CN114804989A - Purification method and racemization recycling of rivastigmine key chiral intermediate - Google Patents
Purification method and racemization recycling of rivastigmine key chiral intermediate Download PDFInfo
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- 238000000034 method Methods 0.000 title claims abstract description 37
- XSVMFMHYUFZWBK-NSHDSACASA-N Rivastigmine Chemical compound CCN(C)C(=O)OC1=CC=CC([C@H](C)N(C)C)=C1 XSVMFMHYUFZWBK-NSHDSACASA-N 0.000 title claims abstract description 26
- 229960004136 rivastigmine Drugs 0.000 title claims abstract description 26
- 238000000746 purification Methods 0.000 title claims abstract description 19
- 230000006340 racemization Effects 0.000 title abstract description 17
- 238000004064 recycling Methods 0.000 title abstract description 7
- 238000006243 chemical reaction Methods 0.000 claims abstract description 76
- CJWGCBRQAHCVHW-UHFFFAOYSA-N 1-(3-methoxyphenyl)ethanamine Chemical compound COC1=CC=CC(C(C)N)=C1 CJWGCBRQAHCVHW-UHFFFAOYSA-N 0.000 claims abstract description 56
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- CJWGCBRQAHCVHW-ZETCQYMHSA-N (1s)-1-(3-methoxyphenyl)ethanamine Chemical compound COC1=CC=CC([C@H](C)N)=C1 CJWGCBRQAHCVHW-ZETCQYMHSA-N 0.000 claims abstract description 29
- 238000010438 heat treatment Methods 0.000 claims abstract description 28
- 238000011084 recovery Methods 0.000 claims abstract description 26
- 238000003756 stirring Methods 0.000 claims abstract description 21
- 238000001914 filtration Methods 0.000 claims abstract description 19
- NPKISZUVEBESJI-AWEZNQCLSA-N N-benzoyl-L-phenylalanine Chemical compound C([C@@H](C(=O)O)NC(=O)C=1C=CC=CC=1)C1=CC=CC=C1 NPKISZUVEBESJI-AWEZNQCLSA-N 0.000 claims abstract description 15
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- BAYUSCHCCGXLAY-UHFFFAOYSA-N 1-(3-methoxyphenyl)ethanone Chemical compound COC1=CC=CC(C(C)=O)=C1 BAYUSCHCCGXLAY-UHFFFAOYSA-N 0.000 claims description 22
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- -1 (S) -1- (3-methoxyphenyl) ethylamine benzoyl-L-phenylalanine salt Chemical class 0.000 claims description 15
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- GQZXRLWUYONVCP-UHFFFAOYSA-N 3-[1-(dimethylamino)ethyl]phenol Chemical compound CN(C)C(C)C1=CC=CC(O)=C1 GQZXRLWUYONVCP-UHFFFAOYSA-N 0.000 description 3
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- GQZXRLWUYONVCP-QMMMGPOBSA-N 3-[(1s)-1-(dimethylamino)ethyl]phenol Chemical compound CN(C)[C@@H](C)C1=CC=CC(O)=C1 GQZXRLWUYONVCP-QMMMGPOBSA-N 0.000 description 1
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- MIOPJNTWMNEORI-OMNKOJBGSA-N [(4s)-7,7-dimethyl-3-oxo-4-bicyclo[2.2.1]heptanyl]methanesulfonic acid Chemical compound C1C[C@@]2(CS(O)(=O)=O)C(=O)CC1C2(C)C MIOPJNTWMNEORI-OMNKOJBGSA-N 0.000 description 1
- OIPILFWXSMYKGL-UHFFFAOYSA-N acetylcholine Chemical compound CC(=O)OCC[N+](C)(C)C OIPILFWXSMYKGL-UHFFFAOYSA-N 0.000 description 1
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- PIJVFDBKTWXHHD-HIFRSBDPSA-N physostigmine Chemical class C12=CC(OC(=O)NC)=CC=C2N(C)[C@@H]2[C@@]1(C)CCN2C PIJVFDBKTWXHHD-HIFRSBDPSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B57/00—Separation of optically-active compounds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B55/00—Racemisation; Complete or partial inversion
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
- C07C213/10—Separation; Purification; Stabilisation; Use of additives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention belongs to the field of drug synthesis, and discloses a purification method and racemization recycling of a rivastigmine key chiral intermediate, wherein the purification of the rivastigmine intermediate comprises the following steps: (1) using racemate 1- (3-methoxyphenyl) ethylamine as a raw material, dissolving the racemate 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, and then filtering to obtain an intermediate 1; (2) and (S) -1- (3-methoxyphenyl) ethylamine can be obtained by dissociating the intermediate 1 by using an alkaline solution. Aiming at the racemate 1- (3-methoxyphenyl) ethylamine, the method can effectively realize purification by using a specific resolution reagent; in addition, the invention also can effectively utilize the by-products obtained by the purification process through a specific recovery step to finally obtain the racemate 1- (3-methoxyphenyl) ethylamine, thereby realizing the recovery.
