Synthesis method of mianserin hydrochloride

Abstract

The invention belongs to the technical field of medicine synthesis, and particularly relates to a synthetic method of mianserin hydrochloride. The synthetic method of mianserin hydrochloride comprises the following steps: carrying out ring-opening reaction on styrene oxide and ethanolamine to obtain an intermediate I; reacting the intermediate I with a chlorination reagent under the action of a chlorination catalyst to obtain an intermediate II; performing ring closing reaction on the intermediate II and o-aminobenzyl alcohol under the action of an acid-binding agent and a ring closing catalyst to obtain an intermediate III; generating an intermediate IV from the intermediate III in a formaldehyde-formic acid system; dehydrating the intermediate IV under the action of concentrated sulfuric acid to generate an intermediate V; and salifying the intermediate V and a hydrogen chloride ethyl acetate solution to obtain the mianserin hydrochloride. The synthetic method of mianserin hydrochloride has the advantages of simple synthetic route, easily available raw materials, mild reaction conditions and high product yield.

Description

Technical Field

[0001] The invention belongs to the technical field of drug synthesis, and particularly relates to a method for synthesizing mianserin hydrochloride. Background Art

[0002] Mianserin hydrochloride Chemical name 1,2,3,4,10,14b-hexahydro-2-methyldibenzo[c,f]pyrazino[1,2-α]azepine Mianserin hydrochloride, in its hydrochloride form, plays a key role in the field of antidepressant and analgesia. Mianserin hydrochloride is a new generation of tetracyclic antidepressants developed by Organon of the Netherlands and launched in 1983. Its antidepressant effect is comparable to various antidepressants currently available. Mianserin hydrochloride has an antidepressant effect similar to other antidepressants currently used, but it also has an anxiolytic effect. Mianserin hydrochloride is well tolerated, especially for elderly patients and patients with cardiovascular disease.

[0003] U.S. Patent No. 4217452A synthesizes mianserin hydrochloride based on the following synthetic route. The route first protects the amino group of ethanolamine, but the yield of each step is low, resulting in a very low overall yield of the synthetic route. The route involved in the patent is as follows:

[0004]

[0005] CN101544644A discloses a method for preparing mianserin hydrochloride, which uses benzaldehyde and ethanolamine as starting materials and is prepared through nine steps of imidization, condensation, chlorination, ring closure, dehydration cyclization, deprotection cyclization, methylation and salt formation. This synthetic route has many steps and is complicated to operate, involving amino protecting groups and their removal, and a reduction reaction using potassium borohydride, and the final product yield is low. The synthetic route involved in this patent is as follows:

[0006]

[0007] In summary, the above synthetic routes all have the problems of cumbersome process steps, complicated operations, low yields, difficult impurity removal, or high-risk reactions such as highly toxic and catalytic reduction. Therefore, it is of great significance to develop a new synthesis process for mianserin hydrochloride. Summary of the invention

[0008] The technical problem to be solved by the present invention is to overcome the above-mentioned defects of the prior art and provide a synthesis method of mianserin hydrochloride, which has a simple synthesis route, readily available raw materials, mild reaction conditions and a high product yield.

[0009] The synthesis method of mianserin hydrochloride of the present invention comprises the following steps:

[0010] (1) Styrene oxide reacts with ethanolamine to form intermediate I;

[0011] (2) intermediate I is dissolved in an organic solvent, a chlorination reagent is added, and intermediate II is obtained by chlorination reaction under the action of a chlorination catalyst;

[0012] (3) Intermediate II is dissolved in an organic solvent and undergoes a ring-closing reaction with o-aminobenzyl alcohol in the presence of an acid-binding agent and a ring-closing catalyst to generate intermediate III;

[0013] (4) Intermediate III undergoes N-methylation in the formaldehyde-formic acid system to generate intermediate IV;

[0014] (5) Intermediate IV undergoes a dehydration ring-closure reaction under the action of concentrated sulfuric acid to generate intermediate V;

[0015] (6) The intermediate V is dissolved in a crystallization solvent, and a hydrogen chloride ethyl acetate solution is added to adjust the pH to acidic, followed by crystallization, suction filtration, washing, and drying to obtain mianserin hydrochloride.

[0016] The reaction scheme involved in the above steps is as follows:

[0017]

[0018] In the step (1), the molar ratio of styrene oxide to ethanolamine is 1:(1-5), preferably the molar ratio of styrene oxide to ethanolamine is 1:(2.2-3.0); the ring-opening reaction temperature is 100-140°C, preferably 125-135°C.

