Preparation method of neostigmine methylsulfate

Abstract

The invention provides a preparation method of neostigmine methylsulfate, which comprises the following steps: taking m-aminophenol and dimethyl carbonate as raw materials, and carrying out methylation reaction to prepare an intermediate 1; preparing an intermediate 2 from the intermediate 1 and 48% hydrobromic acid under a heating condition; reacting the intermediate 2 with dimethyl carbamoyl chloride to prepare an intermediate 3; and carrying out salt forming reaction on the intermediate 3 and dimethyl sulfate, refining, and drying to obtain neostigmine methylsulfate. According to the method, a more environment-friendly reagent dimethyl carbonate is selected as a methylation reagent to replace methylation reagents such as methyl iodide and dimethyl sulfate, so that the adopted reagent is more beneficial to the environment.

Description

Technical Field

[0001] The invention relates to a preparation method of neostigmine methylsulfate, and belongs to the technical field of compound synthesis. Background Art

[0002] Neostigmine Methylsulfate, English name: Neostigmine Methylsulfate, molecular weight: 334.39, molecular formula: C 13 H 22 N2O6S.

[0003] Its structural formula is as follows:

[0004]

[0005] Neostigmine methylsulfate is an organic compound with the chemical formula C 13 H 22 N2O6 S is a commonly used reversible anticholinesterase drug, commonly used in internal medicine, gynecology and ENT departments for various flaccid paralysis, muscle and neurosis, etc.

[0006] A lot of research has been conducted at home and abroad on the preparation of neostigmine methylsulfate. The neostigmine methylsulfate prepared by the methods of the existing public patent literature has the problems of high cost, difficult operation, low yield, etc. Therefore, this paper proposes a preparation method of neostigmine methylsulfate to solve the problems of high cost, difficult operation, low yield, etc. of neostigmine methylsulfate prepared by the prior art.

[0007] Patent IN1078MUM2014A Patent route is as follows:

[0008]

[0009] The disadvantage of this route is that there may be more by-products during the preparation process. For example, in step 1, the reaction tends to stay at the intermediate by-product of monomethyl, and the reaction tends to generate quaternary ammonium salts. The product yield is low and difficult to purify, and the industrialization risk is high.

[0010] Patent CN115353465A patent route is as follows:

[0011]

[0012] This route uses PG protecting group to carry out acylation reaction. The materials of this step are relatively expensive, resulting in increased production cost. Moreover, during the protection, the phenolic hydroxyl group is also easily protected to generate by-products. Summary of the invention

[0013] In view of the problems existing in the prior art, the present invention provides a method for preparing neostigmine methylsulfate. The product has high purity, and the raw materials are economical, environmentally friendly and easy to purchase, which is suitable for process scale-up production.

[0014] The technical solution of the present invention is as follows:

[0015] A method for preparing neostigmine methylsulfate comprises the following steps:

[0016] S1, m-aminophenol and dimethyl carbonate react to generate intermediate 1;

[0017] S2, intermediate 1 is demethylated in the presence of hydrobromic acid to prepare intermediate 2;

[0018] S3, intermediate 2 and dimethylcarbamoyl chloride react to prepare intermediate 3;

[0019] S4, intermediate 3 and dimethyl sulfate react to prepare a crude product of neostigmine methylsulfate, which is then refined and dried to obtain a finished product. The reaction equation is as follows:

[0020]

[0021] In the above-mentioned method for preparing neostigmine methylsulfate, the step S1 specifically comprises:

[0022] (1) adding m-aminophenol and TBAB into dimethyl carbonate, stirring the reaction and controlling the temperature at 160-200° C. to react;

[0023] (2) After the reaction is completed, toluene is added to the reaction solution to dissolve the material therein, and the reaction solution is washed with water twice;

[0024] (3) Concentrate the toluene phase to obtain intermediate 1.

[0025] In the above-mentioned method for preparing neostigmine methylsulfate, the step S2 specifically comprises:

[0026] (1) Add 48% hydrobromic acid to the intermediate 1, set T = 100-140°C, and stir and heat to react;

[0027] (2) After the reaction is completed, the reaction solution is concentrated, toluene is added to the concentrated solution, and the concentrated solution is washed with water;

[0028] (3) concentrating the toluene phase and recrystallizing it using toluene;

[0029] (4) Vacuum drying to obtain intermediate 2.

