synthetic routes for Mianserin that have been publicly disclosed so far are as follows:

[0006] CN101544644A discloses a method for preparing mianserin, the synthetic route of which is shown below:

[0007]

[0008] This technical route first reacts benzaldehyde and ethanolamine to obtain N-benzylethanolamine, which is then reacted with phenyl ethylene oxide, followed by sequential chlorination, condensation, and dehydration cyclization. The resulting intermediate is further debenzylated and remethylated to obtain mianserine. The crude product obtained by this method has a yield of 69.2%.

[0009] The literature J. Med. Chem. 2002, 45, 3280-3285 discloses a synthetic route for levamisole, as shown below:

[0010]

[0011] (a) Phenyl ethylene oxide and 2-methylaminoethanol were reacted at 130 °C, and after 24 hours of reaction, β-hydroxy-N-methyl-N-hydroxyethyl phenethylamine (3) was obtained by rapid chromatography (yield 88%).

[0012] (b) In a cold chloroform solution of β-hydroxy-N-methyl-N-hydroxyethyl phenethylamine (3), thionyl chloride was slowly added and refluxed for 2 hours. The solution was quenched with water, alkalized with NaOH, and then extracted with chloroform to obtain chlorophenethylamine (4) (yield 67%).

[0013] (c) Add an acetone solution of phenylethylamine chloride (4) to an acetonitrile solution of 2-amino-3-methoxybenzyl alcohol and stir at room temperature for 30 minutes. Add N,N-diisopropylethylamine, reflux for 7 hours, stir at room temperature for 16 hours, filter, and recrystallize the resulting solid with acetonitrile to give 1-methyl-3-phenyl-4-(2-methoxy-6-hydroxyethyl)-phenylpiperazine hydrochloride (5) (yield 74%).

[0014] (d) 1-Methyl-3-phenyl-4-(2-methoxy-6-hydroxyethyl)-phenylpiperazine hydrochloride (5) was suspended in polyphosphoric acid and stirred at 100°C for 2 hours. The reaction was quenched with ice and dichloromethane was added. The mixture was alkalized with 2N NaOH aqueous solution. The organic layer was separated from the aqueous layer and then extracted with dichloromethane. The organic layer was washed with brine, dried, concentrated, and purified by rapid chromatography to give 1,2,3,4,10,14b-hexahydro-6-methoxy-2-methyldibenzo-[c,f]pyrazino[1,2-a]azacycloheptane (6) (yield 73%).

[0015] (e) 1,2,3,4,10,14b-hexahydro-6-methoxy-2-methyldibenzo-[c,f]pyrazino[1,2-a]azacycloheptane (6) was chirally separated using a high-performance liquid chromatography chiral column to obtain (-)-6, which was then refluxed with aluminum trichloride in benzene for 17 hours to obtain levorotatory 1,2,3,4,10,14b-hexahydro-6-hydroxy-2-methyldibenzo-[c,f]pyrazino[1,2-a]azacycloheptane. Alkane ((-)-7), unpurified, was trifluorinated in dichloromethane with trifluoromethanesulfonyl anhydride as a base to give levorotatory 1,2,3,4,10,14b-hexahydro-2-methyl-6-trifluoromethanesulfonyl dibenzo-[c,f]pyrazino[1,2-a]azacycloheptane ((-)-8), and then the trifluoromethanesulfonyl group was removed by refluxing in methanol with triphenylphosphine, triethylamine and palladium acetate for 48 hours to give levorotatory mirancerine ((-)-2).

[0016] The above process route first uses a four-step reaction to prepare compound 6, which is then subjected to chiral resolution, demethylation, trifluoromethanesulfonation, and detrifluoromethanesulfonylation to obtain levamisole. Each step uses a different solvent system, necessitating post-reaction product processing. For example, steps (a) and (d) require rapid column chromatography, step (b) involves product extraction, step (c) requires stirring at room temperature for 16 hours followed by recrystallization, and step (e) has a long reaction time and harsh conditions. This route is cumbersome, time-consuming, and yields low results. Furthermore, the solvent systems required for each step demand high reaction temperatures and long reaction times, leading to high industrial energy consumption, increased risk of impurity formation, and greater difficulty in impurity removal, making it unsuitable for industrial production.