Description
Technical Field
The invention belongs to the field of drug synthesis, and particularly relates to a purification method and racemization recycling of a rivastigmine key chiral intermediate, which can realize chiral resolution and racemization recycling of the rivastigmine intermediate.
Background
Alzheimer Disease (AD), also known as senile dementia, is a progressive neurodegenerative disorder whose main clinical manifestations are memory impairment, aphasia, agnosia, executive dysfunction, etc. Studies have demonstrated a significant loss of cholinergic nerve cells in the basal forebrain of AD patients, particularly in the neocortex, hippocampus, and amygdala. And the extent of cholinergic impairment is positively correlated with the severity of AD. Therefore, the current therapeutic drugs for AD are also directed to the acetylcholine system to improve the symptoms of patients.
Rivastigmine, of the formula:
the chemical name of the compound is (S) -N-methyl-N-ethyl-3- [1- (dimethylamino) ethyl ] -phenyl carbamate, which is a derivative of physostigmine. Not only has good selectivity and effect on brain acetylcholinesterase, but also has small side effect. As a representative of a new generation of acetylcholinesterase inhibitors, it is a pseudo-irreversible acetylcholinesterase inhibitor. The traditional Chinese medicine composition is mainly used for symptomatic treatment of mild and moderate Alzheimer's disease, can obviously delay the progress of dementia, improves clinical symptoms, cognitive functions and mental symptoms of patients, and has good compliance. There are three methods for synthesizing rivastigmine: asymmetric synthesis method, chiral acid resolution method and biological enzyme resolution method. Asymmetric synthesis and biological enzyme resolution are costly, complex and not suitable for large-scale production. From the viewpoint of cost and feasibility, the chiral acid is utilized for resolution, so that the raw materials are easy to obtain, the conditions are mild, and the industrial amplification is easy. However, this method has two problems, i.e. the resolution yield is not at a maximum and a more efficient resolving agent can be found. And secondly, the R configuration enantiomer can be recycled as a byproduct, so that the waste of raw materials is avoided, and the industrial cost is reduced.
Chinese patent document CN101580482A discloses that (S) -3- [1- (dimethylamino) ethyl ] phenol is obtained by recrystallization from an intermediate 3- [1- (dimethylamino) ethyl ] phenol from a mixed solution of ethanol and ethyl acetate, and the yield is 27%.
Chinese patent document CN113461554A adopts D- (+) -camphorsulfonic acid to perform repeated recrystallization resolution on the intermediate 3- [1- (dimethylamino) ethyl ] phenol, and the yield is 35.2%.