[0030] In the above-mentioned method for preparing neostigmine methylsulfate, the step S3 specifically comprises:

[0031] (1) Intermediate 2, DMAP and triethylamine were mixed in toluene, stirred and heated to T = 30-50°C;

[0032] (2) adding dimethylaminoformyl chloride dropwise thereto, and after completion of the addition, maintaining the reaction at this temperature for 10-12 hours;

[0033] (3) After the reaction is completed, the product is washed with water and concentrated to obtain intermediate 3.

[0034] In the above-mentioned method for preparing neostigmine methylsulfate, the step S4 specifically comprises:

[0035] (1) Intermediate 3 is dissolved in acetone solvent, dimethyl sulfate is added dropwise under stirring, and the temperature is raised to T = 30-50°C;

[0036] (2) cooling and crystallizing, filtering, and drying to obtain a crude product;

[0037] (3) The crude product is refined with anhydrous ethanol to obtain the product neostigmine methylsulfate.

[0038] Compared with the prior art, the product of the present invention has high purity, and the raw materials are economical, environmentally friendly and easy to purchase, and are suitable for process scale-up production. BRIEF DESCRIPTION OF THE DRAWINGS

[0039] Figure 1 is the related substance spectrum of intermediate 1;

[0040] Figure 2 is the related substance spectrum of intermediate 2;

[0041] Figure 3 Related substance profile of the finished product; DETAILED DESCRIPTION

[0042] The present invention is further described below. The following embodiments are only used to more clearly illustrate the technical solution of the present invention, and cannot be used to limit the protection scope of the present invention.

[0043] Example 1

[0044]

[0045] S1: Add 20g of m-aminophenol, 99.1g of dimethyl carbonate, and 88.6g of TBAB to a round-bottom flask. After the addition of the materials, place it in an oil bath and heat it to 160°C for 24h. After the reaction, add 140g of toluene, wash it with 140g of water, concentrate the toluene phase, and obtain intermediate 1 with a yield of 98.5%. Liquid phase analysis is as follows Figure 1 , the purity of intermediate 1 reached 94.6%.

[0046] S2: Add 27g of intermediate 1 and 270g of hydrobromic acid to a round-bottom flask. After the addition of the materials, place it in an oil bath and heat it to 100°C for 12 hours. After the reaction is completed, concentrate the reaction solution, add 200g of toluene and 150g of water to the concentrated solution, add sodium bicarbonate under stirring, wash the separated liquid with water, and concentrate the toluene phase. Recrystallize the concentrated solution to obtain intermediate 2 with a yield of 70.4%. Liquid phase analysis is as follows: Figure 2 , the purity of intermediate 2 reached 99.4%.

[0047] S3: Add 17.4 g of intermediate 2, 1.4 g of DMAP, 19.3 g of triethylamine, and 227 g of toluene to a round-bottom flask. After the addition, place it in an oil bath, start stirring and heating, and dropwise add 16.4 g of dimethylaminoformyl chloride. At T = 30°C, react for 10 hours. After the reaction is terminated, wash with water and concentrate to prepare intermediate 3 with a yield of 87.4%.

[0048] S4: Add 22.4 g of intermediate 3 and 70.6 g of acetone to a round-bottom flask, place it in an oil bath, stir and heat, add 16.4 g of dimethyl sulfate dropwise, react at T = 30°C for 4 h, prepare a crude product, recrystallize and dry to prepare neostigmine methylsulfate. Yield 81.5%, liquid phase analysis test as follows Figure 3 , the purity of the finished product reaches 99.7%.

[0049] Example 2

[0050] S1: Add 20 g of m-aminophenol, 99.1 g of dimethyl carbonate, and 88.6 g of TBAB to a round-bottom flask. After the addition of the materials, place it in an oil bath and heat it to 200°C for 24 hours. After the reaction is completed, add 140 g of toluene, wash it once with 140 g of water, and concentrate the toluene phase to obtain intermediate 1 with a yield of 97.4% and a purity of 95.7%.

