Synthesis method of medicine, namely, tribenisole hydrochloride, for treating Parkinson's disease

Abstract

The invention is applied to the technical field of medicines, and discloses a synthesis method of a medicine, namely, triphenhydrochlor, for treating Parkinson's disease, which comprises the following steps: S1, taking tetrahydrofuran as a solvent, taking chlorocyclohexane and magnesium powder as raw materials, adding anhydrous lithium chloride as a catalyst, initiating a reaction by using iodine, and performing suction filtration to obtain triphenhydrochlor; preparing a tetrahydrofuran solution of Grignard reagent cyclohexylmagnesium chloride lithium chloride; s2, dissolving propiophenone piperidine hydrochloride in tetrahydrofuran, and slowly dropwise adding into the Grignard reagent obtained in S1 for reaction; and S3, after the reaction is completed, adding diluted hydrochloric acid to terminate the reaction, and separating out the triphenil hydrochloride. According to the synthesis method of the medicine, namely, the triphenhydrochlor hydrochloride, for treating the Parkinson's disease, an anhydrous lithium chloride catalytic system is introduced, so that initiation conditions of a Grignard reaction are remarkably optimized, efficient preparation of a Grignard reagent at normal temperature is realized, the problems of high energy consumption and potential safety hazards caused by a high-temperature reaction in the prior art are avoided, the reaction process is easier to control, and the yield is higher. And the safety of the production process is greatly improved.

Description

TECHNICAL FIELD

[0001] The application relates to the technical field of medicines, in particular to a synthesis method of a drug, i.e. trihexyphenidyl hydrochloride, for treating Parkinson's disease. BACKGROUND

[0002] Trihexyphenidyl hydrochloride is used for treating Parkinson's disease, and has the effect of selectively blocking the cholinergic nerve pathway of the striatum, which is beneficial to restoring the balance between dopamine and acetylcholine in the brain of a Parkinson's disease patient and improving the Parkinson's disease symptoms of the patient. Trihexyphenidyl hydrochloride has been marketed abroad in the 1950s and in China in the 1960s, and is still used as a common drug for treating Parkinson's disease. The chemical name of trihexyphenidyl hydrochloride is (±)-alpha-cyclohexyl-alpha-phenyl-1-piperidine propanol hydrochloride, the molecular formula is C 20 H 31 NO·HCl.

[0003] The structural formula is as follows: A common synthesis path of trihexyphenidyl hydrochloride at present is that phenylacetone is used as raw material, and a Mannich reaction is performed on the phenylacetone, formaldehyde and piperidine hydrochloride in ethanol to obtain piperidine hydrochloride phenylacetone, then the piperidine hydrochloride phenylacetone is used as an intermediate, and a Grignard addition is performed on the piperidine hydrochloride phenylacetone and magnesium turnings, and then hydrolysis is performed, so that trihexyphenidyl hydrochloride can be obtained, and the synthesis route is as shown in the following formula: The Grignard reaction is a key step in the preparation process of the product, and determines the quality, yield and cost of trihexyphenidyl hydrochloride. In the currently published technical literature, methyl tert-butyl ether is used to replace diethyl ether in the Grignard addition reaction in patent CN102030723A, so that the safety problem existing in the preparation process of the existing trihexyphenidyl hydrochloride is solved, and the yield is more than 60%. In patent CN202010983112, methyl tert-butyl ether and ethylene glycol dimethyl ether are used as mixed solvents to make the yield of trihexyphenidyl hydrochloride crude product more than 85%. However, in the above process steps, the preparation of the Grignard reagent cyclohexylmagnesium chloride needs to be heated to a certain temperature, which is high in energy consumption and has certain safety hazards. In order to reduce the cost of trihexyphenidyl hydrochloride, improve the quality and safety of production, it is necessary to develop a more green and environmentally friendly reaction process. SUMMARY

[0004] The purpose of the application is to provide a synthesis method of a drug, i.e. trihexyphenidyl hydrochloride, for treating Parkinson's disease, so as to solve the problems of high energy consumption, great safety hazards and insufficient green environmental protection of the process caused by heating when preparing the Grignard reagent in the background technology.

