A kind of synthetic method of rimantadine hydrochloride

Abstract

The invention belongs to the technical field of pharmaceutical synthesis, and in particular to a synthetic method of rimantadine hydrochloride, using 1-bromoadamantane as raw material, and obtaining target compound through Grignard reaction, nucleophilic addition, amination, and salification. Bromoadamantane in the present invention directly carries out two reactions such as Grignard reaction and subsequent direct amination reaction, and is the first application for preparing rimantadine, and in addition, after each step of the present invention is completed, it is almost unnecessary to directly carry out the operation or reaction of the next link through any complete purification step, and the whole reaction and treatment purification process are relatively simple. The present invention uses 1-bromoadamantane as raw material to synthesize 1-adamantane-1-yl-ethanol, and finally obtains rimantadine hydrochloride, avoids the generation of acidic gas and the use of expensive catalysts, and is safe, environmentally friendly, easy to operate, and has a higher yield.

Description

Technical Field

[0001] The invention belongs to the technical field of pharmaceutical synthesis, and particularly relates to a method for synthesizing rimantadine hydrochloride. Background Art

[0002] Rimantadine hydrochloride is a white crystalline powder that is soluble in ethanol, chloroform or water. It is mainly used as an antiviral drug. It is mainly used clinically to treat Asian influenza A-II virus infection. It can be used for adults and children, as well as for the elderly, immunodeficient patients and chronic patients who are at high risk. The mechanism of action of rimantadine is to change the surface charge of host cells, inhibit the process of virus penetration into sensitive cells and release of nucleic acids, and inhibit the proliferation of viruses. Rimantadine can also be used to treat sudden severe pain and measles. It is absorbed quickly and completely with few adverse reactions.

[0003] At present, the commonly used synthetic routes are as follows:

[0004] (1) First, adamantane is reacted with liquid bromine to obtain 1-bromoadamantane; then 1-bromoadamantane is reacted with magnesium and anhydrous ether and then acidified to obtain adamantane carboxylic acid; then adamantane carboxylic acid and thionyl chloride are refluxed to obtain adamantane carboxylic acid chloride; then adamantane carboxylic acid and (CH 3 ) 2 CdCu reaction to obtain adamantane methyl ketone; finally, adamantane methyl ketone is hydrogenated under sodium borohydride conditions, reacted with hydrochloric acid, and reacted with ammonia water to obtain rimantadine. However, the synthesis steps of this route are cumbersome, and thionyl chloride is used in the preparation process, which produces a large amount of acidic gas.

[0005]

[0006] (2) Adamantanecarboxylic acid is chlorinated to obtain 1-adamantanecarboxylic acid chloride, which is then reacted with diethyl malonate ethoxymagnesium to produce diethyl adamantanecarboxymalonate, which is then decarboxylated by acid hydrolysis to produce a ketone, which is then reacted with hydroxylamine hydrochloride to produce an oxime, which is then hydrogenated with Raney-Ni catalyst, and finally salted in ethyl acetate to obtain adamantine. This method is cumbersome and the expensive Raney-Ni catalyst used in the reaction is too expensive.

[0007] Summary of the invention

[0008] In view of the above problems, the present invention provides a method for synthesizing rimantadine hydrochloride. The synthetic route of the present invention is simple, safe, environmentally friendly and has a high yield.

[0009] The invention discloses a method for synthesizing rimantadine hydrochloride. 1-bromoadamantane is used as a raw material, and rimantadine hydrochloride is obtained through Grignard reaction, nucleophilic addition reaction, amination reaction and salt-forming reaction.