Disclosure of Invention
In view of the above drawbacks or needs for improvement of the prior art, the present invention aims to provide a purification method and racemization recycling of a rivastigmine key chiral intermediate, which can effectively achieve purification of a rivastigmine intermediate, racemic 1- (3-methoxyphenyl) ethylamine, by using benzoyl-L-phenylalanine as a resolving agent and benzoyl-L-phenylglycine as a resolving agent; in addition, the invention also can effectively utilize the by-products (namely, (R) -1- (3-methoxyphenyl) ethylamine benzoyl-L-phenylalanine salt, (R) -1- (3-methoxyphenyl) ethylamine benzoyl-L-phenylglycinate) obtained by the purification process through the recovery step designed by a specific process flow, finally obtain the racemate 1- (3-methoxyphenyl) ethylamine, and realize the recovery of the racemate 1- (3-methoxyphenyl) ethylamine. Compared with other rivastigmine intermediates, the rivastigmine intermediate ((S) -1- (3-methoxyphenyl) ethylamine) prepared by the invention has high yield and good effect, avoids the waste of (R) -1- (3-methoxyphenyl) ethylamine produced during synthesis, is beneficial to large-scale industrial production, and can effectively solve the problems of low yield, high cost, unrecovered split byproducts and the like of the existing synthetic method.
To achieve the above object, according to one aspect of the present invention, there is provided a method for purifying a rivastigmine intermediate, specifically racemic 1- (3-methoxyphenyl) ethylamine, comprising the steps of:
(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.
As a further preferred of the present invention, 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.
According to another aspect of the present invention, the present invention provides a method for recovering a rivastigmine intermediate, specifically racemic 1- (3-methoxyphenyl) ethylamine, comprising the steps of:
(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, 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.
According to another aspect of the present invention, there is provided a method for purifying and recovering a rivastigmine intermediate, which is specifically racemic 1- (3-methoxyphenyl) ethylamine, comprising the steps of:
(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 which corresponds 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 to perform 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 for 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.
As a further preferred aspect of the present invention, in the step (1), the filtrate evaporation is specifically rotary evaporation of the filtrate;
in the step (3), the evaporation is specifically rotary evaporation.
As a further preferred aspect 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 preferred aspect of the present invention, 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.
As a further preferred aspect of the present invention, in the step (S2) and the step (4), the second solvent is selected from: tert-butanol, tert-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.
As a further preferred aspect of the present invention, 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.
As a further preferred aspect of the present invention, in the step (3), the intermediate 2 is dissociated using a basic aqueous solution to obtain (R) -1- (3-methoxyphenyl) ethylamine, specifically: 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.
Compared with the prior art, the technical scheme provided by the invention has the advantages that aiming at the key intermediate of the rivastigmine, namely racemate 1- (3-methoxyphenyl) ethylamine (the structure is shown in formula I), the invention takes the racemate 1- (3-methoxyphenyl) ethylamine as a raw material, improves the purification and racemization recycling process, and further prepares the rivastigmine by carrying out chiral resolution on the rivastigmine intermediate 1- (3-methoxyphenyl) ethylamine through natural amino acid derivatives to obtain an S configuration. Furthermore, the residual (R) -1- (3-methoxyphenyl) ethylamine after the resolution can be subjected to racemization treatment and recycled through secondary resolution.
The invention specifically uses benzoyl-L-phenylalanine as a resolving reagent, uses benzoyl-L-phenylglycine as the resolving reagent, and adopts the resolving reagent, so that the yield of the purification method is as high as 39%, and the resolving effect is better. In the research and development process, natural chiral amino acid is used as a substrate, the space structure is adjusted by modifying the substrate, the resolution influence of the substrate on the key intermediate 1- (3-methoxyphenyl) ethylamine of the rivastigmine is researched, the results of resolution reaction in common solvents such as acetonitrile, ethanol, methanol and the like are compared, two resolution reagents with excellent effects, namely benzoyl-L-phenylalanine and benzoyl-L-phenylglycine, are finally screened, and the total resolution yield is better when the acetonitrile is used as the solvent.
The invention also can effectively utilize the byproducts (namely, (R) -1- (3-methoxyphenyl) ethylamine benzoyl-L-phenylalanine salt, (R) -1- (3-methoxyphenyl) ethylamine benzoyl-L-phenylglycinate) obtained by the purification process through the recovery step designed by a specific process flow, finally obtain the racemate 1- (3-methoxyphenyl) ethylamine, and realize the recovery of the racemate 1- (3-methoxyphenyl) ethylamine. Compared with other methods, the method realizes racemization by using transamination reaction, and uses m-methoxyacetophenone which can be used in the rivastigmine synthesis process as an auxiliary, so that no obvious byproduct is generated in the whole process. The method takes the rivastigmine intermediate m-methoxyacetophenone as an assistant, effectively realizes racemization reaction of the rivastigmine key intermediate (R) -1- (3-methoxyphenyl) ethylamine, and further realizes racemization recovery of a resolution by-product (the m-methoxyacetophenone obtained in the recovery process can also be recycled).
