阅读说明：本技术 一种卡巴拉汀中间体的纯化方法 (Purification method of rivastigmine intermediate ) 是由 李小新 余晓磊 杨日芳 李文明 马淑贤 张宇 于 2020-03-30 设计创作，主要内容包括：本发明公开了一种卡巴拉汀中间体的纯化方法,本发明以3-羟基苯乙酮为原料,通过与二甲胺反应生成中间体3-[1-(二甲氨基)乙基]苯酚,采用特定的拆分体系对该中间体进行拆分纯化,得到S-3-[1-(二甲氨基)乙基]苯酚,然后进一步制备获得卡巴拉汀。采用本申请方法制备的中间体制备的卡巴拉汀与其他卡巴拉汀的制备方法相比,成本低,收率高,效果好,对环境污染少,减少了无机盐的残留,有利于大规模工业化生产。(The invention discloses a purification method of a rivastigmine intermediate, which comprises the steps of taking 3-hydroxyacetophenone as a raw material, reacting with dimethylamine to generate an intermediate 3- [1- (dimethylamino) ethyl ] phenol, adopting a specific resolution system to perform resolution and purification on the intermediate to obtain S-3- [1- (dimethylamino) ethyl ] phenol, and then further preparing to obtain the rivastigmine. Compared with other rivastigmine preparation methods, the rivastigmine prepared by the intermediate prepared by the method has the advantages of low cost, high yield, good effect, less environmental pollution, reduction of inorganic salt residue and contribution to large-scale industrial production.)

1. A method for purifying a rivastigmine intermediate comprises the following steps:

(1) dissolving racemate 3- [1- (dimethylamino) ethyl ] phenol in tetrahydrofuran, and resolving the intermediate by using a resolving agent to obtain an intermediate 2S-3- [1- (dimethylamino) ethyl ] phenol camphorsulfonate;

(2) recrystallizing the intermediate 2S-3- [1- (dimethylamino) ethyl ] phenol camphorsulfonate obtained in the step (1) by using an ethanol and ethyl acetate system to obtain a recrystallized product of S-3- [1- (dimethylamino) ethyl ] phenol camphorsulfonate;

(3) dissociating the product in the step (2) by using an alkaline solvent to obtain S-3- [1- (dimethylamino) ethyl ] phenol, and recrystallizing the S-3- [1- (dimethylamino) ethyl ] phenol by using toluene to obtain a high-purity intermediate S-3- [1- (dimethylamino) ethyl ] phenol;

wherein, the purity of the S-3- [1- (dimethylamino) ethyl ] phenol is more than or equal to 99.9 percent, and related substances are less than 0.1 percent.

2. The purification process according to claim 1, wherein the mass-to-volume ratio of 3- [1- (dimethylamino) ethyl ] phenol to tetrahydrofuran in step (1) is from 1:5 to 1: 10.

3. The purification process according to claim 1, wherein the resolving agent in step (1) is selected from the group consisting of d-tartaric acid, d-mandelic acid and d-camphorsulfonic acid.

4. The purification process according to claim 1, wherein the mass-to-volume ratio of intermediate-2 to ethanol in step (2) is from 1:4 to 1: 9.

5. The purification process according to claim 1, wherein the mass-to-volume ratio of intermediate-2 to ethyl acetate in step (2) is from 1:6 to 1: 11.

6. The purification process according to claim 1, wherein the alkaline solution in the step (3) is selected from sodium carbonate solution, sodium bicarbonate solution, sodium hydroxide solution, potassium carbonate solution, or sodium bicarbonate solution.

7. The purification method according to claim 1, wherein the mass-to-volume ratio of intermediate-3 to toluene used in step (3) is 1:8 to 1: 10.

8. The purification process according to claim 1, wherein the organic solvent in step (3) is selected from dichloromethane or ethyl acetate.

9. The purification process according to claim 1, wherein the racemate 3- [1- (dimethylamino) ethyl ] phenol is prepared by direct reductive amination of 3-hydroxyacetophenone with dimethylamine.

10. The purification method according to claim 9, wherein dimethylamine is present in the form of dimethylamine methanol solution, dimethylamine ethanol solution, dimethylamine hydrochloride or dimethylamine water solution, and the reducing agent is one or more selected from sodium borohydride, potassium borohydride, sodium cyanoborohydride and sodium triacetoxyborohydride, and the reaction temperature is 25-80 ℃ and the reaction time is 3-15 h.

Technical Field

The invention belongs to the field of pharmaceutical chemistry, and particularly relates to a method for purifying a rivastigmine intermediate.