[0010] The reaction route is:

[0011]

[0012] The specific steps are:

[0013] (1) adding magnesium chips and an initiator to a dry reaction bottle protected by nitrogen, controlling the temperature at 0-10° C. and dripping an anhydrous tetrahydrofuran solution containing 1-bromoadamantane therein to obtain a Grignard reagent of 1-bromoadamantane, which is directly used in the next step;

[0014] (2) Control the temperature at 0-10°C, add the Grignard reagent dropwise to acetaldehyde, and after the addition is completed, keep the mixture in the same temperature range for reaction for 30-35 minutes. After the reaction is completed, filter the mixture quickly, evaporate some THF, directly add DMF and ammonium chloride, and slowly raise the temperature to 90°C while stirring, and pass ammonia gas to a pressure of 0.6 MPa. Keep the mixture in the temperature at 90°C for reaction for 1-1.5 hours. After the reaction is completed, add activated carbon for decolorization, and then filter and evaporate DMF. Add ethanol, and pass HCl under cooling to precipitate a large amount of white solid powder. Stir at room temperature and filter to obtain rimantadine hydrochloride.

[0015] In terms of molar ratio, 1-bromoadamantane: magnesium: acetaldehyde = 1: 1.00-1.05: 1.00-1.05.

[0016] In terms of mass ratio, 1-bromoadamantane: anhydrous tetrahydrofuran = 1:4.1-4.2.

[0017] In terms of mass ratio, 1-bromoadamantane:DMF:ammonium chloride=1:3.2-3.4:0.020-0.021.

[0018] In terms of mass ratio, 1-bromoadamantane: alcohol = 1: 1.95-2.15.

[0019] Compared with the prior art, the present invention does not require any purification step after each step of the reaction is completed, only needs to be simply evaporated to remove the solvent, and then the next step of the reaction can be directly carried out. The operation is relatively continuous and the post-treatment is simple. In particular, the two reactions of directly carrying out the Grignard reaction of bromoadamantane and the subsequent direct amination reaction are both the first applications of preparing rimantadine. The present invention uses 1-bromoadamantane as a raw material to synthesize 1-adamantan-1-yl-ethanol, and then prepares rimantadine, thereby avoiding the generation of acidic gas and the use of expensive catalysts, being safe and environmentally friendly, simplifying the steps, and having low cost and improved yield. DETAILED DESCRIPTION

[0020] Example 1

[0021] A method for synthesizing rimantadine hydrochloride, which uses 1-bromoadamantane as a raw material, and obtains rimantadine hydrochloride through Grignard reaction, nucleophilic addition reaction, amination reaction, and salt-forming reaction;

[0022]

[0023] The specific steps are:

[0024] (1) 24.3 g of magnesium chips were placed in a clean and dry round-bottom flask, 5 grains of iodine were added under nitrogen protection, 215 g of 1-bromoadamantane was dissolved in 1000 ml of anhydrous tetrahydrofuran, and the mixture was added dropwise to the round-bottom flask with stirring. The mixture was heated slightly until the color of the iodine faded, and the temperature was controlled at 0-5° C. in an ice-water bath. After the addition was complete, the mixture was stirred at room temperature. The reaction was completed to obtain a Grignard reagent.

[0025] (2) Take 44.05g of acetaldehyde in another flask, cool it to 0-5°C in an ice-water bath, and drop the prepared Grignard reagent. After the dropwise addition, keep it at 0-5°C for 30 minutes. After the detection reaction is completed, filter it quickly and remove about 900ml of THF by rotary evaporation. Stir the concentrate and 4.5g of ammonium chloride into 750ml of DMF, slowly heat it to 90°C and pass ammonia gas to a pressure of 0.6MPa. Keep it at 90°C for 1 hour. After the detection reaction is completed, add activated carbon for decolorization, filter it, and evaporate the DMF. Dissolve the concentrate in 420g of ethanol, cool it down and stir it to pass HCl. A large amount of white solid powder will precipitate out of the system. After the detection reaction is completed, stir it at room temperature for 30 minutes, filter it with suction, and obtain a white solid, namely, rimantadine hydrochloride, with a dry weight of 136.0g, a purity of 99%, and a yield of 62.4%.

