CN114591332A

CN114591332A - Preparation method of alcaftadine and purification method of intermediate thereof

Info

Publication number: CN114591332A
Application number: CN202011416883.6A
Authority: CN
Inventors: 宁东波; 田俊锋; 陈彦; 朱毅; 殷晶莉; 蔡超
Original assignee: Wuhan Wuyao Science & Technology Co ltd
Current assignee: Wuhan Wuyao Science & Technology Co ltd
Priority date: 2020-12-07
Filing date: 2020-12-07
Publication date: 2022-06-07
Anticipated expiration: 2040-12-07
Also published as: CN114591332B

Abstract

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

Description

Preparation method of alcaftadine and purification method of intermediate thereof

Technical Field

The invention relates to a preparation method of a 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: lastacaft is a novel histamine H1 receptor antagonist and mast cell stabilizer developed by Weikang pharmacy, can inhibit histamine release from mast cells, can reduce chemotaxis and activation of eosinophils, is approved by the FDA in the U.S. at 7 months of 2010 and is marketed under the trade name Lastacaft. The alcaftadine is a medicine for treating allergic conjunctivitis-associated eye pruritus after bepotastine besilate developed by ISTA pharmaceutical company, and the medicine is eye drops and is used for treating allergic conjunctivitis-associated eye pruritus of people over 2 years old. Has good clinical application prospect. The structural formula is as follows:

U.S. patent application with publication number US5468743 discloses a method for preparing alcaftadine from 1H-3-benzazepin-2-amine and 2, 2-dimethoxyethylamine as raw materials, which comprises the steps of nucleophilic substitution, cyclization, oxidation, grignard reaction, hydrogenation and dehydration of 1H-3-benzazepin-2-amine and 2, 2-dimethoxyethylamine to obtain an intermediate 6, 11-dihydro-11- (1-methyl-4-piperidylidene) -5H-imidazo [2,1-b ] [3] hydrocinnazazepine (AT 2 for short), hydroxymethylation of AT2 to obtain AT3, and oxidation reaction of AT3 to synthesize alcaftadine.

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

PCT patent with application number WO2014154620 discloses a synthetic method of alcaftadine, which is a method for preparing alcaftadine by taking 1-phenethyl-1H-imidazole as a raw material, and specifically comprises the steps of synthesizing an intermediate AT2 by friedel-crafts acylation and cyclization of 1-phenethyl-1H-imidazole, reacting AT2 with acid to prepare a salt form, and then carrying out hydroxymethylation to obtain AT3 and AT3 to carry out oxidation reaction to synthesize alcaftadine.

In summary, the methods adopted in the last two steps of alcaftadine synthesis in the prior art are the same, and both 6, 11-dihydro-11- (1-methyl-4-piperidylidene) -5H-imidazo [2,1-b ] [3] benzazepine (AT 2 for short) is subjected to hydroxymethylation to obtain AT3, and AT3 is subjected to oxidation reaction to synthesize alcaftadine, so that the step is a key step for synthesizing alcaftadine. The quality, especially the purity, of the intermediate AT3 during the preparation process seriously affects the quality of alcaftadine. However, no effective method for purifying intermediate AT3 is known in the prior art, and the quality of alcaftadine in the prior art is yet to be improved.

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

Disclosure of Invention

The present invention is directed to solving, at least to some extent, one of the technical problems in the related art. 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 alcaftadine.

The inventor finds that the total impurity of the alcaftadine reference preparation is 0.5%, and the purity of alcaftadine raw material medicines in the prior art does not reach the requirement of 99.5%. By the preparation method, the impurity content in the alcaftadine raw material medicine can be effectively controlled, and the purity of the alcaftadine raw material medicine is improved.

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

wherein the AT3 is a compound of formula (I):

the dess-martin reagent is added in batches, which is beneficial to the alleviation of oxidation conditions, the generation of byproducts is reduced, and the purity of the prepared alcaftadine is improved.

According to the embodiment of the invention, the quality of the additive is controlled to be 0.005-0.02 times of the quality of AT 3;

according to the 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, tert-butyl alcohol and water, and preferably, the volume ratio of the dichloromethane to the tert-butyl alcohol 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 invention, the addition of the remaining dess-martin reagent is accompanied by the addition of an additive, preferably EDTA or its sodium salt; more preferably, the additive is selected from EDTA, EDTA-disodium, EDTA-tetrasodium. After the additive is added, the purity of the obtained alcaftadine is further improved.

The inventor also finds that the quality of the intermediate AT3 has an important influence on the quality of the final product alcaftadine in the synthetic process of alcaftadine.

According to an embodiment of the present invention, the AT3 has a purity of above 95%; preferably, the AT3 has a purity of greater than 98.5%.

In order to solve the technical problem, in the research process, the inventor notices that the crude product containing AT3 can be purified to improve the purity of AT3, and further, the alcaftadine prepared by the reaction can be simply post-treated to obtain the alcaftadine with higher purity. Therefore, the invention provides a method capable of effectively improving the purity of the intermediate AT 3.