[0017] While there are many methods for preparing mianselin under current technology, most suffer from problems such as high reaction temperature, long reaction time, and low conversion rate. To accelerate the reaction, the reaction temperature is often increased, leading to poor process safety, poor product quality, low yield, and large amounts of waste. Summary of the Invention

[0018] To address the problems of existing technologies, this invention provides a method for preparing high-purity mianserin sulfate using toluene as the solvent in a one-pot reaction. This method has a short production cycle, generates minimal waste, is environmentally friendly, and boasts a high yield, producing mianserin sulfate with a purity exceeding 99.50%. Furthermore, this method has low production costs, is simple to operate, and operates under mild reaction conditions, making it suitable for industrial production.

[0019] To achieve the above objectives, the present invention adopts the following technical solution:

[0020] (1) 2-[(2-hydroxyethyl)(methyl)amino]-1-phenylethyl-1-ol (abbreviated as: compound 2) was prepared by condensation reaction of N-methylethanolamine and phenyl ethylene oxide.

[0021] (2) Add a chlorination reagent directly to the reaction system of step (1) to prepare (2-chloroethyl)(2-chloro-2-phenylethyl)(methyl)amine hydrochloride (abbreviated as: compound 3). Compound 3 is washed with alkaline water to obtain (2-chloroethyl)(2-chloro-2-phenylethyl)(methyl)amine (abbreviated as: compound 4).

[0022] (3) Compound 4 undergoes a condensation reaction with 2-aminobenzyl alcohol in the presence of a base to generate [2-(4-methyl-2-phenylpiperazin-1-yl)phenyl]methanol (abbreviated as: compound 5);

[0023] (4) Compound 5 undergoes intramolecular dehydration under concentrated sulfuric acid conditions, and after removing the organic phase, it yields mianserin sulfate (abbreviated as: compound 1).

[0024] The specific synthesis route is as follows:

[0025]

[0026] In step (1), the reaction solvent is one or more of isopropyl acetate, butyl acetate, and toluene, preferably toluene; the reaction temperature is 50℃~90℃, preferably 70℃~80℃; and the reaction time is 5~7 hours. Preferably, the mass ratio of N-methylethanolamine to toluene is 1:10, and the mass ratio of N-methylethanolamine to phenyl ethylene oxide is 1:1.6.

[0027] In step (2), the chlorinating agent is one or more of thionyl chloride, phosphorus oxychloride, and phosphorus pentachloride, preferably thionyl chloride; the reaction temperature is 30℃~80℃, preferably 45℃~55℃; the reaction time is 5~7 hours. Preferably, the mass of thionyl chloride is 2~5 times that of N-methylethanolamine in step (1). In a specific example of the present invention, the mass of thionyl chloride is 4.5 times that of N-methylethanolamine in step (1).

[0028] In step (3), base 1 is one or more of DBU, triethylamine, N,N-diisopropylethylamine, and pyridine, preferably triethylamine. The reaction temperature is 50℃~100℃, preferably 70℃~80℃; the reaction time is 5~7 hours. Preferably, the mass of 2-aminobenzyl alcohol is 1.6~3.3 times the mass of N-methylethanolamine in step (1), and the mass of triethylamine is 1.3~2.7 times the mass of N-methylethanolamine in step (1). In a specific example of the present invention, the mass of 2-aminobenzyl alcohol is 1.6 times the mass of N-methylethanolamine in step (1), and the mass of triethylamine is 2.5 times the mass of N-methylethanolamine in step (1).

[0029] The dehydrating agent in step (4) is concentrated sulfuric acid. The reaction temperature is 30℃~60℃, preferably 40℃~50℃; the reaction time is 4~6 hours. Preferably, the mass of concentrated sulfuric acid is 10~15 times the mass of N-methylethanolamine in step (1). In a specific example of the present invention, the mass of concentrated sulfuric acid is 13 times the mass of N-methylethanolamine in step (1).

[0030] Furthermore, step (4) also includes a step of refining mianserin sulfate, which includes adding water to mianserin sulfate after removing the organic phase, cooling, stirring, and filtering.