[0019] In the step (2), the chlorination agent is one of thionyl chloride, phosphorus trichloride and phosphorus oxychloride, preferably thionyl chloride; the molar amount of the chlorination agent is 1.5-5 times the molar amount of the intermediate I, preferably 1.8-3.0 times.

[0020] In the step (2), the chlorination reaction temperature is 50-80°C, preferably 65-75°C; the chlorination catalyst is pyridine, and the amount of the chlorination catalyst is 4-5% of the mass of the intermediate I, preferably 4.5-5%.

[0021] In the step (3), the molar ratio of intermediate II to o-aminobenzyl alcohol is 1:(0.8-1.2), preferably 1:1; the acid binding agent is one of potassium carbonate, sodium carbonate and sodium hydroxide, preferably potassium carbonate; the ring-closing catalyst is benzyltriethylammonium chloride, and the amount of the ring-closing catalyst is 10-15% of the mass of intermediate II, preferably 12-13%; the temperature of the ring-closing reaction is 100-150°C, preferably 130-140°C.

[0022] The organic solvent in step (2) and step (3) is one of benzene, toluene and chlorobenzene, preferably chlorobenzene.

[0023] In the step (4), the molar ratio of intermediate III to formaldehyde and formic acid is 1:(2-5):(2-5), preferably 1:(2.8-4):(2.8-4); the temperature of N-methylation is 80-110°C, preferably 95-105°C.

[0024] Preferably, the specific steps of step (5) are:

[0025] S1: adding intermediate IV to concentrated sulfuric acid, heating the reaction, cooling to 30-36°C after the reaction, then adding the reaction solution to water, stirring, filtering, and washing with water to obtain a solid;

[0026] S2: put the solid obtained in S1 into a mixed solution of toluene, 95wt.% ethanol, anhydrous sodium carbonate and water, heat up and separate the layers to obtain an oil layer, wash the oil layer with 25wt.% sodium chloride solution and distill under reduced pressure to obtain intermediate V; wherein the mass ratio of toluene, 95wt.% ethanol, anhydrous sodium carbonate and water is 2:1:1:2.5.

[0027] In the step (5), the molar ratio of intermediate IV to concentrated sulfuric acid is 1:(8-15), preferably 1:(10-12), and the temperature of the dehydration ring-closure reaction is 60-90°C, preferably 70-80°C.

[0028] In the step (6), the crystallization solvent is one of ethanol, ethyl acetate and acetone, preferably acetone; the amount of the crystallization solvent is 3-8 times the mass of the intermediate V, preferably 5-6 times; the crystallization temperature is 0-30°C, preferably 10-15°C, and the crystallization time is 5-20h, preferably 10-15h.

[0029] Specifically, the synthesis method of mianserin hydrochloride comprises the following steps:

[0030] (1) Add ethanolamine to a reaction flask, heat it to 95±5°C, stir, slowly dropwise add styrene oxide, heat it to 130±5°C after the addition is complete, keep the temperature for 3 hours, and distill under reduced pressure to obtain intermediate I;

[0031] (2) Add intermediate I to a reaction flask, add an organic solvent and a chlorination catalyst, raise the temperature to 55±5°C, slowly dropwise add the chlorination reagent, stir and raise the temperature to 70±5°C after the addition is complete, keep warm for 2 hours, monitor by TLC until the reaction is complete, stop the reaction and wait for the temperature to naturally drop to room temperature, adjust the pH to 5-6 with a 25wt.% sodium hydroxide solution, then layer and distill under reduced pressure to obtain intermediate II;

[0032] (3) Add intermediate II to a reaction flask, add an organic solvent, an acid-binding agent, o-aminobenzyl alcohol, a ring-closure catalyst, and water, stir and heat to 135±5°C, reflux for 3 h, monitor by TLC until the reaction is complete, stop the reaction, cool to 90°C, then separate and distill under reduced pressure to obtain intermediate III;

[0033] (4) Add intermediate III to a reaction flask, add formaldehyde, heat to 100±5°C, reflux for 1h, then add formic acid dropwise, continue to reflux for 6h, distill under reduced pressure until no liquid flows out, cool to 70°C, add sodium hydroxide, toluene, and water, stir for 15min, then layer, wash with 25wt.% sodium chloride solution until neutral, and distill under reduced pressure to obtain intermediate IV;

