Synthesis method of pyridostigmine bromide

Abstract

The invention relates to the technical field of medicine synthesis, in particular to a pyridostigmine bromide synthesis method which is completed in two steps, the first step of 3-dimethylaminoformyloxy pyridine synthesis is consistent with a traditional synthesis method, and the second step of pyridostigmine bromide synthesis is consistent with a traditional synthesis method. A methylation process and a bromination process are different, 3-dimethylamino formyloxy pyridine is methylated by adopting dimethyl sulfate, and then ammonium bromide is added to form salt, so that a highly toxic product triphosgene or bromomethane is not needed in the whole process, and the method is green, environment-friendly and more suitable for industrial production, and solves the problem that the synthesis process of existing pyridostigmine bromide is difficult to carry out when pyridostigmine bromide is synthesized. The technical problems that in the prior art, the adopted highly toxic product triphosgene is not suitable for commercial production, and adopted bromomethane is gas at normal temperature, is liquefied and stored in a commonly used steel cylinder in industry and is inconvenient to use are solved, meanwhile, the total yield of the synthesized pyridostigmine bromide can reach 80% or above, and the wastewater generation amount is greatly reduced.

Description

Technical Field

[0001] The present invention relates to the technical field of drug synthesis, and particularly relates to a method for synthesizing pyridostigmine bromide. Background Art

[0002] Pyridostigmine bromide is a cholinesterase inhibitor developed by Valeant. By enhancing the signal transmission of neuromuscular, it can improve the myasthenia symptoms of patients. Pyridostigmine bromide was first approved by the FDA and launched in the United States on April 6, 1955, with the trade name

[0003] Currently, there are 4 dosage forms of pyridostigmine bromide marketed by Bausch globally: pyridostigmine bromide oral solution, pyridostigmine bromide sustained-release tablets, pyridostigmine bromide injection, and pyridostigmine bromide tablets.

[0004] Patent US2573579 discloses a method for synthesizing pyridostigmine bromide. Using 3-hydroxypyridine and dimethylcarbamyl chloride as starting materials to synthesize the intermediate 3-dimethylaminocarbonyloxypyridine, and then reacting with methyl bromide to obtain pyridostigmine bromide. The synthetic route of this method has only 2 steps, but methyl bromide used in this method is a gas at room temperature and is commonly stored in liquefied form in steel cylinders in industry, which is inconvenient to use.

[0005] The reaction route is as follows:

[0006]

[0007] The literature PREPARATION OF PYRIDOSTIGMINE BROMIDE LABELED WITH CARBON-14ANDTRITIUM, Journal of Labelled Compounds and Radiopharmaceuticals also discloses a method for synthesizing pyridostigmine bromide, but phosgene, a highly toxic substance, is used in the route, which is not suitable for commercial production.

[0008] The reaction route is as follows:

[0009] Summary of the Invention

[0010] The purpose of the present invention is to provide a method for synthesizing pyridostigmine bromide, which solves the technical problems that phosgene, a highly toxic substance used in the existing synthesis of pyridostigmine bromide, is not suitable for commercial production, and methyl bromide used is a gas at room temperature and is commonly stored in liquefied form in steel cylinders in industry, which is inconvenient to use.

[0011] To achieve the above object, the present invention provides a method for synthesizing pyridostigmine bromide, and its synthetic route is as follows:

[0012]

[0013] Among them, the following synthetic steps are included: Put 3-hydroxypyridine, xylene and triethylamine into a three-necked flask, add N,N-dimethylcarbamyl chloride under stirring, heat to reflux and stir for 3 h, and monitor the reaction by TLC. After the reaction is completed, cool to room temperature, quench with saturated sodium bicarbonate, separate the organic phase, extract the aqueous phase twice with xylene, combine the organic phases, wash the organic phase with saturated sodium chloride solution, dry with anhydrous sodium sulfate, distill out xylene, and after the xylene is distilled out, fractionate 3-dimethylaminocarbonyloxypyridine under reduced pressure.

[0014] Among them, the molar ratio of the 3-hydroxypyridine: the triethylamine: the N,N-dimethylcarbamyl chloride is 1:2 - 4:1 - 3.

[0015] Among them, the following synthetic steps are further included: Put 3-dimethylaminocarbonyloxypyridine and anhydrous acetone into a three-necked flask, add dimethyl sulfate under stirring, react for 5 h, and monitor the reaction by TLC. After the reaction is completed, distill out the solvent under reduced pressure, dissolve the residue in water, add ammonium bromide solution under stirring, continue to stir at room temperature for 5 h, concentrate out part of the water, cool and add acetone to crystallize, filter, dissolve in water, add acetone again to crystallize, and obtain pyridostigmine bromide after filtration and drying.