[0031] The method described in this invention further includes a purification step of recrystallization after refining, wherein the filtered filter cake is added to an organic solvent, heated until dissolved, cooled to crystallize, filtered and dried to obtain mianserin sulfate, and the refining solvent is one or more of methanol, ethanol, n-propanol, isopropanol, acetone, acetonitrile, ethyl acetate and toluene, preferably ethanol.

[0032] A specific example of this invention is as follows:

[0033] (1) Add N-methylethanolamine and phenyl ethylene oxide to toluene, heat to 70℃~80℃ and react for 6 hours, then cool to 10℃~20℃. The mass ratio of N-methylethanolamine to toluene is 1:10 and the mass ratio of N-methylethanolamine to phenyl ethylene oxide is 1:1.6.

[0034] (2) Add thionyl chloride to the reaction system of step (1). The mass of thionyl chloride is 4.5 times that of N-methylethanolamine in step (1). After the addition is complete, heat the mixture to 45℃~55℃ and react for 6 hours. Then cool the mixture to 5℃~10℃ and adjust the pH of the reaction solution to 6.5~7.5 (5% sodium carbonate solution). Separate the liquid and discard the aqueous phase.

[0035] (3) Triethylamine and 2-aminobenzyl alcohol are added to the organic phase obtained in step (2). The mass of 2-aminobenzyl alcohol is 1.6 times the mass of N-methylethanolamine in step (1), and the mass of triethylamine is 2.5 times the mass of N-methylethanolamine in step (1). The temperature is raised to 70℃~80℃ and reacted for 6 hours. The temperature is lowered to 10℃~20℃, purified water is added for washing, and the aqueous phase is discarded after separation.

[0036] (4) Cool the organic phase obtained in step (3) to 5℃~10℃, add concentrated sulfuric acid (the mass of which is 13 times the mass of N-methylethanolamine in step (1)), and heat to 40℃~50℃ for 5 hours. Remove the organic solvent under reduced pressure, add purified water to the residue, cool to 10℃~20℃, stir for 2 hours, and filter. Add ethanol to the filter cake, heat until dissolved, cool to 10℃~20℃, stir for 2 hours, filter, and dry to obtain mianserin sulfate.

[0037] By applying the above technical solution, the present invention has the following advantages compared with the prior art:

[0038] (1) The present invention uses toluene as the system solvent and adopts a one-pot process to directly produce mirtserin sulfate. The process is simple, the production cycle is short and the cost is low.

[0039] (2) Using toluene as a reaction solvent not only greatly reduces the reaction temperature, but also shortens the reaction time, thus improving process safety.

[0040] (3) The "one-pot" process effectively reduces the output of "three wastes" and is green and environmentally friendly.

[0041] (4) The reaction conditions of the process of the present invention are mild and the operation is simple.

[0042] (5) Using toluene as a solvent system to prepare mianserin sulfate makes it easy to remove impurities, effectively improves product purity, reduces the number of refining processes, and lowers production costs, making it suitable for industrial production. Attached Figure Description

[0043] Figure 1 The 1H NMR spectrum of mianserin sulfate prepared by the method described in this invention ( 1 H-NMR).

[0044] Figure 2This is the mass spectrum (MS) of mianserin sulfate obtained by the method described in this invention.

[0045] Figure 3 The image shows the liquid phase (HPLC) of mianserin sulfate prepared by the method described in this invention. Detailed Implementation

[0046] The following detailed embodiments further illustrate the above-mentioned content of the present invention. However, these embodiments should not be construed as limiting the present invention in any way. The scope of protection of the present invention is defined by the claims. Unless otherwise specified, the following embodiments are all implemented using conventional prior art. Specific embodiments are described below:

[0047] Example 1: Effect of different reaction solvents on the yield and quality of mianserin sulfate

[0048] (1) Add 100g of different reaction solvents to a 500mL three-necked flask, turn on the stirrer, add 10.0g of N-methylethanolamine and 16.0g of phenyl ethylene oxide, heat to 70℃~80℃ and react for 6h, then cool to 10℃~20℃.

[0049] (2) Add 45.0 g of thionyl chloride. After the addition is complete, heat to 45℃~55℃ and react for 6 hours. Then cool down to 5℃~10℃. Add 5% sodium carbonate solution to the reaction solution to adjust the pH to about 7. Separate the solution and discard the aqueous phase.

