CN114591332B - Preparation method of alcaftadine and purification method of intermediate of alcaftadine - Google Patents

Abstract

The invention relates to a method for preparing alcaftadine and a method for purifying an intermediate, which comprises the steps of washing a crude product containing 6, 11-dihydro-11- (1-methyl-4-piperidylidene) -5H-imidazo [2,1-b ] [3] benzazepine-3-methanol (AT 3 for short) by slurry, and separating to obtain purified AT3. Further, the invention also provides a method for preparing the alcaftadine. By the purification method of the AT3, the purity of the AT3 can be controlled to be more than 95 percent. The purity of the alcaftadine obtained by the method is 99.5% or more.

Description

Preparation method of alcaftadine and purification method of intermediate of alcaftadine

Technical Field

The invention relates to a preparation method of high-content bulk drug, in particular to a preparation method of alcaftadine and a purification method of an intermediate thereof.

Background

Alcaftadine (Alcaftadine), trade name: lastacafe is a novel histamine H1 receptor antagonist and mast cell stabilizer developed in Weikang medicine, can inhibit histamine from being released from mast cells, can reduce chemotaxis and activation of eosinophils, and is approved by the FDA in the United states in 7 months 2010 and is sold under the trade name Lastacafe. Alcaftadine is another drug for treating allergic conjunctivitis-related ocular itching after betasis besylate developed by the company of ISTA pharmaceutical, and is an eye drop for treating allergic conjunctivitis-related ocular itching in people over 2 years old. Has good clinical application prospect. The structural formula is as follows:

U.S. patent application publication No. US5468743 discloses a method for preparing alcaftadine by taking 1H-3-benzazepin-2-amine and 2, 2-dimethoxyethylamine as raw materials, wherein the specific process is that 1H-3-benzazepin-2-amine and 2, 2-dimethoxyethylamine are subjected to nucleophilic substitution, cyclization, oxidation, grignard reaction, hydrogenation and dehydration to obtain an intermediate 6, 11-dihydro-11- (1-methyl-4-piperidylidene) -5H-imidazole [2,1-b ] [3] benzazepine (AT 2 for short), and AT3 are obtained by carrying out hydroxymethylation on AT2 to synthesize alcaftadine.

PCT patent application number WO1992022551 discloses a method for preparing alcaftadine by taking 1-phenethyl-1H-imidazole as a starting material, which comprises the specific processes of Friedel-crafts acylation, deprotection, methylation, cyclization and ethoxycarbonyl protection of the 1-phenethyl-1H-imidazole to obtain an intermediate AT2, and carrying out methylolation on the AT2 to obtain AT3 and carrying out oxidation reaction on the AT3 to synthesize alcaftadine.

PCT patent application number WO2014154620 discloses a synthesis method of alcaftadine, which takes 1-phenethyl-1H-imidazole as a raw material to prepare alcaftadine, and specifically comprises the steps of synthesizing an intermediate AT2 from 1-phenethyl-1H-imidazole through Friedel-crafts acylation reaction and cyclization reaction, reacting AT2 with acid to prepare a salt form, and carrying out methylolation to obtain AT3 and AT3 oxidation reaction to synthesize alcaftadine.

In summary, the last two steps of the synthesis of the alcaftadine in the prior art are the same, and the method is 6, 11-dihydro-11- (1-methyl-4-piperidylidene) -5H-imidazo [2,1-b ] [3] benzazepine (AT 2 for short) is subjected to methylolation to obtain AT3, and the AT3 is oxidized to synthesize the alcaftadine, so that the step is a key step for synthesizing the alcaftadine. During the preparation process, the quality, especially the purity, of the intermediate AT3 can seriously affect the quality of the alcaftadine. However, no effective method for purifying intermediate AT3 is found in the prior art, and in addition, the quality of the prior art alcaftadine is still to be improved.

Therefore, it is important to develop a simple and convenient method which is suitable for industrial application and can effectively improve the purity of AT3 and the quality of alcaftadine.

Disclosure of Invention

The present invention aims to solve at least one of the technical problems in the related art to some extent. Therefore, the invention aims to provide a simple and convenient method which is suitable for industrial application and can effectively improve the purity of AT3 and the quality of the alcaftadine.

The inventor finds that the total impurities of the reference preparation of the alcaftadine are 0.5 percent in the research process, and the purity of the raw material medicines of the alcaftadine in the prior art does not reach the requirement of 99.5 percent. The preparation method can effectively control the impurity content in the alcaftadine bulk drug and improve the purity of the alcaftadine bulk drug.

In a first aspect of the present invention, there is provided a process for the preparation of alcaftadine, obtained by oxidation of AT3 with dess-martin reagent, said oxidation reaction comprising: carrying out oxidation reaction on AT3 and part of the dess-martin reagent, and adding the rest dess-martin reagent after the oxidation reaction is carried out for a period of time; preferably, the weight of the part of the dess-martin reagent is 0.3 to 0.7 times of the total addition amount of the dess-martin reagent,

wherein, AT3 is a compound represented by formula (I):

and the dess-martin reagent is added in batches, so that the oxidation condition is relaxed, the byproduct generation is reduced, and the purity of the prepared alcaftadine is improved.

According to an embodiment of the present invention, the mass control of the additive is 0.005 to 0.02 times the mass of the AT 3;

according to an embodiment of the invention, the period of time is 20-40 min, preferably 20-30 min.

According to the embodiment of the invention, the solvent used in the reaction system comprises dichloromethane, tertiary butanol and water, and preferably, the volume ratio of the dichloromethane to the tertiary butanol to the water in the solvent used in the reaction system is 20:10-20:0.1-0.5.

According to an embodiment of the present invention, an additive, preferably EDTA or a sodium salt thereof, is added simultaneously with the addition of the remaining dess-martin reagent; more preferably, the additive is selected from EDTA, EDTA-disodium, EDTA-tetrasodium. After the addition of the additive, the purity of the obtained alcaftadine is further improved.

The inventors have also found during the course of the study that the quality of intermediate AT3 has an important influence on the quality of the final product, alcaftadine, in the synthesis process of alcaftadine.

According to an embodiment of the present invention, the AT3 has a purity of 95% or more; preferably, the AT3 has a purity of 98.5% or more.

In order to solve the technical problem, the inventor notes that in the research process, the crude product containing AT3 can be purified to improve the purity of the AT3, and further, the higher purity of the acaradine can be obtained by simple post-treatment of the acaradine prepared by the reaction. Therefore, the invention provides a method for effectively improving the purity of the intermediate AT3.

According to an embodiment of the present invention, the AT3 is obtained by subjecting a crude product containing the AT3 to slurry washing and separation; the sizing treatment further comprises: performing slurry washing on the crude product containing AT3 by using a mixed solution; the mixed solution comprises an organic solvent and an aqueous phase solvent. The crude product of AT3, the organic solvent and the aqueous solvent are mutually insoluble, and when the crude product, the organic solvent and the aqueous solvent are in certain dynamic balance, the total dissolving amount or the solvent wrapping amount of the impurity C and the residual AT2 in the mixed solution of the organic solvent and the aqueous solvent reaches the maximum, and AT the moment, the AT3 and the mixed solution are separated, so that the AT3 with higher purity can be obtained.