According to the embodiment of the invention, the AT3 is obtained by carrying out slurry washing and separation on a crude product containing AT 3; the slurry washing treatment further comprises: carrying out 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 phase solvent are mutually insoluble, and are not limited by theory, when the three are in a 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 phase solvent reaches the maximum, and AT3 and the mixed solution are separated, so that 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 methyl halides, preferably dichloromethane. When the organic solvent is methyl halide, specifically methyl chloride, dichloromethane, trichloromethane, tetrachloromethane, bromomethane, dibromomethane, tribromomethane, tetrabromomethane and the like, the organic solvent and an aqueous phase solvent of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate and the like form a mixed solution, and the mixed solution is used for pulp washing a crude AT3 product, so that the impurity C and the residual AT2 can be enriched in a mixed solution system, and the impurity C and the residual AT2 can be dissolved in the mixed solution, can be contacted with the mixed solution and then wrapped in the mixed solution, and further the effect of purifying AT3 can be achieved by separating the mixed solution from AT 3. Thus, the purity of the purified AT3 can reach more than 97.5%, preferably more than 98.5%, even more than 99%, and the residue of AT2 in the purified AT3 is controlled below 2%, preferably below 1%, even below 0.5%, and the residue of impurity C is controlled below 0.6%, preferably below 0.4%, even below 0.2%.

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

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

According to the embodiment of the invention, the mass ratio of the AT 3-containing crude product to the organic solvent to the alkali solution is 1: 2-10: 10-21, preferably, the mass ratio of the AT 3-containing crude product to the organic solvent to the alkali solution is 1: 3-10: 12 to 21. The crude product containing AT3, the organic solvent and the alkali solution are not dissolved mutually, and according to the embodiment of the invention, the mass ratio of the three can influence the purification effect of the crude product containing AT3, and the influence is mainly shown in that: when the amount of the organic solvent is too low and the amount of the alkali solution is too low, the content of the impurities C and the content of the residual AT2 in AT3 are high, when the amount of the organic solvent is too low and the amount of the alkali solution is too high or the amount of the organic solvent is too high and the amount of the alkali solution is too low, the content of the impurities C and the content of the residual AT2 in AT3 are also high, and when the amount of the organic solvent is too high and the amount of the alkali solution is also too high, the purification yield is greatly reduced. The mass ratio of the organic solvent to the alkali solution is controlled, so that the removal effect of the mixed solution 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 the material is increased. Preferably, the mass ratio of the AT 3-containing crude product to the organic solvent to the alkali solution is 1: 3-10: 12-21, the purity of the purified AT3 can reach more than 98.5, even more than 99%, the residue of AT2 in the purified AT3 is controlled below 1%, even below 0.5%, and the residue of impurity C is controlled below 0.4%, even below 0.2%. The content of impurity F in the final acatadine thus obtained can be controlled to 0.05% or less.

According to the embodiment of the invention, the pulp washing temperature is controlled to be 15-45 ℃, preferably 25-45 ℃, and more preferably 30 ℃. When the temperature is too high, the solubility of the residues of AT3 and AT2 and the impurities C in the mixed solution is simultaneously increased, the purification yield is remarkably reduced, and when the temperature is too low, the removal effect of the residues of AT2 and the impurities C is not good.

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

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

the inventors surprisingly found that the purification of a crude product containing AT3 and the subsequent oxidation of the crude product to obtain alcaftadine not only improves the yield of the step of oxidizing AT3 into alcaftadine and reduces the cost, but also improves the stability of the final product alcaftadine and prolongs the storage period of the alcaftadine by purifying the crude product of AT3 to obtain high-purity AT3 and then performing an oxidation reaction to obtain alcaftadine.

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

According to the embodiment of the invention, the AT3 purity of the crude AT3 product can reach more than 95% by carrying out slurry washing treatment, the AT2 residue 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 the impurity C is controlled to less than 1%, preferably less than 0.6%, more preferably less than 0.4%, less than 0.2%. 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 to be below 0.1% by carrying out slurry washing treatment on the AT3 crude product.

According to an embodiment of the invention, a method for purifying acatadine intermediate AT3, comprises: carrying out slurry washing and separation on the crude product containing AT3 to obtain purified AT 3; the pulp washing treatment further comprises: carrying out 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 the AT3 is a compound of formula (I):

the crude product of AT3, the organic solvent and the aqueous phase solvent are mutually insoluble, and are not limited by theory, when the three are in a 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 phase solvent reaches the maximum, and AT3 and the mixed solution are separated, so that AT3 with higher purity can be obtained.

According to an embodiment of the invention, the organic solvent comprises one or more of methyl halides, preferably dichloromethane; when the organic solvent is methyl halide, specifically methyl chloride, dichloromethane, trichloromethane, tetrachloromethane, bromomethane, dibromomethane, tribromomethane, tetrabromomethane and the like, the organic solvent and an aqueous phase solvent of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate and the like form a mixed solution, and the mixed solution is used for pulp washing a crude AT3 product, so that the impurity C and the residual AT2 can be enriched in a mixed solution system, and the impurity C and the residual AT2 can be dissolved in the mixed solution, can be contacted with the mixed solution and then wrapped in the mixed solution, and further the effect of purifying AT3 can be achieved by separating the mixed solution from AT 3. Thus, the purity of the purified AT3 can reach more than 97.5%, preferably more than 98.5%, even more than 99%, and the residue of AT2 in the purified AT3 is controlled below 2%, preferably below 1%, even below 0.5%, and the residue of impurity C is controlled below 0.6%, preferably below 0.4%, even below 0.2%.