[0050] (3) Add 25.0 g of triethylamine and 16.0 g of 2-aminobenzyl alcohol to the organic phase, heat to 70℃~80℃ and react for 6 hours, then cool to 10℃~20℃, add 40.0 g of purified water to wash 3 times, separate the liquid and discard the aqueous phase. Add 5.0 g of anhydrous sodium sulfate to the organic phase and dry for 1 hour, then filter.

[0051] (4) Cool the organic phase to 5℃~10℃, add 130.0g of concentrated sulfuric acid, and heat to 40℃~50℃ to react for 5 hours. Remove the organic phase under reduced pressure, add 130.0g of purified water to the residue, cool to 10℃~20℃, stir for 2 hours, and filter. Add 300.0g of ethanol to the filter cake, heat until dissolved, cool to 10℃~20℃, stir for 2 hours, filter, and dry to obtain mianserin sulfate.

[0052] Detection method: High performance liquid chromatography

[0053] Chromatographic conditions: Use octadecylsilane-bonded silica gel as the stationary phase (Agilent Infinity LabPoroshell 120 EC-C18, 4.6 mm × 250 mm, 4 μm or equivalent column is recommended); use 0.05 mol / L diammonium hydrogen phosphate buffer (adjusted to pH 7.5 with phosphoric acid)-methanol (90:10) as mobile phase A and water-methanol (5:95) as mobile phase B, and perform linear gradient elution according to the table below; flow rate is 1 mL / min; column temperature is 45 °C; detection wavelength is 230 nm; injection plate temperature is 6 °C; injection volume is 10 μL. If gradient peaks interfere with impurity detection, it is recommended to install a ghost peak trapping column (4.0 mm × 30 mm) between the pump mixer and injector of the liquid chromatograph.

[0054]

[0055] The effects of different reaction solvents on the yield and purity of mianserin sulfate are shown in Table 1:

[0056] Table 1

[0057]

[0058] Experimental results show that although isopropyl acetate and butyl acetate can be used as solvents to obtain the target product, the product yield is low and the purity is poor. When toluene is used as a solvent, the yield and purity of the target product are both higher. Considering factors such as yield and purity, toluene is selected as the reaction solvent. In steps (1) and (2), N,N-dimethylformamide is used as the reaction solvent, and the reaction can be completed smoothly. However, after the reaction is completed, water and other organic solvents (such as ethyl acetate) need to be added and extracted multiple times. The organic phase is then evaporated under reduced pressure to obtain compound 4. The post-processing is cumbersome and it is impossible to achieve the "one-pot" preparation of mianserin.

[0059] Example 2 Step (1) Effect of different reaction temperatures on the yield and purity of mianserin sulfate

[0060] (1) Add 100g of toluene to a 500mL three-necked flask, start stirring, add 10.0g of N-methylethanolamine and 16.0g of phenyl ethylene oxide, heat to different reaction temperatures and react for 6h, then cool to 10℃~20℃.

[0061] (2) Add 45.0 g of thionyl chloride. After the addition is complete, heat to 45℃~55℃ and react for 6 hours. Then cool down to 5℃~10℃. Add 5% sodium carbonate solution to the reaction solution to adjust the pH to about 7. Separate the solution and discard the aqueous phase.

[0062] (3) Add 25.0 g of triethylamine and 16.0 g of 2-aminobenzyl alcohol to the organic phase, heat to 70℃~80℃ and react for 6 hours, then cool to 10℃~20℃, add 40.0 g of purified water to wash 3 times, separate the liquid and discard the aqueous phase. Add 5.0 g of anhydrous sodium sulfate to the organic phase and dry for 1 hour, then filter.

[0063] (4) Cool the organic phase to 5℃~10℃, add 130.0g of concentrated sulfuric acid, and heat to 40℃~50℃ to react for 5 hours. Remove the organic phase under reduced pressure, add 130.0g of purified water to the residue, cool to 10℃~20℃, stir for 2 hours, and filter. Add 300.0g of ethanol to the filter cake, heat until dissolved, cool to 10℃~20℃, stir for 2 hours, filter, and dry to obtain mianserin sulfate.

