Synthesis method of cyclobenzaprine hydrochloride

Abstract

The invention belongs to the technical field of medicine synthesis, and particularly relates to a synthesis method of cyclobenzaprine hydrochloride. The synthesis method comprises the following steps: taking 5-dibenzo [A, D] cycloheptenone as an initial raw material, and reacting with 3-(dimethylamino) propionaldehyde under the action of TiCl4 and Zn powder to prepare cyclobenzaprine; according to the method, by controlling the feeding ratio, the feeding sequence and the feeding mode of the reaction materials, side reactions can be remarkably reduced, and various side reactions can be avoided; the cyclobenzaprine can be further salified and refined through an HCl-ethyl acetate system, the whole process is simple and convenient to operate, cyclobenzaprine hydrochloride can be prepared with high yield and high purity, and the method is suitable for industrial application.

Description

Technical Field

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

[0002] Cyclobenzaprine hydrochloride is a drug developed by Merck in the United States for the treatment of muscle spasms in sudden musculoskeletal diseases. Its chemical name is 5-(3-dimethylaminopropylidene)dibenzo[a,d]cycloheptene hydrochloride and its trade name is Flexeril.

[0003] The synthesis method of cyclobenzaprine hydrochloride reported in the literature is as follows:

[0004] The literature J.Org.Chem., 1962, 27(1):230-240 uses 5H-dibenzo[a,d]cycloheptatriene-5-one as the starting material, first reacts with a Grignard reagent, then removes the benzyl group and bromines with hydrogen bromide, and finally reacts with dimethylamine to obtain cyclobenzaprine. The synthetic route is as follows:

[0005]

[0006] In patents US3409640A, US3454643A and literature "Synthesis of Cyclobenzaprine Hydrochloride". Chinese Journal of Pharmaceutical Industry, 2008, 39(8): 569-570, etc., 3-(N,N-dimethylamino) chloropropane is first reacted with metal magnesium in tetrahydrofuran to generate a Grignard reagent, which is then reacted with 5H-dibenzo[a,d]cycloheptatriene-5-one to generate 5-(3-dimethylaminopropyl)-5-hydroxydibenzocycloheptatriene, which is then dehydrated to generate cyclobenzaprine, and finally salified with hydrogen chloride gas to obtain the target product cyclobenzaprine hydrochloride. The synthetic route is as follows:

[0007]

[0008] In patent CN111393305A, 3-(N,N-dimethylamino) chloropropane and metallic zinc are first reacted in tetrahydrofuran with iodine and 1,2-dibromoethane as catalysts to obtain N,N-dimethyl-3-chlorozinc propylamine, which is then further subjected to nucleophilic addition with 5H-dibenzo[a,d]cycloheptatriene-5-one to obtain 5-(3-dimethylaminopropyl)-5-hydroxydibenzocycloheptatriene, which is then dehydrated and salified to generate the target product, cyclobenzaprine hydrochloride. The synthetic route is as follows:

[0009]

[0010] However, the above processes are all applied to organic metal halides for reaction. The related reagents are highly active and require strict control of anhydrous operation. Not only are various side reactions prone to occur and more impurities are introduced, but the operation is also dangerous and cannot meet the requirements of industrial scale-up production.

[0011] In the literature "Study on the Synthesis of Cyclobenzaprine". Journal of Mudanjiang Medical College, 2008, 29(2):18-20 and "Simple Synthesis of Cyclobenzaprine". Contemporary Medicine, 2009, 15(3):15-16, 1,3-dibromopropane is first substituted with triphenylphosphine and then replaced with dimethylamine to obtain the Wittig reagent 3-N,N-dimethyl-triphenylphosphine propylamine; dibenzocycloheptenone is successively subjected to bromination reaction and elimination reaction to obtain 5H-dibenzo[a,d]cycloheptatriene-5-one; then, with benzene as solvent and under the action of strong base sodium amide, the relevant Wittig reagent and dibenzocycloheptenone undergo Wittig reaction to obtain cyclobenzaprine, and finally salify with hydrogen chloride gas to obtain cyclobenzaprine hydrochloride. The synthesis route is as follows:

[0012]

[0013] Patent CN102942489A uses an electrochemical reaction (the working electrode and the auxiliary electrode are platinum electrodes, and the reference cell is a silver chloride / silver electrode) to react the Wittig reagent (the phosphate carbon anion can be diethyl phosphate, dimethyl phosphate or diisopropyl phosphate carbon anion) with 5H-dibenzo[a,d]cycloheptatriene-5-one under nitrogen protection to obtain cyclobenzaprine, and finally obtains the target product as a hydrochloride.