[0051] S2: Add 27g of intermediate 1 and 270g of hydrobromic acid to a round-bottom flask. After the addition of the materials, place it in an oil bath and heat it to 140°C for 12 hours. After the reaction is completed, concentrate the reaction solution, add 200g of toluene and 150g of water to the concentrated solution, add sodium bicarbonate under stirring, wash the separated liquid with water, and concentrate the toluene phase. Recrystallize the concentrated solution to obtain intermediate 2 with a yield of 67.6% and a purity of 98.4%.

[0052] S3: Add 18.6 g of intermediate 2, 1.5 g of DMAP, 20.6 g of triethylamine, and 243 g of toluene to a round-bottom flask. After the addition, place it in an oil bath, start stirring and heating, add 17.5 g of dimethylaminoformyl chloride dropwise, and react at T = 50°C for 10 hours. After the reaction is terminated, wash with water and concentrate to prepare intermediate 3 with a yield of 86.4%.

[0053] S4: Add 23.7 g of intermediate 3 and 74.7 g of acetone to a round-bottom flask, place it in an oil bath, stir and heat, add 17.3 g of dimethyl sulfate dropwise, react at T = 50°C for 4 h to prepare a crude product, and then prepare neostigmine methylsulfate through recrystallization and drying. The yield is 80.4%, and the purity of the finished product is 99.8%.

[0054] The above description is only the preferred embodiment of the present application and is not intended to limit the present application. For those skilled in the art, the present application may have various modifications and variations. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present application shall be included in the protection scope of the present application.

Claims

1. A method for preparing neostigmine methylsulfate, characterized in that Follow these steps: (1) m-Aminophenol and dimethyl carbonate react under heating conditions, and after the reaction is terminated, the reaction is washed with water and concentrated to obtain intermediate 1; (2) Intermediate 1 is heated in a hydrobromic acid solvent for reaction, and after the reaction is terminated, the reaction is concentrated, washed with water, and recrystallized to prepare Intermediate 2; (3) heating the intermediate 2 and dimethylaminoformyl chloride to react, washing with water and concentrating the reaction to prepare the intermediate 3; (4) The intermediate 3 and dimethyl sulfate are heated to react in a solvent to prepare a crude product, which is then recrystallized and dried to prepare neostigmine methylsulfate.

2. The method for preparing intermediate 1 according to claim 1, characterized in that: The preparation of intermediate 1 comprises: (1) adding m-aminophenol and tetrabutylammonium bromide into dimethyl carbonate solvent at room temperature and stirring; (2) Keep the reaction at a temperature of T = 160-200°C and take samples for testing; (3) After the reaction is completed, the temperature is cooled to room temperature, toluene is added to dissolve the material in the toluene phase, and the material is washed with water twice; (4) Concentrate the toluene phase to obtain intermediate 1.

3. The method for preparing intermediate 2 according to claim 1, characterized in that: The preparation of intermediate 2 comprises: (1) Add intermediate 1 to hydrobromic acid solvent, heat to reflux T = 100-140 ° C, and keep the reaction for 24 hours; (2) After the reaction is completed, the reaction solution is concentrated; (3) adding toluene and purified water to the concentrate, slowly adding sodium bicarbonate under stirring, and washing with water twice; (4) The toluene phase was concentrated to obtain intermediate 2.

4. The method for preparing intermediate 3 according to claim 1, characterized in that: The preparation of intermediate 3 comprises: (1) Intermediate 2, DMAP and triethylamine were mixed in toluene, stirred and heated to T = 30-50°C; (2) adding dimethylaminoformyl chloride dropwise thereto, and after completion of the addition, maintaining the reaction at this temperature for 10-12 hours; (3) After the reaction is completed, the product is washed with water and concentrated to obtain intermediate 3.

5. The method for preparing the product according to claim 1, characterized in that: The prepared product comprises: (1) Intermediate 3 is dissolved in acetone solvent, dimethyl sulfate is added dropwise under stirring, and the temperature is raised to T = 30-50°C; (2) cooling and crystallizing, filtering, and drying to obtain a crude product; (3) The crude product is refined with anhydrous ethanol to obtain the product.

6. According to the preparation process of neostigmine methylsulfate according to claims 1-5, a product with stable quality can be obtained, and its purity is greater than or equal to 99.8%.

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