Purification method of rivastigmine intermediate

Abstract

The invention discloses a rivastigmine intermediate purification method which comprises the following steps: reacting 3-hydroxyacetophenone serving as a raw material with dimethylamine to generate an intermediate 3-[1-(dimethylamino) ethyl] phenol, and splitting and purifying the intermediate by adopting a specific splitting system to obtain S-3-[1-(dimethylamino) ethyl] phenol. And further preparing to obtain rivastigmine. Compared with other rivastigmine preparation methods, rivastigmine prepared from the intermediate prepared by the method provided by the invention has the advantages of low cost, high yield, good effect and less environmental pollution, reduces the residue of inorganic salt, and is beneficial to large-scale industrial production.

Description

Technical Field

[0001] The present invention belongs to the field of pharmaceutical chemistry, and specifically relates to a method for purifying a rivastigmine intermediate Background Art

[0002] Alzheimer's disease (AD) is a type of neurodegenerative disease, and its symptoms are mainly the loss of memory and cognitive ability to varying degrees, and behavioral disorders. Based on the "cholinergic damage hypothesis" of AD pathogenesis, the anti-AD drugs currently used in clinical applications and clinical research are mainly to increase the level of acetylcholine in brain nerves, restore acetylcholine nerve conduction, improve patients' memory, cognitive and behavioral abilities, and delay the progression of the disease. Among them, acetylcholinesterase inhibitors are the most studied and widely used in clinical practice.

[0003]

[0004] Figure 1 . (S)-Rivastigmine Rivastigmine tartrate (trade name: Aceton) is a carbamate acetylcholinesterase inhibitor developed by Novartis, Switzerland, which selectively acts on the brain and is used to treat mild to moderate AD. Pharmacological studies have shown that the S-configuration of rivastigmine tartrate is slightly better than the racemate, while its enantiomer is inactive. There are three methods for obtaining a single chiral substance: chiral source synthesis, asymmetric synthesis, and racemate resolution. The chiral source and asymmetric synthesis methods are costly, complex, and have low pure product yields, which are not conducive to large-scale production. Based on cost considerations and from the perspective of industrial feasibility, two methods are currently used to synthesize S-rivastigmine. The first method is to first synthesize the racemic rivastigmine and then perform chemical resolution, and then form a diastereomeric salt with a chiral acid, which is separated by fractional crystallization to obtain the S-isomer ( Figure 1 ), but this method will cause serious material waste, low yield, high cost, and is not conducive to industrial production; the second is to split the rivastigmine intermediate and then synthesize S-rivastigmine.

[0005] Document CN104151176A reports that 3-hydroxyacetophenone is used as a raw material to react to generate an imine, which is then reduced to obtain 3-(1-(methylamino)ethyl)phenol, which is then separated by recrystallization using tetrahydrofuran and toluene to obtain S-3-(1-(methylamino)ethyl)phenol, which is then methylated to prepare (S)-rivastigmine. It is well known to those skilled in the art that the imine intermediate has poor stability and is difficult to obtain during the synthesis process, and has a poor reductive amination effect. At the same time, a quaternary ammonium salt is easily formed as an over-methylated byproduct during methylation.

[0006] Patent document CN101580482A uses a mixed solution of ethanol and ethyl acetate to repeatedly recrystallize the intermediate 3-[1-(dimethylamino)ethyl]phenol to obtain S-3-[1-(dimethylamino)ethyl]phenol, which is further prepared to obtain (S)-rivastigmine. This method has a low yield of only 27% and a high content of related substances, resulting in a low purity of the product.

[0007] In view of the problems of low yield and high impurities in the synthesis of the above-mentioned intermediates, the present application proposes a method for preparing a rivastigmine intermediate with high yield, few impurities and high purity, which is conducive to industrial production. Summary of the invention

[0008] A method for purifying a rivastigmine intermediate, comprising the following steps: The racemic 3-[1-(dimethylamino)ethyl]phenol was dissolved in tetrahydrofuran, and the intermediate was resolved using a resolution agent to obtain the intermediate-2 S-3-[1-(dimethylamino)ethyl]phenol camphorsulfonate; Recrystallize the intermediate-2 S-3-[1-(dimethylamino)ethyl]phenol camphorsulfonate obtained in step (1) using an ethanol and ethyl acetate system to obtain a recrystallized product of S-3-[1-(dimethylamino)ethyl]phenol camphorsulfonate; The product in step (2) is dissociated using an alkaline solvent to obtain S-3-[1-(dimethylamino)ethyl]phenol, and the S-3-[1-(dimethylamino)ethyl]phenol is recrystallized using toluene to obtain a high-purity intermediate S-3-[1-(dimethylamino)ethyl]phenol.