[0014] However, the above-mentioned Wittig reagents all require the use of highly toxic organic phosphides, and their operational safety is relatively low; in addition, the relevant Wittig reagents all contain aliphatic hydrocarbon long-chain structural parts, which have low chemical stability, resulting in their high reaction activity. They also need to strictly control anhydrous conditions and operate under nitrogen flow, and various side reactions will occur, introducing more impurities, which will lead to the problem of low reaction yield (70% to 80%); in addition, the condensation reaction needs to be carried out by electrochemical electrolysis, which has high requirements for reaction equipment and is not suitable for large-scale production.

[0015] In summary, the current preparation method of cyclobenzaprine hydrochloride has the problems of poor process safety, low yield, high production cost, etc. Therefore, it is still a problem to be solved to study and find a synthetic route of cyclobenzaprine hydrochloride with simple operation process, high product yield, high purity and low production cost. Summary of the invention

[0016] Aiming at the problems existing in the current synthesis process of cyclobenzaprine hydrochloride, the invention provides a new synthesis method of cyclobenzaprine hydrochloride. The method is simple to operate and can prepare cyclobenzaprine hydrochloride with high yield and high purity.

[0017] The specific technical solutions of the present invention are as follows:

[0018] A method for synthesizing cyclobenzaprine hydrochloride, characterized in that SM-1 is used as a starting material, 4 Under the action of Zn powder, it reacts with SM-2. After the reaction is completed, cyclobenzaprine hydrochloride is obtained by post-treatment; the reaction formula is as follows:

[0019]

[0020] Specifically, a method for synthesizing cyclobenzaprine hydrochloride comprises the following operations:

[0021] Under nitrogen protection, Zn powder and TiCl 4 The mixture was added to tetrahydrofuran in sequence, stirred at room temperature first, then heated to reflux for activation, then cooled to room temperature and slowly added with tetrahydrofuran solution of SM-2, and after 1 / 3 of the volume was added, the tetrahydrofuran solution of SM-1 was added simultaneously. After the addition was completed, the reaction was refluxed and after the reaction was detected to be complete, cyclobenzaprine hydrochloride was obtained by post-treatment.

[0022] Preferably, the SM-1 and TiCl 4 The molar ratio of SM-2 is 1:4.0~6.0:1.8~2.2, preferably 1:5.0:2.0.

[0023] Preferably, the TiCl 4 The molar ratio of Zn powder to Zn powder is 1:1.3-1.6, preferably 1:1.5.

[0024] Preferably, the low temperature is -10 to 5°C.

[0025] The stirring at room temperature is usually carried out for 20 to 40 minutes; the activation is carried out by heating and refluxing, and the refluxing time is usually carried out for 0.5 to 1.5 hours.

[0026] In one embodiment, the post-treatment steps are as follows: cooling the reaction solution to room temperature, adding it to a saturated alkaline solution, filtering, adjusting the pH of the filtrate to 2-4 with dilute hydrochloric acid, washing with dichloromethane, adjusting the aqueous phase to a pH of about 11-13 with sodium hydroxide solution, stirring, extracting with an organic solvent, combining the organic phases, concentrating the organic phases to dryness under reduced pressure, and then salifying with an HCl-ethyl acetate system to obtain cyclobenzaprine hydrochloride.

[0027] The saturated alkaline solution is a saturated alkaline aqueous solution commonly used in the art, such as a saturated sodium carbonate solution, a saturated potassium carbonate solution, a saturated sodium bicarbonate solution, and the like.

[0028] Preferably, the organic solvent for extraction is one of dichloromethane, chloroform and ethyl acetate, preferably ethyl acetate.

[0029] Beneficial effects of the present invention:

[0030] ① The present invention provides a novel method for preparing cyclobenzaprine hydrochloride, which uses SM-1 as a starting material, and 4 Cyclobenzaprine can be directly prepared by reacting SM-2 with zinc powder. The whole process is simple to operate, with fewer synthetic steps, and can effectively avoid the use of Grignard reagents and organic phosphonates that are more dangerous, and can also avoid the use of electrochemical reaction equipment, which is suitable for industrial production.