[0005] In order to achieve the above-mentioned purpose, the application provides the following technical scheme: a synthesis method of a drug, i.e. trihexyphenidyl hydrochloride, for treating Parkinson's disease, comprising the following steps: S1, a Grignard reagent cyclohexylmagnesium chloride lithium chloride tetrahydrofuran solution is prepared by using tetrahydrofuran as a solvent, using chlorocyclohexane and magnesium powder as raw materials, adding anhydrous lithium chloride as a catalyst, and using iodine to initiate the reaction; S2, phenylpiperidone hydrochloride is dissolved in tetrahydrofuran, and slowly added dropwise into the Grignard reagent obtained in S1 to react; S3, after the reaction is completed, dilute hydrochloric acid is added to terminate the reaction, so that trihexylphenidyl hydrochloride is precipitated; S4, filtering, and drying the filter cake to obtain trihexylphenidyl hydrochloride crude product; S5, trihexylphenidyl hydrochloride crude product is refined with anhydrous ethanol to obtain trihexylphenidyl hydrochloride refined product.

[0006] Preferably, in the step S1, the molar ratio of anhydrous lithium chloride, magnesium powder and chlorocyclohexane is 0.2:1:1 to 1.5:1.5:1.

[0007] By limiting the molar ratio of anhydrous lithium chloride, magnesium powder and chlorocyclohexane, the above technical solution ensures that the raw materials are fully reacted during the preparation of the Grignard reagent, avoids side reactions caused by waste or excess of raw materials, and improves the generation efficiency and stability of the Grignard reagent.

[0008] Preferably, the molar ratio of anhydrous lithium chloride, magnesium powder and chlorocyclohexane is 1:1:1.

[0009] When the molar ratio is 1:1:1, the above technical solution has the best reaction ratio of raw materials, and the yield and activity of the Grignard reagent reach the optimal state, which can significantly improve the yield and product purity of the subsequent Grignard reaction.

[0010] Preferably, in the step S1, the reaction temperature is 20-65℃.

[0011] The above technical solution controls the reaction temperature at 20-65℃, avoiding the energy consumption problem of traditional high-temperature reaction, and realizing efficient initiation of the Grignard reagent in a wide temperature range, making the reaction process more controllable.

[0012] Preferably, the reaction temperature is 20-40℃.

[0013] The above technical solution further limits the reaction temperature to 20-40℃, which can efficiently initiate the Grignard reaction under normal temperature to moderate temperature conditions, ensuring the reaction rate and avoiding solvent evaporation or safety hazards caused by high temperature, improving the process safety.

[0014] Preferably, the catalyst in the step S1 is anhydrous lithium chloride, other lithium salts or anhydrous cuprous chloride.

[0015] By adopting the technical scheme, the catalyst is selected as anhydrous lithium chloride, other lithium salt or anhydrous cuprous chloride, the initiation of the Grignard reaction can be promoted through different catalytic mechanisms, flexible catalyst selection space is provided for the process, and different production requirements are adapted.

[0016] Preferably, the catalyst is preferably anhydrous lithium chloride.

[0017] By adopting the technical scheme, preferably, anhydrous lithium chloride is used as the catalyst, the catalytic activity is high, the cost is low, and the compatibility with the tetrahydrofuran solvent is good, the initiation conditions of the Grignard reaction can be significantly optimized, and the Grignard reagent can be efficiently prepared at normal temperature.

[0018] Preferably, in the step S2, when the tetrahydrofuran solution of phenylacetone piperidine hydrochloride is added dropwise, the reaction temperature is kept at 5-10 DEG C, and after the addition is completed, the temperature is increased to 20-40 DEG C for continuous reaction.