[0009] The purity of related substances of S-3-[1-(dimethylamino)ethyl]phenol obtained in the present application is greater than or equal to 99.9%, and the related substances are less than 0.1%.

[0010] The isomer purity of S-3-[1-(dimethylamino)ethyl]phenol obtained in the present application is greater than or equal to 99.0%, further the isomer purity is greater than or equal to 99.5%, and further the isomer purity is greater than or equal to 99.6%. The recrystallization method in step (2) of the present application can be used repeatedly for the intermediate S-3-[1-(dimethylamino)ethyl]phenol.

[0011] The resolving agent in step (1) described in the present application may be selected from dextrorotatory tartaric acid, dextrorotatory mandelic acid or dextrorotatory camphorsulfonic acid, and in some embodiments dextrorotatory camphorsulfonic acid is preferred.

[0012] The mass volume ratio of 3-[1-(dimethylamino)ethyl]phenol to tetrahydrofuran in step (1) is 1:5-10, preferably 1:10.

[0013] In step (2), ethanol is used to heat the intermediate-2 under reflux until it is dissolved, and ethyl acetate is added. After the titration is completed, the heating is turned off, the temperature is cooled to room temperature, stirred, and the filter cake is filtered and dried to obtain a recrystallized product of the intermediate-2.

[0014] The mass volume ratio of intermediate-2 in step (2) to ethanol is 1:4-9, preferably 1:4.

[0015] The mass volume ratio of intermediate-2 in step (2) to ethyl acetate is 1:6-11, preferably 1:8.

[0016] In step (3), the intermediate-2 is firstly dissociated using an alkaline aqueous solvent, extracted with an organic solvent, the organic solvents are combined, and dried. The intermediate-3 after the filtrate is spin-dried is added with a toluene solution for recrystallization to obtain a recrystallized product of the intermediate-3.

[0017] The alkaline solution in step (3) is selected from sodium carbonate solution, sodium bicarbonate solution, sodium hydroxide solution, potassium carbonate solution or sodium bicarbonate solution.

[0018] The mass volume ratio of the intermediate-3 used in step (3) to toluene is 1:8-1:10.

[0019] The organic solvent in step (3) can be selected from dichloromethane or ethyl acetate.

[0020] The method for preparing the racemic 3-[1-(dimethylamino)ethyl]phenol in step (1) is to directly perform reductive amination on 3-hydroxyacetophenone and dimethylamine. The dimethylamine exists in the form of, but is not limited to, dimethylamine methanol solution, dimethylamine ethanol solution, dimethylamine hydrochloride, and dimethylamine aqueous solution. The reducing agent includes one of sodium borohydride, potassium borohydride, sodium cyanoborohydride, and sodium triacetoxyborohydride, or a mixture thereof. The reaction temperature is 25°C-80°C, and the reaction time is 3-15h. BRIEF DESCRIPTION OF THE DRAWINGS

[0021] Figure 1 HPLC spectrum of intermediate-2 prepared in Example 2; Figure 2 HPLC spectrum of Intermediate-2 in Example 2 after the first crystallization; Figure 3 HPLC spectrum of intermediate-3 in Example 2. Specific embodiments

[0022] Example 1 Racemic 3-[1-(dimethylamino)ethyl]phenol

[0023] Add 3-hydroxyacetophenone and dimethylamine ethanol solution into a three-necked flask, stir at room temperature until completely dissolved, add sodium cyanoborohydride in batches, heat under reflux for reaction for 8 hours; spin dry the system, add water and a mixed solution (DCM:IPA=5:1), separate the liquids, continue to extract the aqueous phase with a mixed solution of DCM:IPA=5:1, then wash once with a saturated sodium chloride aqueous solution, dry the organic phase with anhydrous sodium sulfate, filter, and spin dry the filtrate to obtain an off-white oily substance with a yield of 83.5%.

