A method for synthesizing benserazide hydrochloride

Abstract

The application discloses a preparation method of benserazide hydrochloride, and belongs to the technical field of medicine synthesis. In order to solve the problems of harsh reaction conditions, complicated operation and high cost in the prior art, the application uses commercially available DL-serine methyl ester hydrochloride and 2,3,4-trihydroxytoluene as starting materials, and obtains the target product through five key reactions: 1) DL-serine methyl ester hydrochloride and BOC anhydride are subjected to a protection reaction to obtain BOC-serine methyl ester; 2) BOC-serine methyl ester is subjected to hydrazinolysis to obtain BOC-serine hydrazide; 3) 2,3,4-trihydroxytoluene and NBS are subjected to a bromination reaction to prepare 2,3,4-trihydroxybromobenzene; 4) the two intermediate products are subjected to a nucleophilic substitution reaction under mild conditions to obtain N-BOC-benserazide; and 5) N-BOC-benserazide is subjected to deprotection and salt formation to obtain benserazide hydrochloride.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical synthesis, specifically a method for preparing benzylhydrazine hydrochloride. Background Technology

[0002] Benserazide hydrochloride is a peripheral decarboxylase inhibitor with the following structural formula: .

[0003] Benserazide hydrochloride is a peripheral decarboxylase inhibitor, and its structural formula is shown below. Clinically, it is often used in combination with levodopa to form a compound preparation for the treatment of Parkinson's disease. Levodopa, as a core drug for treating Parkinson's disease, needs to cross the blood-brain barrier to enter brain tissue and be converted to dopamine by central decarboxylases to exert its pharmacological effects. However, under normal administration conditions, most levodopa is metabolized to dopamine peripherally by aromatic amino acid decarboxylases (AADCs), with only a small amount entering the central nervous system to exert its effects. Benserazide hydrochloride, by inhibiting peripheral AADC activity, can significantly reduce the peripheral metabolism of levodopa, increase the concentration of levodopa entering brain tissue, thereby enhancing efficacy and reducing peripheral adverse reactions. It is an important component of current Parkinson's disease treatment regimens.

[0004] The structure of benzylhydrazine hydrochloride contains sensitive functional groups such as phenolic hydroxyl groups and acylhydrazides, making it highly sensitive to pH, temperature and humidity. It is prone to degradation during synthesis and purification, and its stability is difficult to control.

[0005] Currently, numerous domestic and international publications and patents report the synthesis process of benserazide hydrochloride, with the following being a typical route: The synthetic route reported in prior art US Patent 1 (US3178476) is as follows: ; Prior art 1 (US Patent US3178476) uses 2,3,4-trihydroxybenzaldehyde as a starting material, which is condensed with serine hydrazide hydrochloride to generate compound 4, and then reduced to obtain target compound 1. In this process, the step of reducing compound 4 to prepare compound 1 has poor feasibility for large-scale production, and the low solubility of compound 4 and product 1 in methanol leads to a slow reaction rate and low production efficiency.

[0006] The synthetic route reported in existing technology 2 World Patent (WO2022250620) is as follows: ; Existing technology 2 (international patent WO2022250620) adopts the same synthetic route as existing technology 1, only adjusting the reaction solvent. The resulting compound 5 is a DMF solvate, which requires a cumbersome desolventizing process to obtain benzyl hydrazine hydrochloride. The process is complex, energy-intensive, and not conducive to industrial production.

[0007] The synthetic route reported in Chinese Patent No. 3 (CN202110103770) is as follows: ; The existing technology 3 (Chinese patent CN202110103770) has a relatively long synthetic route, which requires first protecting the amino group of serine, and then undergoing multiple steps such as condensation, hydrogenation reduction, and salt formation to obtain the target product. This process relies on fixed-bed hydrogenation equipment, which has high equipment investment and complex operation, and its overall economic and scalability advantages are not significant.

