CN114804989A - Purification method and racemization recycling of rivastigmine key chiral intermediate - Google Patents

Abstract

The invention belongs to the field of pharmaceutical synthesis, and discloses a purification method and racemization recovery and utilization of a key chiral intermediate of rivastigmine, wherein the purification of the rivastigmine intermediate comprises the following steps: (1) using racemate 1 -(3-methoxyphenyl) ethylamine is a raw material, it is dissolved in acetonitrile, using benzoyl-L-phenylalanine as or benzoyl-L-phenylglycine as a resolving reagent, heating Carry out the splitting reaction under stirring conditions, then filter to obtain Intermediate 1; (2) use the alkaline solution to dissociate Intermediate 1 to obtain (S)-1-(3-methoxyphenyl) Ethylamine. The present invention is aimed at racemate 1-(3-methoxyphenyl)ethylamine, and can be effectively purified by using a specific resolution reagent; and, the present invention can also effectively utilize the above-mentioned purification process through a specific recovery step to obtain By product, finally obtains racemate 1-(3-methoxyphenyl) ethylamine, realizes recovery.

Description

Purification method and racemization recovery of key chiral intermediates of rivastigmine

technical field

The invention belongs to the field of drug synthesis, and more particularly relates to a purification method and racemization recovery of a key chiral intermediate of rivastigmine, which can realize the chiral separation and racemization of the rivastigmine intermediate. Recycle.

Background technique

Alzheimer's disease (AD), also known as Alzheimer's disease, is a progressive neurodegenerative disorder with the main clinical manifestations of memory impairment, aphasia, agnosia, and executive dysfunction. Studies have demonstrated a marked loss of cholinergic neurons in the basal forebrain of AD patients, especially in the neocortex, hippocampus, and amygdala. And the degree of cholinergic damage is positively correlated with the severity of AD. Therefore, the current treatment drugs for AD also target the acetylcholine system to improve the symptoms of patients.

Rivastigmine, the structural formula is as follows:

Its chemical name is (S)-N-methyl-N-ethyl-3-[1-(dimethylamino)ethyl]-carbamic acid phenyl ester, which is a derivative of physostigmine. It not only has good selectivity and effect on brain acetylcholinesterase, but also has few side effects. As a representative of a new generation of acetylcholinesterase inhibitors, it is a pseudo irreversible acetylcholinesterase inhibitor. Mainly used for the symptomatic treatment of mild to moderate Alzheimer's disease, it can significantly delay the progress of dementia, improve the clinical symptoms, cognitive function and mental symptoms of patients, and has good compliance. At present, there are three methods for synthesizing rivastigmine: asymmetric synthesis method, chiral acid resolution method and biological enzyme resolution method. The asymmetric synthesis method and the biological enzyme splitting method have high cost, complicated conditions and are not suitable for large-scale production. From the point of view of cost and feasibility, the use of chiral acid separation is not only easy to obtain raw materials, mild conditions, but also easy to scale up. However, there are also two problems with this method. One is that the splitting yield has not reached the maximum value, and whether a more efficient splitting reagent can be found. The second is whether the R configuration enantiomer can be recycled as a by-product to avoid waste of raw materials and reduce industrial costs.

Chinese patent document CN101580482A adopts recrystallization and separation from the intermediate 3-[1-(dimethylamino)ethyl]phenol with a mixed solution of ethanol and ethyl acetate to obtain (S)-3-[1-(dimethylamino) After ethyl]phenol, the yield was 27%.

Chinese patent document CN113461554A adopts D-(+)-camphorsulfonic acid to carry out multiple recrystallization and resolution of intermediate 3-[1-(dimethylamino)ethyl]phenol, and the yield is 35.2%.

SUMMARY OF THE INVENTION

In view of the above defects or improvement requirements of the prior art, the object of the present invention is to provide a purification method and racemization recycling of a key chiral intermediate of rivastigmine, for the racemate 1-(3-methoxyl group) Phenyl)ethylamine, the rivastigmine intermediate, can be effectively purified by using benzoyl-L-phenylalanine and benzoyl-L-phenylglycine as a resolving reagent; Through the recovery step designed by the specific process flow, the by-product (that is, (R)-1-(3-methoxyphenyl)ethanamine benzoyl-L-phenylalanine salt) obtained by the above purification process can be effectively utilized , (R)-1-(3-methoxyphenyl)ethylamine benzoyl-L-phenylglycinate), and finally obtain the racemate 1-(3-methoxyphenyl)ethylamine to achieve elimination Recovery of 1-(3-methoxyphenyl)ethanamine of the cyclohexene. Compared with the preparation methods of other rivastigmine intermediates, the rivastigmine intermediate ((S)-1-(3-methoxyphenyl)ethylamine) prepared by the present invention has high yield, good effect, and avoids the The waste of (R)-1-(3-methoxyphenyl)ethanamine produced during synthesis is beneficial to large-scale industrial production, and can effectively solve the problems of low yield, high cost, and high resolution of existing synthetic methods. The product is not recovered and so on.