The structural formula of the impurity C is shown as follows,

according to an embodiment of the invention, the organic solvent comprises one or more of the halogenated methanes, preferably dichloromethane. The organic solvent is methyl halide, in particular methyl chloride, dichloromethane, chloroform, tetrachloromethane, bromomethane, dibromomethane, bromomethane, tetrabromomethane and other similar solvents, and forms a mixed solution with aqueous phase solvents such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate and the like, the crude AT3 product is subjected to slurry washing by the mixed solution, so that the impurity C and the residual AT2 are enriched in a mixed solution system, the impurity C and the residual AT2 can be dissolved in the mixed solution without being limited by theory, and can be wrapped in the mixed solution after contacting with the mixed solution, and then the AT3 purification effect can be achieved by separating the mixed solution and the AT 3. Thus, the purity of the purified AT3 can be 97.5% or more, preferably 98.5% or more, even 99% or more, and the AT2 residue in the purified AT3 is controlled to be 2% or less, preferably 1% or less, even 0.5% or less, and the impurity C residue is controlled to be 0.6% or less, preferably 0.4% or less, even 0.2% or less.

According to an embodiment of the present invention, the aqueous solvent is an alkaline solution, the pH value of the alkaline solution is controlled to be 9-14, and preferably, the pH-adjusting alkali is selected from any one or more of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, ammonia water, and a buffer solution.

According to an embodiment of the invention, the buffer solution is selected from the group consisting of carbonate-bicarbonate buffer, barbituric sodium-hydrochloric acid buffer, glycine-sodium hydroxide buffer, boric acid-sodium hydroxide buffer. When the alkali solution is a buffer solution, the mixed solution has a better purification effect on the crude product containing AT3, when the alkali solution is a buffer solution, the pH value is stable within a certain range, and in a specific pH range, the mixed solution can better dissolve the impurity C and the residual AT2 in the crude product of AT3, and in addition, in the pH range, the dissolution or the encapsulation of the impurity C and the residual AT2 in the crude product of AT3 in an organic solvent can be further promoted in the sizing process. The purity of the purified AT3 obtained by the method can reach more than 99 percent, and the AT2 residue in the purified AT3 is controlled to be 0.5 percent or less, and the impurity C residue is controlled to be 0.2 percent or less.

According to the embodiment of the invention, the mass ratio of the crude product containing AT3, the organic solvent and the alkali solution is 1: 2-10: 10 to 21, preferably, the mass ratio of the crude product containing AT3, the organic solvent and the alkali solution is 1: 3-10: 12-21. The crude product containing AT3, the organic solvent and the alkali solution are mutually insoluble, and according to the embodiment of the invention, the mass ratio of the crude product containing AT3 and the alkali solution can influence the purification effect of the crude product containing AT3, and the influence is mainly expressed in that: when the amount of organic solvent is too low and the amount of alkali dissolution is too low, the content of impurity C and residual AT2 in AT3 is too high, when the amount of organic solvent is too low, the amount of alkali dissolution is too high or the amount of organic solvent is too high and the amount of alkali dissolution is too low, the content of impurity C and residual AT2 in AT3 is too high, and when the amount of organic solvent is too high and the amount of alkali dissolution is too high, the purification yield is greatly reduced. The quality ratio of the three is controlled, so that the removal effect of the mixed solution consisting of the organic solvent and the alkali solution on the impurity C and the residual AT2 in the AT3 crude product can be effectively improved, and the utilization rate of materials is increased. Preferably, the mass ratio of the crude product containing AT3, the organic solvent and the alkali solution is 1: 3-10: 12-21, thereby obtaining the purified AT3 with the purity of more than 98.5 and even more than 99 percent, and obtaining the purified AT3 with the AT2 residue controlled below 1 percent and even below 0.5 percent and the impurity C residue controlled below 0.4 percent and even below 0.2 percent. The content of impurity F in the finally obtained alcaftadine can be controlled below 0.05%.

According to an embodiment of the present invention, the sizing temperature is controlled to be 15-45 degrees celsius, preferably 25-45 degrees celsius, more preferably 30 degrees celsius. When the temperature is too high, the solubility of AT3, AT2 residues and impurity C in the mixed solution is increased simultaneously, the purification yield is obviously reduced, and when the temperature is too low, the AT2 residues and impurity C removal effect is not good.

According to an embodiment of the invention, the sizing time is controlled to be 0.5-2 hours.

According to an embodiment of the present invention, the crude product containing AT3 contains impurities including AT least one selected from the group consisting of:

the inventors have unexpectedly found that purifying the crude product of AT3 to obtain high-purity AT3 and then oxidizing to obtain alcaftadine can not only increase the yield of the step of oxidizing AT3 to alcaftadine, but also increase the stability of the final product alcaftadine, thereby prolonging the shelf life of the final product alcaftadine.

In a second aspect of the invention, a method for purifying an alcaftadine intermediate, AT3, is provided.

According to the embodiment of the invention, the purity of AT3 can be more than 95%, the residual AT2 is reduced to less than 10%, preferably less than 2%, more preferably less than 1%, less than 0.5%, even less than 0.3%, and the content of impurity C is controlled to less than 1%, preferably less than 0.6%, more preferably less than 0.4%, and less than 0.2% by subjecting the AT3 crude product to a slurry washing treatment. In addition, the purity of the alcaftadine is correspondingly improved, and according to the embodiment of the invention, the content of the impurity F in the finally obtained alcaftadine can be controlled below 0.1% by performing slurry washing treatment on the AT3 crude product.

According to an embodiment of the present invention, a method for purifying an alcaftadine intermediate AT3, comprises: performing slurry washing and separation on the crude product containing the AT3 to obtain purified AT3; the sizing treatment further comprises: performing slurry washing on the crude product containing AT3 by using a mixed solution; the mixed solution comprises an organic solvent and an aqueous phase solvent. Wherein, AT3 is a compound represented by formula (I):

the crude product of AT3, the organic solvent and the aqueous solvent are mutually insoluble, and when the crude product, the organic solvent and the aqueous solvent are in certain dynamic balance, the total dissolving amount or the solvent wrapping amount of the impurity C and the residual AT2 in the mixed solution of the organic solvent and the aqueous solvent reaches the maximum, and AT the moment, the AT3 and the mixed solution are separated, so that the AT3 with higher purity can be obtained.

According to an embodiment of the invention, the organic solvent comprises one or more of the halomethanes, preferably dichloromethane; the organic solvent is methyl halide, in particular methyl chloride, dichloromethane, chloroform, tetrachloromethane, bromomethane, dibromomethane, bromomethane, tetrabromomethane and other similar solvents, and forms a mixed solution with aqueous phase solvents such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate and the like, the crude AT3 product is subjected to slurry washing by the mixed solution, so that the impurity C and the residual AT2 are enriched in a mixed solution system, the impurity C and the residual AT2 can be dissolved in the mixed solution without being limited by theory, and can be wrapped in the mixed solution after contacting with the mixed solution, and then the AT3 purification effect can be achieved by separating the mixed solution and the AT3. Thus, the purity of the purified AT3 can be 97.5% or more, preferably 98.5% or more, even 99% or more, and the AT2 residue in the purified AT3 is controlled to be 2% or less, preferably 1% or less, even 0.5% or less, and the impurity C residue is controlled to be 0.6% or less, preferably 0.4% or less, even 0.2% or less.

