A method for purifying a compound containing a piperidine ring

Abstract

The present invention discloses a method for purifying a compound containing a piperidine ring. Specifically, the present invention provides a method for purifying a compound 1, comprising the following steps: (1) reacting a crude product of the compound 1 with piperazine in the presence of a solvent to generate an intermediate; (2) reacting the intermediate with an acid in a solvent to obtain the compound 1. The purification method provided by the present invention can reduce the content of specific impurities that are difficult to remove in the crude product of the compound 1 to below the detection limit.

Description

Technical Field

[0001] The invention relates to a method for purifying a compound containing a piperidine ring. Background Art

[0002] Compound 1 is a compound with antiplatelet activity, which can generate active metabolites of clopidogrel in vivo through the action of hydrolases, thereby further irreversibly inhibiting platelet coagulation activity.

[0003] ;

[0004] The crude compound 1 obtained by the preparation process of the prior art contains an impurity A with a relative retention time (RRT) of 1.03 times that of the main peak in HPLC, LC-MS [M+1] = 483, and a content of about 0.17%. On the one hand, the impurity A cannot be removed by conventional impurity removal methods such as recrystallization and column chromatography. On the other hand, compound 1 cannot form a salt with a stable crystalline form with conventional acids or bases, such as hydrochloric acid, sulfuric acid, sodium hydroxide, etc. Summary of the invention

[0005] The technical problem to be solved by the present invention is to overcome the defect that impurity A is difficult to remove in the prior art, and to provide a purification method for a compound containing a piperidine ring. The purification method provided by the present invention can reduce the content of impurity A to below the detection limit.

[0006] The present invention solves the above technical problems through the following technical solutions:

[0007] The present invention also provides a method for purifying compound 1, which comprises the following steps: ;

[0008] Step S1, in a solvent, reacting a crude product of compound 1 with piperazine to generate an intermediate;

[0009] Step S2: in a solvent, the intermediate reacts with an acid to obtain compound 1.

[0010] In some embodiments, in step S1, the solvent is one or more of an ether solvent, a nitrile solvent, an aromatic hydrocarbon solvent and water.

[0011] In some embodiments, in step S1, the ether solvent is isopropyl ether or methyl tert-butyl ether.

[0012] In some embodiments, in step S1, the nitrile solvent is acetonitrile.

[0013] In some embodiments, in step S1, the aromatic hydrocarbon solvent is toluene.

[0014] In some embodiments, in step S1, the solvent is a mixed solvent of the ether solvent and water, a mixed solvent of the ether solvent, water and the nitrile solvent, an ether solvent or an aromatic hydrocarbon solvent.

[0015] In some embodiments, in step S1, the solvent is a mixed solvent of isopropyl ether and water, a mixed solvent of isopropyl ether, water and acetonitrile, methyl tert-butyl ether or toluene.

[0016] In some embodiments, in step S1, when the solvent is a mixed solvent of isopropyl ether and water, the volume ratio of isopropyl ether to water may be (100-230):1, preferably 199:1.

[0017] In some embodiments, in step S1, when the solvent is a mixed solvent of isopropyl ether and water, the volume ratio of isopropyl ether: water: acetonitrile may be (10-200): 1: (0.1-15), for example, 21.6: 1.09: 0.11 or 199: 1: 10.

[0018] In the step S1, the amount of the solvent is not limited as long as it does not affect the reaction; for example, the mass volume ratio of the compound 1 to the solvent is 1: (10-50) g / mL, or 1: (15-40) g / mL, such as 1: 20 g / mL or 1: 22.8 g / mL.

[0019] In some embodiments, the purity of the crude compound 1 is 70-99%, preferably 95%.

[0020] In some embodiments, the crude compound 1 includes compound 1 and impurity A; the impurity A is a compound whose relative retention time (RRT) in HPLC is 1.03 times that of the main peak, and LC-MS [M+1] = 483; the parameters of the HPLC are as follows:

[0021] .

[0022] In some embodiments, the content of impurity A in the crude compound 1 is greater than 0.1%, such as 0.1 to 0.2%, for example 0.17%.

[0023] In some embodiments, in step S1, the piperazine is reacted in the form of a solution. Further, the solvent of the solution is preferably a mixed solvent of acetonitrile and water; the volume ratio of acetonitrile to water in the solvent of the solution can be (1-20): 1, or (5-15): 1, for example, 10.9:1.1.

[0024] In some embodiments, in step S1, the molar ratio of the compound 1 to the piperazine is 1:(0.1-2), or 1:(0.5-1.5), for example, 1:0.7.