In order to achieve the above object, according to one aspect of the present invention, a purification method of a rivastigmine intermediate is provided, and the rivastigmine intermediate is specifically racemic 1-(3-methoxyphenyl)ethylamine, It is characterized in that, the purification method comprises the following steps:

(1) Using racemate 1-(3-methoxyphenyl)ethanamine as raw material, dissolving racemate 1-(3-methoxyphenyl)ethanamine in acetonitrile, using benzoyl- L-phenylalanine or benzoyl-L-phenylglycine as the resolution reagent, carry out the separation reaction under the condition of heating and stirring, cool after the reaction, and then filter; the product corresponding to the filter residue is intermediate 1, then :

When the resolving reagent is benzoyl-L-phenylalanine, the filter residue obtained by filtration is (S)-1-(3-methoxyphenyl)ethanamine benzoyl-L-phenylalanine salt, corresponding to intermediate 1;

When the resolving reagent is benzoyl-L-phenylglycine, the filter residue obtained by filtration is (S)-1-(3-methoxyphenyl)ethylaminobenzoyl-L-phenylglycine salt, corresponding to the middle body 1;

(2) The intermediate 1 is dissociated using an alkaline solution to obtain (S)-1-(3-methoxyphenyl)ethanamine.

As a further preference of the present invention, in the step (1), the ratio of the mass of the racemate 1-(3-methoxyphenyl)ethylamine to the volume of the acetonitrile is 1:5 to 1: 20g/mL;

The heating and stirring are carried out at a heating temperature of 50°C to 90°C, more preferably at a heating temperature of 80°C;

In described step (2), described alkaline solution is selected from sodium hydroxide solution, potassium hydroxide solution, sodium carbonate solution;

Preferably, the step (2) is specifically as follows: first, the intermediate 1 is dissociated with an alkaline aqueous solution, extracted with dichloromethane, combined with organic solvents, dried, filtered and spin-dried to obtain (S)-1-( 3-methoxyphenyl)ethanamine.

According to another aspect of the present invention, the present invention provides a method for recovering a rivastigmine intermediate, and the rivastigmine intermediate is specifically racemic 1-(3-methoxyphenyl)ethanamine, characterized by Yes, including the following steps:

(S1) with (R)-1-(3-methoxyphenyl)ethanamine as raw material to be recovered, mark this (R)-1-(3-methoxyphenyl)ethanamine as intermediate 3; The intermediate 3 is dissolved in the first solvent, and m-methoxyacetophenone and tetraisopropyl titanate are added, and the reaction is carried out by heating under reflux; after the reaction, the first solvent is removed by cooling and evaporation to obtain a reaction concentrate ;

(S2) the reaction concentrate obtained in the step (S1) is dissolved in the second solvent, and potassium tert-butoxide and dimethyl sulfoxide are added, and the reaction is carried out under reflux; after the reaction, cooling is obtained by post-processing m-methoxyacetophenone and racemic 1-(3-methoxyphenyl)ethylamine can realize the recovery of racemic 1-(3-methoxyphenyl)ethylamine.

According to another aspect of the present invention, the present invention provides a purification and recovery method of a rivastigmine intermediate, the rivastigmine intermediate is specifically racemic 1-(3-methoxyphenyl)ethylamine, It is characterized in that, the purification and recovery method comprises the following steps:

(1) Using racemate 1-(3-methoxyphenyl)ethanamine as raw material, dissolving racemate 1-(3-methoxyphenyl)ethanamine in acetonitrile, using benzoyl- L-phenylalanine as or benzoyl-L-phenylglycine as the resolution reagent, carry out the separation reaction under the condition of heating and stirring, cool after the reaction, and then filter; record the corresponding product of the filter residue as intermediate 1, and the filtrate The corresponding product is intermediate 2, then:

When the resolving reagent is benzoyl-L-phenylalanine, the filter residue obtained by filtration is (S)-1-(3-methoxyphenyl)ethanamine benzoyl-L-phenylalanine salt, corresponding to Intermediate 1; (R)-1-(3-methoxyphenyl)ethylaminobenzoyl-L-phenylalanine salt can be obtained by evaporation of the filtrate, corresponding to Intermediate 2;

When the resolving reagent is benzoyl-L-phenylglycine, the filter residue obtained by filtration is (S)-1-(3-methoxyphenyl)ethylaminobenzoyl-L-phenylglycine salt, corresponding to the middle Body 1; (R)-1-(3-methoxyphenyl)ethylaminobenzoyl-L-phenylglycinate can be obtained by evaporating the filtrate, corresponding to intermediate 2;

(2) dissociating the intermediate 1 with an alkaline solution to obtain (S)-1-(3-methoxyphenyl)ethylamine;

(3) The intermediate 2 is dissociated using an alkaline solution to obtain (R)-1-(3-methoxyphenyl)ethanamine, referred to as (R)-1-(3-methoxyphenyl)ethylamine phenyl) ethylamine is intermediate 3; then, the intermediate 3 is dissolved in the first solvent, and m-methoxyacetophenone and tetraisopropyl titanate are added, and the reaction is carried out under reflux; after the reaction is completed , cooling, evaporating and removing the first solvent to obtain the reaction concentrate;

(4) the reaction concentrate obtained in the step (3) is dissolved in the second solvent, potassium tert-butoxide and dimethyl sulfoxide are added, and the reaction is carried out by heating under reflux; after the reaction is completed, cooling is obtained by post-processing m-methoxyacetophenone and racemic 1-(3-methoxyphenyl)ethylamine can realize the recovery of racemic 1-(3-methoxyphenyl)ethylamine.

As a further preference of the present invention, in the step (1), the evaporation of the filtrate is specifically rotary evaporation of the filtrate;

In the step (3), the evaporation is specifically rotary evaporation.

As a further preference of the present invention, in the step (2) and the step (3), the alkaline solution is independently selected from: sodium hydroxide solution, potassium hydroxide solution, and sodium carbonate solution.