According to an embodiment of the present invention, the aqueous solvent is an alkaline solution, the pH value of the alkaline solution is controlled to be 9-14, preferably, the pH-adjusting alkali is selected from any one or more of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, ammonia water, and a buffer solution, more preferably, the buffer solution is selected from a carbonate-bicarbonate buffer solution, a barbital sodium-hydrochloric acid buffer solution, a glycine-sodium hydroxide buffer solution, and a boric acid-sodium hydroxide buffer solution; when the alkali solution is a buffer solution, the mixed solution has a better purification effect on the crude product containing AT3, when the alkali solution is a buffer solution, the pH value is stable within a certain range, and in a specific pH range, the mixed solution can better dissolve the impurity C and the residual AT2 in the crude product of AT3, and in addition, in the pH range, the dissolution or the encapsulation of the impurity C and the residual AT2 in the crude product of AT3 in an organic solvent can be further promoted in the sizing process. The purity of the purified AT3 obtained by the method can reach more than 99 percent, and the AT2 residue in the purified AT3 is controlled to be 0.5 percent or less, and the impurity C residue is controlled to be 0.2 percent or less.

According to the embodiment of the invention, the mass ratio of the crude product containing AT3, the organic solvent and the alkali solution is 1: 2-10: 10 to 21, preferably, the mass ratio of the crude product containing AT3, the organic solvent and the alkali solution is 1: 3-10: 12-21. The crude product containing AT3, the organic solvent and the alkali solution are mutually insoluble, and according to the embodiment of the invention, the mass ratio of the crude product containing AT3 and the alkali solution can influence the purification effect of the crude product containing AT3, and the influence is mainly expressed in that: when the amount of organic solvent is too low and the amount of alkali dissolution is too low, the content of impurity C and residual AT2 in AT3 is too high, when the amount of organic solvent is too low, the amount of alkali dissolution is too high or the amount of organic solvent is too high and the amount of alkali dissolution is too low, the content of impurity C and residual AT2 in AT3 is too high, and when the amount of organic solvent is too high and the amount of alkali dissolution is too high, the purification yield is greatly reduced. The quality ratio of the three is controlled, so that the removal effect of the mixed solution consisting of the organic solvent and the alkali solution on the impurity C and the residual AT2 in the AT3 crude product can be effectively improved, and the utilization rate of materials is increased. Preferably, the mass ratio of the crude product containing AT3, the organic solvent and the alkali solution is 1: 3-10: 12-21, thereby obtaining the purified AT3 with the purity of more than 98.5 and even more than 99 percent, and obtaining the purified AT3 with the AT2 residue controlled below 1 percent and even below 0.5 percent and the impurity C residue controlled below 0.4 percent and even below 0.2 percent. The content of impurity F in the finally obtained alcaftadine can be controlled below 0.05%.

According to an embodiment of the present invention, the sizing temperature is controlled to be 15-45 degrees celsius, preferably 25-45 degrees celsius, more preferably 30 degrees celsius. When the temperature is too high, the solubility of AT3, AT2 residues and impurity C in the mixed solution is increased simultaneously, the purification yield is obviously reduced, and when the temperature is too low, the AT2 residues and impurity C removal effect is not good.

According to an embodiment of the invention, the sizing time is controlled to be 0.5-2 hours;

the invention has the beneficial effects that:

1) By the AT3 purification method, the content of AT3 impurity C can be controlled below 1%, below 0.5% and even below 0.3%; the AT3 purity can be controlled to be more than 95%, 98.5%, even more than 99%, and the purification yield is more than 90%.

2) The purity of the alcaftadine can be controlled to be more than 99.5 percent, even more than 99.9 percent;

3) The alcaftadine obtained by the invention has good stability and stable purity after being placed for 6 months and 12 months for a long time.

Detailed Description

The following detailed description of embodiments of the invention, it should be noted that the described embodiments are exemplary and intended to be illustrative of the invention and should not be construed as limiting the invention.

Preparation method of alcaftadine product

In a first aspect of the invention, the invention proposes a process for the preparation of alcaftadine, obtained according to an embodiment of the invention from the oxidation of AT3 by dess-martin reagent, said oxidation reaction comprising: carrying out oxidation reaction on AT3 and part of the dess-martin reagent, and adding the rest dess-martin reagent after the oxidation reaction is carried out for a period of time; preferably, the weight of the part of the dess-martin reagent is 0.3 to 0.7 times of the total addition amount of the dess-martin reagent,

wherein, AT3 is a compound represented by formula (I):

the oxidant dess-martin reagent was added in portions.

According to an embodiment of the present invention, the mass control of the additive is 0.005 to 0.02 times the mass of the AT 3;

according to an embodiment of the invention, the period of time is 20-40 min, preferably 20-30 min.

According to the embodiment of the invention, the solvent used in the reaction system comprises dichloromethane, tertiary butanol and water, and preferably, the volume ratio of the dichloromethane to the tertiary butanol to the water in the solvent used in the reaction system is 20:10-20:0.1-0.5. The purity of the obtained alcaftadine is improved to more than 99.5%.

According to an embodiment of the present invention, the additive is added at the same time as the remaining dess-martin reagent is added.

According to an embodiment of the invention, the additive is EDTA or a sodium salt thereof. Specifically, EDTA-disodium, EDTA-tetrasodium may be mentioned. After the addition of the additive, the purity of the final product of the alcaftadine is improved to 99.9% or more.

According to an embodiment of the present invention, the AT3 has a purity of 95% or more; preferably, the AT3 has a purity of 98.5% or more.

According to an embodiment of the present invention, the AT3 is obtained by subjecting a crude product containing the AT3 to slurry washing and separation; the sizing treatment further comprises: performing slurry washing on the crude product containing AT3 by using a mixed solution; the mixed solution comprises an organic solvent and an aqueous phase solvent.

According to an embodiment of the invention, the organic solvent comprises one or more of the halomethanes, preferably dichloromethane;

according to the embodiment of the invention, the aqueous phase solvent is an alkali solution, and the pH value of the alkali solution is controlled to be 9-14.

According to an embodiment of the present invention, the base for adjusting the pH is selected from any one or more of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, aqueous ammonia, buffer solution.

According to an embodiment of the invention, the buffer solution is selected from the group consisting of carbonate-bicarbonate buffer, barbituric sodium-hydrochloric acid buffer, glycine-sodium hydroxide buffer, boric acid-sodium hydroxide buffer.

According to the embodiment of the invention, the mass ratio of the crude product containing AT3, the organic solvent and the alkali solution is 1: 2-10: 10 to 21, preferably, the mass ratio of the crude product containing AT3, the organic solvent and the alkali solution is 1: 3-10: 12-21.

According to an embodiment of the present invention, the sizing temperature is controlled to be 15 to 45 degrees celsius, preferably 25 to 45 degrees celsius, more preferably 30 degrees celsius.

According to an embodiment of the invention, the sizing time is controlled to be 0.5-2 hours.

According to an embodiment of the present invention, the crude product containing AT3 contains impurities including AT least one selected from the group consisting of:

purification method of alcaftadine intermediate AT3

In a third aspect of the present invention, the present invention provides a method for purifying an alcaftadine intermediate AT3, comprising: performing slurry washing and separation on the crude product containing the AT3 to obtain purified AT3; the sizing treatment further comprises: performing slurry washing on the crude product containing AT3 by using a mixed solution; the mixed solution comprises an organic solvent and an aqueous phase solvent.