[0019] By adopting the technical scheme, when the solution of phenylacetone piperidine hydrochloride is added dropwise, the temperature is controlled at 5-10 DEG C, the occurrence of side reactions can be reduced, after the addition is completed, the temperature is increased to 20-40 DEG C for continuous reaction, the main reaction is ensured to proceed fully, and the yield and purity of the product are improved.

[0020] Preferably, in the step S3, when the dilute hydrochloric acid is added dropwise to terminate the reaction, the temperature is controlled to be not more than 40 DEG C.

[0021] By adopting the technical scheme, when the dilute hydrochloric acid is added dropwise to terminate the reaction, the temperature is controlled to be not more than 40 DEG C, the decomposition or side reaction of the product caused by sudden temperature rise can be avoided, and the precipitation effect and crystal quality of the trihexyphenidyl hydrochloride are ensured.

[0022] Compared with the prior art, the method for synthesizing the trihexyphenidyl hydrochloride has the following beneficial effects: 1. By introducing the anhydrous lithium chloride catalytic system, the initiation conditions of the Grignard reaction are significantly optimized, the Grignard reagent is efficiently prepared at normal temperature, the problems of high energy consumption and safety hazards caused by high-temperature reaction in the prior art are avoided, the reaction process is more easily controlled, and the safety of the production process is greatly improved. 2. A single solvent system of tetrahydrofuran is adopted, combined with the optimized reaction steps, the operation process is simple and easy to control, complex mixed solvents or high-temperature equipment are not needed, the complexity and equipment requirements of the production operation are reduced, the catalyst cost is low, the dosage is reasonable, the production cost is effectively controlled, and the industrialization feasibility and economy of the process are significantly improved. 3. Through the innovation of the catalytic system and the process parameters, while ensuring the high purity and high yield of the trihexyphenidyl hydrochloride, the use of toxic and harmful solvents is reduced, the energy consumption and waste discharge are reduced, the green and environmental protection production requirements are met, and an efficient, safe and environment-friendly technical scheme is provided for the large-scale production of the anti-Parkinson drug trihexyphenidyl hydrochloride. Attached Figure Description

[0023] Figure 1 This is a reaction temperature curve for the present invention. Detailed Implementation

[0024] The technical solutions of the embodiments of the present invention will be clearly and completely described below with reference to the accompanying drawings. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0025] Please see Figure 1 The present invention provides a technical solution: a method for synthesizing trihexyphenidyl hydrochloride, a drug for treating Parkinson's disease.

[0026] Example 1: Preparation of Grignard reagent S1: Weigh 76.3 kg of tetrahydrofuran (water content ≤ 0.15%) and add it to a 1000 L reactor. Add 18.3 kg of chlorocyclohexane (1.2 eq) and stir to dissolve. Under nitrogen protection, add anhydrous lithium chloride (6.5 kg, 1.2 eq), magnesium powder (7.4 g, 1.2 eq), and iodine (1.3 kg, 0.04 eq) in sequence. Stir at 20℃~40℃ until the Grignard reagent is successfully initiated (initiation is successful, the color of iodine disappears). Continue stirring for 2 hours (take about 5 ml of sample for testing, monitor the mass fraction of cyclohexyl chloride and magnesium chloride to be 9%~15%). Stop the reaction, and the preparation of Grignard reagent is complete. Cool to 0~10℃ to obtain a tetrahydrofuran solution of cyclohexyl chloride and magnesium chloride.