Background

Alzheimer's Disease (AD) is a type of neurodegenerative Disease, and symptoms of the Alzheimer's Disease mainly include loss of memory and cognitive ability of patients to different degrees and dysfunction of behavioral activities. The current anti-AD drugs in the clinical application basis and clinical research are mainly used for improving the acetylcholine level in cranial nerves, recovering acetylcholine nerve conduction, improving the memory, cognition and behavior ability of patients and delaying the development of diseases. Among the most studied and widely used in the clinical setting are acetylcholinesterase inhibitors.

FIG. 1. (S) -Rivastigmine

Rivastigmine tartrate (trade name: Astronic) is a carbamate acetylcholinesterase inhibitor developed by Novartis, Switzerland, which selectively acts on the brain and is used for treating mild to moderate AD. Pharmacological studies show that the S-configuration of rivastigmine is slightly better than that of the racemate, and the enantiomer is inactive. There are three methods for obtaining a single chiral species: chiral source synthesis, asymmetric synthesis and racemate resolution. The chiral source and the asymmetric synthesis method have the advantages of high cost, complex process and low pure product yield, and are not beneficial to large-scale production. Based on the consideration of cost, from the starting of industrial feasibility, two methods are mainly adopted for synthesizing S-rivastigmine at present, wherein the first method is to synthesize racemate rivastigmine and then carry out chemical resolution, then form diastereomer salt with chiral acid, and separate the diastereomer salt by fractional crystallization to obtain S-isomer (figure 1), but the method can cause serious material waste, has low yield and high cost, and is not beneficial to industrial production; the second method is to split the rivastigmine intermediate and then synthesize the S-rivastigmine.

Document CN104151176A reports that 3-hydroxyacetophenone is used as a raw material, imine is generated by reaction, then 3- (1- (methylamino) ethyl) phenol is obtained by reduction, then tetrahydrofuran and toluene are used for recrystallization to obtain S-3- (1- (methylamino) ethyl) phenol, and (S) -rivastigmine is prepared after methylation.

The patent CN101580482A adopts repeated recrystallization of intermediate 3- [1- (dimethylamino) ethyl ] phenol with a mixed solution of ethanol and ethyl acetate, and the S-3- [1- (dimethylamino) ethyl ] phenol is obtained by resolution, and then (S) -rivastigmine is further prepared, the yield of the method is only 27 percent, and the content of related substances is high, which results in low purity of the product.

Aiming at the problems of low yield, high impurity and the like in the synthesis of the intermediate, the application provides the method for preparing the rivastigmine intermediate, which has high yield, less impurities and high purity and is beneficial to industrial production.

Disclosure of Invention

A method for purifying a rivastigmine intermediate comprises the following steps:

(1) dissolving racemate 3- [1- (dimethylamino) ethyl ] phenol in tetrahydrofuran, and resolving the intermediate by using a resolving agent to obtain an intermediate 2S-3- [1- (dimethylamino) ethyl ] phenol camphorsulfonate;

(2) recrystallizing the intermediate 2S-3- [1- (dimethylamino) ethyl ] phenol camphorsulfonate obtained in the step (1) by using an ethanol and ethyl acetate system to obtain a recrystallized product of S-3- [1- (dimethylamino) ethyl ] phenol camphorsulfonate;

(3) and (3) dissociating the product in the step (2) by using an alkaline solvent to obtain S-3- [1- (dimethylamino) ethyl ] phenol, and recrystallizing the S-3- [1- (dimethylamino) ethyl ] phenol by using toluene to obtain a high-purity intermediate S-3- [1- (dimethylamino) ethyl ] phenol.

The purity of related substances of the S-3- [1- (dimethylamino) ethyl ] phenol obtained by the method is more than or equal to 99.9 percent, and the purity of related substances is less than 0.1 percent.

The isomer purity of the S-3- [1- (dimethylamino) ethyl ] phenol obtained by the method is more than or equal to 99.0 percent, the further isomer purity is more than or equal to 99.5 percent, and the further isomer purity is more than or equal to 99.6 percent

Wherein the recrystallization method in the step (2) of the application can be repeatedly used for the intermediate S-3- [1- (dimethylamino) ethyl ] phenol.

Wherein the resolving agent in step (1) described herein may be selected from d-tartaric acid, d-mandelic acid or d-camphorsulfonic acid, with d-camphorsulfonic acid being preferred in certain embodiments.

Wherein the mass volume ratio of the 3- [1- (dimethylamino) ethyl ] phenol to the tetrahydrofuran in the step (1) is 1:5-10, and 1:10 is preferred.

Heating and refluxing the intermediate-2 by using ethanol in the step (2) until the intermediate-2 is dissolved, adding ethyl acetate, stopping heating after titration, cooling to room temperature, stirring, performing suction filtration to obtain a filter cake, and drying to obtain a recrystallization product of the intermediate-2.

