A kind of preparation method of memantine hydrochloride

Abstract

The invention belongs to the technical field of organic synthesis, and is particularly related to a method for preparing memantine hydrochloride. The present invention uses halogenated dimethyladamantane as a starting material, anhydrous N, N-dimethylformamide as a reaction solvent, adds an active catalyst silver oxide and an acid binding agent triethylamine, passes ammonia at 0.5MPa and 80-85°C for reaction for 5-6h, and after suction filtration, the filtrate is reacted with concentrated hydrochloric acid to obtain memantine hydrochloride. The solvent anhydrous N, N-dimethylformamide used in the preparation method of memantine hydrochloride of the present invention is non-toxic, and the reaction is directly passed through ammonia under a certain pressure in the presence of an active catalyst, and a carbon-halogen bond directly forms a carbon-nitrogen bond to obtain adamantine compounds, so that the process for preparing memantine hydrochloride is greatly simplified, the process route is short and easy to operate, the production cost is low, the yield and purity are high, and it is suitable for large-scale industrial production.

Description

Technical Field

[0001] The invention belongs to the technical field of organic synthesis, and particularly relates to a preparation method of memantine hydrochloride. Background Art

[0002] Memantine hydrochloride, also known as 1-amino-3,5-dimethyladamantane hydrochloride and memantine hydrochloride, is a low-to-moderate affinity, voltage-dependent and non-competitive NMDA receptor antagonist developed by Merz, Germany. It can prevent cell apoptosis and improve memory. It is a new generation of drugs to improve cognitive function. Therefore, memantine hydrochloride has great potential for economic and social benefits.

[0003] Common synthesis methods for memantine hydrochloride mainly include urea method (CN1594277A), acetonitrile method (CN102432473A), formamide method (Huber FA, Gallo G, Faveri CD. product: WO, 2009115334A2[P]. 2009-09-24.), nitration method (Huang Bin, Ao Guizhen, Yu Jian. Improved synthesis process of memantine hydrochloride[J]. China Pharmaceutical Industry, 2009, 18(22): 17-18.), etc. However, the urea method is difficult to react with 1-bromo-3,5-dimethyladamantane and urea, the reaction yield is less than 70%, and the industrial production cost is high; the acetonitrile method uses concentrated sulfuric acid and organic acid to react, the reaction is violent, toxic, and the yield is not high; the formamide method produces a large amount of red-brown toxic gas NO2 during the reaction, and the post-treatment is complicated; the nitration method needs to be hydrogenated by Pd / C catalysis, which is very dangerous, and the time is long and the cost is high. The existing synthesis methods all have problems such as high production cost, great harm to the human body, and low yield to varying degrees. Summary of the invention

[0004] In view of the above problems, the present invention provides a method for preparing memantine hydrochloride, which uses commercial general chemicals as raw materials, has high yield, low synthesis cost, uses active catalysts for catalysis, has a short reaction route and time, and has little harm to the human body.

[0005] The technical solution of the present invention is as follows:

[0006] A preparation method of memantine hydrochloride, the specific steps are as follows:

[0007] (1) Dissolve halogenated dimethyladamantane in anhydrous N,N-dimethylformamide, add silver oxide and triethylamine, increase the temperature, introduce ammonia gas, and after the reaction is complete, cool to room temperature and filter to obtain a filtrate;

[0008] (2) After the filtrate is cooled to room temperature, concentrated hydrochloric acid is added, stirred at room temperature, filtered with suction, and the filter cake is dried to obtain memantine hydrochloride.

[0009] The reaction equation is shown in Formula I:

[0010]

[0011] Preferably, in step (1), the temperature when ammonia is introduced is 80-85° C. and the pressure is 0.5 MPa.

[0012] Preferably, in step (1), the reaction time is 5 to 6 hours.

[0013] Preferably, in the step (1), the mass ratio of halogenated dimethyladamantane to anhydrous N,N-dimethylformamide is 1:4.5-5.5.

[0014] Preferably, in the step (1), the molar ratio of halogenated dimethyladamantane to triethylamine is 1:1.0-1.1.