As a further preference of the present invention, in the step (S1) and the step (3), the first solvent is selected from: toluene, chlorobenzene, and p-xylene;

The ratio of the mass of the intermediate 3 to the volume of the first solvent is 1:1 to 1:20 g/mL;

The mass ratio of described intermediate 3 and described m-methoxyacetophenone is 1:0.2 to 1:2;

The mass ratio of the intermediate 3 to the tetraisopropyl titanate is 1:0.6 to 1:6;

The reaction temperature used in the heating and refluxing is 90° C. to 140° C., and the reaction time is 1 h to 48 h.

As a further preference of the present invention, in the step (S2) and the step (4), the second solvent is selected from: tert-butanol, tert-amyl alcohol, and ethylene glycol;

The reaction temperature used in the heating and refluxing is 80°C to 180°C, and the reaction time is 1h to 24h;

The ratio of the mass of the intermediate 3 that the reaction concentrate adopts to the volume of the second solvent is 1:1 to 1:20 g/mL;

The mass ratio of the intermediate 3 and the potassium tert-butoxide that the reaction concentrate adopts is 1:0.45 to 1:4.5;

The mass ratio of the intermediate 3 to the dimethyl sulfoxide used in the reaction concentrate is 1:0.25 to 1:3.

As a further preference of the present invention, the step (2) is specifically: firstly dissociate the intermediate 1 with an alkaline aqueous solution, extract with dichloromethane, combine organic solvents, filter and spin dry after drying to obtain (S) -1-(3-Methoxyphenyl)ethanamine.

As a further preference of the present invention, in the step (3), the intermediate 2 is dissociated using an alkaline aqueous solution to obtain (R)-1-(3-methoxyphenyl)ethanamine, specifically : First, the intermediate 2 is dissociated with an alkaline aqueous solution, extracted with dichloromethane, combined with organic solvents, dried, filtered and spin-dried to obtain (R)-1-(3-methoxyphenyl)ethanamine.

Through the above technical scheme conceived by the present invention, compared with the prior art, for the key intermediate of rivastigmine, the racemate 1-(3-methoxyphenyl)ethylamine (its structure is shown in formula I) , the present invention uses the racemate 1-(3-methoxyphenyl)ethylamine as a raw material, improves the process of purification and racemization and recycling, and uses natural amino acid derivatives to treat rivastigmine intermediates. 1-(3-methoxyphenyl)ethanamine was subjected to chiral resolution, and the obtained S configuration was further prepared to obtain rivastigmine. Further, the (R)-1-(3-methoxyphenyl)ethanamine remaining after the resolution can also be subjected to racemization treatment, and recycled through secondary resolution.

Specifically, in the present invention, benzoyl-L-phenylalanine is used as the resolution reagent, and benzoyl-L-phenylglycine is used as the resolution reagent, so that the yield of the purification method of the present invention is as high as 39%. Better results. In the research and development process of the present invention, natural chiral amino acids are used as substrates, and the spatial structure is adjusted by modifying them, and the resolution of 1-(3-methoxyphenyl)ethanamine, the key intermediate of rivastigmine, is explored. Influence, and compared the results of splitting reactions in common solvents such as acetonitrile, ethanol, methanol, etc., and finally screened out benzoyl-L-phenylalanine and benzoyl-L-phenylglycine. Reagents were separated, and the overall yield was better when acetonitrile was used as the solvent.

The present invention also can effectively utilize the by-product (ie, (R)-1-(3-methoxyphenyl)ethylaminobenzoyl-L-phenylpropane) obtained by the above-mentioned purification process through the recovery step designed by the specific process flow. acid salt, (R)-1-(3-methoxyphenyl)ethanamine benzoyl-L-phenylglycinate), and finally obtain the racemate 1-(3-methoxyphenyl)ethanamine , to achieve the recovery of the racemate 1-(3-methoxyphenyl)ethylamine. Compared with other methods, the method utilizes transamination reaction to realize the racemization process, and utilizes m-methoxyacetophenone that will be used in the synthesis of rivastigmine as an aid, and no obvious by-products are generated in the whole process. The present invention is assisted by the rivastigmine intermediate m-methoxyacetophenone, and effectively realizes the racemization reaction of the rivastigmine key intermediate (R)-1-(3-methoxyphenyl)ethanamine, Thus, the racemization recovery of the split by-product is realized (the m-methoxyacetophenone obtained in the recovery process can also be reused).

The purity of 1-(3-methoxyphenyl)ethylamine obtained by the recovery process of the invention is greater than or equal to 99.9%, and the relevant impurities are less than 0.1%.

To sum up, the present invention provides a method for preparing and recovering a key intermediate of rivastigmine with high yield and few by-products, which is beneficial to industrial production, and can effectively solve the problems of low yield, high cost, and disassembly of existing synthetic methods. The by-products are not recovered and so on.

Description of drawings

Fig. 1 is the HPLC spectrum of (S)-(1-(3-methoxyphenyl)ethyl)carbamic acid tert-butyl ester produced by the reaction of intermediate-1 and di-tert-butyl dicarbonate in Example 1 .

Fig. 2 is the tertiary (1-(3-methoxyphenyl)ethyl)carbamic acid generated by the reaction of 1-(3-methoxyphenyl)ethylamine and di-tert-butyl dicarbonate recovered in Example 3 HPLC spectrum of butyl ester.

Fig. 3 is the tertiary (1-(3-methoxyphenyl)ethyl)carbamic acid generated by the reaction of 1-(3-methoxyphenyl)ethylamine and di-tert-butyl dicarbonate recovered in Example 4 HPLC spectrum of butyl ester.