The purity of related substances of the 1- (3-methoxyphenyl) ethylamine obtained by the recovery process is more than or equal to 99.9 percent, and related impurities are less than 0.1 percent.
In conclusion, the invention provides a preparation and recovery method of a rivastigmine key intermediate with high yield and few byproducts, which is beneficial to industrial production, and can effectively solve the problems of low yield, high cost, unrecovered split byproducts and the like of the existing synthetic method.
Drawings
FIG. 1 is an HPLC chromatogram of tert-butyl (S) - (1- (3-methoxyphenyl) ethyl) carbamate formed by reacting the intermediate-1 prepared in example 1 with di-tert-butyl dicarbonate.
FIG. 2 is an HPLC chromatogram of tert-butyl (1- (3-methoxyphenyl) ethyl) carbamate obtained by reacting di-tert-butyl dicarbonate with 1- (3-methoxyphenyl) ethylamine recovered in example 3.
FIG. 3 is an HPLC chromatogram of tert-butyl (1- (3-methoxyphenyl) ethyl) carbamate obtained by reacting di-tert-butyl dicarbonate with 1- (3-methoxyphenyl) ethylamine recovered in example 4.
FIG. 4 is an HPLC chromatogram of tert-butyl (1- (3-methoxyphenyl) ethyl) carbamate formed by reacting di-tert-butyl dicarbonate with 1- (3-methoxyphenyl) ethylamine recovered in example 5.
FIG. 5 is an HPLC chromatogram of tert-butyl (1- (3-methoxyphenyl) ethyl) carbamate formed by reacting di-tert-butyl dicarbonate with 1- (3-methoxyphenyl) ethylamine recovered in example 6.
FIG. 6 is a reaction flow of splitting and recovering a key intermediate 1- (3-methoxyphenyl) ethylamine of rivastigmine; wherein (a) in FIG. 6 corresponds to the resolution of racemic 1- (3-methoxyphenyl) ethylamine and (b) in FIG. 6 corresponds to the racemization recovery of the resolution by-product (R) -1- (3-methoxyphenyl) ethylamine.
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more apparent, the present invention is described in further detail below with reference to the accompanying drawings and embodiments. It should be understood that the specific embodiments described herein are merely illustrative of the invention and are not intended to limit the invention. In addition, the technical features involved in the embodiments of the present invention described below may be combined with each other as long as they do not conflict with each other.
Example 1(S) -1- (3-methoxyphenyl) ethylamine
The synthetic route is as follows:
the specific steps adopted in this embodiment are as follows:
acetonitrile (200mL), 1- (3-methoxyphenyl) ethylamine (15.1g,100mmol), and benzoyl-L-phenylalanine (26.9g,100mmol) were added sequentially to a 500mL round bottom flask at room temperature, stirred at 80 ℃ until clear, and stirred for 1 h. The heating is turned off and the stirring is stopped, the mixture is naturally cooled to room temperature and is placed for a plurality of hours until no white insoluble substances are separated out. The reaction solution was filtered with suction through a fritted funnel and the solid was washed with acetonitrile (50mL), and the filter cake was dried by forced air at 50 ℃ to give benzoyl-L-phenylalanine salt of (S) -1- (3-methoxyphenyl) ethylamine (intermediate 1,16.4g, 39 mmol).
The filtrate was rotary evaporated to give the benzoyl-L-phenylalanine salt of (R) -1- (3-methoxyphenyl) ethylamine (intermediate 2,25.6g,61mmol), which intermediate 2 can be further subjected to a recovery step (see below for details, especially examples 3-7).