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

According to the embodiment of the invention, the pulp washing 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 the AT3 impurity C can be controlled below 1%, below 0.5%, even below 0.3%; the purity of AT3 can be controlled to be above 95%, above 98.5%, even above 99%, and the purification yield is above 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 has good stability, and the alcaftadine obtained by the method is placed for 6 months and 12 months in a fixed period, so that the purity is stable and good.

Detailed Description

The embodiments of the present invention are described in detail below, and it should be noted that the described embodiments are exemplary, are intended to explain the present invention and should not be construed as limiting the present 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 by oxidation of AT3 with a dess-martin reagent, said oxidation reaction comprising: carrying out oxidation reaction on AT3 and part of the dess-martin reagent, and adding the rest of the 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 0.3-0.7 times of the total addition amount of the dess-martin reagent,

wherein the AT3 is a compound of formula (I):

the oxidant dess-martin reagent is added in portions.

According to the embodiment of the invention, the solvent used in the reaction system comprises dichloromethane, tert-butyl alcohol and water, and preferably, the volume ratio of the dichloromethane to the tert-butyl alcohol to the water in the solvent used in the reaction system is 20: 10-20: 0.1-0.5. The purity of the alcaftadine obtained by the method is improved to more than 99.5 percent.

According to an embodiment of the invention, the additive is added at the same time as the rest of the 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 additive is added, the purity of the final product alcaftadine is improved to 99.9 percent or more.

According to the embodiment of the invention, the AT3 is obtained by carrying out slurry washing and separation on a crude product containing AT 3; the pulp washing treatment further comprises: carrying out slurry washing on the crude product containing AT3 by using a mixed solution; the mixed solution includes an organic solvent and an aqueous phase solvent.

According to an embodiment of the invention, the organic solvent comprises one or more of methyl halides, 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 pH 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 a carbonate-bicarbonate buffer, a barbiturate-hydrochloric acid buffer, a glycine-sodium hydroxide buffer, a boric acid-sodium hydroxide buffer.

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

According to the embodiment of the invention, the pulp washing temperature is controlled to be 15-45 ℃, preferably 25-45 ℃, and more preferably 30 ℃.

According to an embodiment of the invention, the AT 3-containing crude product contains impurities including AT least one selected from the group consisting of:

purification method of alcaftadine intermediate AT3

In a third aspect of the invention, the invention provides a method for purifying alcaftadine intermediate AT3, comprising: carrying out slurry washing on the crude product containing AT3, and separating to obtain purified AT 3; the slurry washing treatment further comprises: carrying out 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 the AT3 is a compound of formula (I):

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

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

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

According to the embodiment of the invention, the pulp washing temperature is controlled to be 15-45 ℃, preferably 25-45 ℃, and more preferably 30 ℃. The purity of the purified AT3 can reach more than 96.5 percent, and the content of impurity C can be controlled below 0.4 percent.

According to the embodiment of the invention, the pulp washing 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 a carbonate-bicarbonate buffer, a barbiturate-hydrochloric acid buffer, a glycine-sodium hydroxide buffer, a boric acid-sodium hydroxide buffer. The purity of the purified AT3 can reach more than 99.5 percent, and the content of impurity C can be controlled below 0.2 percent.

The invention has the advantages that after the crude product containing AT3 is purified, the acatadine is obtained by oxidation, and the inventors surprisingly found that the crude product of AT3 is purified to obtain high-purity AT3, and then the acatadine is obtained by oxidation reaction, so that the yield of the step of oxidizing AT3 into the acatadine is improved, the cost is reduced, the stability of the final product of the acatadine is improved, and the storage period of the final product of the acatadine is prolonged.

The scheme of the invention will be explained with reference to the examples. It will be appreciated by those skilled in the art that the following examples are illustrative of the invention only and should not be taken as limiting the scope of the invention. The examples, where specific techniques or conditions are not indicated, are to be construed according to the techniques or conditions described in the literature in the art or according to the product specifications. The reagents or instruments used are not indicated by the manufacturer, and are all conventional products commercially available.

Example 1

Prepared from AT2 to give AT3, which has the formula:

the specific operation steps are as follows: adding 2.2kg of AT2, acetic acid (0.55kg), 37% formaldehyde solution (6L) and 1.25kg of anhydrous sodium acetate into a reaction kettle, heating to 80-100 ℃, stirring for 18-30 hours, and cooling the reaction mixture to 25-30 ℃. Dichloromethane (22L) was added to the reaction mixture and stirred for 30 min. The pH of the aqueous layer was adjusted to 8-11 with 20% sodium hydroxide. Stirring is continued for 0.5 hour, the organic layer is separated, washed twice with 20% sodium hydroxide solution, stirred uniformly with anhydrous sodium sulfate, and kept stand to dry. And (3) performing suction filtration, concentrating the obtained filtrate AT 35-45 ℃ under reduced pressure until solids are separated out, and performing suction filtration to obtain a filter cake, namely a crude product containing AT3, wherein the purity of AT3 in the crude product containing AT3 is 77.98%, the residue of AT2 is 19.16%, and the content of impurity C is 2.86%.

Example 2

The general concepts of the following experimental and comparative groups were: the crude product containing AT3 prepared in example 1 was subjected to a slurry washing treatment to obtain purified AT 3.