[0015] Preferably, in the step (1), the mass ratio of halogenated dimethyladamantane to silver oxide is 1:0.01-0.05.

[0016] Preferably, in step (1), the halogenated dimethyladamantane is 1-chloro-3,5-dimethyladamantane or 1-bromo-3,5-dimethyladamantane.

[0017] Preferably, in step (2), the mass ratio of halogenated dimethyladamantane to concentrated hydrochloric acid is 1:5-6; the concentration of the concentrated hydrochloric acid is 35%-38%.

[0018] Preferably, in step (2), the stirring time is 1 h.

[0019] The beneficial effects of the present invention are as follows:

[0020] (1) The present invention provides a new method for preparing memantine hydrochloride. The synthetic route avoids the use of reagents such as acetonitrile and ether that are harmful to the environment and human body. The solvent used in the method is basically non-toxic, the raw materials are common and less toxic, and the price is low, so the production cost is low;

[0021] (2) The present invention has a short synthesis route, uses an active catalyst for catalysis, is simple and easy to operate, does not require purification, reduces the number of operating steps, has high product stability, and does not produce highly polluting gases and by-products during the production process. It is relatively safe and environmentally friendly and is suitable for large-scale industrial production;

[0022] (3) The product purity and yield can be improved by selecting the reaction temperature and pressure when ammonia is introduced and the reagents used; when the reaction temperature is higher than 85°C, more by-products are produced, and when the temperature is lower than 80°C, the reaction time will be prolonged; when the pressure is higher than 0.5MPa, impurities are easily generated, and when the pressure is lower than 0.5MPa, the reaction is slow or does not react; the final product yield and purity of other reagents are not as good as the reagents used in this method. The total yield of the final product prepared by this method can reach more than 80%, and the purity can reach more than 98%. DETAILED DESCRIPTION

[0023] The present invention will be further described in detail below in conjunction with the examples. The concentration of concentrated hydrochloric acid used in the examples is 36%, which will not be described in detail below.

[0024] Example 1

[0025] Anhydrous N,N-dimethylformamide (995.5 g) and 1-chloro-3,5-dimethyladamantane (199 g) were added to the autoclave, and then silver oxide (2.13 g) and triethylamine (101.8 g) were added in a dark environment, and then the temperature was raised to 80°C, the pressure was controlled at 0.5 MPa, ammonia was introduced, and the reaction was continued for 5.5 hours. After the reaction was completed, the ammonia was stopped, the temperature was lowered, and the filtrate was obtained by suction filtration; after the filtrate was cooled, concentrated hydrochloric acid (1000 g) was added, and the mixture was stirred at room temperature for 1 hour and then suction filtered. The filter cake was dried to obtain 178 g of memantine hydrochloride, with a yield of 82.4% and a purity of 98.2%. The obtained product was white powder in color and had a melting point of 292°C. 1 H-NMR (CDC13): 0.85 (s, 6H), 1.15 (m, 2H), 1.26 (q, J=12.5Hz, 4H), 1.65 (d, J=11.5Hz, 4H), 1.85 (s, 2H), 8.27 (s, 3H).

[0026] Example 2

[0027] Anhydrous N,N-dimethylformamide (899.6 g) and 1-chloro-3,5-dimethyladamantane (199 g) were added to the autoclave, and then silver oxide (5.97 g) and triethylamine (110.9 g) were added in a dark environment. The temperature was then raised to 85°C, the pressure was controlled at 0.5 MPa, ammonia was introduced, and the reaction was carried out for 5 h. After the reaction was completed, the ammonia was stopped, the temperature was lowered, and the filtrate was obtained by suction filtration. After the filtrate was cooled, concentrated hydrochloric acid (1095 g) was added, the mixture was stirred at room temperature for 1 h, and then suction filtered. The filter cake was dried to obtain 181 g of memantine hydrochloride with a yield of 83.9% and a purity of 98.4%.