[0024] Example 2 S-3-[1-(Dimethylamino)ethyl]phenol

[0025] At room temperature, 30.00g of intermediate-1 was dissolved in 300ml THF, and 46.39g of D-(+)-camphorsulfonic acid was added at once. The temperature was raised to about 60℃ to dissolve. After the mixture was completely dissolved, stirring was continued for 5min. The heating was turned off, and the mixture was cooled to room temperature naturally. Stirring was performed at room temperature for 6h, and then filtered. The filter cake was dried at 50℃. Intermediate-2 was obtained by drying, 31.4g; yield: 43%; HPLC related substance purity: 99.15%; isomer purity: 88.8%.

[0026] First crystallization: 30.00g of intermediate-2 was heated to reflux with 120ml of anhydrous ethanol until the solid was completely dissolved, and 240ml of ethyl acetate was added at once. After the solid was precipitated, the heating was turned off, and the temperature was naturally cooled to room temperature. Stirring was performed for 1h, and suction was filtered. The filter cake was dried at 50°C by air to obtain 27.18g of intermediate-2; HPLC related substance purity: 99.19%; isomer purity: 97.09%.

[0027] Second crystallization: 452.7 ml of 15% aqueous sodium carbonate solution was added to a reaction flask containing 30.18 g of intermediate-2, stirred at room temperature for 1 h, extracted 3 times with 300 ml of dichloromethane, the organic phases were combined, dried with 30 g of anhydrous sodium sulfate for 1 h, filtered, and the filtrate was dried to obtain 12.47 g of crude intermediate-3. 100 ml of toluene was added and heated to reflux to dissolve the system. After the solution was clear, the heating was turned off and stirred at room temperature for crystallization for 3 h. The filter cake was dried in a vacuum oven at 45 ° C for 8 h and dried to obtain 10.27 g of intermediate-3; HPLC purity of related substances: 100.00%, isomer purity: 99.69%; The total yield of splitting is: 35.2%. Example 3 S-3-[1-(Dimethylamino)ethyl]phenol At room temperature, 6.00 g of intermediate-1 was dissolved in 48 ml of THF, and 9.28 g of D-(+)-camphorsulfonic acid was added at once, and the mixture was heated to dissolve. The system was dissolved at 63°C, stirred for 5 minutes after dissolving, and the heating was turned off. The mixture was stirred at room temperature for 5 hours and filtered. The filter cake was dried at 50°C by forced air. Intermediate-2 was obtained by drying, 6.59 g; yield: 43%; First crystallization: 5.00g of Intermediate-2 was heated to reflux with 40ml of anhydrous ethanol until the solid was completely dissolved, and 50ml of ethyl acetate was added at once. After the solid was precipitated, the heating was turned off and the mixture was cooled to room temperature naturally. The mixture was stirred for 1h and filtered. The filter cake was dried at 50°C to obtain 4.48g of Intermediate-2.

[0028] Second crystallization: Prepare 54 ml of 15% sodium carbonate aqueous solution and add it to the reaction bottle containing 3.00 g of intermediate-2, stir at room temperature for 1 hour, extract with 24 ml of dichloromethane 3 times, combine the organic phases, dry with 8.00 g of anhydrous sodium sulfate for 1 hour, filter with suction, and spin-dry the filtrate to obtain 1.25 g of crude intermediate-3, heat and reflux with 12.5 ml of toluene for recrystallization, stir and crystallize at room temperature for 3 hours after dissolving, filter with suction, and dry the filter cake in a vacuum drying oven at 45°C for 8 hours to obtain 0.96 g of intermediate-3; the isomer purity is: 99.78%; Example 4 S-3-[1-(Dimethylamino)ethyl]phenol At room temperature, 10.00 g of intermediate-1 was dissolved in 70 ml of THF, and 15.45 g of D-(+)-camphorsulfonic acid was added at once. The temperature was raised to about 60°C to dissolve the mixture. After the mixture was completely dissolved, stirring was continued for 5 min. The heating was turned off, and the mixture was cooled to room temperature naturally. Stirring was continued for 6 h at room temperature, and then filtered. The filter cake was dried by air at 50°C. Intermediate-2 was obtained by drying, 11.45 g; yield: 45%; First crystallization: 10.00g of Intermediate-2 was heated to reflux with 90ml of anhydrous ethanol until the solid was completely dissolved, 110ml of ethyl acetate was added at once, solid was precipitated after the addition, heating was turned off, the temperature was naturally cooled to room temperature, stirred for 1h, filtered, and the filter cake was dried at 50℃ with air blowing to obtain 9.40g of Intermediate-2; Second crystallization: Prepare 120 ml of 15% sodium carbonate aqueous solution and add it to the reaction bottle containing 8.00 g of intermediate-2. Stir at room temperature for 1 h, extract with 80 ml of dichloromethane 3 times, combine the organic phases, dry with 40 g of anhydrous sodium sulfate for 1 h, filter with suction, and spin-dry the filtrate to obtain 3.32 g of crude intermediate-3. Add 30 ml of toluene and heat under reflux to dissolve the system. After dissolving, turn off the heating, stir at room temperature for crystallization for 3 h, filter with suction, and dry the filter cake in a vacuum drying oven at 45 ° C for 8 h. Dry to obtain 2.49 g of intermediate-3; the isomer purity is: 99.71%.