[0027] S2 Grignard reaction: Weigh 32.8 kg of phenylacetone piperidine hydrochloride (1 eq), dissolve it in 164 kg of tetrahydrofuran, and transfer it to a high-level tank. Add it dropwise to the above Grignard reagent, keeping the temperature at 5-10°C during the process. After the addition is complete, raise the temperature to 20-40°C and continue stirring for 2 hours (take samples for testing during the process; when phenylacetone piperidine hydrochloride is ≤10%, the reaction ends; otherwise, continue the reaction for 2 hours and take samples for testing until the test results are qualified). After the reaction was completed, the temperature was lowered to 0-10℃, and dilute hydrochloric acid was added dropwise to terminate the reaction. During the process, the temperature was controlled not to exceed 40℃. The mixture was stirred for 2 hours, centrifuged, and rinsed with purified water (2 kg, 1 eq). The mixture was centrifuged until almost no liquid flowed out. The filter cake was dried to obtain 37.25 kg of crude benztropine hydrochloride, with a yield of 85.2% and a purity of 98.3%.

[0028] Example 2: Preparation of S1 Grignard reagent: Tetrahydrofuran (250 ml), chlorocyclohexane (35.6 g, 0.3 mol, 1.2 eq), magnesium powder (7.2 g, 0.3 mol, 1.2 eq), anhydrous lithium chloride (16.5 g, 0.375 mol, 1.5 eq), a small amount of iodine were added into a dry 500 ml four-necked flask under nitrogen protection, and the mixture was stirred at 20-40 °C for 3 h. After the reaction was completed, the temperature was lowered to 5-10 °C to obtain a Grignard reagent cyclohexylmagnesium chloride lithium chloride solution.

[0029] S2 Grignard reaction: Benzilpiperidine hydrochloride (63.4 g, 0.25 mol, 1 eq) was dissolved in 30 g of tetrahydrofuran and then transferred into a constant pressure dropping funnel. The Grignard reagent was added dropwise, and the temperature was maintained at 5-10 °C. After the addition was completed, the temperature was raised to 20-40 °C, and the stirring was continued for 2 h. After the reaction was completed, dilute hydrochloric acid was added to terminate the reaction (the temperature was controlled to be not higher than 40 °C during the process). The stirring was continued for 2 h. The mixture was filtered, and the filtrate was washed with water until the pH was 3-4. The filter cake was dried to obtain crude benhexol hydrochloride 71.0 g, with a yield of 84.1% and a purity of 98.0%.

[0030] Example 3: Preparation of S1 Grignard reagent: Tetrahydrofuran (250 ml), chlorocyclohexane (35.6 g, 0.3 mol, 1.2 eq), magnesium powder (8.9 g, 0.375 mol, 1.5 eq), anhydrous lithium chloride (16.5 g, 0.375 mol, 1.5 eq), a small amount of iodine were added into a dry 500 ml four-necked flask under nitrogen protection, and the mixture was stirred at 20-40 °C for 2 h. After the reaction was completed, the temperature was lowered to 5-10 °C to obtain a Grignard reagent cyclohexylmagnesium chloride lithium chloride solution.

[0031] S2 Grignard reaction: Benzilpiperidine hydrochloride (63.4 g, 0.25 mol, 1 eq) was dissolved in 30 g of tetrahydrofuran and then transferred into a constant pressure dropping funnel. The Grignard reagent was added dropwise, and the temperature was maintained at 5-10 °C. After the addition was completed, the temperature was raised to 20-40 °C, and the stirring was continued for 2 h. After the reaction was completed, dilute hydrochloric acid was added to terminate the reaction (the temperature was controlled to be not higher than 40 °C during the process). The stirring was continued for 2 h. The mixture was filtered, and the filtrate was washed with water until the pH was 3-4. The filter cake was dried to obtain crude benhexol hydrochloride 73.6 g, with a yield of 87.1% and a purity of 98.2%.

[0032] Example 4: Preparation of S1 Grignard reagent: Tetrahydrofuran (250 ml), chlorocyclohexane (35.6 g, 0.3 mol, 1.0 eq), magnesium powder (8.9 g, 0.375 mol, 1.5 eq), anhydrous lithium chloride (16.5 g, 0.375 mol, 1.5 eq), a small amount of iodine were added into a dry 500 ml four-necked flask under nitrogen protection, and the reaction was stirred at 20-40 °C for 2 h. After the incubation was completed, the temperature was lowered to 5-10 °C to obtain a Grignard reagent cyclohexylmagnesium chloride lithium chloride solution.