Experimental group 1

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

Experimental group 2

20g of the crude product containing AT3 obtained in example 1 (AT3 content 77.. 98%, AT2 residue 19.16%, impurity C content 2.86%), 60g of methylene chloride, and 420g of an aqueous solution of sodium hydrogencarbonate having a pH of 8 were put into a 1L three-necked flask, heated to 25 ℃, stirred for 0.5 hour, filtered while hot, and the cake was dried to obtain purified AT3 with a yield of 96.7%. In the purified AT3, the AT3 content was 98.88%, the AT2 remained 0.79%, and the impurity C content was 0.33%.

Experimental group 3

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

Experimental group 4

20g of the crude product containing AT3 (AT3 content 77.98%, AT2 residue 19.16%, impurity C content 2.86%) obtained in example 1, 80g of chloroform, and 320g of an aqueous solution of potassium carbonate having a pH of 10 were put into a 1L three-necked flask, heated to 30 ℃, stirred for 1 hour, suction-filtered while hot, and the filter cake was dried to obtain purified AT3 with a yield of 96.1%. In the purified AT3, the AT3 content is 98.61%, the AT2 residue is 0.98%, and the impurity C content is 0.41%.

Experimental group 5

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

Compared with the experimental group 1, the result shows that when the alkaline solution is a 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 the impurity C is further controlled, which may be because the impurities are more stably enriched in the slurry washing solution when the pH in the alkaline solution is stable, so that the purity of AT3 is higher, the AT2 residue is reduced, and the content of the impurity C is reduced when the AT3 is separated after the slurry washing.

Experimental group 6

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

Compared with the experimental group 1, the result shows that when the mass ratio of the AT3 crude product to the chloroform to the alkali solution is changed, the purity of the purified AT3 is reduced, the residue of the AT2 is increased, and the content of the impurity C is increased, because the crude product, the organic solvent and the alkali solution containing the AT3 in the system are not mutually soluble, the impurity can be maximally enriched in the slurry washing solution only when the mass ratio is within a certain range, the dissolving amount of the AT3 in the slurry washing solution is small, and when the mass ratio exceeds a certain mass ratio, the purification effect is reduced.

Experimental group 7

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

Compared with the experimental group 1, the result of the experiment group 7 shows that when the temperature is changed, the purity of the purified AT3 is reduced, the residue of AT2 is increased, and the content of the impurity C is increased, because the crude product containing AT3, the organic solvent and the alkali solution are not soluble with each other in the system, and the solubility of AT3, AT2 and the impurity C in the organic solvent and the alkali water solution is changed due to different temperatures, thereby affecting the purification effect.

Comparative group 1

20g of the crude product containing AT3 obtained in example 1 (AT3 content 77.98%, AT2 residue 19.16%, impurity C content 2.86%), 80g of ethyl acetate, and 320g of an aqueous solution of potassium carbonate having a pH of 10 were put into a 1L three-necked flask, heated to 30 ℃, stirred for 1 hour, suction-filtered while 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 residue of AT2 was 7.42%, and the content of impurity C was 0.91%.

Comparative group 2

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

Compared with the experimental group 1, the comparative group 1 and the comparative group 2 show that when the type of the slurry washing solution is changed (the type of the organic solvent is changed, and the pH value of the aqueous phase solvent is changed), the purity of the purified AT3 is significantly reduced, the residue of AT2 is increased, and the content of impurity C is increased, because the AT3 crude product may need to be washed with a specific system slurry to achieve the purification effect.

Comparative group 3

20g of the crude AT3 obtained in example 1 (AT3 content 77.98%, AT2 residue 19.16%, impurity C content 2.86%) and 80g of methylene chloride were put in a 1L three-necked flask, heated to 30 ℃, stirred for 1 hour, suction-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 residue of AT2 is 15.01%, and the content of impurity C is 1.96%.

Comparative group 4

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

Comparative group 5

20g of the crude AT3 obtained in example 1 (AT3 content 77.98%, AT2 residue 19.16%, impurity C content 2.86%) and 80g of dichloromethane were put in a 1L three-necked flask, the temperature was raised to 30 ℃, stirring was carried out for 1 hour, suction filtration was carried out while hot, the cake was dried, 320g of an aqueous solution of potassium carbonate having pH 10 was put in a 1L three-necked flask, the temperature was raised to 30 ℃, stirring was carried out for 1 hour, suction filtration was carried out while hot, and the cake was dried to obtain purified AT3 with a yield of 89.8%. The purity of AT3 was 89.97%, the residue of AT2 was 8.84%, and the content of impurity C was 1.19%.

Compared with the experimental group 1, the results show that when the mixed solvent of dichloromethane and alkali solution is used for carrying out slurry washing on the AT3 crude product, the purification effect of the mixed solvent is obviously superior to that of independent slurry washing by using an organic solvent or alkali solution, and is also superior to that of slurry washing by alkali after dichloromethane slurry washing, and the unexpected technical effect that 1+1 is more than 2 is achieved.

Comparative group 6

The crude product obtained in example 1, containing AT3 (AT3 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 portion of the eluent was evaporated, the residue crystallized from acetonitrile, the product filtered off and dried, and the filter cake was dried to afford purified AT 3. The yield was 13.11%, the purity of AT3 was 97.14%, the raw material AT2 remained 1.83%, and the content of impurity C was 1.03%.