Fig. 4 is the tertiary (1-(3-methoxyphenyl)ethyl)carbamic acid generated by the reaction of 1-(3-methoxyphenyl)ethylamine and di-tert-butyl dicarbonate recovered in Example 5 HPLC spectrum of butyl ester.

Fig. 5 is the tertiary (1-(3-methoxyphenyl)ethyl)carbamic acid generated by the reaction of 1-(3-methoxyphenyl)ethylamine and di-tert-butyl dicarbonate recovered in Example 6 HPLC spectrum of butyl ester.

Fig. 6 is the reaction scheme of rivastigmine key intermediate 1-(3-methoxyphenyl) ethylamine resolution and recovery; Wherein, (a) in Fig. 6 corresponds to racemic 1-(3-methoxyphenyl) (b) in Figure 6 corresponds to the racemization recovery of the by-product (R)-1-(3-methoxyphenyl)ethanamine.

Detailed ways

In order to make the objectives, technical solutions and advantages of the present invention clearer, the present invention will be further described in detail below with reference to the accompanying drawings and embodiments. It should be understood that the specific embodiments described herein are only used to explain the present invention, but not to limit the present invention. In addition, the technical features involved in the various embodiments of the present invention described below can be combined with each other as long as they do not conflict with each other.

Example 1(S)-1-(3-methoxyphenyl)ethanamine

The synthetic route is as follows:

The concrete steps adopted in this embodiment are as follows:

To a 500 mL round bottom flask at room temperature were added acetonitrile (200 mL), 1-(3-methoxyphenyl)ethanamine (15.1 g, 100 mmol) and benzoyl-L-phenylalanine (26.9 g) sequentially , 100 mmol), stirred at 80 ° C until clear and then stirred for 1 h. Turn off heating and stop stirring, naturally cool to room temperature, and stand for several hours until white insoluble matter no longer precipitates. The reaction solution was suction filtered with a porous funnel, the solid was washed with acetonitrile (50 mL), and the filter cake was air-dried at 50°C to obtain the benzoyl-L-benzene of (S)-1-(3-methoxyphenyl)ethanamine. Alanine salt (Intermediate 1, 16.4 g, 39 mmol).

The filtrate was rotary evaporated to obtain the benzoyl-L-phenylalanine salt of (R)-1-(3-methoxyphenyl)ethylamine (Intermediate 2, 25.6 g, 61 mmol), which could be further Throwing into the recovery step (see below for details, especially Examples 3-7).

Intermediate 1 was then dissolved in sodium hydroxide solution (2M, 150 mL) and extracted three times with ethyl acetate (3 x 100 mL). The organic phases were combined, dried with 30 g of anhydrous sodium sulfate for 1 h, filtered, and the solvent was removed by rotary evaporation to obtain (S)-1-(3-methoxyphenyl)ethanamine (5.9 g, 39 mmol).

The overall yield of the split was 39%.

The NMR detection result of the product (S)-1-(3-methoxyphenyl)ethanamine is:

¹ H NMR (400MHz, CDCl ₃ )δ7.25-7.20(m,1H),6.95-6.89(m,2H),6.80-6.75(m,1H),4.09(q,J=6.6Hz,1H), 3.80(s, 3H), 1.39(d, J=6.6Hz, 3H).

(S)-(S)-(1-(3-methoxyphenyl)ethyl)carbamic acid tert-butyl ester derived from (S)-1-(3-methoxyphenyl)ethanamine, the ee value of which is obtained by highly efficient Detected by liquid chromatography, test conditions: AS-H chiral column, mobile phase is n-hexane:isopropanol (99.2:0.8), flow rate 0.8mL/min, column temperature 25°C. The HPLC spectrum is shown in Figure 1, in which the R-type peak is about 19 minutes, and the S-type peak is about 21 minutes. The peak area indicated that the ee value of the product was greater than 99.

Comparative Example 1-1: In this comparative example, except that ethanol was used to replace acetonitrile, other reaction participants, reaction conditions, parameters, etc. were the same as those in Example 1, and (S)-1-(3-methoxyphenyl)ethyl acetate was obtained. The total yield corresponding to the resolution of the amine was 10%.

Comparative Example 1-2: Except that methanol was used to replace acetonitrile in this comparative example, other reaction participants, reaction conditions, parameters, etc. were the same as those in Example 1, and (S)-1-(3-methoxyphenyl)ethyl acetate was obtained. The total yield of the resolution corresponding to the amine was 5%.

Example 2(S)-1-(3-methoxyphenyl)ethanamine

The synthetic route is as follows:

The concrete steps adopted in this embodiment are as follows:

To a 500 mL round-bottomed flask at room temperature were added acetonitrile (200 mL), 1-(3-methoxyphenyl)ethanamine (15.1 g, 100 mmol) and benzoyl-L-phenylglycine (25.5 g, 100 mmol) sequentially ), stirred at 70°C until clear and then stirred for 1 h. Turn off heating and stop stirring, naturally cool to room temperature, and stand for several hours until white insoluble matter no longer precipitates. The reaction solution was suction filtered with a porous funnel, the solid was washed with acetonitrile (50 mL), and the filter cake was air-dried at 50°C to obtain the benzoyl-L-benzene of (S)-1-(3-methoxyphenyl)ethanamine. Glycinate (15.0 g, 37 mmol).

The filtrate was rotary evaporated to give the benzoyl-L-phenylglycinate of (R)-1-(3-methoxyphenyl)ethanamine (25.6 g, 63 mmol), the (R)-1-(3-methoxyphenyl)ethylamine The benzoyl-L-phenylglycinate of phenyl)ethylamine can likewise be further put into the recovery step.