Intermediate 1 was then dissolved in sodium hydroxide solution (2M,150mL) and extracted 3 times with ethyl acetate (3 × 100 mL). The organic phases were combined, dried over 30g anhydrous sodium sulfate for 1h, filtered and the solvent removed by rotary evaporation to give (S) -1- (3-methoxyphenyl) ethylamine (5.9g,39 mmol).
The total resolution yield was 39%.
The nuclear magnetic detection result of the product (S) -1- (3-methoxyphenyl) ethylamine is as follows:
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).
tert-butyl (S) - (1- (3-methoxyphenyl) ethyl) carbamate derived from (S) -1- (3-methoxyphenyl) ethylamine, whose ee value is determined by high performance 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 ℃. The HPLC profile is shown in FIG. 1, wherein the peak is about 19 minutes for R-type and about 21 minutes for S-type. The peak areas indicated that the ee value of the product was greater than 99.
Comparative example 1-1: the comparative example is the same as example 1 except that ethanol is used instead of acetonitrile, and other reaction participants, reaction conditions, parameters and the like are the same, so that the total resolution yield corresponding to the (S) -1- (3-methoxyphenyl) ethylamine is 10%.
Comparative examples 1 to 2: this comparative example was conducted in the same manner as in example 1 except that methanol was used instead of acetonitrile, and the other reaction participants, reaction conditions, parameters and the like were changed to obtain (S) -1- (3-methoxyphenyl) ethylamine in a corresponding total resolution yield of 5%.
Example 2(S) -1- (3-methoxyphenyl) ethylamine
The synthetic route is as follows:
the specific steps adopted in this embodiment are as follows:
acetonitrile (200mL), 1- (3-methoxyphenyl) ethylamine (15.1g,100mmol), and benzoyl-L-phenylglycine (25.5g,100mmol) were added sequentially to a 500mL round bottom flask at room temperature, stirred at 70 ℃ until clear, and stirred for 1 h. The heating is turned off and the stirring is stopped, the mixture is naturally cooled to room temperature and is placed for a plurality of hours until no white insoluble substances are separated out. The reaction solution was filtered with suction through a fritted funnel and the solid was washed with acetonitrile (50mL), and the filter cake was dried by air blowing at 50 ℃ to obtain benzoyl-L-phenylglycinate salt of (S) -1- (3-methoxyphenyl) ethylamine (15.0g, 37 mmol).
The filtrate was rotary evaporated to give benzoyl-L-phenylglycinate (25.6g,63mmol) of (R) -1- (3-methoxyphenyl) ethylamine, which was also further subjected to a recovery step.
The benzoyl-L-phenylglycinate salt of (S) -1- (3-methoxyphenyl) ethylamine was dissolved in sodium hydroxide solution (2M,150mL) and extracted 3 times with ethyl acetate (3X 100 mL). The organic phases were combined, dried over 30g anhydrous sodium sulphate for 1h, filtered and the solvent removed by rotary evaporation to give (S) -1- (3-methoxyphenyl) ethylamine (5.6g,37 mmol).
The total yield of the resolution was 37%.
Comparative example 2-1: this comparative example was conducted in the same manner as in example 2 except that isopropanol was used instead of acetonitrile, and the other reaction participants, reaction conditions, parameters and the like were changed to obtain (S) -1- (3-methoxyphenyl) ethylamine in a total resolution yield of 14%.
Comparative examples 2 to 2: this comparative example was conducted in the same manner as in example 2 except that methanol was used instead of acetonitrile, and the other reaction participants, reaction conditions, parameters and the like were changed to obtain (S) -1- (3-methoxyphenyl) ethylamine in a corresponding total resolution yield of 18%.
Taking the intermediate 2 obtained in example 1 as an example, the recovery procedure can be as follows in general:
(S1) dissociating the intermediate 2 with a basic solution to obtain (R) -1- (3-methoxyphenyl) ethylamine, and using the (R) -1- (3-methoxyphenyl) ethylamine as the intermediate 3; dissolving the intermediate 3 in a first solvent, adding m-methoxyacetophenone and tetraisopropyl titanate, and heating and refluxing to react; 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 is carried out, and the m-methoxyacetophenone and the racemic 1- (3-methoxyphenyl) ethylamine are obtained through post-treatment, so that the recovery of the racemic 1- (3-methoxyphenyl) ethylamine can be realized (the obtained m-methoxyacetophenone can be recovered and can be recycled in the same way).