[0031] ② The new process can significantly reduce the occurrence of side reactions by controlling the feed ratio, feed sequence and feed method of the reaction materials. Although the relevant process will produce a small amount of impurities of SM-1 carbonyl reduction to methylene, the impurity can be effectively removed by a simple dichloromethane washing operation under acidic conditions, and the operation is simple; it avoids the use of Grignard reagents, which are highly active organometallic compounds, and Wittig reagents, which are alkyl organophosphine halides, in the prior art, thereby avoiding the generation of more impurities.

[0032] ③ The cyclobenzaprine prepared in the new process can be further refined by salt formation through an HCl-ethyl acetate system to obtain the target product cyclobenzaprine hydrochloride with high yield and purity. DETAILED DESCRIPTION

[0033] The present invention is further illustrated by the following examples. It should be correctly understood that the examples of the present invention are only used to illustrate the present invention, rather than to limit the present invention. Therefore, simple improvements to the present invention based on the method of the present invention all fall within the scope of protection claimed by the present invention.

[0034] The present invention adopts HPLC to measure the purity of cyclobenzaprine hydrochloride, and the chromatographic conditions are as follows:

[0035] Chromatographic column: Octylsilane bonded silica as filler (GL Sciences Inertsil C 8-3 , 4.6mm×250mm, 5μm or chromatographic column with equivalent performance);

[0036] Mobile phase: methanol-ammonium acetate solution (5.7 g of ammonium acetate was dissolved in 1000 mL of water and the pH value was adjusted to 7.2 with 25% ammonia water) (60:40);

[0037] Column temperature: 30°C;

[0038] Detection wavelength: 240nm;

[0039] Flow rate: 1.0ml / min;

[0040] Injection volume: 20 μL;

[0041] Among them, the retention time of cyclobenzaprine is about 26 minutes.

[0042] In the following embodiments, various processes and methods not described in detail are conventional methods known in the art.

[0043] Example 1

[0044] Under nitrogen protection, at low temperature -5 to 0°C, Zn powder (4.90 g, 0.075 mol) and TiCl 4 (9.48 g, 0.05 mol) were added to dry tetrahydrofuran (100 mL) in sequence, stirred at room temperature for 30 min, then heated to reflux for 1 h, cooled to room temperature, and SM-2 (2.02 g, 0.02 mol) in tetrahydrofuran (30 mL) was slowly added dropwise. After 1 / 3 of the solution was added, SM-1 (2.06 g, 0.01 mol) in tetrahydrofuran (30 mL) was added dropwise at the same time. After the addition was completed, the reflux reaction was continued. After the reaction was completed, the reaction mixture was cooled to room temperature. The mixture was cooled to room temperature, added to a saturated aqueous potassium carbonate solution (80 mL), filtered with diatomaceous earth, the filtrate was adjusted to pH 3 with 0.2 N dilute hydrochloric acid, washed with dichloromethane (70 mL × 2), the aqueous phase was adjusted to pH about 13 with 10% sodium hydroxide solution, stirred, and then extracted with ethyl acetate (100 mL × 3), the organic phases were combined, washed with saturated brine (100 mL × 2) and concentrated to dryness, the concentrate was dissolved with a small amount of ethyl acetate (8 mL), salified with 2.0 mol / L HCl-ethyl acetate, filtered to obtain a white solid, and dried to obtain cyclobenzaprine hydrochloride with a yield of 92.5% and a purity of 99.42%.

[0045] Example 2

[0046] Under nitrogen protection, at low temperature of 0-5°C, Zn powder (4.90 g, 0.075 mol) and TiCl 4(9.48 g, 0.05 mol) were added to dry tetrahydrofuran (100 mL) in sequence, stirred at room temperature for 30 min, then heated to reflux for 1 h, cooled to room temperature, and SM-2 (2.23 g, 0.022 mol) in tetrahydrofuran (30 mL) solution was slowly added dropwise. After 1 / 3 of the solution was added, SM-1 (2.06 g, 0.01 mol) in tetrahydrofuran (30 mL) solution was added dropwise at the same time. After the addition was completed, the reflux reaction was continued. After the reaction was completed, the reaction was cooled to room temperature. The mixture was cooled to room temperature, added to a saturated aqueous potassium carbonate solution (80 mL), filtered with diatomaceous earth, the filtrate was adjusted to pH 3 with 0.2 N dilute hydrochloric acid, washed with dichloromethane (70 mL × 2), the aqueous phase was adjusted to pH about 13 with 10% sodium hydroxide solution, stirred, and then extracted with ethyl acetate (100 mL × 3), the organic phases were combined, washed with saturated brine (100 mL × 2) and concentrated to dryness, the concentrate was dissolved with a small amount of ethyl acetate (8 mL), salified with 2.0 mol / L HCl-ethyl acetate, filtered to obtain a white solid, and dried to obtain cyclobenzaprine hydrochloride with a yield of 92.2% and a purity of 99.28%.