The benzoyl-L-phenylglycinate salt of (S)-1-(3-methoxyphenyl)ethanamine was then dissolved in sodium hydroxide solution (2M, 150 mL) and extracted three times with ethyl acetate (3 ×100mL). The organic phases were combined, dried with 30 g of anhydrous sodium sulfate for 1 h, filtered, and the solvent was removed by rotary evaporation to obtain (S)-1-(3-methoxyphenyl)ethanamine (5.6 g, 37 mmol).

The overall yield of the split was 37%.

Comparative Example 2-1: Except for the use of isopropanol to replace acetonitrile in this comparative example, other reaction participants, reaction conditions, parameters, etc. are the same as those in Example 2, and (S)-1-(3-methoxyphenyl) is obtained. ) ethylamine corresponds to a total yield of 14%.

Comparative Example 2-2: In this comparative example, except that methanol was used to replace acetonitrile, other reaction participants, reaction conditions, parameters, etc. were the same as those in Example 2, and (S)-1-(3-methoxyphenyl)ethyl was obtained. The total yield of the resolution corresponding to the amine was 18%.

Taking the intermediate 2 obtained in Example 1 as an example, the recovery step can be as follows in general:

(S1) dissociating intermediate 2 using an alkaline solution to obtain (R)-1-(3-methoxyphenyl)ethanamine, referred to as (R)-1-(3-methoxyphenyl) ) ethylamine is the intermediate 3; then, the intermediate 3 is dissolved in the first solvent, and m-methoxyacetophenone and tetraisopropyl titanate are added, and the reaction is carried out under reflux; after the reaction, cooling, evaporation Remove the first solvent to obtain a reaction concentrate;

(S2) the reaction concentrate obtained in the step (S1) is dissolved in the second solvent, and potassium tert-butoxide and dimethyl sulfoxide are added, and the reaction is carried out under reflux; Oxyacetophenone and racemic 1-(3-methoxyphenyl)ethylamine can realize the recovery of racemic 1-(3-methoxyphenyl)ethylamine (recovered m-methoxyphenyl) acetophenone, which can also be reused).

Of course, for the R-type by-products obtained by other resolution methods, these R-type by-products can also be converted into (R)-1-(3-methoxyphenyl)ethanamine (that is, intermediate body 3), and then recycle according to the above steps, and the recovery of racemic 1-(3-methoxyphenyl)ethanamine can also be realized.

Wherein, the post-processing can be specifically: in the reaction liquid system where the heating and refluxing reaction finishes and is cooled, adding an acidic solution and stirring for 5 min, then evaporating to remove the low-boiling point solvent, and extracting with an organic solvent to obtain m-methoxyacetophenone, then adding an acidic solution to the cooling system. The aqueous phase is added with an alkaline solution to adjust the pH to alkaline, and is extracted with an organic solvent to obtain racemic 1-(3-methoxyphenyl)ethylamine, thereby realizing racemic 1-(3-methoxyphenyl) Recovery of ethylamine (wherein, the acidic solution can be selected from: sulfuric acid solution, hydrochloric acid solution; the alkaline solution can be selected from: sodium hydroxide solution, potassium hydroxide solution, sodium carbonate solution).

The following are specific examples:

Example 3 Racemization of (R)-1-(3-methoxyphenyl)ethylamine

The synthetic route is as follows:

The concrete steps adopted in this embodiment are as follows:

Intermediate 2 was dissolved in sodium hydroxide solution (2M, 200 mL) and extracted three times with ethyl acetate (3 x 100 mL). The organic phases were combined, dried with 50 g of anhydrous sodium sulfate for 1 h, filtered, and the solvent was removed by rotary evaporation to obtain (R)-1-(3-methoxyphenyl)ethanamine (Intermediate 3, 9.2 g, 61 mmol).

At room temperature, connect a 500mL two-necked flask to a water separator and a reflux condenser, use an oil pump to evacuate, and use a nitrogen balloon to replace the nitrogen atmosphere, and sequentially add p-xylene (120mL), intermediate 3 (9.2g, 61mmol), Methoxyacetophenone (13.5g, 90mmol), tetraisopropyl titanate (8.5g, 30mmol), magnetically stirred at 100°C for 30h, cooled to room temperature, removed toluene by rotary evaporation, transferred to a 200mL sealed tube, and then Add tert-butanol (90 mL), dimethyl sulfoxide (19.1 g, 240 mmol), potassium tert-butoxide (6.7 g, 60 mmol) in turn, stir at 140° C. for 8 h, and after cooling to room temperature, add sulfuric acid solution (1 M) to adjust the reaction solution The pH was about 2 and stirred for 5 min, the reaction solution was concentrated by rotary evaporation, and the insolubles were removed by suction filtration with a sand core funnel, washed three times with ethyl acetate (3×50 mL), and the aqueous phase was adjusted to pH with sodium hydroxide solution (2M). ≈10, extracted three times with ethyl acetate (3×25 mL), combined the organic phases, dried with 30 g of anhydrous sodium sulfate, and concentrated by rotary evaporation to obtain 1-(3-methoxyphenyl)ethylamine.

The overall yield of racemic recovery was 72%.

1-(3-Methoxyphenyl)ethylamine-derived (1-(3-methoxyphenyl)ethyl)carbamic acid tert-butyl ester, its ee value is detected by high performance liquid chromatography, the test Conditions: AS-H chiral column, mobile phase is n-hexane:isopropanol (99.2:0.8), flow rate 0.8mL/min, column temperature 25°C. The HPLC spectrum is shown in Figure 2, in which the R-type peak is about 19 minutes, and the S-type peak is about 21 minutes. The peak area indicated that the ee value of the product was less than 5.