Of course, for the R-type byproducts obtained by other resolution methods, the R-type byproducts can be converted into (R) -1- (3-methoxyphenyl) ethylamine (i.e., intermediate 3) by pretreatment, and then recovered according to the steps, and the recovery of racemic 1- (3-methoxyphenyl) ethylamine can also be realized.
Wherein, the post-treatment specifically comprises the following steps: adding an acid solution into a reaction liquid system which is cooled after the heating reflux reaction is finished, stirring for 5min, evaporating to remove a low-boiling point solvent, extracting by using an organic solvent to obtain m-methoxyacetophenone, adding an alkaline solution into a water phase to adjust the pH to be alkaline, and extracting by using the organic solvent to obtain the racemic 1- (3-methoxyphenyl) ethylamine, thereby realizing the recovery of the racemic 1- (3-methoxyphenyl) ethylamine (wherein the acid solution can be selected from a sulfuric acid solution and a hydrochloric acid solution, and the alkaline solution can be selected from a sodium hydroxide solution, a potassium hydroxide solution and a sodium carbonate solution).
The following are specific examples:
EXAMPLE 3 racemization reaction of (R) -1- (3-methoxyphenyl) ethylamine
The synthetic route is as follows:
the specific steps adopted in this embodiment are as follows:
intermediate 2 was dissolved in sodium hydroxide solution (2M,200mL) and extracted 3 times with ethyl acetate (3 × 100 mL). The combined organic phases were dried over 50g anhydrous sodium sulphate for 1h, filtered and the solvent removed by rotary evaporation to give (R) -1- (3-methoxyphenyl) ethylamine (intermediate 3,9.2g,61 mmol).
At room temperature, a 500mL two-necked flask is connected with a water separator and a reflux condenser tube, then is vacuumized by using an oil pump, nitrogen atmosphere is replaced by using a nitrogen balloon, p-xylene (120mL), intermediate 3(9.2g,61mmol), M-methoxyacetophenone (13.5g,90mmol), tetraisopropyl titanate (8.5g,30mmol) are sequentially added, magnetic stirring is carried out at 100 ℃ for 30h, after cooling to room temperature, toluene is removed by rotary evaporation and transferred to a 200mL sealed tube, tert-butanol (90mL), dimethyl sulfoxide (19.1g,240mmol), potassium tert-butoxide (6.7g,60mmol) are sequentially added, stirring is carried out at 140 ℃ for 8h, after cooling to room temperature, sulfuric acid solution (1M) is added to adjust the pH of the reaction solution to about 2 and stirring is carried out for 5min, the reaction solution is concentrated by rotary evaporation, after removing insoluble substances by suction filtration by using a sand core funnel, washing is carried out for three times (3X 50mL) by using ethyl acetate, the aqueous phase is adjusted to pH 10 by using sodium hydroxide solution (2M), extraction was carried out three times with ethyl acetate (3X 25mL), and the organic phases were combined, dried over 30g of anhydrous sodium sulfate and concentrated by rotary evaporation to give 1- (3-methoxyphenyl) ethylamine.
The overall yield of racemic recovery was 72%.
Tert-butyl 1- (3-methoxyphenyl) ethyl carbamate derived from 1- (3-methoxyphenyl) ethylamine, whose ee value is determined by high performance 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 ℃. The HPLC profile is shown in FIG. 2, wherein the peak is about 19 minutes for R-type and about 21 minutes for S-type. The peak area indicated that the ee value of the product was less than 5.
EXAMPLE 4 racemization reaction of (R) -1- (3-methoxyphenyl) ethylamine
The synthetic route is as follows:
the specific steps adopted in this embodiment are as follows:
intermediate 2 was dissolved in sodium hydroxide solution (2M,200mL) and extracted 3 times with ethyl acetate (3 × 100 mL). The combined organic phases were dried over 50g anhydrous sodium sulphate for 1h, filtered and the solvent removed by rotary evaporation to give (R) -1- (3-methoxyphenyl) ethylamine (intermediate 3,9.2g,61 mmol).