[0034] (5) S1 Add concentrated sulfuric acid to the reaction flask, slowly add intermediate IV, raise the temperature to 75±5°C, react for 1 hour, monitor by TLC until the reaction is complete, cool to 32.5±2.5°C after the reaction is complete, slowly add the reaction solution to 1.6 kg of water, stir at 34±2°C for 1 hour, then cool to 30°C, filter, and wash with water until the pH is 6 to obtain a solid;

[0035] S2: toluene, 95wt.% ethanol, anhydrous sodium carbonate and water are added to a reaction flask, and the above solid is added under stirring, the temperature is raised to 75°C, and the reaction is carried out for 40 minutes. The oil layer is separated and washed with 25wt.% sodium chloride solution until the pH is 7, and then distilled under reduced pressure to obtain intermediate V;

[0036] (6) Add the crystallization solvent and intermediate V to the reaction flask in sequence, heat and stir to dissolve, then cool to room temperature, add hydrochloric acid ethyl acetate solution dropwise, adjust the pH to 2-3, then cool to 12.5±2.5°C, stir and crystallize for 10-15h, filter, wash with acetone, and dry to obtain mianserin hydrochloride.

[0037] Compared with the prior art, the beneficial effects of the present invention are as follows: the synthesis method of mianserin hydrochloride of the present invention has shortened process steps, cheap and easily available raw materials, avoids the use of bromine and hydrogenation reaction in the original patent, simplifies the process operation, has mild reaction conditions, high total yield, is environmentally friendly, has low equipment requirements, reduces production costs, and is more suitable for industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0038] Figure 1 This is the NMR spectrum of mianserin hydrochloride prepared in Example 1 of the present invention. DETAILED DESCRIPTION

[0039] The present invention is further described below in conjunction with specific examples. Unless otherwise specified, the raw materials used in the following examples are all commercially available products, and the processes used are all conventional processes in the art.

[0040] Example 1

[0041] The synthesis method of mianserin hydrochloride comprises the following steps:

[0042] (1) Add 134.38 g of ethanolamine to a reaction flask, heat it to 95±5°C, stir, slowly dropwise add 120.15 g of styrene oxide, heat it to 130±5°C after the addition is complete, keep the temperature for 3 h, and distill under reduced pressure to obtain 163.47 g of intermediate I with a yield of 90.2%.

[0043] (2) 163.47 g of intermediate I was added to a reaction flask, and 500 g of chlorobenzene and 7.67 g of pyridine were added. The temperature was raised to 55±5°C, and 193.16 g of thionyl chloride was slowly added dropwise. After the addition was complete, the temperature was raised to 70±5°C with stirring, and the temperature was kept at this temperature for 2 h. The reaction was monitored by TLC until the reaction was complete. The reaction was stopped and the temperature was naturally reduced to room temperature. The pH was adjusted to 5-6 with 25 wt.% sodium hydroxide solution, and then the mixture was layered and distilled under reduced pressure to obtain 160.35 g of intermediate II with a yield of 81.5%.

[0044] (3) 160.35 g of intermediate II was added to a reaction flask, and 1000 g of chlorobenzene, 280 g of potassium carbonate, 90.53 g of o-aminobenzyl alcohol, 263.50 g of water, and 20.00 g of benzyltriethylammonium chloride were added. The mixture was stirred and heated to 135±5° C., refluxed for 3 h, and monitored by TLC until the reaction was complete. The reaction was stopped and the temperature was lowered to 90° C., followed by layering and vacuum distillation to obtain 147.77 g of intermediate III with a yield of 74.9%.

[0045] (4) 147.77 g of intermediate III was added to a reaction flask, and 66.14 g of formaldehyde was added. The temperature was raised to 100±5°C, and refluxed for 1 h. Then 101.38 g of formic acid was added dropwise, and refluxed for 6 h. The mixture was distilled under reduced pressure until no liquid flowed out. The temperature was lowered to 70°C, and 25.00 g of sodium hydroxide, 106.00 g of toluene, and 120.00 g of water were added. The mixture was stirred for 15 min, and then layered, washed with 25 wt.% sodium chloride solution until neutral, and distilled under reduced pressure to obtain 109.93 g of intermediate IV with a yield of 70.7%.