[0008] In summary, existing processes for synthesizing benzylhydrazine hydrochloride generally suffer from problems such as harsh reaction conditions, difficulty in scale-up, complex control of solvent residues, and high equipment requirements. Therefore, developing a simple, mild, easy-to-operate, and quality-controllable method for preparing benzylhydrazine hydrochloride suitable for large-scale industrial production has significant application value and market significance. Summary of the Invention

[0009] To overcome the shortcomings of existing technologies, such as harsh reaction conditions, high production costs, and cumbersome operations, and to meet the needs of efficient and stable industrial production, the present invention aims to provide a method for preparing benzyl hydrazine hydrochloride that is simple in process, mild in reaction conditions, convenient in post-processing, low in cost, stable in quality and yield, and suitable for large-scale production.

[0010] To achieve the above-mentioned technical objectives, this invention discloses a method for synthesizing benzylhydrazine hydrochloride, the method comprising the following steps: The synthesis route is as follows: .

[0011] Specifically, the following steps are included: The reaction formula for step 1 is as follows: ; Commercially available DL-serine methyl ester hydrochloride was used as the starting material and reacted with BOC anhydride to obtain BOC-protected serine methyl ester. Specifically, DL-serine methyl ester hydrochloride was dissolved in solvent 1, base 1 was added, and then BOC anhydride was added. After the reaction was completed, BOC-serine methyl ester was obtained. In step 1, the molar ratio of DL-serine methyl ester hydrochloride to BOC anhydride is 1:1.1 to 1.4, preferably 1:1.1 to 1.2. The base used in step 1 is one or a mixture of several of the following: triethylamine, diisopropylethylamine, pyridine, and DBU. In step 1, solvent 1 is selected from one or a mixture of several of tetrahydrofuran (THF), methyltetrahydrofuran (Me-THF), acetonitrile, ethyl acetate, and dichloromethane (DCM); In step 1, the mass-to-volume ratio of DL-serine methyl ester hydrochloride to solvent 1 is 1:4 to 6, preferably 1:4 to 5.

[0012] The reaction formula for step 2 is as follows: ; BOC-serine methyl ester is subjected to hydrazinolysis to obtain BOC-serine hydrazide. Specifically, BOC-serine methyl ester is dissolved in solvent 2, hydrazine hydrate is added to react, and after the reaction is completed, BOC-serine hydrazide is obtained. In step 2, the molar ratio of BOC-serine methyl ester to hydrazine hydrate is 1:1.5 to 2.0, preferably 1:1.5 to 1.6. In step 2, solvent 2 is selected from one or a mixture of several of tetrahydrofuran (THF), methyltetrahydrofuran (Me-THF), acetonitrile, methanol, and ethanol; In step 2, the mass-to-volume ratio of BOC-serine methyl ester to solvent 2 is 1:5 to 10, preferably 1:5 to 7.

[0013] The reaction formula for step 3 is as follows: ; Commercially available 2,3,4-trihydroxytoluene was used as a starting material and brominated with NBS to obtain 2,3,4-trihydroxybenzyl bromide. Specifically, 2,3,4-trihydroxytoluene was dissolved in solvent 3 under nitrogen protection, NBS was added, and after the reaction was completed, 2,3,4-trihydroxybenzyl bromide was obtained. In step 3, the molar ratio of 2,3,4-trihydroxytoluene to NBS is 1:1.1 to 1.4, preferably 1:1.1 to 1.2. In step 3, the solvent 3 is selected from one or a mixture of several of tetrahydrofuran (THF), methyltetrahydrofuran (Me-THF), dichloromethane (DCM), and chloroform; In step 3, the mass-to-volume ratio of 2,3,4-trihydroxytoluene to solvent 3 is 1:5 to 10, preferably 1:5 to 7.