[0026] Example 2

[0027] A method for synthesizing rimantadine hydrochloride, which uses 1-bromoadamantane as a raw material, and performs Grignard reaction, nucleophilic addition reaction, amination reaction, and salt-forming reaction to obtain rimantadine hydrochloride;

[0028]

[0029] The specific steps are:

[0030] (1) 25.4 g of magnesium chips were placed in a clean and dry round-bottom flask, 5 grains of iodine were added under nitrogen protection, 215 g of 1-bromoadamantane was dissolved in 1000 ml of anhydrous tetrahydrofuran, and the mixture was added dropwise to the round-bottom flask with stirring. The mixture was heated slightly until the color of the iodine faded, and the temperature was controlled at 5-10° C. in an ice-water bath. After the addition was complete, the mixture was stirred at room temperature. The reaction was completed to obtain a Grignard reagent.

[0031] (2) Take 46.22g of acetaldehyde in another flask, cool it to 5-10℃ in an ice-water bath, and add the prepared Grignard reagent dropwise. After the addition is completed, keep it warm at 5-10℃ for 30 minutes. After the reaction is completed, filter it quickly and remove about 900ml of THF by rotary evaporation. Stir the concentrate and 4.3g of ammonium chloride into 770ml of DMF, slowly heat it to 90℃ and pass ammonia gas to a pressure of 0.6MPa. Keep it at 90℃ for 1 hour. After the reaction is completed, add activated carbon for decolorization, filter it, and evaporate the DMF. Dissolve the concentrate in 460g of ethanol, cool it down and stir it while passing HCl. A large amount of white solid powder will precipitate in the system. After the reaction is completed, stir it at room temperature for 30 minutes, filter it with suction, and obtain a white solid, namely, rimantadine hydrochloride, with a dry weight of 133.8g, a purity of 99%, and a yield of 61.4%. Melting point 373℃--375℃HNMR (D 2 O): δppm 1.11(d,3H),1.48(m,9H),1.63(d,3H),1.91(s,3H),2.87(q,1H).

Claims

1. A method for synthesizing rimantadine hydrochloride, characterized in that: Using 1-bromoadamantane as the raw material, rimantadine hydrochloride is obtained through Grignard reaction, nucleophilic addition reaction, amination reaction, and salt formation reaction; the reaction route is: 。 2. The method for synthesizing rimantadine hydrochloride according to claim 1, characterized in that: The consecutive operation steps are: (1) Magnesium chips and an initiator are added to a dry reaction bottle protected by nitrogen, the temperature is controlled at 0-10°C, and an anhydrous tetrahydrofuran solution containing 1-bromoadamantane is added dropwise thereto to obtain a Grignard reagent of 1-bromoadamantane; (2) Control the temperature at 0-10°C, add the Grignard reagent dropwise to acetaldehyde, and keep the mixture in the same temperature range for reaction for 30-35 minutes. Detect the completion of the reaction, filter quickly, evaporate some THF, directly add DMF and ammonium chloride, and slowly raise the temperature to 90°C while stirring, and pass ammonia gas to a pressure of 0.6 MPa. Keep the mixture in the temperature at 90°C for reaction for 1-1.5 hours. Detect the completion of the reaction, add activated carbon for decolorization, and then filter and evaporate DMF. Add ethanol, and pass HCl under cooling to precipitate a large amount of white solid powder. Stir at room temperature and filter to obtain rimantadine hydrochloride.

3. The method for synthesizing rimantadine hydrochloride according to claim 2, characterized in that: In terms of molar ratio, 1-bromoadamantane: magnesium: acetaldehyde = 1: 1.00-1.05: 1.00-1.

05.

4. The method for synthesizing rimantadine hydrochloride according to claim 2, characterized in that: In terms of mass ratio, 1-bromoadamantane: anhydrous tetrahydrofuran = 1:4.1-4.

2.

5. The method for synthesizing rimantadine hydrochloride according to claim 2, characterized in that: In terms of mass ratio, 1-bromoadamantane:DMF:ammonium chloride=1:3.2-3.4:0.020-0.

021.

6. The method for synthesizing rimantadine hydrochloride according to claim 2, characterized in that: In terms of mass ratio, 1-bromoadamantane:ethanol=1:1.95-2.15.

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