Compared with the experimental group, the result of the comparison group 6 shows that the purification method of the AT 3-containing crude product is obviously superior to the prior art, the purification effect is better, and the yield is higher.

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

Example 3

The general concepts of the following experimental and comparative groups were: the purified AT3 prepared in example 2 was oxidized with dess-martin reagent to give alcaftadine, the chemical reaction formula of which is shown below:

experimental group 1

Adding 330.9g (0.1mol) of purified AT330, 200mL of dichloromethane, 100mL of tert-butyl alcohol and 5mL of water in the experimental group 1 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 adding, continuing to stir for 25min, cooling to 15-20 ℃, weighing 25.4g of the dess-Martin reagent, adding into the reaction system, heating to 20-30 ℃ after adding, continuing to stir for 20-30 min, cooling to 15-20 ℃, monitoring by TLC until the reaction is complete, performing suction filtration, washing the filtrate once with 100mL of 10% sodium thiosulfate solution, separating an organic layer, washing with 100mL of saturated 5% sodium bicarbonate solution, separating the organic layer, adding anhydrous sodium sulfate, drying, performing suction filtration, and performing reduced pressure concentration. Adding 50mL of isopropanol into the obtained oily matter, stirring, cooling to separate out a solid, and performing suction filtration and drying to obtain a white-like solid, namely the alcaftadine. The purity of the obtained alcaftadine is 99.74%.

Experimental group 2

Adding 330.9g (0.1mol) of purified AT330, 200mL of dichloromethane, 200mL of tert-butyl alcohol and 2mL of water in the experimental group 1 in the example 2 into a 1000 three-neck flask, stirring and dissolving at 10-20 ℃, adding 19.1g of dess-Martin reagent, heating to 20-30 ℃ after adding, continuing to stir for 20min, cooling to 15-20 ℃, weighing 44.5g of the dess-Martin reagent, adding into the reaction system, heating to 20-30 ℃ after adding, continuing to stir for 20-30 min, cooling to 15-20 ℃, monitoring by TLC until the reaction is complete, performing suction filtration, washing the filtrate once with 100mL of 10% sodium thiosulfate solution, separating an organic layer, washing with 100mL of saturated 5% sodium bicarbonate solution, separating the organic layer, adding anhydrous sodium sulfate, drying, performing suction filtration, and performing reduced pressure concentration. Adding 50mL of isopropanol into the obtained oily matter, stirring, cooling to separate out a solid, and performing suction filtration and drying to obtain a white-like solid, namely the alcaftadine. The purity of the obtained alcaftadine is 99.68%.

Experimental group 3

Adding 330.9g (0.1mol) of purified AT330, 200mL of dichloromethane, 150mL of tert-butyl alcohol and 10mL of water in the experimental group 1 in the example 2 into a 1000 three-neck flask, stirring and dissolving at 10-20 ℃, adding 44.5g of dess-Martin reagent, heating to 20-30 ℃ after adding, continuing stirring for 30min, cooling to 15-20 ℃, weighing 19.1g of dess-Martin reagent, adding into the reaction system, heating to 20-30 ℃ after adding, continuing stirring for 20-30 min, cooling to 15-20 ℃, monitoring by TLC until the reaction is complete, performing suction filtration, washing the filtrate once with 100mL of 10% sodium thiosulfate solution, separating an organic layer, washing with 100mL of saturated 5% sodium bicarbonate solution, separating the organic layer, adding anhydrous sodium sulfate, drying, performing suction filtration, and performing reduced pressure concentration. And adding 50mL of isopropanol into the obtained oily matter, stirring, cooling to separate out a solid, and performing suction filtration and drying to obtain a white-like solid, namely the alcaftadine. The purity of the obtained alcaftadine is 99.62%.

Experimental group 4

Adding 330.9g (0.1mol) of purified AT330, 200mL of dichloromethane, 200mL of tert-butyl alcohol and 5mL of water in the experimental group 1 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 adding, continuing stirring for 25min, cooling to 15-20 ℃, weighing 25.4g of dess-Martin reagent and 0.31g of disodium EDTA, adding into the reaction system, heating to 20-30 ℃ after adding, continuing stirring for 20-30 min, cooling to 15-20 ℃, monitoring by TLC until the reaction is complete, performing suction filtration, washing the filtrate once with 100mL of 10% sodium thiosulfate solution, separating an organic layer, washing with 100mL of saturated 5% sodium bicarbonate solution, separating the organic layer, adding anhydrous sodium sulfate, drying, performing suction filtration, and concentrating under reduced pressure. Adding 50mL of isopropanol into the obtained oily matter, stirring, cooling to separate out a solid, and performing suction filtration and drying to obtain a white-like solid, namely the alcaftadine. The purity of the obtained alcaftadine is 99.94%.

As can be seen from the comparison between 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 percent.

Comparative group 1

Adding 330.9g (0.1mol) of purified AT330, 200mL of dichloromethane, 200mL of tert-butyl alcohol and 5mL of water in the experimental group 1 in the example 2 into a 1000 three-neck flask, stirring and dissolving at 10-20 ℃, adding 50.9g of dess-Martin reagent, heating to 20-30 ℃ after adding, continuing stirring for 25min, cooling to 15-20 ℃, weighing 12.7g of dess-Martin reagent, adding into the reaction system, heating to 20-30 ℃ after adding, continuing stirring for 20-30 min, cooling to 15-20 ℃, monitoring by TLC until the reaction is complete, performing suction filtration, washing the filtrate once with 100mL of 10% sodium thiosulfate solution, separating an organic layer, washing with 100mL of saturated 5% sodium bicarbonate solution, separating the organic layer, adding anhydrous sodium sulfate, drying, performing suction filtration, and performing reduced pressure suction filtration and concentration. Adding 50mL of isopropanol into the obtained oily matter, stirring, cooling to separate out a solid, and performing suction filtration and drying to obtain a white-like solid, namely the alcaftadine. The purity of the obtained alcaftadine is 99.28%.