[0028] Example 3

[0029] Anhydrous N,N-dimethylformamide (1091.2 g) and 1-chloro-3,5-dimethyladamantane (199 g) were added to the autoclave, and then silver oxide (9.91 g) and triethylamine (105.6 g) were added in a dark environment. The temperature was then raised to 83°C, the pressure was controlled at 0.5 MPa, ammonia was introduced, and the reaction was carried out for 6 h. After the reaction was completed, the ammonia was stopped, the temperature was lowered, and the filtrate was obtained by suction filtration. After the filtrate was cooled, concentrated hydrochloric acid (1191 g) was added, and the mixture was stirred at room temperature for 1 h and then filtered. The filter cake was dried to obtain 183 g of memantine hydrochloride with a yield of 84.8% and a purity of 98.5%.

[0030] Example 4

[0031] Anhydrous N,N-dimethylformamide (1095.4 g) and 1-bromo-3,5-dimethyladamantane (243 g) were added to the autoclave, and then silver oxide (3.25 g) and triethylamine (102.2 g) were added in a dark environment. The temperature was then raised to 80°C, the pressure was controlled at 0.5 MPa, ammonia was introduced, and the reaction was carried out for 5 h. After the reaction was completed, the ammonia was stopped, the temperature was lowered, and the filtrate was obtained by suction filtration. After the filtrate was cooled, concentrated hydrochloric acid (1220 g) was added, the mixture was stirred at room temperature for 1 h, and then suction filtered. The filter cake was dried to obtain 180 g of memantine hydrochloride with a yield of 83.4% and a purity of 98.4%.

[0032] Example 5

[0033] Anhydrous N,N-dimethylformamide (1331.2 g) and 1-bromo-3,5-dimethyladamantane (243 g) were added to the autoclave, and then silver oxide (11.92 g) and triethylamine (110.5 g) were added in a dark environment. The temperature was then raised to 85°C, the pressure was controlled at 0.5 MPa, ammonia was introduced, and the reaction was carried out for 6 h. After the reaction was completed, the ammonia was stopped, the temperature was lowered, and the filtrate was obtained by suction filtration. After the filtrate was cooled, concentrated hydrochloric acid (1450 g) was added, the mixture was stirred at room temperature for 1 h, and then suction filtered. The filter cake was dried to obtain 177 g of memantine hydrochloride with a yield of 82.1% and a purity of 98.3%.

[0034] Example 6

[0035] Anhydrous N,N-dimethylformamide (1215.5 g) and 1-bromo-3,5-dimethyladamantane (243 g) were added to the autoclave, and then silver oxide (8.55 g) and triethylamine (105.9 g) were added in a dark environment. The temperature was then raised to 82°C, the pressure was controlled at 0.5 MPa, ammonia was introduced, and the reaction was carried out for 5.5 h. After the reaction was completed, the ammonia was stopped, the temperature was lowered, and the filtrate was obtained by suction filtration. After the filtrate was cooled, concentrated hydrochloric acid (1337 g) was added, the mixture was stirred at room temperature for 1 h, and then suction filtered. The filter cake was dried to obtain 175 g of memantine hydrochloride with a yield of 81.1% and a purity of 98.1%.

[0036] Comparative Example 1 Screening of Temperature and Pressure

[0037] 1.1 Temperature screening

[0038] This comparative example provides a method for preparing memantine hydrochloride. The preparation process is the same as that of Example 1. The difference from Example 1 is that the reaction temperature in Example 1 is changed alone. The other aspects are the same as those of Example 1. The yield and purity of the product are shown in Table 1.

[0039] Table 1 Product yield purity table

[0040]

[0041] During the entire experimental process, temperatures below 80°C will prolong the reaction time and reduce the yield; temperatures above 85°C will increase by-products and affect purity; therefore, the optimal reaction temperature for memantine hydrochloride is 80-85°C.

[0042] 1.2 Pressure screening

[0043] This comparative example provides a method for preparing memantine hydrochloride. The preparation process is the same as that of Example 1. The difference from Example 1 is that the reaction pressure in Example 1 is changed alone. The other aspects are the same as those of Example 1. The yield and purity of the product are shown in Table 2.