[0047] Example 3

[0048] Under nitrogen protection, at low temperature of 0-5°C, Zn powder (4.90 g, 0.075 mol) and TiCl 4 (9.48 g, 0.05 mol) were added to dry tetrahydrofuran (100 mL) in sequence, stirred at room temperature for 30 min, then heated to reflux for 1 h, cooled to room temperature, and SM-2 (1.82 g, 0.018 mol) in tetrahydrofuran (30 mL) was slowly added dropwise. After 1 / 3 of the solution was added, SM-1 (2.06 g, 0.01 mol) in tetrahydrofuran (30 mL) was added dropwise at the same time. After the addition was completed, the reflux reaction was continued. After the reaction was completed, the reaction was cooled to room temperature. The mixture was cooled to room temperature, added to a saturated aqueous potassium carbonate solution (80 mL), filtered with diatomaceous earth, the filtrate was adjusted to pH 3 with 0.2 N dilute hydrochloric acid, washed with dichloromethane (70 mL × 2), the aqueous phase was adjusted to pH about 13 with 10% sodium hydroxide solution, stirred, and then extracted with ethyl acetate (100 mL × 3), the organic phases were combined, washed with saturated brine (100 mL × 2) and concentrated to dryness, the concentrate was dissolved with a small amount of ethyl acetate (8 mL), salified with 2.0 mol / L HCl-ethyl acetate, filtered to obtain a white solid, and dried to obtain cyclobenzaprine hydrochloride with a yield of 90.9% and a purity of 99.14%.

[0049] Example 4

[0050] Under nitrogen protection, at low temperature -5 to 0°C, Zn powder (5.88 g, 0.09 mol) and TiCl 4(11.38 g, 0.06 mol) were added to dry tetrahydrofuran (100 mL) in sequence, stirred at room temperature for 30 min, then heated to reflux for 1 h, cooled to room temperature, and slowly added a solution of SM-2 (2.23 g, 0.022 mol) in tetrahydrofuran (30 mL) dropwise. After 1 / 3 of the solution was added, a solution of SM-1 (2.06 g, 0.01 mol) in tetrahydrofuran (30 mL) was added dropwise at the same time. After the addition was completed, the reflux reaction was continued. After the reaction was completed, the reaction mixture was cooled to room temperature. The reaction mixture was cooled to room temperature, added to a saturated aqueous sodium carbonate solution (80 mL), and filtered through diatomaceous earth. The filtrate was adjusted to pH 2 with 0.2 N dilute hydrochloric acid, washed with dichloromethane (70 mL × 2), and the aqueous phase was adjusted to pH about 13 with 10% sodium hydroxide solution, stirred, and then extracted with ethyl acetate (100 mL × 3). The organic phases were combined, washed with saturated brine (100 mL × 2) and concentrated to dryness. The concentrate was dissolved with a small amount of ethyl acetate (8 mL), salified with 2.0 mol / L HCl-ethyl acetate, filtered to obtain a white solid, and dried to obtain cyclobenzaprine hydrochloride with a yield of 91.0% and a purity of 99.22%.

[0051] Example 5

[0052] Under nitrogen protection, at low temperature -5 to 0°C, Zn powder (6.28 g, 0.096 mol) and TiCl 4 (11.38 g, 0.06 mol) were added to dry tetrahydrofuran (100 mL) in sequence, stirred at room temperature for 30 min, then heated to reflux for 1 h, cooled to room temperature, and slowly added a solution of SM-2 (2.23 g, 0.022 mol) in tetrahydrofuran (30 mL) dropwise. After 1 / 3 of the solution was added, a solution of SM-1 (2.06 g, 0.01 mol) in tetrahydrofuran (30 mL) was added dropwise at the same time. After the addition was completed, the reflux reaction was continued. After the reaction was completed, the reaction mixture was cooled to room temperature. The reaction mixture was cooled to room temperature, added to a saturated aqueous sodium carbonate solution (80 mL), and filtered through diatomaceous earth. The filtrate was adjusted to pH 2 with 0.2 N dilute hydrochloric acid, washed with dichloromethane (70 mL × 2), and the aqueous phase was adjusted to pH about 13 with 10% sodium hydroxide solution, stirred, and then extracted with ethyl acetate (100 mL × 3). The organic phases were combined, washed with saturated brine (100 mL × 2) and concentrated to dryness. The concentrate was dissolved with a small amount of ethyl acetate (8 mL), salified with 2.0 mol / L HCl-ethyl acetate, filtered to obtain a white solid, and dried to obtain cyclobenzaprine hydrochloride with a yield of 89.4% and a purity of 99.20%.