The comparison between the comparative group 1 and the experimental group 1 shows that the alcaftadine purity is reduced when the first addition amount of the dess-martin reagent is changed, and the reason may be that the oxidation reaction can be controlled within a certain intensity range by controlling the first addition amount of the oxidant dess-martin reagent, so that the alcaftadine with higher purity can be obtained.

Comparative group 2

Adding 330.9g (0.1mol) of purified AT330, 200mL of dichloromethane, 100mL of tert-butyl alcohol and 5mL of water in the experimental group 1 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 adding, continuing to stir for 40min, cooling to 15-20 ℃, weighing 25.4g of the dess-Martin reagent, adding into the reaction system, heating to 20-30 ℃ after adding, continuing to stir for 20-30 min, cooling to 15-20 ℃, monitoring by TLC until the reaction is complete, performing suction filtration, washing the filtrate once with 100mL of 10% sodium thiosulfate solution, separating an organic layer, washing with 100mL of saturated 5% sodium bicarbonate solution, separating the organic layer, adding anhydrous sodium sulfate, drying, performing suction filtration, and performing reduced pressure concentration. Adding 50mL of isopropanol into the obtained oily matter, stirring, cooling to separate out a solid, and performing suction filtration and drying to obtain a white-like solid, namely the alcaftadine. The purity of the obtained alcaftadine is 99.40%.

As can be seen from comparison of the comparative group 2 with the experimental group 1, when the time interval between the first addition and the second addition of the dess-martin reagent is changed, the purity of the alcaftadine is reduced, and the reason may be that the oxidation reaction process can be properly controlled by controlling the time interval between the first addition and the second addition of the oxidant dess-martin reagent, so that the higher-purity alcaftadine can be obtained.

Comparative group 3

Adding 330.9g (0.1mol) of purified AT330, 200mL of dichloromethane and 100mL of tert-butyl alcohol of the experimental group 1 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 adding, continuing to stir for 25min, cooling to 15-20 ℃, weighing 25.4g of dess-martin reagent, adding into the reaction system, heating to 20-30 ℃ after adding, continuing to stir for 20-30 min, cooling to 15-20 ℃, monitoring by TLC until the reaction is complete, performing suction filtration, washing the filtrate once by using 100mL of 10% sodium thiosulfate solution, separating an organic layer, washing by using 100mL of saturated 5% sodium bicarbonate solution, separating the organic layer, adding anhydrous sodium sulfate, drying, performing suction filtration, and performing vacuum filtration and concentration under reduced pressure. And adding 50mL of isopropanol into the obtained oily matter, stirring, cooling to separate out a solid, and performing suction filtration and drying to obtain a white-like solid, namely the alcaftadine. The purity of the obtained alcaftadine is 99.33%.

As can be seen from comparison of the comparative group 3 with the experimental group 1, when the solvent of the reaction system does not contain water, the purity of the obtained alcaftadine is reduced, which may be caused by that the addition of water inhibits the production of some impurities and improves the product purity.

Comparative group 4

Adding 330.9g (0.1mol) of purified AT330, 200mL of dichloromethane, 200mL of tert-butyl alcohol and 5mL of water of the experimental group 1 in the example 2 into a 1000 three-neck flask, stirring and dissolving at 10-20 ℃, adding 63.6g of dess-Martin reagent, heating to 20-30 ℃ after the addition, continuing stirring for 20-30 min, cooling to 15-20 ℃, monitoring by TLC until the reaction is complete, performing suction filtration, washing the filtrate once by using 100mL of 10% sodium thiosulfate solution, separating an organic layer, washing by using 100mL of saturated 5% sodium bicarbonate solution, separating the organic layer, adding anhydrous sodium sulfate, drying, performing suction filtration, and performing suction filtration and reduced pressure concentration. Adding 50mL of isopropanol into the obtained oily matter, stirring, cooling to separate out a solid, and performing suction filtration and drying to obtain a white-like solid, namely the alcaftadine. The purity of the obtained alcaftadine is 99.01%.

As shown in the experimental groups 1 to 4 and the comparative groups 1 to 4 of example 3, in the step of oxidizing the purified AT3 into alcaftadine, the dess-martin reagent is added in batches, the solvent is a mixed solvent of tert-butyl alcohol, dichloromethane and water, the first addition amount of the dess-martin reagent is 0.3 to 0.7 times of the total addition amount, and the time interval between the first addition and the second addition of the dess-martin reagent is 20 to 30min, the purity of alcaftadine is improved to 99.5% or more. When the disodium EDTA is added into the reaction system, the purity of the disodium EDTA is further improved to over 99.9 percent.