[0033] S2 Grignard reaction: Benzil piperidine hydrochloride (63.4 g, 0.25 mol, 1 eq) was dissolved in 30 g of tetrahydrofuran and transferred into a constant pressure dropping funnel. It was added dropwise to the above Grignard reagent, and the temperature was maintained at 5-10 °C during the process. After the addition was completed, the temperature was raised to 20-40 °C, and the stirring was continued for 2 h. After the reaction was completed, dilute hydrochloric acid was added to terminate the reaction (the temperature was controlled not to exceed 40 °C during the process), and the stirring was continued for 2 h. After filtration, the filtrate was washed with water until the pH was 3-4. The filter cake was dried to obtain crude benhexol hydrochloride 73.5 g, with a yield of 87.0% and a purity of 98.60%.

[0034] Example 5: Preparation of S1 Grignard reagent: Tetrahydrofuran (250 ml), chlorocyclohexane (35.6 g, 0.3 mol, 1.2 eq), magnesium powder (7.2 g, 0.30 mol, 1.2 eq), anhydrous lithium chloride (12.7 g, 0.30 mol, 1.2 eq) were added into a dry 500 ml four-necked flask under nitrogen protection, and heated to reflux. A small amount of iodine dissolved in tetrahydrofuran was added, and the reaction was stirred at reflux for 1 h. After the incubation was completed, the temperature was lowered to 5-10 °C to obtain a Grignard reagent cyclohexylmagnesium chloride lithium chloride solution.

[0035] S2 Grignard reaction: After the above Grignard reagent was cooled to 5-10 °C, benzil piperidine hydrochloride (63.4 g, 0.25 mol, 1 eq) was dissolved in 30 g of tetrahydrofuran and transferred into a constant pressure dropping funnel. It was added dropwise to the above Grignard reagent, and the temperature was maintained at 5-10 °C during the process. After the addition was completed, the temperature was raised to 20-40 °C, and the stirring was continued for 2 h. After the reaction was completed, dilute hydrochloric acid was added to terminate the reaction (the temperature was controlled not to exceed 40 °C during the process), and the stirring was continued for 2 h. After filtration, the filtrate was washed with water until the pH was 3-4. The filter cake was dried to obtain crude benhexol hydrochloride 67.6 g, with a yield of 80.1% and a purity of 98.6%.

[0036] Example 6: Preparation of S1 Grignard reagent: Tetrahydrofuran (250 ml), chlorocyclohexane (35.6 g, 0.3 mol, 1.2 eq), magnesium powder (7.2 g, 0.30 mol, 1.2 eq), anhydrous lithium chloride (12.7 g, 0.30 mol, 1.2 eq) were weighed into a dry 500 ml four-necked flask under nitrogen protection, heated to 40 ± 2 °C, a small amount of iodine was dissolved in tetrahydrofuran and added, stirred for 1 h, after the incubation was completed, the temperature was lowered to 5-10 °C to obtain a Grignard reagent cyclohexylmagnesium chloride lithium chloride solution.

[0037] S2 Grignard reaction: After the above Grignard reagent was cooled to 5-10 °C, benzil piperidine hydrochloride (63.4 g, 0.25 mol, 1 eq) was dissolved in 30 g of tetrahydrofuran and transferred into a constant pressure dropping funnel, and was added dropwise to the above Grignard reagent, the temperature was maintained at 5-10 °C during the process, after the addition was completed, the temperature was raised to 20-40 °C, and stirring was continued for 2 h, after the reaction was completed, dilute hydrochloric acid was added to terminate the reaction (the temperature was controlled not to exceed 40 °C during the process), stirring was continued for 2 h, filtration was performed, and the filtrate was washed with water until the pH was 3-4, the filter cake was dried, the filter cake was dried, and 66.7 g of crude trihexylphenidyl hydrochloride was obtained, with a yield of 79.0% and a purity of 98.0%.