[0053] Example 6

[0054] Under nitrogen protection, at low temperature -5 to 0°C, Zn powder (3.92 g, 0.06 mol) and TiCl 4The mixture was stirred at room temperature for 20 min, then heated to reflux for 1.5 h, cooled to room temperature, and slowly added with a solution of SM-2 (2.02 g, 0.02 mol) in tetrahydrofuran (30 mL). After 1 / 3 of the mixture was added, a solution of SM-1 (2.06 g, 0.01 mol) in tetrahydrofuran (30 mL) was added simultaneously. After the addition was completed, the mixture was refluxed for 1 h. After the reaction was completed, the mixture was cooled to room temperature. The reaction mixture was cooled to room temperature, added to a saturated aqueous potassium carbonate solution (80 mL), and filtered through diatomaceous earth. The filtrate was adjusted to pH 2 with 0.2N dilute hydrochloric acid, washed with dichloromethane (70 mL×2), and the aqueous phase was adjusted to pH about 13 with 10% sodium hydroxide solution, stirred, and then extracted with ethyl acetate (100 mL×3). The organic phases were combined, washed with saturated brine (100 mL×2), and concentrated to dryness. The concentrate was dissolved with a small amount of ethyl acetate (8 mL), salified with 2.0 mol / L HCl-ethyl acetate, filtered to obtain a white solid, and dried to obtain cyclobenzaprine hydrochloride with a yield of 90.3% and a purity of 99.26%.

[0055] Example 7

[0056] Under nitrogen protection, at low temperature -5 to 0°C, Zn powder (3.40 g, 0.052 mol) and TiCl 4 The mixture was stirred at room temperature for 20 min, then heated to reflux for 1.5 h, cooled to room temperature, and slowly added with a solution of SM-2 (2.02 g, 0.02 mol) in tetrahydrofuran (30 mL). After 1 / 3 of the mixture was added, a solution of SM-1 (2.06 g, 0.01 mol) in tetrahydrofuran (30 mL) was added simultaneously. After the addition was completed, the mixture was refluxed for 1 h. After the reaction was completed, the mixture was cooled to room temperature. The reaction mixture was cooled to room temperature, added to a saturated aqueous potassium carbonate solution (80 mL), and filtered through diatomaceous earth. The filtrate was adjusted to pH 2 with 0.2N dilute hydrochloric acid, washed with dichloromethane (70 mL×2), and the aqueous phase was adjusted to pH about 13 with 10% sodium hydroxide solution, stirred, and then extracted with ethyl acetate (100 mL×3). The organic phases were combined, washed with saturated brine (100 mL×2), and concentrated to dryness. The concentrate was dissolved with a small amount of ethyl acetate (8 mL), salified with 2.0 mol / L HCl-ethyl acetate, filtered to obtain a white solid, and dried to obtain cyclobenzaprine hydrochloride with a yield of 86.9% and a purity of 99.13%.

[0057] Example 8

[0058] Under nitrogen protection, at low temperature -5 to 0°C, Zn powder (3.14 g, 0.048 mol) and TiCl 4(7.59 g, 0.04 mol) was successively added to dry tetrahydrofuran (100 mL). After stirring at room temperature for 20 min, the temperature was raised to reflux for 1.5 h. Then it was cooled to room temperature, and a solution of SM-2 (2.02 g, 0.02 mol) in tetrahydrofuran (30 mL) was slowly added dropwise. After 1 / 3 of it was added dropwise, a solution of SM-1 (2.06 g, 0.01 mol) in tetrahydrofuran (30 mL) was simultaneously added dropwise. After the addition was complete, the reflux reaction was continued. After detecting that the reaction was complete, the reaction solution was cooled to room temperature and added to saturated potassium carbonate aqueous solution (80 mL). It was filtered by suction with diatomaceous earth as a pad. The filtrate was adjusted to pH 4 with 0.2 N dilute hydrochloric acid, washed with dichloromethane (70 mL × 2). The aqueous phase was adjusted to pH about 13 with 10% sodium hydroxide solution, stirred, and then extracted with ethyl acetate (100 mL × 3). The organic phases were combined, washed with saturated brine (100 mL × 2), and concentrated to dryness. The concentrate was dissolved in a small amount of ethyl acetate (8 mL), salted out with 2.0 mol / L HCl-ethyl acetate, filtered to obtain a white solid, dried, and cyclobenzaprine hydrochloride was prepared with a yield of 72.7% and a purity of 98.48%.