[0016] Among them, the molar ratio of the 3-dimethylaminocarbonyloxypyridine: the dimethyl sulfate is 1:1 - 2.

[0017] Among them, the optimal molar ratio of the 3-dimethylaminocarbonyloxypyridine: the dimethyl sulfate is 1:1.2.

[0018] Among them, the reaction temperature for the reaction of the 3-dimethylaminocarbonyloxypyridine and the dimethyl sulfate is 20 - 70 °C.

[0019] A synthetic method of pyridostigmine bromide according to the present invention. This synthetic method is completed in two steps. The first step for the synthesis of 3-dimethylaminocarbonyloxypyridine is the same as the traditional synthetic method. For the second step, the synthetic method of pyridostigmine bromide is different from the traditional synthetic method in the methylation and bromination processes. Dimethyl sulfate is used for the methylation of 3-dimethylaminocarbonyloxypyridine, and then ammonium bromide is added to form a salt, so that phosgene or methyl bromide, which are highly toxic substances, are not required in the whole process. It is environmentally friendly and more suitable for industrial production, solving the technical problems that phosgene, a highly toxic substance used in the existing synthesis of pyridostigmine bromide, is not suitable for commercial production, and methyl bromide is a gas at room temperature and is commonly stored in liquefied form in steel cylinders in industry, which is inconvenient to use. At the same time, the total yield of the synthesized pyridostigmine bromide can reach more than 80%, and the amount of wastewater generated is greatly reduced. BRIEF DESCRIPTION OF THE DRAWINGS

[0020] In order to more clearly illustrate the technical solutions in the embodiments of the present application or the prior art, the following will briefly introduce the drawings required for use in the description of the embodiments or the prior art.

[0021] Figure 1 It is a specific flowchart of the synthesis of 3-dimethylaminocarbonyloxypyridine in the synthetic method of pyridostigmine bromide according to the first embodiment of the present invention.

[0022] Figure 2 It is a specific flowchart of the synthesis of pyridostigmine bromide in the synthetic method of pyridostigmine bromide according to the first embodiment of the present invention. DETAILED DESCRIPTION OF THE EMBODIMENTS

[0023] The following will describe in detail the embodiments of the present invention. The examples of the embodiments are shown in the drawings. The embodiments described below with reference to the drawings are exemplary and are intended to explain the present invention and should not be construed as a limitation to the present invention.

[0024] First Embodiment:

[0025] Please refer to Figure 1 and Figure 2 wherein Figure 1 is a specific flowchart of the synthesis of 3-dimethylaminocarbonyloxypyridine in the synthetic method of pyridostigmine bromide according to the first embodiment of the present invention, Figure 2 is a specific flowchart of the synthesis of pyridostigmine bromide in the synthetic method of pyridostigmine bromide according to the first embodiment of the present invention. The present invention provides a synthetic method of pyridostigmine bromide, and its synthetic route is as follows:

[0026]

[0027] Among them, it includes the following synthetic steps:

[0028] S101. Place 3-hydroxypyridine, xylene, and triethylamine in a three-necked flask. While stirring, add N,N-dimethylcarbamyl chloride. Heat to reflux and stir for 3 h, and monitor the reaction by TLC.

[0029] S102. After the reaction is completed, cool to room temperature, quench with saturated sodium bicarbonate, separate the organic phase, extract the aqueous phase twice with xylene, combine the organic phases, and wash the organic phase with saturated sodium chloride solution.

[0030] S103. After drying with anhydrous sodium sulfate, distill out xylene. After the xylene is distilled out, fractionate 3-dimethylaminocarbonyloxypyridine under reduced pressure.

[0031] Secondly, the molar ratio of the 3-hydroxypyridine: the triethylamine: the N,N-dimethylcarbamyl chloride is 1: 2 - 4: 1 - 3.

[0032] Meanwhile, the following synthesis steps are further included:

[0033] S104. Place 3-dimethylaminocarbonyloxypyridine and anhydrous acetone in a three-necked flask. While stirring, add dimethyl sulfate, and react for 5 h, and monitor the reaction by TLC.

[0034] S105. After the reaction is completed, distill out the solvent under reduced pressure. Dissolve the residue in water. While stirring, add ammonium bromide solution, and continue to stir at room temperature for 5 h, and concentrate out part of the water.

[0035] S106. Then cool and add acetone to crystallize. After filtration, dissolve in water, add acetone again to crystallize, and obtain pyridostigmine bromide after filtration and drying.