[0046] (5) S1 Add 458.28 g of concentrated sulfuric acid to a reaction flask, slowly add 109.93 g of intermediate IV, raise the temperature to 75±5°C, react for 1 h, monitor by TLC until the reaction is complete, cool to 32.5±2.5°C after the reaction is complete, slowly add the reaction solution to 1.6 kg of water, stir at 34±2°C for 1 h, then cool to 30°C, filter, and wash with water until the pH is 6 to obtain a solid;

[0047] S2: Add 500 g of toluene, 300 g of 95 wt.% ethanol, 300 g of anhydrous sodium carbonate and 700 g of water into a reaction bottle, add the above solids under stirring, raise the temperature to 75°C and react for 40 min, separate the layers to obtain the oil layer, wash with 25 wt.% sodium chloride solution to pH 7, and then distill under reduced pressure to obtain 86.35 g of intermediate V with a yield of 83.9%.

[0048] (6) Add 431.75 g of acetone and 86.35 g of intermediate V to the reaction flask in sequence, heat and stir to dissolve, then cool to room temperature, add hydrochloric acid ethyl acetate solution dropwise, adjust the pH to 2-3, then cool to 12.5±2.5°C, stir and crystallize for 10 h, filter, wash with 100 ml of acetone, and dry to obtain 91.58 g of mianserin hydrochloride, with a yield of 93.2%. The NMR spectrum of mianserin hydrochloride is shown in Figure 1 , 1 H NMR (400MHz, MeOD) δ7.26-7.12(m,5H), 7.09(dd,J=9.1,5.8Hz,2H), 6.93(td,J=7.4,0.9Hz,1H), 4.80(d,J=12 .8Hz,1H), 4.33(d,J=10.4Hz,1H), 3.69(d,J=11.9Hz,1H), 3.64-3.49(m,3H), 3.45-3.32(m,3H), 2.97(s,3H).

[0049] Example 2

[0050] The synthesis method of mianserin hydrochloride comprises the following steps:

[0051] (1) Add 183.24 g of ethanolamine to a reaction flask, heat it to 95±5°C, stir, slowly dropwise add 120.15 g of styrene oxide, heat it to 130±5°C after the addition is complete, keep the temperature for 3 h, and distill under reduced pressure to obtain 165.28 g of intermediate I with a yield of 91.2%.

[0052] (2) 165.28 g of intermediate I was added to a reaction flask, and 500 g of chlorobenzene and 8.25 g of pyridine were added. The temperature was raised to 55±5°C, and 321.93 g of thionyl chloride was slowly added dropwise. After the addition was complete, the temperature was raised to 70±5°C with stirring, and the temperature was kept for 2 h. The reaction was monitored by TLC until the reaction was complete. The reaction was stopped and the temperature was naturally reduced to room temperature. The pH was adjusted to 5-6 with 25 wt.% sodium hydroxide solution, and then the organic phase was separated and distilled under reduced pressure to obtain 163.89 g of intermediate II with a yield of 83.3%.

[0053] (3) 163.89 g of intermediate II was added to a reaction flask, and 1000 g of chlorobenzene, 280 g of potassium carbonate, 92.53 g of o-aminobenzyl alcohol, 263.50 g of water, and 19.8 g of benzyltriethylammonium chloride were added. The mixture was stirred and heated to 135±5°C. The mixture was refluxed for 3 h. After TLC monitoring, the reaction was stopped and the temperature was lowered to 90°C. The mixture was then layered and distilled under reduced pressure to obtain 151.83 g of intermediate III. The yield was 75.3%.

[0054] (4) 151.83 g of intermediate III was added to a reaction flask, and 51.43 g of formaldehyde was added. The temperature was raised to 100±5°C, and the mixture was refluxed for 1 h. Subsequently, 78.13 g of formic acid was added dropwise, and the mixture was refluxed for 6 h. The mixture was distilled under reduced pressure until no liquid flowed out. The temperature was lowered to 70°C, and 25.00 g of sodium hydroxide, 106.00 g of toluene, and 120.00 g of water were added. The mixture was stirred for 15 min, and then layered, washed with 25 wt.% sodium chloride solution until neutral, and distilled under reduced pressure to obtain 110.08 g of intermediate IV with a yield of 68.9%.