Wherein, AT3 is a compound represented by formula (I):

according to an embodiment of the invention, the organic solvent comprises one or more of the halogenated methanes, preferably dichloromethane.

According to an embodiment of the present invention, the aqueous solvent is an alkaline solution, the pH value of the alkaline solution is controlled to be 9-14, and preferably, the pH-adjusting alkali is selected from any one or more of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, ammonia water, and a buffer solution. The purity of the purified AT3 can reach more than 95 percent.

According to the embodiment of the invention, the mass ratio of the crude product containing AT3, the organic solvent and the alkali solution is 1: 2-10: 10 to 21, preferably, the mass ratio of the crude product containing AT3, the organic solvent and the alkali solution is 1: 3-10: 12-21. The purity of the purified AT3 can reach more than 96 percent, and the content of impurity C can be controlled below 0.5 percent.

According to an embodiment of the present invention, the sizing temperature is controlled to be 15-45 degrees celsius, preferably 25-45 degrees celsius, more preferably 30 degrees celsius. The purity of the AT3 after purification can reach more than 96.5%, and the content of impurity C can be controlled below 0.4%.

According to an embodiment of the invention, the sizing time is controlled to be 0.5-2 hours. The purity of the purified AT3 can reach more than 98.5 percent.

According to an embodiment of the invention, the buffer solution is selected from the group consisting of carbonate-bicarbonate buffer, barbituric sodium-hydrochloric acid buffer, glycine-sodium hydroxide buffer, boric acid-sodium hydroxide buffer. The purity of the AT3 after purification can reach more than 99.5%, and the content of impurity C can be controlled below 0.2%.

The inventors have unexpectedly found that purifying the crude product of AT3 to obtain high-purity AT3 and then oxidizing to obtain alcaftadine can not only increase the yield of the step of oxidizing AT3 to alcaftadine, but also increase the stability of the final product alcaftadine, thereby prolonging the shelf life of the final product alcaftadine.

The scheme of the present invention will be explained below with reference to examples. It will be appreciated by those skilled in the art that the following examples are illustrative of the present invention and should not be construed as limiting the scope of the invention. The examples are not to be construed as limiting the specific techniques or conditions described in the literature in this field or as per the specifications of the product. The reagents or apparatus used were conventional products commercially available without the manufacturer's attention.

Example 1

AT3 was prepared from AT2 and has the following chemical formula:

the specific operation steps are as follows: 2.2kg of AT2, acetic acid (0.55 kg), 37% formaldehyde solution (6L) and 1.25kg of anhydrous sodium acetate were added to the reaction vessel, heated to 80 to 100℃and stirred for 18 to 30 hours, and the reaction mixture was cooled to 25 to 30 ℃. Dichloromethane (22L) was added to the reaction mixture and stirred for 30 minutes. The pH of the aqueous layer was adjusted to 8-11 with 20% sodium hydroxide. Stirring was continued for 0.5 hour, the organic layer was separated, washed twice with 20% sodium hydroxide solution, stirred well with anhydrous sodium sulfate, left to stand and dried. Vacuum filtering, concentrating the filtrate AT 35-45 deg.c to separate out solid, vacuum filtering to obtain coarse AT3 product with AT3 purity of 77.98%, AT2 residue of 19.16% and impurity C content of 2.86%.

Example 2

The following experimental and comparative groups have the general concept: the crude product containing AT3 prepared in example 1 was subjected to a slurry washing treatment to obtain purified AT3.

Experiment group 1

20g of the crude product (AT 3 content 77.98%, AT2 residue 19.16%, impurity C content 2.86%) containing AT3 obtained in example 1, 80g of methylene chloride and 320g of aqueous potassium carbonate solution with pH of 10 were added into a 1L three-necked flask, the temperature was raised to 30 ℃, the mixture was stirred for 1 hour, the mixture was filtered while it was hot, and the filter cake was dried to obtain purified AT3 with a yield of 96.1%. In the purified AT3, the content of AT3 was 98.98%, the residual content of AT2 was 0.74%, and the content of impurity C was 0.28%.

Experiment group 2

20g of the crude product obtained in example 1 (77.98% AT3 content, 19.16% AT2 residue, 2.86% impurity C content) containing AT3, 60g of methylene chloride and 420g of aqueous sodium bicarbonate solution with pH 8 were added to a 1L three-neck flask, the temperature was raised to 25 ℃, stirred for 0.5 hour, filtered off while hot, and the filter cake was dried to obtain purified AT3 with a yield of 96.7%. In the purified AT3, the content of AT3 is 98.88%, the residual content of AT2 is 0.79%, and the content of impurity C is 0.33%.

Experiment group 3

20g of the crude product (AT 3 content 77.98%, AT2 residue 19.16%, impurity C content 2.86%) containing AT3 obtained in example 1, 200g of methylene chloride, 240g of aqueous potassium hydroxide solution with pH of 14 were added into a 1L three-necked flask, the temperature was raised to 45 ℃, the mixture was stirred for 2 hours, suction filtration was carried out while the mixture was still hot, and the filter cake was dried to obtain purified AT3 with a yield of 96.3%. The AT3 content was 98.89%, the AT2 residue was 0.85%, and the impurity C content was 0.26%.

Experiment group 4

20g of the crude product (AT 3 content 77.98%, AT2 residue 19.16%, impurity C content 2.86%) containing AT3 obtained in example 1, 80g of chloroform, 320g of aqueous potassium carbonate solution having a pH of 10 were charged into a 1L three-necked flask, the temperature was raised to 30℃and stirred for 1 hour, suction filtration was carried out while the mixture was still hot, and the filter cake was dried to obtain purified AT3 in a yield of 96.1%. In the purified AT3, the content of AT3 was 98.61%, the residual content of AT2 was 0.98%, and the content of impurity C was 0.41%.

Experiment group 5

20g of the crude product (AT 3 content 77.98%, AT2 residue 19.16%, impurity C content 2.86%) containing AT3 obtained in example 1, 80g of methylene chloride and 320g of sodium carbonate-sodium bicarbonate buffer solution with pH of 10 were added into a 1L three-neck flask, the temperature was raised to 30 ℃, the mixture was stirred for 1 hour, the mixture was filtered while hot, and the filter cake was dried to obtain purified AT3, the yield was 96.1%. In the purified AT3, the AT3 content was 99.51%, the AT2 residue was 0.36%, and the impurity C content was 0.13%.

The comparison of experiment set 5 with experiment set 1 shows that when the alkali solution is the buffer system in the slurry washing solution, the purity of the purified AT3 is further improved, the AT2 residue is reduced, and the content of impurity C is further controlled, probably because the impurity is more stably enriched in the slurry washing solution when the pH in the alkali solution is stable, thereby, the purity of AT3 is higher, the AT2 residue is reduced, and the content of impurity C is reduced when AT3 is separated after the slurry washing.

Experiment group 6

20g of the crude product (AT 3 content 77.98%, AT2 residue 19.16%, impurity C content 2.86%) containing AT3 obtained in example 1, 40g of methylene chloride and 200g of aqueous potassium carbonate solution with pH of 10 were added into a 1L three-necked flask, the temperature was raised to 30 ℃, the mixture was stirred for 1 hour, the mixture was filtered while it was hot, and the filter cake was dried to obtain purified AT3 with a yield of 96.6%. In the purified AT3, the content of AT3 was 95.95%, the residual content of AT2 was 3.46%, and the content of impurity C was 0.59%.