Example 4 Racemization of (R)-1-(3-methoxyphenyl)ethylamine

The synthetic route is as follows:

The concrete steps adopted in this embodiment are as follows:

Intermediate 2 was dissolved in sodium hydroxide solution (2M, 200 mL) and extracted three times with ethyl acetate (3 x 100 mL). The organic phases were combined, dried with 50 g of anhydrous sodium sulfate for 1 h, filtered, and the solvent was removed by rotary evaporation to obtain (R)-1-(3-methoxyphenyl)ethanamine (Intermediate 3, 9.2 g, 61 mmol).

At room temperature, a 250mL two-necked flask was connected to a water separator and a reflux condenser, and then an oil pump was used to evacuate and a nitrogen ball was used to replace the nitrogen atmosphere, followed by adding toluene (40mL), intermediate 3 (9.2g, 61mmol), m-methoxy Ethyl acetophenone (4.5g, 30mmol), tetraisopropyl titanate (34.7g, 122mmol), magnetic stirring at 90°C for 48h, after cooling to room temperature, toluene was removed by rotary evaporation, and then added to a sealed tube, and sequentially Ethylene glycol (180 mL), dimethyl sulfoxide (23.4 g, 300 mmol), potassium tert-butoxide (33.7 g, 300 mmol) were added, and the mixture was refluxed at 180° C. for 6 h. After cooling to room temperature, sulfuric acid solution (1 M) was added to adjust the reaction solution. The pH was about 2 and stirred for 5 min, the reaction solution was concentrated by rotary evaporation, and the insolubles were removed by suction filtration with a sand core funnel, washed three times with ethyl acetate (3×50 mL), and the aqueous phase was adjusted to pH with sodium hydroxide solution (2M). ≈10, extracted three times with ethyl acetate (3×25 mL), combined the organic phases, dried with 30 g of anhydrous sodium sulfate, and concentrated by rotary evaporation to obtain 1-(3-methoxyphenyl)ethylamine.

The overall yield of racemic recovery was 77%.

The HPLC spectrum is shown in Figure 3, in which the R-type peak is about 19 minutes, and the S-type peak is about 22 minutes. The peak area indicated that the ee value of the product was less than 10.

Example 5 Racemization of (R)-1-(3-methoxyphenyl)ethanamine

The synthetic route is as follows:

The concrete steps adopted in this embodiment are as follows:

Intermediate 2 was dissolved in sodium hydroxide solution (2M, 200 mL) and extracted three times with ethyl acetate (3 x 100 mL). The organic phases were combined, dried with 50 g of anhydrous sodium sulfate for 1 h, filtered, and the solvent was removed by rotary evaporation to obtain (R)-1-(3-methoxyphenyl)ethanamine (Intermediate 3, 9.2 g, 61 mmol).

At room temperature, a 250mL two-necked flask was connected to a water separator and a reflux condenser, and then an oil pump was used to evacuate and a nitrogen ball was used to replace the nitrogen atmosphere, and chlorobenzene (70mL), intermediate 3 (9.2g, 61mmol), m-toluene were added in turn. Oxyacetophenone (15g, 100mmol), tetraisopropyl titanate (51.2g, 180mmol), magnetically stirred at 130°C for 30h, cooled to room temperature, removed toluene by rotary evaporation, and then added tert-amyl alcohol (150mL), Dimethyl sulfoxide (15.6g, 200mmol), potassium tert-butoxide (22.4g, 200mmol), stirred at 80°C for 24h, cooled to room temperature, added sulfuric acid solution (1M) to adjust the pH of the reaction solution to about 2 and stirred for 5min, The reaction solution was concentrated by rotary evaporation, and the insoluble matter was removed by suction filtration with a sand core funnel, then washed three times with ethyl acetate (3×50 mL), the aqueous phase was adjusted to pH≈10 with sodium hydroxide solution (2M), and extracted with ethyl acetate Three times (3×25 mL), the organic phases were combined, dried with 30 g of anhydrous sodium sulfate, and concentrated by rotary evaporation to obtain 1-(3-methoxyphenyl)ethylamine.

The overall yield of racemic recovery was 85%.

The HPLC spectrum is shown in Figure 4, in which the R-type peak is about 19 minutes, and the S-type peak is about 22 minutes. The peak area indicated that the ee value of the product was less than 8.

Example 6 Racemization of (R)-1-(3-methoxyphenyl)ethylamine

The synthetic route is as follows:

The concrete steps adopted in this embodiment are as follows:

Intermediate 2 was dissolved in sodium hydroxide solution (2M, 200 mL) and extracted three times with ethyl acetate (3 x 100 mL). The organic phases were combined, dried with 50 g of anhydrous sodium sulfate for 1 h, filtered, and the solvent was removed by rotary evaporation to obtain (R)-1-(3-methoxyphenyl)ethanamine (Intermediate 3, 9.2 g, 61 mmol).