[0059] Example 9

[0060] Under nitrogen protection, at a low temperature of -5 to 0 °C, Zn powder (7.06 g, 0.108 mol) and TiCl 4 (11.38 g, 0.06 mol) were successively added to dry tetrahydrofuran (100 mL). After stirring at room temperature for 30 min, the temperature was raised to reflux for 1 h. Then it was cooled to room temperature, and a solution of SM-2 (2.23 g, 0.022 mol) in tetrahydrofuran (30 mL) was slowly added dropwise. After 1 / 3 of it was added dropwise, a solution of SM-1 (2.06 g, 0.01 mol) in tetrahydrofuran (30 mL) was simultaneously added dropwise. After the addition was complete, the reflux reaction was continued. After detecting that the reaction was complete, the reaction solution was cooled to room temperature and added to saturated sodium carbonate aqueous solution (80 mL). It was filtered by suction with diatomaceous earth as a pad. The filtrate was adjusted to pH 4 with 0.2 N dilute hydrochloric acid, washed with dichloromethane (70 mL × 2). The aqueous phase was adjusted to pH about 13 with 10% sodium hydroxide solution, stirred, and then extracted with ethyl acetate (100 mL × 3). The organic phases were combined, washed with saturated brine (100 mL × 2), and concentrated to dryness. The concentrate was dissolved in a small amount of ethyl acetate (8 mL), salted out with 2.0 mol / L HCl-ethyl acetate, filtered to obtain a white solid, dried, and cyclobenzaprine hydrochloride was prepared with a yield of 78.5% and a purity of 98.61%.

Claims

1. A method for synthesizing cyclobenzaprine hydrochloride, It is characterized in that Using SM-1 as the starting material, in TiCl 4 Under the action of Zn powder, it reacts with SM-2. After the reaction is completed, cyclobenzaprine hydrochloride is obtained by post-treatment; the reaction formula is as follows:

2. The synthesis method according to claim 1, It is characterized in that The following operations are included: nitrogen protection, Zn powder and TiCl 4 The mixture was added to tetrahydrofuran in sequence, stirred at room temperature first, then heated to reflux for activation, then cooled to room temperature and slowly added with tetrahydrofuran solution of SM-2, and after 1 / 3 of the volume was added, the tetrahydrofuran solution of SM-1 was added simultaneously. After the addition was completed, the reaction was refluxed and cyclobenzaprine hydrochloride was obtained after detection of the completion of the reaction.

3. The synthesis method according to claim 1 or 2, It is characterized in that The SM-1 and TiCl 4 The feeding molar ratio of SM-2 is 1:4.0~6.0:1.8~2.

2.

4. The synthesis method according to claim 1 or 2, It is characterized in that The TiCl 4 The molar ratio of Zn powder to Zn powder is 1:1.3-1.

6.

5. The synthesis method according to claim 2, It is characterized in that The low temperature is -10 to 5°C.

6. The synthesis method according to claim 1 or 2, It is characterized in that The post-treatment steps are as follows: cooling the reaction solution to room temperature, adding it to a saturated alkaline solution, filtering, adjusting the pH of the filtrate to 2-4 with dilute hydrochloric acid, washing with dichloromethane, adjusting the aqueous phase to a pH of 11-13 with a sodium hydroxide solution, stirring, extracting with an organic solvent, combining the organic phases, concentrating the organic phases to dryness under reduced pressure, and then salifying with an HCl-ethyl acetate system to obtain cyclobenzaprine hydrochloride.

7. The synthesis method according to claim 6, It is characterized in that The saturated alkaline solution includes saturated sodium carbonate solution, saturated potassium carbonate solution, and saturated sodium bicarbonate solution.

8. The synthesis method according to claim 6, It is characterized in that The organic solvent for extraction is one of dichloromethane, chloroform and ethyl acetate.

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