Example 4

The general concept of the following experimental groups was: alcaftadine was prepared using typical purified AT3 obtained in example 2 (example 2, experimental group 1, example 2, experimental group 5, example 2, experimental group 6, example 2, comparative group 2, example 2, comparative group 5) using the preparation process of alcaftadine optimized in example 3 (example 3, experimental group 4), and the effects of the preparation process of example 2 and purified AT3 on the preparation process of alcaftadine and alcaftadine were explored. The reaction scheme is shown in example 3. In this example, the yield is the actual yield of alcaftadine/theoretical yield of alcaftadine, wherein the theoretical yield of alcaftadine is (mass × purity of AT 3/molar mass of AT3) × molar mass of AT 4.

Experimental group 1

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

Experimental group 2

Adding 330.9g (0.1mol) of purified AT330, 200mL of dichloromethane, 200mL of tert-butyl alcohol and 5mL of water of 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 adding, continuing stirring for 25min, cooling to 15-20 ℃, weighing 25.4g of the dess-Martin reagent and 0.31g of disodium EDTA, adding into the reaction system, heating to 20-30 ℃ after adding, continuing stirring for 20-30 min, cooling to 15-20 ℃, monitoring by TLC until the reaction is complete, performing suction filtration, washing the filtrate once by using 100mL of 10% sodium thiosulfate solution, separating an organic layer, washing by using 100mL of saturated 5% sodium bicarbonate solution, separating the organic layer, adding anhydrous sodium sulfate, drying, performing suction filtration, and performing vacuum concentration under reduced pressure. Adding 50mL of isopropanol into the obtained oily matter, stirring, cooling to separate out a solid, and performing suction filtration and drying to obtain a white-like solid, namely the alcaftadine. The yield thereof was found to be 96.9%.

Experimental group 3

Adding 330.9g (0.1mol) of purified AT330, 200mL of dichloromethane, 200mL of tert-butyl alcohol and 5mL of water of 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 adding, continuing stirring for 25min, cooling to 15-20 ℃, weighing 25.4g of dess-Martin reagent and 0.31g of disodium EDTA, adding into the reaction system, heating to 20-30 ℃ after adding, continuing stirring for 20-30 min, cooling to 15-20 ℃, monitoring by TLC until the reaction is complete, performing suction filtration, washing the filtrate once with 100mL of 10% sodium thiosulfate solution, separating an organic layer, washing with 100mL of saturated 5% sodium bicarbonate solution, separating the organic layer, adding anhydrous sodium sulfate, drying, performing suction filtration, and concentrating under reduced pressure. Adding 50mL of isopropanol into the obtained oily matter, stirring, cooling to separate out a solid, and performing suction filtration and drying to obtain a white-like solid, namely the alcaftadine. The yield thereof was found to be 91.3%.

Comparative group 1

Adding 330.9g (0.1mol) of purified AT330, 200mL of dichloromethane, 200mL of tert-butyl alcohol and 5mL of water of a comparative group 2 in example 2 into a 1000 three-necked flask, stirring and dissolving at 10-20 ℃, adding 38.2g of dess-Martin reagent, heating to 20-30 ℃ after adding, continuing stirring for 25min, cooling to 15-20 ℃, weighing 25.4g of dess-Martin reagent and 0.31g of disodium EDTA, adding into the reaction system, heating to 20-30 ℃ after adding, continuing stirring for 20-30 min, cooling to 15-20 ℃, monitoring by TLC until the reaction is complete, performing suction filtration, washing the filtrate once with 100mL of 10% sodium thiosulfate solution, separating an organic layer, washing with 100mL of saturated 5% sodium bicarbonate solution, separating the organic layer, adding anhydrous sodium sulfate, drying, performing suction filtration, and concentrating under reduced pressure. Adding 50mL of isopropanol into the obtained oily matter, stirring, cooling to separate out a solid, and performing suction filtration and drying to obtain a white-like solid, namely the alcaftadine. The yield thereof was found to be 89.3%.

Comparative group 2

Adding 330.9g (0.1mol) of purified AT330, 200mL of dichloromethane, 200mL of tert-butyl alcohol and 5mL of water of the comparative group 5 in the example 2 into a 1000 three-necked flask, stirring and dissolving at 10-20 ℃, adding 38.2g of dess-Martin reagent, heating to 20-30 ℃ after adding, continuing stirring for 25min, cooling to 15-20 ℃, weighing 25.4g of dess-Martin reagent and 0.31g of disodium EDTA, adding into the reaction system, heating to 20-30 ℃ after adding, continuing stirring for 20-30 min, cooling to 15-20 ℃, monitoring by TLC until the reaction is complete, performing suction filtration, washing the filtrate once with 100mL of 10% sodium thiosulfate solution, separating an organic layer, washing with 100mL of saturated 5% sodium bicarbonate solution, separating the organic layer, adding anhydrous sodium sulfate, drying, performing suction filtration, and concentrating under reduced pressure. Adding 50mL of isopropanol into the obtained oily matter, stirring, cooling to separate out a solid, and performing suction filtration and drying to obtain a white-like solid, namely the alcaftadine. The yield thereof was found to be 82.6%.