At room temperature, a 250mL two-necked flask was connected to a water separator and a reflux condenser, and the oil pump was used to evacuate and a nitrogen balloon was used to replace the nitrogen atmosphere, and p-xylene (80mL), intermediate 3 (9.2g, 61mmol), Methoxyacetophenone (15g, 100mmol), tetraisopropyl titanate (45.5g, 160mmol), magnetically stirred at 140°C for 30h, cooled to room temperature, toluene was removed by rotary evaporation, added to a sealed tube, and then sequentially Add tert-amyl alcohol (150 mL), dimethyl sulfoxide (11.7 g, 150 mmol), potassium tert-butoxide (16.8 g, 150 mmol), reflux at 150 ° C and stir for 15 h, after cooling to room temperature, add sulfuric acid solution (1 M) to adjust the reaction solution The pH was about 2 and stirred for 5 min, the reaction solution was concentrated by rotary evaporation, and the insolubles were removed by suction filtration with a sand core funnel, washed three times with ethyl acetate (3×50 mL), and the aqueous phase was adjusted to pH with sodium hydroxide solution (2M). ≈10, extracted three times with ethyl acetate (3×25 mL), combined the organic phases, dried with 30 g of anhydrous sodium sulfate, and concentrated by rotary evaporation to obtain 1-(3-methoxyphenyl)ethylamine.

The overall yield of racemic recovery was 85%.

The HPLC spectrum is shown in Figure 5, in which the R-type peak is about 18 minutes, and the S-type peak is about 21 minutes. The peak area indicated that the ee value of the product was less than 20.

Example 7 Racemization of (R)-1-(3-methoxyphenyl)ethanamine

The synthetic route is as follows:

The concrete steps adopted in this embodiment are as follows:

Intermediate 2 was dissolved in sodium hydroxide solution (2M, 200 mL) and extracted three times with ethyl acetate (3 x 100 mL). The organic phases were combined, dried with 50 g of anhydrous sodium sulfate for 1 h, filtered, and the solvent was removed by rotary evaporation to obtain (R)-1-(3-methoxyphenyl)ethanamine (Intermediate 3, 9.2 g, 61 mmol).

At room temperature, a 250mL two-necked flask was connected to a water separator and a reflux condenser, and an oil pump was used to evacuate and a nitrogen balloon was used to replace the nitrogen atmosphere, followed by adding toluene (120mL), intermediate 3 (9.2g, 61mmol), m-methoxy Ethyl acetophenone (9.1 g, 61 mmol), tetraisopropyl titanate (17.3 g, 61 mmol), magnetically stirred at 120 °C for 17 h, cooled to room temperature, toluene was removed by rotary evaporation, and tert-amyl alcohol (120 mL), Dimethyl sulfoxide (9.5g, 122mmol), potassium tert-butoxide (13.7g, 122mmol), stirred at 100°C for 4h under reflux, cooled to room temperature, added sulfuric acid solution (1M) to adjust the pH of the reaction solution to about 2 and stirred for 5min, The reaction solution was concentrated by rotary evaporation, and the insoluble matter was removed by suction filtration with a sand core funnel, then washed three times with ethyl acetate (3×50 mL), the aqueous phase was adjusted to pH≈10 with sodium hydroxide solution (2M), and extracted with ethyl acetate Three times (3×25 mL), the organic phases were combined, dried with 30 g of anhydrous sodium sulfate, and concentrated by rotary evaporation to obtain 1-(3-methoxyphenyl)ethylamine.

The overall yield of racemic recovery was 80%.

Those skilled in the art can easily understand that the above descriptions are only preferred embodiments of the present invention, and are not intended to limit the present invention. Any modifications, equivalent replacements and improvements made within the spirit and principles of the present invention, etc., All should be included within the protection scope of the present invention.

Claims (10)

1. A purification method of a rivastigmine intermediate, which is specifically racemic 1- (3-methoxyphenyl) ethylamine, is characterized by comprising the following steps:

(1) using racemate 1- (3-methoxyphenyl) ethylamine as a raw material, dissolving the racemate 1- (3-methoxyphenyl) ethylamine in acetonitrile, using benzoyl-L-phenylalanine or benzoyl-L-phenylglycine as a resolution reagent, carrying out resolution reaction under the condition of heating and stirring, cooling after the reaction, and then filtering; and recording the product corresponding to the filter residue as an intermediate 1, and then:

when the resolving agent is benzoyl-L-phenylalanine, the filter residue obtained by filtering is (S) -1- (3-methoxyphenyl) ethylamine benzoyl-L-phenylalanine salt corresponding to the intermediate 1;

when the resolving agent is benzoyl-L-phenylglycine, the filter residue obtained by filtering is (S) -1- (3-methoxyphenyl) ethylamine benzoyl-L-phenylglycinate which corresponds to the intermediate 1;

(2) and dissociating the intermediate 1 by using an alkaline solution to obtain the (S) -1- (3-methoxyphenyl) ethylamine.

2. The purification method according to claim 1, wherein in the step (1), the ratio of the mass of the racemic 1- (3-methoxyphenyl) ethylamine to the volume of the acetonitrile is 1:5 to 1:20 g/mL;

the heating and stirring are carried out at a heating temperature of 50 ℃ to 90 ℃, more preferably at a heating temperature of 80 ℃;

in the step (2), the alkaline solution is selected from sodium hydroxide solution, potassium hydroxide solution and sodium carbonate solution;

preferably, the step (2) is specifically: firstly, dissociating the intermediate 1 by using an alkaline aqueous solution, extracting by using dichloromethane, combining organic solvents, drying, filtering and spin-drying to obtain the (S) -1- (3-methoxyphenyl) ethylamine.