[0038] Example 7: Preparation of S1 Grignard reagent: Tetrahydrofuran (250 ml), chlorocyclohexane (35.6 g, 0.3 mol, 1.2 eq), magnesium powder (7.2 g, 0.30 mol, 1.2 eq), anhydrous copper chloride (29.9 g, 0.30 mol, 1.2 eq) were weighed into a dry 500 ml four-necked flask under nitrogen protection, heated to 30 ± 2 °C, a small amount of iodine was dissolved in tetrahydrofuran and added, stirred for 1 h, after the incubation was completed, the temperature was lowered to 5-10 °C to obtain a Grignard reagent cyclohexylmagnesium chloride lithium chloride solution.

[0039] S2 Grignard reaction: After the above Grignard reagent was cooled to 5-10 °C, benzil piperidine hydrochloride (63.4 g, 0.25 mol, 1 eq) was dissolved in 30 g of tetrahydrofuran and transferred into a constant pressure dropping funnel, and was added dropwise to the above Grignard reagent, the temperature was maintained at 5-10 °C during the process, after the addition was completed, the temperature was raised to 20-40 °C, and stirring was continued for 2 h, after the reaction was completed, dilute hydrochloric acid was added to terminate the reaction (the temperature was controlled not to exceed 40 °C during the process), stirring was continued for 2 h, filtration was performed, and the filtrate was washed with water until the pH was 3-4, the filter cake was dried, the filter cake was dried, and 66.7 g of crude trihexylphenidyl hydrochloride was obtained, with a yield of 79.0% and a purity of 98.0%.

[0040] Comparative Example 1: Preparation of S1 Grignard reagent: Tetrahydrofuran (250 ml), chlorocyclohexane (35.6 g, 0.3 mol, 1.2 eq), magnesium powder (7.2 g, 0.30 mol, 1.2 eq), a small amount of iodine were added into a dry 500 ml four-necked flask under nitrogen protection, and the reaction was stirred at 60°C to reflux for 4 h. After the reaction was completed, the temperature was lowered to 0-10°C to obtain a Grignard reagent cyclohexylmagnesium chloride solution.

[0041] S2 Grignard reaction: After the Grignard reagent was cooled to 5-10°C, phenylpropanone piperidine hydrochloride (63.4 g, 0.25 mol, 1 eq) was dissolved in 30 g of tetrahydrofuran and transferred into a constant pressure dropping funnel. The Grignard reagent was added dropwise while the temperature was maintained at 5-10°C. After the addition was completed, the temperature was raised to reflux and the stirring was continued for 2 h. After the reaction was completed, the temperature was lowered to 0-10°C. Dilute hydrochloric acid was added dropwise to terminate the reaction, and the temperature was controlled to be no more than 10°C. The stirring was continued for 2 h. Filtration was performed, and the filtrate was washed with water until the pH was 3-4. The filter cake was dried to obtain crude trihexylphenidyl hydrochloride 56.8 g with a yield of 67.2% and a purity of 95.4%.

[0042] Comparative Example 2: Preparation of S1 Grignard reagent: Tetrahydrofuran (250 ml), chlorocyclohexane (35.6 g, 0.3 mol, 1.2 eq), magnesium powder (7.2 g, 0.30 mol, 1.2 eq), a small amount of iodine were added into a dry 500 ml four-necked flask under nitrogen protection, and the reaction was stirred at 20°C±2 for 4 h. The reaction was not initiated.

[0043] As shown in FIG. 1, the reaction temperature was monitored, and the reaction temperature curves with and without lithium chloride catalysis were compared. Figure 1 As shown in FIG. 1, the reaction temperature was monitored, and the reaction temperature curves with and without lithium chloride catalysis were compared. Under the same conditions, when lithium chloride exists in the reaction system, the Grignard reaction can be initiated at room temperature. After the reaction is successfully initiated, the solution temperature rapidly rises, and after the reaction is completed, the solution temperature begins to drop. When lithium chloride is not added, the reaction cannot be initiated at room temperature, and the solution temperature does not change significantly.