[0055] (5) S1 Add 382.42 g of concentrated sulfuric acid to a reaction flask, slowly add 110.08 g of intermediate IV, raise the temperature to 75±5°C, react for 1 h, monitor by TLC until the reaction is complete, cool to 32.5±2.5°C after the reaction is complete, slowly add the reaction solution to 1.6 kg of water, stir at 34±2°C for 1 h, then cool to 30°C, filter, and wash with water until the pH is 6 to obtain a solid;

[0056] S2: Add 500 g of toluene, 300 g of 95 wt.% ethanol, 300 g of anhydrous sodium carbonate and 700 g of water into a reaction bottle, add the above solids under stirring, heat to 75°C and react for 40 min, separate the layers to obtain the oil layer, wash with 25 wt.% sodium chloride solution to pH 7, and then distill under reduced pressure to obtain 85.22 g of intermediate V with a yield of 82.7%.

[0057] (6) Add 511.32 g of acetone and 85.22 g of intermediate V to the reaction flask in sequence, heat and stir to dissolve, then cool to room temperature, add hydrochloric acid ethyl acetate solution dropwise, adjust the pH to 2-3, then cool to 12.5±2.5°C, stir and crystallize for 15 h, filter with suction, wash with 100 ml of acetone, and dry to obtain 88.73 g of mianserin hydrochloride, with a yield of 91.5%.

[0058] Example 3

[0059] The synthesis method of mianserin hydrochloride comprises the following steps:

[0060] (1) Add 158.81 g of ethanolamine to a reaction flask, heat it to 95±5°C, stir, slowly drop 120.15 g of styrene oxide, heat it to 130±5°C after the addition is complete, keep the temperature for 3 h, and distill under reduced pressure to obtain 164.56 g of intermediate I with a yield of 90.8%.

[0061] (2) 164.56 g of intermediate I was added to a reaction flask, and 500 g of chlorobenzene and 7.87 g of pyridine were added. The temperature was raised to 55±5°C, and 259.26 g of thionyl chloride was slowly added dropwise. After the addition was complete, the temperature was raised to 70±5°C with stirring, and the temperature was kept for 2 h. The reaction was monitored by TLC until the reaction was complete. The reaction was stopped and the temperature was naturally reduced to room temperature. The pH was adjusted to 5-6 with 25 wt.% sodium hydroxide solution, and then the organic phase was separated and distilled under reduced pressure to obtain 167.56 g of intermediate II with a yield of 84.6%.

[0062] (3) 167.56 g of intermediate II was added to a reaction flask, and 1000 g of chlorobenzene, 280 g of potassium carbonate, 94.60 g of o-aminobenzyl alcohol, 263.50 g of water, and 21.5 g of benzyltriethylammonium chloride were added. The mixture was stirred and heated to 135±5°C. The mixture was refluxed for 3 h. After TLC monitoring, the reaction was stopped and the temperature was lowered to 90°C. The mixture was then layered and distilled under reduced pressure to obtain 157.09 g of intermediate III. The yield was 74.9%.

[0063] (4) 157.09 g of intermediate III was added to a reaction flask, and 61.53 g of formaldehyde was added. The temperature was raised to 100±5°C, and refluxed for 1 h. Then 94.31 g of formic acid was added dropwise, and refluxed for 6 h. The mixture was distilled under reduced pressure until no liquid flowed out. The temperature was lowered to 70°C, and 25.00 g of sodium hydroxide, 106.00 g of toluene, and 120.00 g of water were added. The mixture was stirred for 15 min, and then layered, washed with 25 wt.% sodium chloride solution until neutral, and distilled under reduced pressure to obtain 114.22 g of intermediate IV with a yield of 69.1%.

[0064] (5) S1 Add 436.49 g of concentrated sulfuric acid to a reaction flask, slowly add 114.22 g of intermediate IV, raise the temperature to 75±5°C, react for 1 h, monitor by TLC until the reaction is complete, cool to 32.5±2.5°C after the reaction is complete, slowly add the reaction solution to 1.6 kg of water, stir at 34±2°C for 1 h, then cool to 30°C, filter, and wash with water until the pH is 6 to obtain a solid;

[0065] S2: Add 500 g of toluene, 300 g of 95 wt.% ethanol, 300 g of anhydrous sodium carbonate and 700 g of water into a reaction bottle, add the above solids under stirring, heat to 75°C and react for 40 min, separate the layers to obtain the oil layer, wash with 25 wt.% sodium chloride solution to pH 7, and then distill under reduced pressure to obtain 88.44 g of intermediate V with a yield of 82.7%.