[0064] The effects of different reaction temperatures on the yield and purity of mianserin sulfate in step (1) are shown in Table 2:

[0065] Table 2

[0066]

[0067] Experimental results show that the target product can be obtained by using different reaction temperatures in step (1), but the product yield and quality are low when reacting in the temperature ranges of 50℃~60℃, 60℃~70℃, and 80℃~90℃. Therefore, 70℃~80℃ is selected as the optimal reaction temperature range.

[0068] Example 3 Step (2) Effect of different chlorination reagents on the yield and purity of mianserin sulfate

[0069] (1) Add 100g of toluene to a 500mL three-necked flask, start stirring, add 10.0g of N-methylethanolamine and 16.0g of phenyl ethylene oxide, heat to 70℃~80℃ and react for 6h, then cool to 10℃~20℃.

[0070] (2) Add different chlorination reagents, and after the addition is complete, heat to 45℃~55℃ and react for 6 hours, then cool to 5℃~10℃. Add 5% sodium carbonate solution to the reaction solution to adjust the pH to about 7, separate the liquids, and discard the aqueous phase.

[0071] (3) Add 25.0 g of triethylamine and 16.0 g of 2-aminobenzyl alcohol to the organic phase, heat to 70℃~80℃ and react for 6 hours, then cool to 10℃~20℃, add 40.0 g of purified water to wash 3 times, separate the liquid and discard the aqueous phase. Add 5.0 g of anhydrous sodium sulfate to the organic phase and dry for 1 hour, then filter.

[0072] (4) Cool the organic phase to 5℃~10℃, add 130.0g of concentrated sulfuric acid, and heat to 40℃~50℃ to react for 5 hours. Remove the organic phase under reduced pressure, add 130.0g of purified water to the residue, cool to 10℃~20℃, stir for 2 hours, and filter. Add 300.0g of ethanol to the filter cake, heat until dissolved, cool to 10℃~20℃, stir for 2 hours, filter, and dry to obtain mianserin sulfate.

[0073] The effects of different chlorination reagents on the yield and purity of mianserin sulfate in step (2) are shown in Table 3:

[0074] Table 3

[0075]

[0076] Experimental results show that the target product can be obtained by using different chlorination reagents in step (2), but the product yields of phosphorus oxychloride and phosphorus pentachloride are low. Therefore, thionyl chloride is selected as the chlorination reagent.

[0077] Example 4: Effect of step (3) 1 type of alkali on the yield and purity of mianserin sulfate

[0078] (1) Add 100g of toluene to a 500mL three-necked flask, start stirring, add 10.0g of N-methylethanolamine and 16.0g of phenyl ethylene oxide, heat to 70℃~80℃ and react for 6h, then cool to 10℃~20℃.

[0079] (2) Add 45.0 g of thionyl chloride. After the addition is complete, heat to 45℃~55℃ and react for 6 hours. Then cool down to 5℃~10℃. Add 5% sodium carbonate solution to the reaction solution to adjust the pH to about 7. Separate the solution and discard the aqueous phase.

[0080] (3) Add different bases 1 to the organic phase, add 16.0 g of 2-aminobenzyl alcohol, heat to 70℃~80℃ and react for 6 hours, cool to 10℃~20℃, add 40.0 g of purified water for washing 3 times, separate the liquid and discard the aqueous phase. Add 5.0 g of anhydrous sodium sulfate to the organic phase and dry for 1 hour, then filter.

[0081] (4) Cool the organic phase to 5℃~10℃, add 130.0g of concentrated sulfuric acid, and heat to 40℃~50℃ to react for 5 hours. Remove the organic phase under reduced pressure, add 130.0g of purified water to the residue, cool to 10℃~20℃, stir for 2 hours, and filter. Add 300.0g of ethanol to the filter cake, heat until dissolved, cool to 10℃~20℃, stir for 2 hours, filter, and dry to obtain mianserin sulfate.

[0082] The effects of different bases on the yield and purity of mianserin sulfate in step (3) are shown in Table 4:

[0083] Table 4

[0084]

[0085] Experimental results show that the target product can be obtained by using different bases in step (3), but the product yields of DBU, N,N-diisopropylethylamine and pyridine are low, while the product yields and purity of the product obtained by using triethylamine as a base are both high. Therefore, triethylamine is selected as the base.