The alcaftadine obtained from experimental groups 1, 2 and 3 and comparative groups 1 and 2 was packaged and then placed at 25 ℃ ± 2 ℃ and relative humidity RH 60% ± 10%, and sampled and detected at 0 day, 6 months and 12 months respectively, and the impurity and purity data after long-term test are shown in table 1:

TABLE 1 long-term experimental impurity and purity data for alcaftadine obtained in experimental groups 1, 2, 3, 4, comparative example 1

As can be seen from example 4, the purification step of AT3 has a certain effect on the yield of the step of oxidizing AT3 to alcaftadine, probably because, when AT3 is not completely purified, some impurities remained have a negative effect on the step of oxidizing AT3 to alcaftadine, which decreases the yield; on the other hand, the purification step of AT3 may have some influence on the stability of alcaftadine, which may be because, when AT3 is not purified thoroughly, some impurities remaining may also affect the quality of the final product alcaftadine. When the purity of AT3 reaches more than 95%, the final product alcaftadine raw material drug has a purity of more than 99.5% after being placed for 12 months, and can meet the requirement of safe medication. The AT3 crude product is purified to obtain high-purity AT3, and then the high-purity AT3 is subjected to oxidation reaction to obtain alcaftadine, so that the yield of the step of oxidizing AT3 into alcaftadine is improved, the cost is reduced, the stability of the final product alcaftadine is improved, and the storage period of the alcaftadine is prolonged.

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

In the description herein, references to the description of the term "one embodiment," "some embodiments," "an example," "a specific example," or "some examples," etc., mean 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 invention. In this specification, the schematic representations of the terms used above are not necessarily intended to refer 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, various embodiments or examples and features of different embodiments or examples described in this specification can be combined and combined by one skilled in the art without contradiction.

Although embodiments of the present invention have been shown and described above, it is understood that the above embodiments are exemplary and should not be construed as limiting the present invention, and that variations, modifications, substitutions and alterations can be made to the above embodiments by those of ordinary skill in the art within the scope of the present invention.

Claims

1. A preparation method of alcaftadine, which is obtained by oxidizing AT3 by a dess-martin reagent, wherein the oxidation reaction comprises the following steps: carrying out oxidation reaction on AT3 and part of the dess-martin reagent, and adding the rest of the 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 0.3-0.7 time of the total addition amount of the dess-Martin reagent,

wherein the AT3 is a compound of formula (I):

2. the method according to claim 1, wherein the solvent used in the reaction system comprises dichloromethane, tert-butyl alcohol and water, and preferably the volume ratio of dichloromethane to tert-butyl alcohol to water in the solvent used in the reaction system is 20: 10-20: 0.1-0.5;

optionally, the period of time is 20-40 min, preferably 20-30 min.

3. The method according to claim 1, wherein the addition of the remaining dess-martin reagent is accompanied by the addition of an additive, preferably EDTA or its sodium salt;

more preferably, the additive is selected from EDTA, EDTA-disodium, EDTA-tetrasodium;

optionally, the mass of the additive is controlled to be 0.005-0.02 time of the mass of AT 3.

4. The method of claim 1, wherein the AT3 has a purity of 95% or greater; preferably, the AT3 has a purity of greater than 98.5%.

5. The method of claim 1, wherein the AT3 is obtained by washing a crude product containing AT3 with a slurry and isolating; the slurry washing treatment further comprises: carrying out 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;

optionally, the organic solvent comprises one or more of methyl halides, preferably dichloromethane; optionally, the aqueous phase solvent is an alkaline solution.

6. The method according to claim 5, wherein the pH value of the alkali solution is controlled to be 9-14, preferably, the alkali for adjusting the pH value is selected from any one or more of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, ammonia water and buffer solution, more preferably, the buffer solution is selected from carbonate-bicarbonate buffer solution, barbiturate-hydrochloric acid buffer solution, glycine-sodium hydroxide buffer solution and boric acid-sodium hydroxide buffer solution.

7. The method as claimed in claim 6, wherein the mass ratio of the AT 3-containing crude product to the organic solvent to the alkali solution is 1: 2-10: 10-21, preferably, the mass ratio of the AT 3-containing crude product to the organic solvent to the alkali solution is 1: 3-10: 12 to 21.

8. The method according to claim 5, characterized in that the pulp washing temperature is controlled to be 15-45 degrees Celsius, preferably 25-45 degrees Celsius;

optionally, the slurry washing time is controlled to be 0.5-2 hours.

9. A method for purifying alcaftadine intermediate AT3, comprising: carrying out slurry washing and separation on the crude product containing AT3 to obtain purified AT 3; the slurry washing treatment further comprises: carrying out 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 the AT3 is a compound of formula (I):

optionally, the organic solvent comprises one or more of methyl halides, preferably dichloromethane;

optionally, the aqueous phase solvent is an alkali solution, the pH value of the alkali solution is controlled to be 9-14, preferably, the alkali for adjusting the pH value is selected from any one or more of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, ammonia water and buffer solution, and more preferably, the buffer solution is selected from carbonate-bicarbonate buffer solution, barbital sodium-hydrochloric acid buffer solution, glycine-sodium hydroxide buffer solution and boric acid-sodium hydroxide buffer solution;

optionally, the mass ratio of the AT 3-containing crude product to the organic solvent to the alkali solution is 1: 2-10: 10-21, preferably, the mass ratio of the AT 3-containing crude product to the organic solvent to the alkali solution is 1: 3-10: 12 to 21 parts;

optionally, the pulp washing temperature is controlled to be 15-45 ℃, preferably 25-45 ℃;

optionally, the slurry washing time is controlled to be 0.5-2 hours.