[0036] In addition, the molar ratio of the 3-dimethylaminocarbonyloxypyridine: the dimethyl sulfate is 1: 1 - 2. Preferably, the optimal molar ratio of the 3-dimethylaminocarbonyloxypyridine: the dimethyl sulfate is 1: 1.2.

[0037] Finally, the reaction temperature for the reaction of the 3-dimethylaminocarbonyloxypyridine with the dimethyl sulfate is 20 - 70 °C.

[0038] When using the synthesis method of pyridostigmine bromide in this embodiment, since in the prior art, dimethyl sulfate is a relatively common methylation reagent and is often used in the methylation reaction of pyridine. For example, CN101216668A discloses a method of adding dimethyl sulfate dropwise to the organic phase of a pyridine derivative for methylation. Those skilled in the art can think of using dimethyl sulfate to methylate 3-dimethylaminocarbonyloxypyridine based on the basic properties of pyridine and its derivatives. Finally, using ammonium bromide for bromination and salt formation is a common method for pyridine bromination. Therefore, in the synthesis process of pyridostigmine bromide, dimethyl sulfate can be used to replace the highly toxic triphosgene or methyl bromide, which is more environmentally friendly and suitable for industrial production.

[0039] This synthesis method is completed in two steps. The first step for the synthesis of 3-dimethylaminocarbonyloxypyridine is the same as the traditional synthesis method. The second step for the synthesis of pyridostigmine bromide is different from the traditional synthesis method in the methylation and bromination processes. Dimethyl sulfate is used to methylate 3-dimethylaminocarbonyloxypyridine, and then ammonium bromide is added to form a salt, so that highly toxic triphosgene or methyl bromide is not required in the whole process, which is environmentally friendly and more suitable for industrial production. It solves the technical problems that the highly toxic triphosgene used in the existing synthesis of pyridostigmine bromide is not suitable for commercial production, and methyl bromide is a gas at room temperature and is commonly stored in liquefied form in steel cylinders in industry, which is inconvenient to use. At the same time, the total yield of the synthesized pyridostigmine bromide can reach more than 80%, and the amount of wastewater generated is greatly reduced.

[0040] Among them, the quality and efficiency of the products of the methylation or bromination reaction of this synthesis method vary under different conditions. The specific examples are as follows:

[0041] Example 1

[0042] In a 500 mL three-necked flask, add 3-hydroxypyridine (20.0 g, 1 equivalent), xylene (200 mL), and triethylamine (3 equivalents). While stirring, add N,N-dimethylcarbamoyl chloride (36.2 g, 1.6 equivalents), heat to reflux and stir for 3 hours, and monitor the reaction by TLC. After the reaction is completed, cool to room temperature, quench with saturated sodium bicarbonate, separate the organic phase, extract the aqueous phase twice with xylene, combine the organic phases, and wash the organic phase three times with saturated sodium chloride solution. After drying with anhydrous sodium sulfate, distill out xylene. After the xylene is distilled out, 28.0 g of 3-dimethylaminocarbonyloxypyridine is fractionated under reduced pressure at 148 °C, and the yield is 80.1%.

[0043] Example 2

[0044] In a 250 mL three-necked flask, add 3-dimethylaminocarbonyloxypyridine (16.6 g, 1 equivalent), anhydrous acetone (150 mL). While stirring, add dimethyl sulfate (17.64 g, 1.4 equivalents). Heat up to 50 °C and react for 5 hours, monitoring the reaction by TLC. After the reaction is complete, distill off the solvent under reduced pressure. Dissolve the residue in 60 mL of water. While stirring, add 60 mL of ammonium bromide solution (13.7 g, 1.4 equivalents). Continue to stir at room temperature for 5 hours. Concentrate out some water, cool down and add acetone to crystallize. After filtration, dissolve in water and add acetone again to crystallize. After filtration and drying, 20.9 g is obtained, with a yield of 80.0% and a purity of 99.5%. 1H NMR (DMSO-d6, 400 MHz) δ ppm: 9.34 (s, 1H), 8.70 (d, 2H), 8.37 (m, 2H), 8.26 (d, 1H), 4.41 (s, 3H), 3.27 (s, 6H), MS: 262.5 [M+1].

[0045] Example 3

[0046] In a 500 mL three-necked flask, add 3-hydroxypyridine (20.0 g, 1 equivalent), xylene (200 mL) and triethylamine (3 equivalents). While stirring, add N,N-dimethylcarbamoyl chloride (27.15 g, 1.2 equivalents). Heat to reflux and stir for 3 hours, monitoring the reaction by TLC. After the reaction is complete, cool down to room temperature, quench with saturated sodium bicarbonate, separate the organic phase. Extract the aqueous phase with xylene twice, combine the organic phases, and wash the organic phase with saturated sodium chloride solution three times. After drying over anhydrous sodium sulfate, distill off xylene. After the xylene is distilled off, fractionate under reduced pressure at 148 °C to obtain 28.5 g of 3-dimethylaminocarbonyloxypyridine, with a yield of 81.5%.