[0086] Example 5: Effect of step (3) on the yield and purity of mianserin sulfate

[0087] (1) Add 100g of toluene to a 500mL three-necked flask, start stirring, add 10.0g of N-methylethanolamine and 16.0g of phenyl ethylene oxide, heat to 70℃~80℃ and react for 6h, then cool to 10℃~20℃.

[0088] (2) Add 45.0 g of thionyl chloride. After the addition is complete, heat to 45℃~55℃ and react for 6 hours. Then cool down to 5℃~10℃. Add 5% sodium carbonate solution to the reaction solution to adjust the pH to about 7. Separate the solution and discard the aqueous phase.

[0089] (3) Add 25.0 g of triethylamine and 16.0 g of 2-aminobenzyl alcohol to the organic phase, heat to different reaction temperatures and react for 6 hours, cool down to 10℃~20℃, add 40.0 g of purified water for washing 3 times, separate the liquid and discard the aqueous phase. Add 5.0 g of anhydrous sodium sulfate to the organic phase and dry for 1 hour, then filter.

[0090] (4) Cool the organic phase to 5℃~10℃, add 130.0g of concentrated sulfuric acid, and heat to 40℃~50℃ to react for 5 hours. Remove the organic phase under reduced pressure, add 130.0g of purified water to the residue, cool to 10℃~20℃, stir for 2 hours, and filter. Add 300.0g of ethanol to the filter cake, heat until dissolved, cool to 10℃~20℃, stir for 2 hours, filter, and dry to obtain mianserin sulfate.

[0091] The effects of different reaction temperatures on the purity of mianserin sulfate in step (3) are shown in Table 5:

[0092] Table 5

[0093]

[0094] Experimental results show that the target product can be obtained by using different reaction temperatures in step (3), but the product yield and quality are poor when reacting in the temperature range of 50℃~60℃ and 60℃~70℃; the product purity is high but the yield is low when reacting in the temperature range of 80℃~90℃ and 90℃~100℃. Therefore, 70℃~80℃ is selected as the optimal reaction temperature range.

[0095] Example 6: Effect of step (4) on the yield and purity of mianserin sulfate

[0096] (1) Add 100g of toluene to a 500mL three-necked flask, start stirring, add 10.0g of N-methylethanolamine and 16.0g of phenyl ethylene oxide, heat to 70℃~80℃ and react for 6h, then cool to 10℃~20℃.

[0097] (2) Add 45.0 g of thionyl chloride. After the addition is complete, heat to 45℃~55℃ and react for 6 hours. Then cool down to 5℃~10℃. Add 5% sodium carbonate solution to the reaction solution to adjust the pH to about 7. Separate the solution and discard the aqueous phase.

[0098] (3) Add 25.0 g of triethylamine and 16.0 g of 2-aminobenzyl alcohol to the organic phase, heat to 70℃~80℃ and react for 6 hours, then cool to 10℃~20℃, add 40.0 g of purified water to wash 3 times, separate the liquid and discard the aqueous phase. Add 5.0 g of anhydrous sodium sulfate to the organic phase and dry for 1 hour, then filter.

[0099] (4) Cool the organic phase to 5℃~10℃, add 130.0g of concentrated sulfuric acid, and heat to different reaction temperatures for 5 hours. Remove the organic phase under reduced pressure, add 130.0g of purified water to the residue, cool to 10℃~20℃, stir for 2 hours, and filter. Add 300.0g of ethanol to the filter cake, heat until dissolved, cool to 10℃~20℃, stir for 2 hours, filter, and dry to obtain mianserin sulfate.

[0100] The effects of different reaction temperatures on the yield and purity of mianserin sulfate in step (4) are shown in Table 6:

[0101] Table 6

[0102]

[0103] Experimental results show that the target product can be obtained by using different reaction temperatures in step (4), but the product yield and quality are poor when reacting in the temperature range of 30℃~40℃ and 50℃~60℃; the product yield and purity are higher when reacting in the temperature range of 40℃~50℃. Therefore, 40℃~50℃ is selected as the optimal reaction temperature range.

[0104] Example 7 Effect of the refining solvent in step (4) on the yield and purity of mianserin sulfate

[0105] (1) Add 100g of toluene to a 500mL three-necked flask, start stirring, add 10.0g of N-methylethanolamine and 16.0g of phenyl ethylene oxide, heat to 70℃~80℃ and react for 6h, then cool to 10℃~20℃.