The comparison of the experimental group 6 with the experimental group 1 shows that when the mass ratio of the AT3 crude product, chloroform and alkali solution is changed, the purity of the purified AT3 is reduced, the AT2 residue is increased, the content of the impurity C is increased, the reason is that the crude product containing the AT3, the organic solvent and the alkali solution in the system are mutually insoluble, the impurity can reach the maximum enrichment in the slurry washing liquid only if the mass ratio is within a certain range, the dissolution amount of the AT3 in the slurry washing liquid is less, and the purification effect is reduced when the mass ratio is exceeded.

Experiment group 7

20g of the crude product (AT 3 content 77.98%, AT2 residue 19.16%, impurity C content 2.86%) containing AT3 obtained in example 1, 80g of methylene chloride and 320g of aqueous potassium carbonate solution with pH of 10 were added into a 1L three-necked flask, the temperature was raised to 15 ℃, the mixture was stirred for 1 hour, the mixture was filtered while it was hot, and the filter cake was dried to obtain purified AT3 with a yield of 96.1%. In the purified AT3, the content of AT3 was 96.65%, the residual content of AT2 was 2.89%, and the content of impurity C was 0.46%.

Compared with the experiment group 1, the experiment group 7 shows that when the temperature is changed, the purity of the purified AT3 is reduced, the AT2 residue is increased, the content of the impurity C is increased, and the reasons are that the crude product containing the AT3, the organic solvent and the alkali solution in the system are mutually insoluble, the temperature is different, the solubility of the AT3, the AT2 and the impurity C in the organic solvent and the alkali solution is also changed, and the purification effect is further influenced.

Comparative group 1

20g of the crude product (AT 3 content 77.98%, AT2 residue 19.16%, impurity C content 2.86%) containing AT3 obtained in example 1, 80g of ethyl acetate and 320g of aqueous potassium carbonate solution with pH 10 were added into a 1L three-neck flask, the temperature was raised to 30 ℃, the mixture was stirred for 1 hour, the mixture was filtered while it was hot, and the filter cake was dried to obtain purified AT3 with a yield of 95.7%. In the purified AT3, the content of AT3 was 91.67%, the AT2 remained 7.42%, and the content of impurity C was 0.91%.

Comparative group 2

20g of the crude product (AT 3 content 77.98%, AT2 residue 19.16%, impurity C content 2.86%) containing AT3 obtained in example 1, 80g of methylene chloride and 320g of water were added into a 1L three-necked flask, the temperature was raised to 30 ℃, the mixture was stirred for 1 hour, the mixture was filtered while it was hot, and the filter cake was dried to obtain purified AT3, the yield of which was 96.1%. In the purified AT3, the content of AT3 was 94.46%, the residual content of AT2 was 4.56%, and the content of impurity C was 0.98%.

Comparison of comparison group 1 and comparison group 2 with experiment group 1 shows that when the type of the sizing agent is changed (the type of the organic solvent is changed, the pH value of the aqueous phase solvent is changed), the purity of the purified AT3 is obviously reduced, the AT2 residue is increased, and the content of impurity C is increased, because the purification effect of the AT3 crude product can be achieved only by sizing with a specific system.

Comparative group 3

20g of the crude AT3 product obtained in example 1 (AT 3 content 77.98%, AT2 residue 19.16%, impurity C content 2.86%) and 80g of methylene chloride were added into a 1L three-necked flask, the temperature was raised to 30 ℃, the mixture was stirred for 1 hour, the mixture was filtered while hot, and the filter cake was dried to obtain purified AT3 with a yield of 93.4%. The purity of the purified AT3 is 83.03%, the AT2 residue is 15.01%, and the impurity C content is 1.96%.

Comparative group 4

20g of the crude AT3 product obtained in example 1 (AT 3 content 77.98%, AT2 residue 19.16%, impurity C content 2.86%) and 320g of aqueous potassium carbonate solution having a pH of 10 were added to a 1L three-necked flask, the temperature was raised to 30℃and stirred for 1 hour, and the mixture was filtered while hot and the filter cake was dried to obtain purified AT3 in a yield of 94.5%. The purity of AT3 is 80.05%, the residue of AT2 is 18.55%, and the content of impurity C is 1.40%.

Comparative group 5

20g of the crude AT3 product obtained in example 1 (AT 3 content 77.98%, AT2 residue 19.16%, impurity C content 2.86%) and 80g of methylene chloride were added into a 1L three-neck flask, the temperature was raised to 30 ℃, the mixture was stirred for 1 hour, the filter cake was filtered while hot, the filter cake was dried, 320g of an aqueous potassium carbonate solution with pH of 10 was added into the 1L three-neck flask, the temperature was raised to 30 ℃, the mixture was stirred for 1 hour, the filter cake was filtered while hot, and the dried filter cake was obtained as purified AT3 in 89.8% yield. The purity of AT3 was 89.97%, the residual content of AT2 was 8.84%, and the impurity C content was 1.19%.

The comparison of the comparison groups 3-5 with the experimental group 1 shows that when the AT3 crude product is pulped by the mixed solvent of dichloromethane and alkali solution, the purification effect is obviously better than that of the organic solvent or alkali solution which is solely pulped, and is also better than that of the alkaline water which is pulped after the dichloromethane is pulped, thus obtaining the unexpected technical effect that 1+1 is more than 2.

Comparative group 6

The crude AT 3-containing product obtained in example 1 (AT 3 content 77.98%, AT2 residue 19.16%, impurity C content 2.86%) was purified by column chromatography (silica gel; CH2Cl2/CH3OH 95:5). The desired fraction of the eluent was evaporated, the residue was crystallized from acetonitrile, the product was filtered off and dried, and the filter cake was dried to give purified AT3. The yield was 13.11%, the AT3 purity was 97.14%, the AT2 raw material remained 1.83%, and the impurity C content was 1.03%.

The comparison between the comparison group 6 and the experimental group shows that the purification method of the crude product containing AT3 is obviously superior to the prior art method, and the purification effect is better and the yield is higher.

As is clear from the results of experimental groups 1 to 7 and comparative groups 1 to 6 in example 2, the AT3 purity can reach more than 95% by subjecting the crude AT3 to a slurry washing treatment. In the purification process of the alcaftadine intermediate AT3, the mass ratio of the crude product containing AT3, the organic solvent and the alkaline solution is controlled, preferably, when the mass ratio of the crude product containing AT3, the organic solvent and the alkaline solution is 1: 3-10: 12-21, wherein the organic solvent is halogenated alkane, and the pH value of the alkali solution is 8-14, AT2 residue and impurity C in the AT3 crude product can be more enriched in the mixed solution composed of the organic solvent and the alkali solution, and then AT3 with higher purity is obtained when the AT3 is separated from the mixed solution. The purity of the purified AT3 can reach more than 98.5%, and the AT2 residue in the purified AT3 is controlled to be less than 1%, and the impurity C residue is controlled to be less than 0.5%. When the alkali solution is a buffer system, the purity of AT3 can be further improved to more than 99%, the residual AT2 in AT3 can be further reduced to less than 0.6%, and the residual impurity C can be further reduced to less than 0.2%. In addition, when the AT3 crude product is subjected to slurry washing by using the mixed solvent, the effect is obviously better than that of single slurry washing by using an organic solvent or an alkali solution, and is better than that of alkaline water slurry washing after dichloromethane slurry washing, and is better than that of the column chromatography technology in the prior art, and the yield of the slurry washing by using the method is more than 90 percent, and is obviously better than that of 10-20 percent of the column chromatography in the prior art.