[0047] Example 4

[0048] In a 250 mL three-necked flask, add 3-dimethylaminocarbonyloxypyridine (16.6 g, 1 equivalent), anhydrous acetone (150 mL). While stirring, add dimethyl sulfate (17.64 g, 1.8 equivalents). Heat up to 50 °C and react for 5 hours, monitoring the reaction by TLC. After the reaction is complete, distill off the solvent under reduced pressure. Dissolve the residue in 60 mL of water. While stirring, add 60 mL of ammonium bromide solution (13.7 g, 1.8 equivalents). Continue to stir at room temperature for 5 hours. Concentrate out some water, cool down and add acetone to crystallize. After filtration, dissolve in water and add acetone again to crystallize. After filtration and drying, 19.6 g is obtained, with a yield of 75.0% and a purity of 99.2%.

[0049] Example 5

[0050] In a 250 mL three-necked flask, add 3-dimethylaminocarbonyloxypyridine (16.6 g, 1 equivalent), anhydrous acetone (150 mL), and add dimethyl sulfate (17.64 g, 1.2 equivalents) under stirring. Heat the temperature to 50 °C and react for 5 hours, monitoring the reaction by TLC. After the reaction is completed, distill off the solvent under reduced pressure. Dissolve the residue in 60 mL of water, add 60 mL of ammonium bromide solution (13.7 g, 1.2 equivalents) under stirring, continue to stir at room temperature for 5 hours, concentrate out part of the water, cool down and add acetone to crystallize. After filtration, dissolve it in water and add acetone to crystallize again. After filtration and drying, 22.08 g is obtained, with a yield of 84.5% and a purity of 99.5%.

[0051] The above disclosure is only one or more preferred embodiments of the present application, and cannot be used to limit the scope of rights of the present application. Those of ordinary skill in the art can understand all or part of the processes of implementing the above embodiments, and the equivalent changes made according to the claims of the present application still fall within the scope covered by the present application.

Claims

1. A method for synthesizing pyridostigmine bromide, characterized in that: Its synthetic route is as follows: 。 2. The synthetic method of pyridostigmine bromide as claimed in claim 1, characterized in that: The method comprises the following synthesis steps: placing 3-hydroxypyridine, xylene and triethylamine in a three-necked flask, adding N,N-dimethylaminoformyl chloride under stirring, heating to reflux and stirring for 3 hours, and monitoring the reaction by TLC; after the reaction is completed, cooling to room temperature, quenching with saturated sodium bicarbonate, separating the organic phase, extracting the aqueous phase twice with xylene, combining the organic phases, washing the organic phase with a saturated sodium chloride solution, drying with anhydrous sodium sulfate, distilling out xylene, and after the xylene is distilled out, fractionating under reduced pressure to obtain 3-dimethylaminoformyloxypyridine.

3. The synthetic method of pyridostigmine bromide as claimed in claim 2, characterized in that: The molar ratio of the 3-hydroxypyridine: the triethylamine: the N,N-dimethylcarbamoyl chloride is 1:2-4:1-3.

4. The synthetic method of pyridostigmine bromide as claimed in claim 3, characterized in that: The method also includes the following synthesis steps: placing 3-dimethylaminoformyloxypyridine and anhydrous acetone in a three-necked flask, adding dimethyl sulfate under stirring, reacting for 5 hours, and monitoring the reaction by TLC. After the reaction is completed, the solvent is distilled off under reduced pressure, the residue is dissolved in water, and ammonium bromide solution is added under stirring, and stirring is continued at room temperature for 5 hours, part of the water is concentrated, the temperature is lowered, acetone is added for crystallization, and after filtering, water is added to dissolve, acetone is added again for crystallization, and pyridostigmine bromide is obtained after filtering and drying.

5. The synthetic method of pyridostigmine bromide as claimed in claim 4, characterized in that: The molar ratio of the 3-dimethylaminoformyloxypyridine to the dimethyl sulfate is 1:1-2.

6. The synthetic method of pyridostigmine bromide as claimed in claim 5, characterized in that: The optimal molar ratio of the 3-dimethylaminoformyloxypyridine: the dimethyl sulfate is 1:1.

2.

7. The synthetic method of pyridostigmine bromide as claimed in claim 5, characterized in that: The reaction temperature of the reaction of the 3-dimethylaminoformyloxypyridine and the dimethyl sulfate is 20-70°C.

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