[0106] (2) Add 45.0 g of thionyl chloride. After the addition is complete, heat to 45℃~55℃ and react for 6 hours. Then cool down to 5℃~10℃. Add 5% sodium carbonate solution to the reaction solution to adjust the pH to about 7. Separate the solution and discard the aqueous phase.

[0107] (3) Add 25.0 g of triethylamine and 16.0 g of 2-aminobenzyl alcohol to the organic phase, heat to 70℃~80℃ and react for 6 hours, then cool to 10℃~20℃, add 40.0 g of purified water to wash 3 times, separate the liquid and discard the aqueous phase. Add 5.0 g of anhydrous sodium sulfate to the organic phase and dry for 1 hour, then filter.

[0108] (4) Cool the organic phase to 5℃~10℃, add 130.0g of concentrated sulfuric acid, and heat to 40℃~50℃ to react for 5 hours. Remove the organic phase under reduced pressure, add 130.0g of purified water to the residue, cool to 10℃~20℃, stir for 2 hours, and filter. Add different solvents to the filter cake to purify and obtain mianserin sulfate.

[0109] The effects of different refining solvents on the yield and purity of mianserin sulfate in step (4) are shown in Table 7:

[0110] Table 7

[0111]

[0112] Experimental results show that in step (4), different solvents are used for purification. The product purity is high but the yield is low when methanol and acetone are used for purification; the product yield is high but the purity is poor when n-propanol, isopropanol, acetonitrile, and ethyl acetate are used for purification; the product yield and purity are both high when anhydrous ethanol is used for purification. Therefore, anhydrous ethanol is selected as the purification solvent.

[0113] Figure 1 The 1H NMR spectrum of mianserin sulfate prepared by the method described in this invention ( 1 H-NMR). Figure 2 This is the mass spectrum (MS) of mianserin sulfate obtained by the method described in this invention. Figure 3 The image shows the HPLC chromatogram of mianserin sulfate, number 2.

[0114] Example 8. Preparation of Mianserin by method described in J. Med. Chem. 2002, 45, 3280-3285.

[0115] The starting material 2-amino-3-methoxybenzyl alcohol used in the preparation of 1,2,3,4,10,14b-hexahydro-6-methoxy-2-methyldibenzo-[c,f]pyrazino[1,2-a]azacycloheptane (6) was replaced with 2-amino-benzyl alcohol to prepare miancerin.

[0116] (a) Preparation of 2-[(2-hydroxyethyl)(methyl)amino]-1-phenylethyl-1-ol;

[0117] 14.7 g of N-methylethanolamine was added to a 100 mL three-necked flask. Stirring and heating were started, and the mixture was heated to 100 °C. 15.9 g of phenyl ethylene oxide was slowly added, and the mixture was heated to 130 °C and stirred for 24 hours. Column purification yielded 20.1 g of a pale yellow oily substance, 2-[(2-hydroxyethyl)(methyl)amino]-1-phenylethyl-1-ol, with a yield of 77.79%.

[0118] (b) Preparation of (2-chloroethyl)(2-chloro-2-phenylethyl)(methyl)amine

[0119] Add 200 ml of chloroform to a 1000 mL three-necked flask, then add 13.0 g of 2-[(2-hydroxyethyl)(methyl)amino]-1-phenylethyl-1-ol, and slowly add a chloroform (200 ml) solution of 100 ml of thionyl chloride. After the addition is complete, reflux the reaction for 2 hours, quench with 100 ml of water, adjust the alkali with 2N sodium hydroxide solution, separate the layers, extract the aqueous layer with chloroform again, combine the chloroform layers, wash with sodium chloride solution, dry the organic phase, and concentrate under reduced pressure to obtain 9.8 g of brown oily substance (2-chloroethyl)(2-chloro-2-phenylethyl)(methyl)amine, with a yield of 63.41%.

[0120] (c) Preparation of [2-(4-methyl-2-phenylpiperazin-1-yl)phenyl]methanol.