At room temperature, a 250mL two-necked flask is connected with a water separator and a reflux condenser tube, then is vacuumized by using an oil pump, nitrogen atmosphere is replaced by using a nitrogen balloon, toluene (40mL), intermediate 3(9.2g,61mmol), M-methoxyacetophenone (4.5g,30mmol), tetraisopropyl titanate (34.7g,122mmol) are sequentially added, magnetic stirring is carried out at 90 ℃ for 48h, after cooling to room temperature, toluene is removed by rotary evaporation, then the mixture is added into a sealed tube, ethylene glycol (180mL), dimethyl sulfoxide (23.4g,300mmol) and potassium tert-butoxide (33.7g,300mmol) are sequentially added, reflux stirring is carried out at 180 ℃ for 6h, after cooling to room temperature, sulfuric acid solution (1M) is added to adjust the pH of the reaction solution to about 2 and stirring is carried out for 5min, the reaction solution is concentrated by rotary evaporation, after removing insoluble substances by suction filtration by using a sand core funnel, washing is carried out for three times (3X 50mL) by using ethyl acetate, the aqueous phase is adjusted to pH 10 by using sodium hydroxide solution (2M), extraction was carried out three times with ethyl acetate (3X 25mL), and the organic phases were combined, dried over 30g of anhydrous sodium sulfate and concentrated by rotary evaporation to give 1- (3-methoxyphenyl) ethylamine.
The overall yield of racemic recovery was 77%.
The HPLC profile is shown in FIG. 3, where the peak is about 19 minutes for R-type and about 22 minutes for S-type. The peak areas indicated that the ee value of the product was less than 10.
EXAMPLE 5 racemization reaction of (R) -1- (3-methoxyphenyl) ethylamine
The synthetic route is as follows:
the specific steps adopted in this embodiment are as follows:
intermediate 2 was dissolved in sodium hydroxide solution (2M,200mL) and extracted 3 times with ethyl acetate (3 × 100 mL). The combined organic phases were dried over 50g anhydrous sodium sulphate for 1h, filtered and the solvent removed by rotary evaporation to give (R) -1- (3-methoxyphenyl) ethylamine (intermediate 3,9.2g,61 mmol).
At room temperature, connecting a 250mL two-necked flask with a water separator and a reflux condenser pipe, vacuumizing by using an oil pump, replacing the nitrogen atmosphere by using a nitrogen balloon, sequentially adding chlorobenzene (70mL), intermediate 3(9.2g,61mmol), M-methoxyacetophenone (15g,100mmol), tetraisopropyl titanate (51.2g,180mmol), magnetically stirring at 130 ℃ for 30h, cooling to room temperature, removing toluene by rotary evaporation, sequentially adding tert-amyl alcohol (150mL), dimethyl sulfoxide (15.6g,200mmol) and potassium tert-butoxide (22.4g,200mmol), refluxing and stirring at 80 ℃ for 24h, cooling to room temperature, adding sulfuric acid solution (1M) to adjust the pH of the reaction solution to about 2 and stirring for 5min, concentrating the reaction solution by rotary evaporation, removing insoluble substances by suction filtration by using a sand core funnel, washing with ethyl acetate three times (3X 50mL), adjusting the aqueous phase to pH 10 by using sodium hydroxide solution (2M), extraction was carried out three times with ethyl acetate (3X 25mL), and the organic phases were combined, dried over 30g of anhydrous sodium sulfate and concentrated by rotary evaporation to give 1- (3-methoxyphenyl) ethylamine.
The overall yield of racemic recovery was 85%.
The HPLC profile is shown in FIG. 4, where the peak is about 19 minutes for R-type and about 22 minutes for S-type. The peak areas indicated that the ee value of the product was less than 8.