Wherein the mass volume ratio of the intermediate-2 to the ethanol in the step (2) is 1:4-9, preferably 1: 4.

Wherein the mass volume ratio of the intermediate-2 to the ethyl acetate in the step (2) is 1:6-11, preferably 1: 8.

In the step (3), firstly, the intermediate-2 is dissociated by using an alkaline aqueous solvent, the organic solvent is extracted, the organic solvent is combined and dried, the intermediate-3 obtained after the filtrate is dried in a spinning mode is added into a toluene solution for recrystallization, and a recrystallization product of the intermediate-3 is obtained.

Wherein the alkaline solution in the step (3) is selected from sodium carbonate solution, sodium bicarbonate solution, sodium hydroxide solution, potassium carbonate solution or sodium bicarbonate solution, etc.

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

Wherein the organic solvent in step (3) can be selected from dichloromethane or ethyl acetate.

The preparation method of the racemate 3- [1- (dimethylamino) ethyl ] phenol in the step (1) is that 3-hydroxyacetophenone and dimethylamine are directly subjected to reductive amination to prepare the racemate. Dimethylamine is present in forms including, but not limited to, dimethylamine methanol solution, dimethylamine ethanol solution, dimethylamine hydrochloride, and dimethylamine water solution. The reducing agent comprises one of sodium borohydride, potassium borohydride, sodium cyanoborohydride and sodium triacetoxyborohydride or a mixture thereof. The reaction temperature is 25-80 ℃, and the reaction time is 3-15 h.

Drawings

FIG. 1 HPLC chromatogram of intermediate-2 prepared in example 2;

FIG. 2 HPLC chromatogram after the first crystallization of intermediate-2 in example 2;

FIG. 3 HPLC chromatogram of intermediate-3 of example 2.

Detailed description of the preferred embodiments

EXAMPLE 1 racemate 3- [1- (dimethylamino) ethyl ] phenol

Adding 3-hydroxyacetophenone and dimethylamine ethanol solution into a three-necked bottle, stirring at room temperature until the solution is completely dissolved, adding sodium cyanoborohydride in batches, and heating and refluxing for reaction for 8 hours; the system was spin-dried, water and mixed solution (DCM: IPA =5: 1) were added, liquid separation was performed, the aqueous phase was further extracted with DCM: IPA =5:1 mixed solution, and then washed once with saturated aqueous sodium chloride solution, the organic phase was dried over anhydrous sodium sulfate, suction filtration was performed, the filtrate was spin-dried to obtain off-white oil, yield: 83.5 percent.

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

At room temperature, dissolving 130.00 g of intermediate with 300ml of THF, adding 46.39g of D- (+) -camphorsulfonic acid at one time, heating, dissolving at about 60 ℃ to clear, continuously stirring for 5min after complete dissolution, closing heating, naturally cooling to room temperature, stirring for 6h at room temperature, and filtering. The filter cake was air-dried at 50 ℃. Drying to obtain an intermediate-2, 31.4 g; yield: 43 percent; purity of HPLC-related substances: 99.15 percent; isomer purity: 88.8 percent.

First crystallization:

heating 30.00g of intermediate-2 by 120ml of absolute ethyl alcohol, refluxing until the solid is completely dissolved, adding 240ml of ethyl acetate at one time, dripping to separate out the solid, closing heating, naturally cooling to room temperature, stirring for 1h, carrying out suction filtration, and carrying out forced air drying on a filter cake at 50 ℃ to obtain 227.18 g of intermediate; purity of HPLC-related substances: 99.19%, isomer purity: 97.09 percent.

And (3) second crystallization:

preparing 15% sodium carbonate aqueous solution 452.7ml, adding the sodium carbonate aqueous solution into a reaction bottle containing 30.18g of intermediate-2, stirring for 1h at room temperature, extracting for 3 times by using 300ml of dichloromethane, combining organic phases, drying for 1h by using 30g of anhydrous sodium sulfate, carrying out suction filtration, spin-drying filtrate to obtain 12.47g of an intermediate-3 crude product, adding 100ml of toluene, heating for refluxing, dissolving the system clearly, closing to heat after dissolving clearly, stirring for crystallization for 3h at room temperature, carrying out suction filtration, drying a filter cake for 8h in a vacuum drying oven at 45 ℃, and drying to obtain intermediate-310.27 g; purity of HPLC-related substances: 100.00%, isomer purity: 99.69 percent.

The total resolution yield is: 35.2 percent.