Example 3

The following experimental and comparative groups have the general concept: the purified AT3 prepared in example 2 was oxidized with dess-martin reagent to give alcaftadine, which had the following chemical reaction formula:

experiment group 1

Adding 30.9g (0.1 mol) of AT3 purified in the experimental group 1 in the example 2, 200mL of dichloromethane, 100mL of tertiary butanol and 5mL of water into a 1000 three-neck flask, stirring and dissolving AT 10-20 ℃, adding 38.2g of dess-martin reagent, heating to 20-30 ℃ after the addition, continuously stirring for 25min, cooling to 15-20 ℃, weighing 25.4g of dess-martin reagent, adding the dess-martin reagent into a reaction system, heating to 20-30 ℃ after the addition, continuously stirring for 20-30 min, cooling to 15-20 ℃, monitoring until the reaction is complete by TLC, filtering, washing the filtrate once by 100mL of 10% sodium thiosulfate solution, separating an organic layer, washing by 100mL of saturated 5% sodium bicarbonate solution, separating the organic layer, adding anhydrous sodium sulfate for drying, filtering, and concentrating under reduced pressure. Adding 50mL of isopropanol into the obtained oily matter, stirring, cooling to separate out solid, and carrying out suction filtration and drying to obtain an off-white solid, namely the alcaftadine. The purity of the obtained alcaftadine is 99.74%.

Experiment group 2

Adding 30.9g (0.1 mol) of AT3 purified in the experimental group 1 in the example 2, 200mL of dichloromethane, 200mL of tertiary butanol and 2mL of water into a 1000 three-neck flask, stirring and dissolving AT 10-20 ℃, adding 19.1g of dess-martin reagent, heating to 20-30 ℃ after the addition, continuously stirring for 20min, cooling to 15-20 ℃, weighing 44.5g of dess-martin reagent, adding the dess-martin reagent into a reaction system, heating to 20-30 ℃ after the addition, continuously stirring for 20-30 min, cooling to 15-20 ℃, monitoring until the reaction is complete by TLC, filtering, washing the filtrate once by 100mL of 10% sodium thiosulfate solution, separating an organic layer, washing by 100mL of saturated 5% sodium bicarbonate solution, separating the organic layer, adding anhydrous sodium sulfate for drying, filtering, and concentrating under reduced pressure. Adding 50mL of isopropanol into the obtained oily matter, stirring, cooling to separate out solid, and carrying out suction filtration and drying to obtain an off-white solid, namely the alcaftadine. The purity of the obtained alcaftadine is 99.68%.

Experiment group 3

Adding 30.9g (0.1 mol) of AT3 purified in the experimental group 1 in the example 2, 200mL of dichloromethane, 150mL of tertiary butanol and 10mL of water into a 1000 three-neck flask, stirring and dissolving AT 10-20 ℃, adding 44.5g of dess-martin reagent, heating to 20-30 ℃ after the addition, continuously stirring for 30min, cooling to 15-20 ℃, weighing 19.1g of dess-martin reagent, adding into a reaction system, heating to 20-30 ℃ after the addition, continuously stirring for 20-30 min, cooling to 15-20 ℃, monitoring until the reaction is complete by TLC, filtering, washing the filtrate once by 100mL of 10% sodium thiosulfate solution, separating an organic layer, washing by 100mL of saturated 5% sodium bicarbonate solution, separating the organic layer, adding anhydrous sodium sulfate for drying, filtering, and concentrating under reduced pressure. Adding 50mL of isopropanol into the obtained oily matter, stirring, cooling to separate out solid, and carrying out suction filtration and drying to obtain an off-white solid, namely the alcaftadine. The purity of the obtained alcaftadine is 99.62%.

Experiment group 4

Adding 30.9g (0.1 mol) of purified AT 3.9 g (200 mL) of the experimental group 1, 200mL of dichloromethane, 200mL of tertiary butanol and 5mL of water into a 1000 three-neck flask, stirring and dissolving AT 10-20 ℃, adding 38.2g of dess-martin reagent, heating to 20-30 ℃ after the addition, continuously stirring for 25min, cooling to 15-20 ℃, weighing 25.4g of dess-martin reagent and 0.31g of disodium EDTA into a reaction system, heating to 20-30 ℃ after the addition, continuously stirring for 20-30 min, cooling to 15-20 ℃, monitoring the reaction to be complete by TLC, carrying out suction filtration, washing the filtrate once by 100mL of 10% sodium thiosulfate solution, separating out an organic layer, washing by 100mL of saturated 5% sodium bicarbonate solution, separating out organic layer, adding anhydrous sodium sulfate, drying, carrying out suction filtration, and concentrating under reduced pressure. Adding 50mL of isopropanol into the obtained oily matter, stirring, cooling to separate out solid, and carrying out suction filtration and drying to obtain an off-white solid, namely the alcaftadine. The purity of the obtained alcaftadine is 99.94%.

As can be seen from comparison of the experimental group 4 and the experimental group 1, when the additive EDTA disodium is added into the reaction system, the purity of the obtained alcaftadine is improved to more than 99.9%.

Comparative group 1

Adding 30.9g (0.1 mol) of AT3 purified in the experimental group 1 in the example 2, 200mL of dichloromethane, 200mL of tertiary butanol and 5mL of water into a 1000 three-neck flask, stirring and dissolving AT 10-20 ℃, adding 50.9g of dess-martin reagent, heating to 20-30 ℃ after the addition, continuously stirring for 25min, cooling to 15-20 ℃, weighing 12.7g of dess-martin reagent, adding into a reaction system, heating to 20-30 ℃ after the addition, continuously stirring for 20-30 min, cooling to 15-20 ℃, monitoring until the reaction is complete by TLC, filtering, washing the filtrate once by 100mL of 10% sodium thiosulfate solution, separating an organic layer, washing by 100mL of saturated 5% sodium bicarbonate solution, separating the organic layer, adding anhydrous sodium sulfate for drying, filtering, and concentrating under reduced pressure. Adding 50mL of isopropanol into the obtained oily matter, stirring, cooling to separate out solid, and carrying out suction filtration and drying to obtain an off-white solid, namely the alcaftadine. The purity of the obtained alcaftadine is 99.28%.

Comparison of comparative group 1 with experimental group 1 shows that when the amount of dess-martin reagent added for the first time is changed, the purity of the alcaftadine is reduced, probably because the oxidation reaction can be controlled within a certain intensity range by controlling the amount of the oxidant dess-martin reagent added for the first time, and thus higher purity of alcaftadine can be obtained.