[0044] The reaction conditions and yield of each example were counted as follows: In the preparation of the Grignard reagent cyclohexylmagnesium chloride, the addition of an appropriate amount of anhydrous lithium chloride can significantly reduce the required reaction temperature, the process is simple, more energy-saving, and the yield is 79.0%-87.1%.

[0045] The above specific embodiments further illustrate the purpose, technical scheme and beneficial effects of the present application, and it should be understood that the above are only specific embodiments of the present application and do not limit the present application. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present application is included in the protection scope of the present application.

Claims

1. A process for the synthesis of the drug for the treatment of Parkinson's, Trbenzylidene hyd rochloride, characterized by: The method comprises the following steps: S1, preparing a Grignard reagent cyclohexylmagnesium chloride lithium chloride tetrahydrofuran solution by using tetrahydrofuran as a solvent, using chlorocyclohexane and magnesium powder as raw materials, adding anhydrous lithium chloride as a catalyst, and using iodine to initiate a reaction; S2, dissolving benzene propyl ketone piperidine hydrochloride in tetrahydrofuran, and slowly adding the Grignard reagent obtained in S1 to perform a reaction; S3, after the reaction is completed, adding dilute hydrochloric acid to terminate the reaction, and allowing benperidol hydrochloride to be precipitated; S4, filtering, and drying the filter cake to obtain crude benperidol hydrochloride; S5, refining the crude benperidol hydrochloride by using anhydrous ethanol to obtain refined benperidol hydrochloride.

2. A process for the synthesis of a drug for the treatment of Parkinson's, the drug being the pharmaceutical salt of phenothiazine, namely, trimeprazine hydrochloride, according to claim 1, characterized by: In the step S1, the molar ratio of the anhydrous lithium chloride, the magnesium powder and the chlorocyclohexane is 0.2:1:1 to 1.5:1.5:

1.

3. A process for the synthesis of the drug for the treatment of Parkinson's, the pharmaceutical Trbenzylidenehydramine hydrochloride, according to claim 2, characterized by the fact that: The molar ratio of the anhydrous lithium chloride, the magnesium powder and the chlorocyclohexane is 1:1:

1.

4. The synthesis method of the drug for treating Parkinson's, the phenothiazine hydrochloride, according to claim 1, characterized by: In the step S1, the reaction temperature is 20-65℃.

5. The process for synthesis of a drug for treatment of Parkinson's, the drug being the pharmaceutical salt of phenothiazine, namely, Trasentine, as claimed in claim 4, wherein the process is characterized by: The reaction temperature is 20-40℃.

6. The synthesis method of the drug for treating Parkinson's, the phenothiazine hydrochloride, according to claim 1, characterized by: The catalyst in the step S1 is anhydrous lithium chloride, other lithium salts or anhydrous cuprous chloride.

7. A process for the synthesis of a drug for the treatment of Parkinson's, the drug being the pharmaceutical salt of phenothiazine, namely, the hydrochloride of phenothiazine, according to claim 6, characterized by the fact that: The catalyst is preferably anhydrous lithium chloride.

8. The synthesis method of the drug for treating Parkinson's, the phenothiazine hydrochloride, according to claim 1, characterized by: In the step S2, when the tetrahydrofuran solution of benzene propyl ketone piperidine hydrochloride is added dropwise, the reaction temperature is kept at 5-10℃, and after the addition is completed, the temperature is increased to 20-40℃ for continuous reaction.

9. The synthesis method of the drug for treating Parkinson's, the phenothiazine hydrochloride, according to claim 1, characterized by: In the step S3, when the dilute hydrochloric acid is added dropwise to terminate the reaction, the temperature is controlled to be not more than 40℃.

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