[0066] (6) 442.2 g of acetone and 88.44 g of intermediate V were added to the reaction flask in sequence, heated and stirred to dissolve, then cooled to room temperature, hydrochloric acid ethyl acetate solution was added dropwise to adjust the pH to 2-3, then cooled to 12.5±2.5°C, stirred for crystallization for 12 h, filtered, washed with 100 ml of acetone, and dried to obtain 94.5 g of mianserin hydrochloride, with a yield of 93.9%.

Claims

1. A method for synthesizing mianserin hydrochloride, characterized in that: The following steps are involved: (1) Styrene oxide reacts with ethanolamine to form intermediate I; (2) intermediate I is dissolved in an organic solvent, a chlorination reagent is added, and a chlorination reaction is carried out under the action of a chlorination catalyst to obtain intermediate II; (3) Intermediate II is dissolved in an organic solvent and undergoes a ring-closing reaction with o-aminobenzyl alcohol in the presence of an acid-binding agent and a ring-closing catalyst to generate intermediate III; (4) Intermediate III undergoes N-methylation in the formaldehyde-formic acid system to generate intermediate IV; (5) Intermediate IV undergoes a dehydration ring-closure reaction under the action of concentrated sulfuric acid to generate intermediate V; (6) The intermediate V is dissolved in a crystallization solvent, and a hydrogen chloride ethyl acetate solution is added to adjust the pH to acidic, followed by crystallization, suction filtration, washing, and drying to obtain mianserin hydrochloride.

2. The method for synthesizing mianserin hydrochloride according to claim 1, characterized in that: In the step (1), the molar ratio of styrene oxide to ethanolamine is 1:(1-5), and the ring-opening reaction temperature is 100-140°C.

3. The method for synthesizing mianserin hydrochloride according to claim 1, characterized in that: In the step (2), the chlorination agent is one of thionyl chloride, phosphorus trichloride and phosphorus oxychloride; and the molar amount of the chlorination agent is 1.5-5 times the molar amount of the intermediate I.

4. The method for synthesizing mianserin hydrochloride according to claim 1, characterized in that: In the step (2), the chlorination reaction temperature is 50-80°C; the chlorination catalyst is pyridine, and the amount of the chlorination catalyst is 4-5% of the mass of the intermediate I.

5. The method for synthesizing mianserin hydrochloride according to claim 1, characterized in that: In the step (3), the molar ratio of intermediate II to o-aminobenzyl alcohol is 1:(0.8-1.2); the acid binding agent is one of potassium carbonate, sodium carbonate and sodium hydroxide; the ring-closing catalyst is benzyltriethylammonium chloride, and the amount of the ring-closing catalyst is 10-15% of the mass of intermediate II; and the ring-closing reaction temperature is 100-150°C.

6. The method for synthesizing mianserin hydrochloride according to claim 1, characterized in that: The organic solvent in step (2) and step (3) is one of benzene, toluene and chlorobenzene.

7. The method for synthesizing mianserin hydrochloride according to claim 1, characterized in that: In the step (4), the molar ratio of intermediate III to formaldehyde and formic acid is 1:(2-5):(2-5); and the N-methylation temperature is 80-110°C.

8. The method for synthesizing mianserin hydrochloride according to claim 1, characterized in that: The specific steps of step (5) are: S1: adding intermediate IV to concentrated sulfuric acid, heating to 60-90°C for reaction, cooling to 30-36°C after the reaction, then adding the reaction solution to water, stirring, filtering, and washing with water to obtain a solid; S2: The solid obtained in S1 is put into a mixed solution of toluene, 95wt.% ethanol, anhydrous sodium carbonate and water, the temperature is raised to separate the layers to obtain an oil layer, the oil layer is washed with a 25wt.% sodium chloride solution and distilled under reduced pressure to obtain intermediate V.

9. The method for synthesizing mianserin hydrochloride according to claim 1, characterized in that: In the step (5), the molar ratio of intermediate IV to concentrated sulfuric acid is 1:(8-15), and the temperature of the dehydration ring-closure reaction is 60-90°C.

10. The method for synthesizing mianserin hydrochloride according to claim 1, characterized in that: In the step (6), the crystallization solvent is one of ethanol, ethyl acetate and acetone; the amount of the crystallization solvent is 3-8 times the mass of the intermediate V; the crystallization temperature is 0-30°C, and the crystallization time is 5-20h.

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