[0014] The reaction formula for step 4 is as follows:

[0015] Under nitrogen protection, 2,3,4-trihydroxybenzyl bromide was reacted with BOC-serine hydrazide to obtain N-BOC benzyl hydrazide. Specifically, 2,3,4-trihydroxybenzyl bromide was dissolved in solvent 4, a base was added, and BOC-serine hydrazide was added. After the reaction was completed, N-BOC benzyl hydrazide was obtained. In step 4, the molar ratio of 2,3,4-trihydroxybenzyl bromide to BOC-serine hydrazide is 1:1.0 to 1.2, preferably 1:1.0 to 1.1. In step 4, the base 4 used is one or a mixture of several of the following: triethylamine, diisopropylethylamine, pyridine, and DBU. In step 4, the solvent 4 is selected from one or a mixture of several of tetrahydrofuran (THF), methyltetrahydrofuran (Me-THF), dichloromethane (DCM), and chloroform; In step 4, the mass-to-volume ratio of 2,3,4-trihydroxybenzyl bromide to solvent 4 is 1:5 to 8, preferably 1:5 to 6; The reaction temperature used in step 4 is -5 to 10°C, preferably -5 to 0°C.

[0016] The reaction formula for step 5 is as follows:

[0017] Under nitrogen protection, N-BOC-benzirshydrazine underwent deprotection and salt formation reaction to obtain benzylhydrazine hydrochloride. Specifically, N-BOC-benzirshydrazine was dissolved in solvent 5, concentrated hydrochloric acid was added, and after the reaction was completed, benzylhydrazine hydrochloride was obtained. In step 5, the molar ratio of N-BOC-benzirsine to concentrated hydrochloric acid (36-38%) is 1:2.5-4, preferably 1:2.5-3; In step 5, solvent 5 is selected from one or a mixture of tetrahydrofuran (THF), methanol, ethanol, and acetone. In step 5, the mass-to-volume ratio of N-BOC-benzylhydrazine to solvent 5 is 1:5 to 10, preferably 1:5 to 8; The reaction temperature used in step 5 is 0 to 10°C, preferably 0 to 5°C.

[0018] The beneficial effects of the present invention are as follows: The present invention provides a preparation route and method for benzylhydrazine hydrochloride. Compared with the existing process technology, the preparation route is simple, the raw materials are cheap and readily available, the operation is simple, it does not require Pd / C hydrogenation reduction, the yield is high, the impurities are few, and the product purity is high. The purity of the prepared benzylhydrazine hydrochloride is >99.9%, and the yield of each reaction step can reach more than 95%. Specific Implementation

[0019] To further understand the present invention, the preparation method of benzylhydrazine hydrochloride provided by the present invention will be described in detail below with reference to embodiments. It should be understood that these embodiments are described only to further illustrate the features of the present invention, and not to limit the scope of the present invention or the scope of the claims.

[0020] Example 1 1) Preparation of N-BOC-serine methyl ester 100 g (0.643 mol) of DL-serine methyl ester hydrochloride was added to 450 mL of anhydrous dichloromethane and stirred. Then, 130.13 g (1.286 mol) of triethylamine was added, and the mixture was stirred at 20-25 °C for 30 min. The system was then cooled to 0-5 °C, and 154.47 g (0.707 mol) of BOC anhydride was added. After the addition was complete, the temperature was naturally raised to 20-25 °C, and the reaction was continued with stirring for 2 h. After the reaction was complete, 200 mL of purified water was added, and the aqueous phase was extracted with 100 mL of dichloromethane. The organic phases were combined. The organic phase was washed with 200 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and dried to obtain 139 g of N-BOC-DL-serine methyl ester, with a yield of 98% and an HPLC purity of 99.4%.

[0021] 2) Preparation of N-BOC-serine hydrazide 150 g (0.684 mol) of BOC-serine methyl ester was added to a reaction flask, followed by 1050 mL of anhydrous methanol. Stirring was initiated and the mixture was kept at 20–25 °C until completely dissolved. Then, 68.52 g (80%) of hydrazine hydrate was added, and the reaction continued at this temperature until complete. After the reaction was complete, methanol and excess hydrazine hydrate were removed by vacuum distillation. The residue was then slurried in 300 mL of ethyl acetate for 30 min, filtered, and dried to obtain 155.7 g of solid, with a yield of 98% and an HPLC purity of 99.5%.