[0121] Add 120 mL of acetonitrile to a 500 mL three-necked flask, add 8.6 g of 2-aminobenzyl alcohol, add a 60 mL solution of (2-chloroethyl)(2-chloro-2-phenylethyl)(methyl)amine (9.2 g) in acetonitrile, stir at room temperature for 30 minutes, add 6.6 g of N,N-diisopropylethylamine, reflux the reaction solution for 7 hours, cool to room temperature and stir for 16 hours, filter to obtain a pale yellow solid, recrystallize the obtained solid with acetonitrile to obtain 9.5 g of off-white solid [2-(4-methyl-2-phenylpiperazin-1-yl)phenyl]methanol, yield 84.89%.

[0122] (d) Preparation of Mianselin

[0123] 108.0 g of polyphosphoric acid and 9.4 g of [2-(4-methyl-2-phenylpiperazin-1-yl)phenyl]methanol were added to a 500 mL three-necked flask. The mixture was heated to 100 °C and reacted for 2 hours. The reaction solution was transferred to a 5 L three-necked flask, quenched with 1080 mL of ice water, and then 1080 mL of dichloromethane was added. The solution was adjusted to alkali with 2 N sodium hydroxide solution. The mixture was separated, and the aqueous layer was extracted with dichloromethane. The organic phases were combined, washed with sodium chloride solution, dried, and concentrated under reduced pressure to obtain 6.5 g of a pale yellow solid. The yield was 73.86%, the total yield was 30.93%, and the purity was 97.63%.

Claims

1. A method for preparing mianserin sulfate, characterized in that... The synthesis of mianserin sulfate using a one-pot method includes the following steps: (1) Using toluene as the reaction solvent, N-methylethanolamine and phenyl ethylene oxide are reacted by condensation to obtain 2-[(2-hydroxyethyl)(methyl)amino]-1-phenylethyl-1-ol, and the reaction temperature is 50℃~90℃; (2) Add thionyl chloride, a chlorinating agent, directly to the reaction system of step (1) to prepare (2-chloroethyl)(2-chloro-2-phenylethyl)(methyl)amine hydrochloride. The reaction temperature is 30℃~80℃. After washing with alkaline water, (2-chloroethyl)(2-chloro-2-phenylethyl)(methyl)amine is obtained. (3) (2-chloroethyl)(2-chloro-2-phenylethyl)(methyl)amine and 2-aminobenzyl alcohol undergo a condensation reaction in the presence of triethylamine to generate [2-(4-methyl-2-phenylpiperazin-1-yl)phenyl]methanol, and the reaction temperature is 50℃~100℃; (4) [2-(4-methyl-2-phenylpiperazin-1-yl)phenyl]methanol undergoes intramolecular dehydration under concentrated sulfuric acid conditions at a temperature of 30℃~60℃, and the organic phase is removed to obtain mianserin sulfate.

2. The method according to claim 1, characterized in that, Step (1) The reaction temperature is 70℃~80℃; Step (2) The reaction temperature is 45℃~55℃; Step (3) The reaction temperature is 70℃~80℃; Step (4) The reaction temperature is 40℃~50℃.

3. The method according to claim 1, characterized in that, Step (1) The mass ratio of N-methylethanolamine to toluene is 1:2 to 1:10, and the mass ratio of N-methylethanolamine to phenyl ethylene oxide is 1:1.4 to 1:2.

4.

4. The method according to claim 1, characterized in that, The mass of thionyl chloride in step (2) is 2 to 5 times the mass of N-methylethanolamine in step (1).

5. The method according to claim 1, characterized in that, In step (3), the mass of 2-aminobenzyl alcohol is 1.6 to 3.3 times the mass of N-methylethanolamine in step (1), and the mass of triethylamine is 1.3 to 2.7 times the mass of N-methylethanolamine in step (1).

6. The method according to claim 1, characterized in that, The mass of concentrated sulfuric acid in step (4) is 10 to 15 times the mass of N-methylethanolamine in step (1).

7. The method according to any one of claims 1-6, characterized in that, Step (4) also includes a step of refining mianserin sulfate, which involves adding water to mianserin sulfate after removing the organic phase, cooling, stirring, and filtering.

8. The method according to claim 7, characterized in that, Step (4) also includes a recrystallization purification step, in which the filtered cake is added to ethanol, heated until dissolved, cooled to crystallize, filtered and dried to obtain mianserin sulfate.

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