Example 3S-3- [1- (dimethylamino) ethyl ] phenol

Dissolving 16.00 g of intermediate in 48ml of THF at room temperature, adding 9.28g of D- (+) -camphorsulfonic acid at one time, heating for dissolving, dissolving the system at 63 ℃, stirring for 5min after dissolving, turning off heating, stirring for 5h at room temperature, and filtering. The filter cake was air-dried at 50 ℃. Drying to obtain an intermediate 2, 6.59 g; yield: and 43 percent.

First crystallization:

heating and refluxing 5.00g of intermediate-2 by 40ml of absolute ethyl alcohol until the solid is completely dissolved, adding 50ml of ethyl acetate at one time, dripping to separate out the solid, closing and heating, naturally cooling to room temperature, stirring for 1h, carrying out suction filtration, and carrying out forced air drying on a filter cake at 50 ℃ to obtain-24.48 g of intermediate.

And (3) second crystallization:

preparing 15% sodium carbonate aqueous solution 54ml, adding the sodium carbonate aqueous solution into a reaction bottle containing 3.00g of intermediate-2, stirring for 1h at room temperature, extracting for 3 times by using 24ml of dichloromethane, combining organic phases, drying for 1h by using 8.00g of anhydrous sodium sulfate, performing suction filtration, spin-drying filtrate to obtain 1.25g of an intermediate-3 crude product, heating, refluxing and recrystallizing by using 12.5ml of toluene, stirring for crystallization for 3h at room temperature after clearing, performing suction filtration, drying a filter cake for 8h in a vacuum drying oven at 45 ℃, and drying to obtain 30.96 g of an intermediate; the isomer purity was: 99.78 percent.

Example 4S-3- [1- (dimethylamino) ethyl ] phenol

At room temperature, dissolving 110.00 g of the intermediate with 70ml of THF, adding 15.45g of D- (+) -camphorsulfonic acid at one time, heating, dissolving at about 60 ℃ for cleaning, continuously stirring for 5min after complete dissolution, turning off heating, naturally cooling to room temperature, stirring for 6h at room temperature, and filtering. The filter cake was air-dried at 50 ℃. Drying to obtain an intermediate 2, 11.45 g; yield: 45 percent.

First crystallization:

heating and refluxing 10.00g of intermediate-2 by 90ml of absolute ethyl alcohol until the solid is completely dissolved, adding 110ml of ethyl acetate at one time, dripping to separate out the solid, closing and heating, naturally cooling to room temperature, stirring for 1h, carrying out suction filtration, and carrying out forced air drying on a filter cake at 50 ℃ to obtain 29.40 g of intermediate.

And (3) second crystallization:

preparing 15% sodium carbonate aqueous solution 120ml, adding the sodium carbonate aqueous solution into a reaction bottle containing 8.00g of intermediate-2, stirring for 1h at room temperature, extracting for 3 times by using 80ml of dichloromethane, combining organic phases, drying for 1h by using 40g of anhydrous sodium sulfate, carrying out suction filtration, carrying out spin drying on filtrate to obtain 3.32g of an intermediate-3 crude product, adding 30ml of toluene, carrying out heating reflux, dissolving the system clearly, closing heating after the solution clearly is dissolved, stirring for crystallization for 3h at room temperature, carrying out suction filtration, drying a filter cake for 8h in a vacuum drying oven at 45 ℃, and drying to obtain 32.49 g of an intermediate; the isomer purity was: 99.71 percent.

Comparative example 1

Adding 50g of 3- [1- (dimethylamino) ethyl ] phenol (0.303 mol) into 300ml of ethyl acetate, heating and refluxing to completely dissolve, adding 42.2g (0.182 mol) of S- (+) camphorsulfonic acid into 62.5ml of absolute ethyl alcohol to dissolve, then dripping into the solution at 70 ℃, stirring for 10min, stopping stirring after the reaction is finished, cooling to room temperature, carrying out damp-proof standing at-10 to-15 ℃ for more than 24h, separating out crystals, carrying out suction filtration and drying to obtain 47.5g of white crystals, wherein m.p = 173-: 88.36 percent; isomer purity: 74.80 percent; the yield thereof was found to be 35.2%.

Adding the crystals into 87.5ml of ethanol, heating to reflux to completely dissolve, slowly adding 175ml of ethyl acetate into the solution, cooling to-5 to-10 ℃ after the completion of the reaction, carrying out damp-proof standing for 24 hours at the temperature, carrying out suction filtration on the obtained crystals, and drying to obtain 39.8g of crystals, wherein m.p =176-178 ℃; purity of related substances: 91.15 percent; isomer purity: 89.62 percent.

The resulting crystals were recrystallized once more from 75ml ethanol and 150ml ethyl acetate as described above to give 37.3g of white crystals, m.p =178-180 ℃; purity of related substances: 96.42 percent; isomer purity: 93.68 percent.