EXAMPLE 6 racemization reaction of (R) -1- (3-methoxyphenyl) ethylamine
The synthetic route is as follows:
the specific steps adopted in this embodiment are as follows:
intermediate 2 was dissolved in sodium hydroxide solution (2M,200mL) and extracted 3 times with ethyl acetate (3 × 100 mL). The combined organic phases were dried over 50g anhydrous sodium sulphate for 1h, filtered and the solvent removed by rotary evaporation to give (R) -1- (3-methoxyphenyl) ethylamine (intermediate 3,9.2g,61 mmol).
At room temperature, a 250mL two-necked flask is connected with a water separator and a reflux condenser tube, then is vacuumized by using an oil pump, nitrogen atmosphere is replaced by using a nitrogen balloon, p-xylene (80mL), intermediate 3(9.2g,61mmol), M-methoxyacetophenone (15g,100mmol), tetraisopropyl titanate (45.5g,160mmol) are sequentially added, magnetic stirring is carried out at 140 ℃ for 30h, after cooling to room temperature, toluene is removed by rotary evaporation, the obtained mixture is added into a sealed tube, tert-amyl alcohol (150mL), dimethyl sulfoxide (11.7g,150mmol) and potassium tert-butoxide (16.8g,150mmol) are sequentially added, reflux stirring is carried out at 150 ℃ for 15h, after cooling to room temperature, sulfuric acid solution (1M) is added to adjust the pH of the reaction solution to about 2 and stirring is carried out for 5min, the reaction solution is concentrated by rotary evaporation, after suction filtration is carried out by using a sand core funnel, ethyl acetate is used for three times (3X 50mL), the aqueous phase is adjusted to pH 10 by sodium hydroxide solution (2M), extraction was carried out three times with ethyl acetate (3X 25mL), and the organic phases were combined, dried over 30g of anhydrous sodium sulfate and concentrated by rotary evaporation to give 1- (3-methoxyphenyl) ethylamine.
The overall yield of racemic recovery was 85%.
The HPLC profile is shown in FIG. 5, in which the peak is about 18 minutes for R-type and about 21 minutes for S-type. The peak areas indicated that the ee value of the product was less than 20.
EXAMPLE 7 racemization reaction of (R) -1- (3-methoxyphenyl) ethylamine
The synthetic route is as follows:
the specific steps adopted in this embodiment are as follows:
intermediate 2 was dissolved in sodium hydroxide solution (2M,200mL) and extracted 3 times with ethyl acetate (3 × 100 mL). The combined organic phases were dried over 50g anhydrous sodium sulphate for 1h, filtered and the solvent removed by rotary evaporation to give (R) -1- (3-methoxyphenyl) ethylamine (intermediate 3,9.2g,61 mmol).
At room temperature, a 250mL two-necked flask was connected to a water separator and a reflux condenser, then evacuated with an oil pump and the nitrogen atmosphere was replaced with a nitrogen balloon, toluene (120mL), intermediate 3(9.2g,61mmol), M-methoxyacetophenone (9.1g,61mmol), tetraisopropyl titanate (17.3g,61mmol) were sequentially added, magnetic stirring was carried out at 120 ℃ for 17 hours, cooling was carried out to room temperature, toluene was removed by rotary evaporation, tert-amyl alcohol (120mL), dimethyl sulfoxide (9.5g,122mmol), potassium tert-butoxide (13.7g,122mmol) were sequentially added, reflux stirring was carried out at 100 ℃ for 4 hours, cooling was carried out to room temperature, sulfuric acid solution (1M) was added to adjust the pH of the reaction solution to about 2 and stirring was carried out for 5 minutes, the reaction solution was concentrated by rotary evaporation, after removing insoluble matter by suction filtration with a sand core funnel, washing was carried out three times with ethyl acetate (3X 50mL), the aqueous phase was adjusted to pH 10 with sodium hydroxide solution (2M), extraction was carried out three times with ethyl acetate (3X 25mL), and the organic phases were combined, dried over 30g of anhydrous sodium sulfate and concentrated by rotary evaporation to give 1- (3-methoxyphenyl) ethylamine.
The overall yield of racemic recovery was 80%.
It will be understood by those skilled in the art that the foregoing is only a preferred embodiment of the present invention, and is not intended to limit the invention, and that any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the 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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