[0029] Comparative Example 1

[0030] Add 50g 3-[1-(dimethylamino)ethyl]phenol (0.303mol) to 300ml ethyl acetate, heat under reflux to dissolve completely, add 42.2g (0.182mol) of S-(+)camphorsulfonic acid to 62.5ml anhydrous ethanol to dissolve, then add dropwise to the above solution at 70℃, stir for 10min, and after the reaction is complete, stop stirring, cool to room temperature, and stand at -10 to -15℃ in a moisture-proof environment for more than 24h. Crystals precipitate, filter with suction, and dry to obtain 47.5g of white crystals, mp=173-175℃, purity of related substances: 88.36%; purity of isomers: 74.80%; yield 35.2%.

[0031] The above crystals were added to 87.5 ml of ethanol and heated to reflux to dissolve completely. 175 ml of ethyl acetate was slowly added to the solution. After completion, the temperature was lowered to -5 to -10°C and allowed to stand at this temperature for 24 hours in a moisture-proof manner. The obtained crystals were filtered and dried to obtain 39.8 g of crystals, mp = 176-178°C; purity of related substances: 91.15%; purity of isomers: 89.62%; The obtained crystals were recrystallized once more using 75 ml of ethanol and 150 ml of ethyl acetate according to the above method to obtain 37.3 g of white crystals, mp = 178-180°C; purity of related substances: 96.42%; purity of isomers: 93.68%.

Claims

1. A method for purifying a rivastigmine intermediate, comprising the following steps: The racemic 3-[1-(dimethylamino)ethyl]phenol was dissolved in tetrahydrofuran, and the intermediate was resolved using dextrorotatory camphorsulfonic acid to obtain the intermediate-2 S-3-[1-(dimethylamino)ethyl]phenol camphorsulfonate, wherein the mass volume ratio of 3-[1-(dimethylamino)ethyl]phenol to tetrahydrofuran was 1:10; Recrystallize the intermediate-2 S-3-[1-(dimethylamino)ethyl]phenol camphorsulfonate obtained in step (1) using an ethanol and ethyl acetate system to obtain a recrystallized product of S-3-[1-(dimethylamino)ethyl]phenol camphorsulfonate, wherein the mass volume ratio of the intermediate-2 to the ethanol is 1:4, and the mass volume ratio of the intermediate-2 to the ethyl acetate is 1:8; The product in step (2) is dissociated with an aqueous sodium carbonate solution, extracted with dichloromethane, and the filtrate is spin-dried to obtain S-3-[1-(dimethylamino)ethyl]phenol, and the S-3-[1-(dimethylamino)ethyl]phenol is recrystallized with toluene to obtain a high-purity intermediate S-3-[1-(dimethylamino)ethyl]phenol, wherein the mass volume ratio of the intermediate-3 to toluene is 1:8-1:10; The racemic 3-[1-(dimethylamino)ethyl]phenol was prepared by direct reductive amination of 3-hydroxyacetophenone with dimethylamine; in, The purity of related substances of S-3-[1-(dimethylamino)ethyl]phenol is greater than or equal to 99.9%, and the related substances are less than 0.1%.

2. The purification method according to claim 1, characterized in that The dimethylamine exists in the form of dimethylamine solution, dimethylamine ethanol solution, dimethylamine hydrochloride or dimethylamine aqueous solution.

3. The purification method according to claim 1, characterized in that The reducing agent is selected from one or more of sodium borohydride, sodium cyanoborohydride and sodium triacetoxyborohydride.

4. The purification method according to claim 1, characterized in that the reductive amination reaction temperature is 25°C-80°C and the reaction time is 3-15h.

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