3. A method for recovering a rivastigmine intermediate, which is racemic 1- (3-methoxyphenyl) ethylamine, is characterized by comprising the following steps:

(S1) taking (R) -1- (3-methoxyphenyl) ethylamine as a raw material to be recovered, and recording the (R) -1- (3-methoxyphenyl) ethylamine as an intermediate 3; dissolving the intermediate 3 in a first solvent, adding m-methoxyacetophenone and tetraisopropyl titanate, and heating and refluxing for reaction; after the reaction is finished, cooling and evaporating to remove the first solvent to obtain a reaction concentrated solution;

(S2) dissolving the reaction concentrate obtained in the step (S1) in a second solvent, and adding potassium tert-butoxide and dimethyl sulfoxide, and heating under reflux to effect a reaction; after the reaction is finished, cooling, and performing post-treatment to obtain m-methoxyacetophenone and racemic 1- (3-methoxyphenyl) ethylamine, so that the racemic 1- (3-methoxyphenyl) ethylamine can be recovered.

4. A method for purifying and recovering a rivastigmine intermediate, which is racemic 1- (3-methoxyphenyl) ethylamine, is characterized by comprising the following steps:

(1) using racemate 1- (3-methoxyphenyl) ethylamine as a raw material, dissolving the racemate 1- (3-methoxyphenyl) ethylamine in acetonitrile, using benzoyl-L-phenylalanine or benzoyl-L-phenylglycine as a resolution reagent, carrying out resolution reaction under the condition of heating and stirring, cooling after the reaction, and then filtering; and recording that the product corresponding to the filter residue is an intermediate 1 and the product corresponding to the filtrate is an intermediate 2, then:

when the resolving agent is benzoyl-L-phenylalanine, the filter residue obtained by filtering is (S) -1- (3-methoxyphenyl) ethylamine benzoyl-L-phenylalanine salt corresponding to the intermediate 1; evaporating the filtrate to obtain (R) -1- (3-methoxyphenyl) ethylamine benzoyl-L-phenylalanine salt corresponding to the intermediate 2;

when the resolving agent is benzoyl-L-phenylglycine, the filter residue obtained by filtering is (S) -1- (3-methoxyphenyl) ethylamine benzoyl-L-phenylglycinate which corresponds to the intermediate 1; evaporating the filtrate to obtain (R) -1- (3-methoxyphenyl) ethylamine benzoyl-L-phenylglycinate corresponding to the intermediate 2;

(2) dissociating the intermediate 1 by using an alkaline solution to obtain (S) -1- (3-methoxyphenyl) ethylamine;

(3) dissociating the intermediate 2 by using an alkaline solution to obtain (R) -1- (3-methoxyphenyl) ethylamine, and recording the (R) -1- (3-methoxyphenyl) ethylamine as an intermediate 3; then, dissolving the intermediate 3 in a first solvent, adding m-methoxyacetophenone and tetraisopropyl titanate, and heating and refluxing for reaction; after the reaction is finished, cooling and evaporating to remove the first solvent to obtain a reaction concentrated solution;

(4) dissolving the reaction concentrated solution obtained in the step (3) in a second solvent, adding potassium tert-butoxide and dimethyl sulfoxide, and heating and refluxing to react; after the reaction is finished, cooling, and performing post-treatment to obtain m-methoxyacetophenone and racemic 1- (3-methoxyphenyl) ethylamine, so that the racemic 1- (3-methoxyphenyl) ethylamine can be recovered.

5. The purification and recovery method according to claim 4, wherein in the step (1), the filtrate is evaporated, specifically, the filtrate is subjected to rotary evaporation;

in the step (3), the evaporation is specifically rotary evaporation.

6. The purification and recovery process according to claim 4, wherein in step (2) and step (3), the alkaline solution is independently selected from the group consisting of: sodium hydroxide solution, potassium hydroxide solution and sodium carbonate solution.

7. The method according to claim 3 or 4, wherein in the step (S1) and the step (3), the first solvent is selected from the group consisting of: toluene, chlorobenzene, p-xylene;

the ratio of the mass of the intermediate 3 to the volume of the first solvent is 1:1 to 1:20 g/mL;

the mass ratio of the intermediate 3 to the m-methoxyacetophenone is 1: 0.2-1: 2;

the mass ratio of the intermediate 3 to the tetraisopropyl titanate is 1:0.6 to 1: 6;

the reaction temperature adopted by the heating reflux is 90-140 ℃, and the reaction time is 1-48 h.

8. The method according to claim 3 or 4, wherein in the step (S2) and the step (4), the second solvent is selected from the group consisting of: t-butanol, t-amyl alcohol, ethylene glycol;

the reaction temperature adopted by the heating reflux is 80-180 ℃, and the reaction time is 1-24 h;

the ratio of the mass of the intermediate 3 to the volume of the second solvent, which is correspondingly adopted by the reaction concentrated solution, is 1:1 to 1:20 g/mL;

the mass ratio of the intermediate 3 to the potassium tert-butoxide correspondingly adopted by the reaction concentrated solution is 1: 0.45-1: 4.5;

the mass ratio of the intermediate 3 to the dimethyl sulfoxide correspondingly adopted by the reaction concentrated solution is 1: 0.25-1: 3.

9. The purification and recovery method according to claim 4, wherein the step (2) is specifically: firstly, dissociating the intermediate 1 by using an alkaline aqueous solution, extracting by using dichloromethane, combining organic solvents, drying, filtering and spin-drying to obtain the (S) -1- (3-methoxyphenyl) ethylamine.

10. The purification and recovery method according to claim 4, wherein in the step (3), the intermediate 2 is dissociated using a basic aqueous solution to obtain (R) -1- (3-methoxyphenyl) ethylamine, and the method comprises the following steps: firstly, dissociating the intermediate 2 by using alkaline aqueous solution, extracting by using dichloromethane, combining organic solvents, drying, filtering and spin-drying to obtain the (R) -1- (3-methoxyphenyl) ethylamine.

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