[0022] 3) Preparation of 2,3,4-trihydroxybenzyl bromide Under nitrogen protection, 100 g (0.704 mol) of 2,3,4-trihydroxytoluene was added to a reaction flask, followed by 600 mL of anhydrous dichloromethane. The mixture was stirred to dissolve the toluene, and then 1.15 g (0.014 mol) of AIBN initiator was added. The mixture was stirred and the temperature was controlled at 0-10 °C. 150.39 g (0.845 mol) of NBS was added. After the addition was complete, the temperature was raised to 20-25 °C, and the mixture was stirred for 6 h. After the reaction was completed, the mixture was filtered, and the filtrate was washed with 200 mL of 10% sodium sulfite solution and 200 mL of saturated brine. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 152 g of solid, with a yield of 98.1% and a purity of 99.3%.

[0023] 4) Preparation of N-BOC-benzirs Under nitrogen protection, 100 g (0.452 mol) of 2,3,4-trihydroxybenzyl bromide and 550 mL of anhydrous dichloromethane were added to a reaction flask, stirred and dissolved, and cooled to -5 to 0 °C. 50.29 g (0.497 mol) of triethylamine was added dropwise, and the mixture was stirred for 10 min after the addition was complete. Then, 116.4 g (0.497 mol) of BOC-serine hydrazide was slowly added dropwise, and the mixture was stirred at -5 to 0 °C for 6 h. After the reaction was complete, 200 mL of saturated ammonium chloride solution was added to quench the reaction, and the mixture was stirred to separate the layers. The aqueous layer was extracted once with 200 mL of dichloromethane, and the organic phases were combined and washed with 200 mL of saturated brine. The resulting dichloromethane layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure. The residue was slurried with 300 mL of n-hexane for 30 min, filtered, and dried under vacuum to obtain 171 g of N-BOC-benzyl hydrazide as a white solid, with a yield of 98% and a purity of 99.2%.

[0024] 5) Preparation of benzylhydrazine hydrochloride Under nitrogen protection, 100 g (0.259 mol) of N-BOC-benzirshydrazine and 600 mL of anhydrous ethanol were dissolved by stirring. The mixture was cooled to 0-5 °C, and 65 g (0.777 mol, 36-38%) of concentrated hydrochloric acid was added dropwise. After the addition was complete, the mixture was kept at this temperature and stirred for 2 h. Then, the temperature was raised to 20-25 °C and stirred for 1 h. After the reaction was completed, the temperature was lowered to 0-5 °C and stirred for 3 h to induce crystallization. The mixture was filtered, and the filter cake was washed twice with cold anhydrous ethanol (80 mL) and dried to obtain 74 g of white solid benzyl hydrazine hydrochloride, with a yield of 97% and a purity of 99.9%.

Claims

1. A method for preparing benzylhydrazine hydrochloride, characterized in that, Includes the following steps: 。 2. The preparation method according to claim 1, characterized in that, The reaction formula for step 1 is as follows: ； Commercially available DL-serine methyl ester hydrochloride was used as the starting material and reacted with BOC anhydride to obtain BOC-protected serine methyl ester. Specifically, DL-serine methyl ester was dissolved in solvent 1, base 1 was added, and then BOC anhydride was added. After the reaction was completed, BOC-serine methyl ester was obtained. In step 1, the molar ratio of DL-serine methyl ester hydrochloride to BOC anhydride is 1:1.1 to 1.