Comparative group 2

Adding 30.9g (0.1 mol) of AT3 purified in the experimental group 1 in the example 2, 200mL of dichloromethane, 100mL of tertiary butanol and 5mL of water into a 1000 three-neck flask, stirring and dissolving AT 10-20 ℃, adding 38.2g of dess-martin reagent, heating to 20-30 ℃ after the addition, continuously stirring for 40min, cooling to 15-20 ℃, weighing 25.4g of dess-martin reagent, adding the dess-martin reagent into a reaction system, heating to 20-30 ℃ after the addition, continuously stirring for 20-30 min, cooling to 15-20 ℃, monitoring until the reaction is complete by TLC, filtering, washing the filtrate once by 100mL of 10% sodium thiosulfate solution, separating an organic layer, washing by 100mL of saturated 5% sodium bicarbonate solution, separating the organic layer, adding anhydrous sodium sulfate for drying, filtering, and concentrating under reduced pressure. Adding 50mL of isopropanol into the obtained oily matter, stirring, cooling to separate out solid, and carrying out suction filtration and drying to obtain an off-white solid, namely the alcaftadine. The purity of the obtained alcaftadine is 99.40%.

Comparison of comparative group 2 with experimental group 1 shows that there is a decrease in the purity of alcaftadine when the time interval between the first and second additions of dess-martin reagent is varied, probably because the time interval between the first and second additions of dess-martin reagent, which is an oxidizing agent, can be controlled appropriately to control the progress of the oxidation reaction, and thus can help to obtain higher purity alcaftadine.

Comparative group 3

Adding 30.9g (0.1 mol) of purified AT3 of the experimental group 1, 200mL of dichloromethane and 100mL of tertiary butanol into a 1000 three-neck flask, stirring and dissolving AT 10-20 ℃, adding 38.2g of dess-martin reagent, heating to 20-30 ℃ after the addition is finished, continuing stirring for 25min, cooling to 15-20 ℃, weighing 25.4g of dess-martin reagent, adding the reaction system, heating to 20-30 ℃ after the addition, continuing stirring for 20-30 min, cooling to 15-20 ℃, monitoring until the reaction is complete by TLC, carrying out suction filtration, washing the filtrate once by 100mL of 10% sodium thiosulfate solution, separating out an organic layer, washing by 100mL of saturated 5% sodium bicarbonate solution, separating out the organic layer, adding anhydrous sodium sulfate, drying by suction filtration, and concentrating under reduced pressure. Adding 50mL of isopropanol into the obtained oily matter, stirring, cooling to separate out solid, and carrying out suction filtration and drying to obtain an off-white solid, namely the alcaftadine. The purity of the obtained alcaftadine is 99.33%.

Comparison of comparative group 3 with experimental group 1 shows that when the solvent of the reaction system does not contain water, the purity of the obtained alcaftadine is lowered, probably because the addition of water suppresses the formation of certain impurities and improves the purity of the product.

Comparative group 4

The purified AT 3.9 g (0.1 mol), 200mL of dichloromethane, 200mL of tertiary butanol and 5mL of water in the experimental group 1 of example 2 are added into a 1000 three-neck flask, stirred and dissolved AT the temperature of 10-20 ℃, 63.6g of dess-Martin reagent is added, the temperature is raised to 20-30 ℃ after the addition, the stirring is continued for 20-30 min, the temperature is reduced to 15-20 ℃, TLC monitors that the reaction is complete, suction filtration is carried out, the filtrate is washed once by 100mL of 10% sodium thiosulfate solution, the organic layer is separated out by 100mL of saturated 5% sodium bicarbonate solution, anhydrous sodium sulfate is added for drying, suction filtration is carried out, and vacuum filtration and concentration are carried out. Adding 50mL of isopropanol into the obtained oily matter, stirring, cooling to separate out solid, and carrying out suction filtration and drying to obtain an off-white solid, namely the alcaftadine. The purity of the obtained alcaftadine is 99.01%.

From the experimental groups 1 to 4 and comparative groups 1 to 4 of example 3, it is understood that, in the step of oxidizing purified AT3 into acaradine, the dess-martin reagent is added in batches, the solvent is a mixed solvent of tert-butanol, dichloromethane and water, the first batch of dess-martin reagent is added in an amount of 0.3 to 0.7 times the total addition amount, and the purity of acaradine is increased to 99.5% or more when the time interval between the first addition and the second addition of dess-martin reagent is 20 to 30 minutes. When EDTA disodium is added into the reaction system, the purity is further improved to more than 99.9 percent.

Example 4

The following experimental groups had the general concept: the typical purified AT3 obtained in example 2 (example 2 experiment set 1, example 2 experiment set 5, example 2 experiment set 6, example 2 comparison set 2, example 2 comparison set 5) was used to prepare alcaftadine using the example 3 optimized alcaftadine preparation process (example 3 experiment set 4), and the effect of the example 2 preparation process and purified AT3 on the alcaftadine preparation process and alcaftadine was explored. The reaction scheme is shown in example 3. In this example, yield = actual yield of alcaftadine/theoretical yield of alcaftadine, where the theoretical yield of alcaftadine is (mass of AT3 x purity/molar mass of AT 3) x molar mass of AT 4.

Experiment group 1

Experimental group 4 as in example 3. The yield thereof was found to be 95.1%.

Experiment group 2

Adding 30.9g (0.1 mol) of AT3, 200mL of dichloromethane, 200mL of tertiary butanol and 5mL of water purified in the experimental group 5 in the example 2 into a 1000 three-neck flask, stirring and dissolving AT 10-20 ℃, adding 38.2g of dess-martin reagent, heating to 20-30 ℃ after the addition, continuously stirring for 25min, cooling to 15-20 ℃, weighing 25.4g of dess-martin reagent and 0.31g of EDTA disodium, adding into a reaction system, heating to 20-30 ℃ after the addition, continuously stirring for 20-30 min, cooling to 15-20 ℃, monitoring the reaction to be complete by TLC, carrying out suction filtration, washing the filtrate once by 100mL of 10% sodium thiosulfate solution, separating out an organic layer, washing by 100mL of saturated 5% sodium bicarbonate solution, separating out organic layer, adding anhydrous sodium sulfate, drying by suction filtration, and concentrating under reduced pressure. Adding 50mL of isopropanol into the obtained oily matter, stirring, cooling to separate out solid, and carrying out suction filtration and drying to obtain an off-white solid, namely the alcaftadine. The yield thereof was found to be 96.9%.

Experiment group 3

Adding 30.9g (0.1 mol) of purified AT3, 200mL of dichloromethane, 200mL of tertiary butanol and 5mL of water in the experimental group 6 in the example 2 into a 1000 three-neck flask, stirring and dissolving AT 10-20 ℃, adding 38.2g of dess-martin reagent, heating to 20-30 ℃ after the addition, continuously stirring for 25min, cooling to 15-20 ℃, weighing 25.4g of dess-martin reagent and 0.31g of EDTA disodium, adding into a reaction system, heating to 20-30 ℃ after the addition, continuously stirring for 20-30 min, cooling to 15-20 ℃, monitoring the reaction to be complete by TLC, carrying out suction filtration, washing the filtrate once by 100mL of 10% sodium thiosulfate solution, separating out an organic layer, washing by 100mL of saturated 5% sodium bicarbonate solution, separating out organic layer, adding anhydrous sodium sulfate, drying by suction filtration, and concentrating under reduced pressure. Adding 50mL of isopropanol into the obtained oily matter, stirring, cooling to separate out solid, and carrying out suction filtration and drying to obtain an off-white solid, namely the alcaftadine. The yield thereof was found to be 91.3%.