[0044] Table 2 Product yield purity table

[0045]

[0046] During the entire experimental process, if the pressure is lower than 0.5 MPa, the reaction time will be prolonged or even no reaction will occur; if the temperature is higher than 0.5 MPa, by-products will increase and the purity of the product will be affected; therefore, the reaction pressure of memantine hydrochloride should be controlled at 0.5 MPa.

[0047] 2.1 Catalyst screening

[0048] This comparative example provides a method for preparing memantine hydrochloride. The preparation process is the same as that of Example 1. The difference from Example 1 is that the type of catalyst in Example 1 is changed alone. The other conditions are the same as those of Example 1. The yield and purity of the product are shown in Table 3.

[0049] Table 3 Product yield purity table

[0050]

[0051] 2.2 Screening of acid binding agents

[0052] This comparative example provides a method for preparing memantine hydrochloride. The preparation process is the same as that of Example 1. The difference from Example 1 is that the type of the acid-binding agent in Example 1 is changed alone. The other conditions are the same as those of Example 1. The yield and purity of the product are shown in Table 4.

[0053] Table 4 Product yield purity table

[0054]

[0055] 2.3 Screening of reaction solvents

[0056] This comparative example provides a method for preparing memantine hydrochloride. The preparation process is the same as that of Example 1. The difference from Example 1 is that the reaction solvent anhydrous N,N-dimethylformamide in Example 1 is replaced by dimethyl sulfoxide. The other properties are the same as those of Example 1. The final product has a yield of 76.2% and a purity of 97.3%.

[0057] In summary, changes in catalyst, acid binding agent and reaction solvent will reduce product yield to a certain extent, generate impurities and affect product purity. Therefore, the present invention selects silver oxide as catalyst, triethylamine as acid binding agent and anhydrous N,N-dimethylformamide as reaction solvent to prepare memantine hydrochloride.

[0058] The above are all preferred embodiments of the present invention, but this should not be understood as the scope of the above subject matter of the present invention being limited to the above embodiments. Without departing from the technical concept of the present invention, various substitutions and changes can be made according to common technical knowledge and customary means in the art, which should all be included in the scope of the present invention.

Claims

1. A method for preparing memantine hydrochloride, characterized in that, The specific steps are as follows: (1) Dissolve halogenated dimethyladamantane in anhydrous N,N-dimethylformamide, add silver oxide and triethylamine, increase the temperature, introduce ammonia gas, start the reaction, and after the reaction is completed, cool and filter to obtain a filtrate; (2) After the filtrate is cooled, concentrated hydrochloric acid is added, stirred at room temperature, filtered with suction, and the filter cake is dried to obtain memantine hydrochloride.

2. The method for preparing memantine hydrochloride according to claim 1, wherein In step (1), the temperature when ammonia is introduced is 80-85° C. and the pressure is 0.5 MPa.

3. The preparation method of memantine hydrochloride according to claim 1, characterized in that, In step (1), the reaction time is 5 to 6 hours.

4. The preparation method of memantine hydrochloride according to claim 1, characterized in that, In the step (1), the mass ratio of halogenated dimethyladamantane to anhydrous N,N-dimethylformamide is 1:4.5-5.

5.

5. The method for preparing memantine hydrochloride according to claim 1, characterized in that, In the step (1), the molar ratio of halogenated dimethyladamantane to triethylamine is 1:1.0-1.

1.

6. The method for preparing memantine hydrochloride according to claim 1, characterized in that: In the step (1), the mass ratio of halogenated dimethyladamantane to silver oxide is 1:0.01-0.

05.

7. The method for preparing memantine hydrochloride according to claim 1, characterized in that: In step (1), the halogenated dimethyladamantane is 1-chloro-3,5-dimethyladamantane or 1-bromo-3,5-dimethyladamantane.

8. The method for preparing memantine hydrochloride according to claim 1, characterized in that: In the step (2), the mass ratio of halogenated dimethyladamantane to concentrated hydrochloric acid is 1:5-6.

9. The method for preparing memantine hydrochloride according to claim 1, characterized in that: In the step (2), the stirring time is 1 h.

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