2. The base used in step 1 is one or a mixture of several of the following: triethylamine, diisopropylethylamine, pyridine, and DBU. In step 1, solvent 1 is selected from one or a mixture of several of tetrahydrofuran (THF), methyltetrahydrofuran (Me-THF), acetonitrile, ethyl acetate, and dichloromethane (DCM); In step 1, the mass-to-volume ratio of DL-serine methyl ester hydrochloride to solvent 1 is 1:4-5.

3. The preparation method according to claim 1, characterized in that, The reaction formula for step 2 is as follows: ； BOC-serine methyl ester is subjected to hydrazinolysis to obtain BOC-serine hydrazide. Specifically, BOC-serine methyl ester is dissolved in solvent 2, hydrazine hydrate is added to react, and after the reaction is completed, BOC-serine hydrazide is obtained. In step 2, the molar ratio of BOC-serine methyl ester to hydrazine hydrate is 1:1.5 to 1.

6. In step 2, solvent 2 is selected from one or a mixture of several of tetrahydrofuran (THF), methyltetrahydrofuran (Me-THF), acetonitrile, methanol, and ethanol; In step 2, the mass-to-volume ratio of BOC-serine methyl ester to solvent 2 is 1:5 to 7.

4. The preparation method according to claim 1, characterized in that, The reaction formula for step 3 is as follows: ； Commercially available 2,3,4-trihydroxytoluene was used as a starting material and brominated with NBS to obtain 2,3,4-trihydroxybenzyl bromide. Specifically, 2,3,4-trihydroxytoluene was dissolved in solvent 3 under nitrogen protection, NBS was added, and after the reaction was completed, 2,3,4-trihydroxybenzyl bromide was obtained. In step 3, the molar ratio of 2,3,4-trihydroxytoluene to NBS is 1:1.1 to 1.

2. In step 3, the solvent 3 is selected from one or a mixture of several of tetrahydrofuran (THF), methyltetrahydrofuran (Me-THF), dichloromethane (DCM), and chloroform; In step 3, the mass-to-volume ratio of 2,3,4-trihydroxytoluene to solvent 3 is 1:5 to 7.

5. The preparation method according to claim 1, characterized in that, The reaction formula for step 4 is as follows: ； Under nitrogen protection, 2,3,4-trihydroxybenzyl bromide was reacted with BOC-serine hydrazide to obtain N-BOC benzyl hydrazide. Specifically, 2,3,4-trihydroxybenzyl bromide was dissolved in solvent 4, a base was added, and BOC-serine hydrazide was added. After the reaction was completed, N-BOC benzyl hydrazide was obtained. In step 4, the molar ratio of 2,3,4-trihydroxybenzyl bromide to BOC-serine hydrazide is 1:1.0 to 1.

1. In step 4, the base 4 used is one or a mixture of several of the following: triethylamine, diisopropylethylamine, pyridine, and DBU. In step 4, the solvent 4 is selected from one or a mixture of several of tetrahydrofuran (THF), methyltetrahydrofuran (Me-THF), dichloromethane (DCM), and chloroform; In step 4, the mass-to-volume ratio of 2,3,4-trihydroxybenzyl bromide to solvent 4 is 1:5 to 6. The reaction temperature used in step 4 is -5 to 0℃.

6. The preparation method according to claim 1, characterized in that, The reaction formula for step 5 is as follows: ； Under nitrogen protection, N-BOC-benzirsium underwent deprotection and salt formation reaction to obtain benzylhydrazine hydrochloride. Specifically, N-BOC-benzirsium was dissolved in solvent 5, concentrated hydrochloric acid was added, and after the reaction was completed, benzylhydrazine hydrochloride was obtained. In step 5, the molar ratio of N-BOC-benzisine to concentrated hydrochloric acid (36-38%) is 1:2.5-3. In step 5, solvent 5 is selected from one or a mixture of tetrahydrofuran (THF), methanol, ethanol, and acetone. In step 5, the mass-to-volume ratio of N-BOC-benzylhydrazine to solvent 5 is 1:5 to 8; The reaction temperature used in step 5 is 0 to 5°C.

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