Comparative group 1

Adding 30.9g (0.1 mol) of AT3, 200mL of dichloromethane, 200mL of tertiary butanol and 5mL of water purified in the comparative group 2 in the example 2 into a 1000 three-neck flask, stirring and dissolving AT 10-20 ℃, adding 38.2g of dess-martin reagent, heating to 20-30 ℃ after the addition, continuously stirring for 25min, cooling to 15-20 ℃, weighing 25.4g of dess-martin reagent and 0.31g of EDTA disodium, adding into a reaction system, heating to 20-30 ℃ after the addition, continuously stirring for 20-30 min, cooling to 15-20 ℃, monitoring the reaction to be complete by TLC, carrying out suction filtration, washing the filtrate once by 100mL of 10% sodium thiosulfate solution, separating out an organic layer, washing by 100mL of saturated 5% sodium bicarbonate solution, separating out organic layer, adding anhydrous sodium sulfate, drying by suction filtration, and concentrating under reduced pressure. Adding 50mL of isopropanol into the obtained oily matter, stirring, cooling to separate out solid, and carrying out suction filtration and drying to obtain an off-white solid, namely the alcaftadine. The yield thereof was found to be 89.3%.

Comparative group 2

Adding 30.9g (0.1 mol) of AT3, 200mL of dichloromethane, 200mL of tertiary butanol and 5mL of water purified in the comparative group 5 in the example 2 into a 1000 three-neck flask, stirring and dissolving AT 10-20 ℃, adding 38.2g of dess-martin reagent, heating to 20-30 ℃ after the addition, continuously stirring for 25min, cooling to 15-20 ℃, weighing 25.4g of dess-martin reagent and 0.31g of EDTA disodium, adding into a reaction system, heating to 20-30 ℃ after the addition, continuously stirring for 20-30 min, cooling to 15-20 ℃, monitoring the reaction to be complete by TLC, carrying out suction filtration, washing the filtrate once by 100mL of 10% sodium thiosulfate solution, separating out an organic layer, washing by 100mL of saturated 5% sodium bicarbonate solution, separating out organic layer, adding anhydrous sodium sulfate, drying by suction filtration, and concentrating under reduced pressure. Adding 50mL of isopropanol into the obtained oily matter, stirring, cooling to separate out solid, and carrying out suction filtration and drying to obtain an off-white solid, namely the alcaftadine. The yield thereof was found to be 82.6%.

The acaradine obtained in the experimental groups 1, 2, 3 and the comparative groups 1 and 2 is packaged and placed under the conditions of 25 ℃ +/-2 ℃ and relative humidity RH60% +/-10%, and is sampled and detected respectively in 0 day, 6 months and 12 months, and the impurity and purity data after long-term test are shown in table 1:

TABLE 1 experiment groups 1, 2, 3, 4, alcatedine obtained in comparative example 1 was subjected to long-term test of impurities and purity data

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From example 4, it is clear that the purification step of AT3 has a certain effect on the yield of the step of oxidizing AT3 to alcaftadine, which is probably because, when AT3 is not purified thoroughly enough, some impurities remain which have a negative effect on the step of oxidizing AT3 to alcaftadine, resulting in a reduced yield; on the other hand, the purification step of AT3 has a certain effect on the stability of the alcaftadine, probably because, when AT3 is not purified thoroughly enough, some impurities remain which also affect the quality of the final product alcaftadine. When the purity of AT3 reaches more than 95%, the purity of the final product of the alcaftadine bulk drug is more than 99.5% after being placed for 12 months for a long time, and the requirement of safe drug administration can be met. The AT3 crude product is purified to obtain high-purity AT3, and the high-purity AT3 is subjected to oxidation reaction to obtain the alcaftadine, so that the yield of the step of oxidizing the AT3 into the alcaftadine can be improved, the cost can be reduced, the stability of the final product of the alcaftadine can be improved, and the storage period of the final product of the alcaftadine can be prolonged.

The terms "first," "second," and the like herein are used for descriptive purposes only and are not to be construed as indicating or implying relative importance or implicitly indicating the number of technical features indicated. Thus, a feature defining "a first" or "a second" may explicitly or implicitly include at least one such feature. In the description of the present invention, the meaning of "plurality" means at least two, for example, two, three, etc., unless specifically defined otherwise.

In the description of the present specification, a description referring to terms "one embodiment," "some embodiments," "examples," "specific examples," or "some examples," etc., means that a particular feature, structure, material, or characteristic described in connection with the embodiment or example is included in at least one embodiment or example of the present invention. In this specification, schematic representations of the above terms are not necessarily directed to the same embodiment or example. Furthermore, the particular features, structures, materials, or characteristics described may be combined in any suitable manner in any one or more embodiments or examples. Furthermore, the different embodiments or examples described in this specification and the features of the different embodiments or examples may be combined and combined by those skilled in the art without contradiction.

While embodiments of the present invention have been shown and described above, it will be understood that the above embodiments are illustrative and not to be construed as limiting the invention, and that variations, modifications, alternatives and variations may be made to the above embodiments by one of ordinary skill in the art within the scope of the invention.

Claims (12)

1. A process for the preparation of alcaftadine, characterized in that it is obtained by oxidation of AT3 with dess-martin reagent, said oxidation reaction comprising: carrying out oxidation reaction on AT3 and part of the dess-martin reagent, and adding the rest dess-martin reagent after the oxidation reaction is carried out for a period of time; the weight of the part of the dess-martin reagent is 0.3-0.7 times of the total addition amount of the dess-martin reagent, and the solvent used in the reaction system comprises dichloromethane, tertiary butanol and water, wherein the period of time is 20-30 min;

wherein, AT3 is a compound represented by formula (I):

in the solvent used in the reaction system, the volume ratio of dichloromethane to tertiary butanol to water is 20:10-20:0.1-0.5; the purity of the AT3 is above 98.5%.

2. The method of claim 1, wherein the remaining dess-martin reagent is added simultaneously with the addition of an additive, said additive being EDTA or a sodium salt thereof.

3. The method of claim 2, wherein the additive is selected from EDTA, EDTA-disodium, EDTA-tetrasodium.

4. The method according to claim 2, wherein the mass control of the additive is 0.005 to 0.02 times the mass of AT 3.

5. The method according to claim 1, wherein the AT3 is obtained by subjecting a crude product containing AT3 to a slurry wash, and separating; the sizing treatment comprises: performing slurry washing on the crude product containing AT3 by using a mixed solution; the mixed solution comprises an organic solvent and an aqueous phase solvent; the organic solvent includes one or more of halogenated methane.

6. The method of claim 5, wherein the organic solvent is methylene chloride; the aqueous phase solvent is an alkali solution.

7. The method according to claim 6, wherein the pH of the alkaline solution is controlled to 9-14.

8. The method of claim 7, wherein the pH adjusting base is selected from any one or more of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, ammonia, a buffer solution selected from the group consisting of carbonate-bicarbonate buffer, barbituric sodium-hydrochloric acid buffer, glycine-sodium hydroxide buffer, boric acid-sodium hydroxide buffer.

9. The method according to claim 6, wherein the mass ratio of the crude product containing AT3, the organic solvent and the alkaline solution is 1: 2-10: 10 to 21.

10. The method according to claim 6, wherein the mass ratio of the crude product containing AT3, the organic solvent and the alkaline solution is 1: 3-10: 12-21.

11. The method of claim 5, wherein the slurry wash temperature is controlled to be 15-45 degrees celsius.

12. The method of claim 11, wherein the slurry wash temperature is controlled to be 25-45 degrees celsius; the sizing time is controlled to be 0.5-2 hours.