[0025] In some embodiments, in step S1, the piperazine is preferably added in batches; the batch addition can be divided into 2 to 7 times, for example, divided into 4 times; for example, at 0 to 5°C, 1 / 6, 1 / 3, 1 / 3, 1 / 6 wt is added each time; more preferably, stirring is performed for 2 hours after each addition.

[0026] In some embodiments, in step S1, the temperature for the reaction of the crude compound 1 and piperazine can be a conventional temperature for such reactions in the art, such as 0±15°C, and preferably 0±5°C in the present invention.

[0027] In some embodiments, in step S1, the progress of the reaction between the crude compound 1 and piperazine can be detected by conventional monitoring methods in the art (such as TLC, HPLC or NMR), and the disappearance or no-reaction of compound 1 is generally used as the reaction endpoint. The reaction time can be 1 to 10 hours, or 2 hours.

[0028] In some embodiments, the reaction material of step S1 consists of the following: the solvent, the crude compound 1 and the piperazine.

[0029] In some embodiments, the step S1 further comprises the following post-processing step: after the reaction is completed, filtering is performed and the filter cake is collected to obtain the intermediate.

[0030] In step S2, the solvent is a conventional solvent for this type of reaction in the art, preferably an ester solvent; further, the ester solvent is selected from one or more of methyl formate, ethyl acetate, ethyl formate and methyl acetate, for example, methyl acetate.

[0031] In step S2, the amount of the solvent may not be limited as long as it does not affect the reaction; for example, the mass volume ratio of the intermediate to the solvent may be 1: (1-30) g / mL, or 1: (5-15) g / mL, such as 1:10 g / mL.

[0032] In some embodiments, in step S2, the acid is a conventional acid for such reactions in the art, such as an organic acid, formic acid and / or acetic acid, or formic acid. Further, the formic acid is added in the form of an aqueous formic acid solution. Furthermore, the mass percentage of formic acid in the aqueous formic acid solution may be 1%.

[0033] In some embodiments, in step S2, the mass volume ratio of the intermediate to the acid is 1:(5-30) g / mL, or 1:(10-30) g / mL, for example 1:16 g / mL.

[0034] In some embodiments, in step S2, the reaction temperature of the reaction between the intermediate and the acid is a conventional temperature for such reactions in the art, such as 25±15°C, preferably 25±5°C.

[0035] In some embodiments, in step S2, the progress of the reaction between the intermediate and the acid can be detected by conventional monitoring methods in the art (such as TLC, HPLC or NMR). The reaction time can be 10 to 80 minutes, or 20 minutes.

[0036] In some embodiments, the reaction material of step S2 consists of: the intermediate, the solvent and the acid.

[0037] In some embodiments, step S2 also includes post-treatment, and the post-treatment operation can be a conventional post-treatment operation in this type of preparation method in the art, which includes the following steps: after the reaction is completed, filtering, washing, drying, first concentration, second concentration, dissolving, second filtration, and freeze-drying.

[0038] In the post-treatment of step S2, the washing may be a conventional washing method in this type of reaction in the art, such as washing with a sodium chloride solution. The drying may be a conventional drying method in this type of reaction in the art, such as drying with anhydrous Na2SO4. The concentration may be a conventional concentration method in this type of reaction in the art. After the first concentration, a solvent (such as n-hexane) is added and then a second concentration is performed. The dissolving may be a conventional dissolving method in this type of reaction in the art, such as dissolving with acetonitrile. The filtering may be a conventional filtering method in this type of reaction in the art, and water needs to be added to the filtrate after the second filtration.

[0039] In some embodiments, the purification method can reduce the content of impurity A from above 0.15% (eg, 0.17%) to below the detection limit (0.1%).

[0040] In some embodiments, the crude compound 1 is prepared by the following method, which comprises the following steps:

[0041] ;

[0042] In a halogenated hydrocarbon solvent, in the presence of an organic acid, compound 1-16 undergoes a deprotection reaction to obtain a crude product of compound 1.

[0043] In some embodiments, in the deprotection reaction, the halogenated hydrocarbon solvent is dichloromethane.

[0044] In some embodiments, in the deprotection reaction, the mass volume ratio of the compound 1-16 to the halogenated hydrocarbon solvent is 1:(5-30), for example 1:9 g / mL.

[0045] In some embodiments, in the deprotection reaction, the organic acid is trifluoroacetic acid.

[0046] In some embodiments, in the deprotection reaction, the molar ratio of the compound 1-16 to the organic acid is 1:(10-40), for example 1:20.

[0047] In some embodiments, the reaction temperature of the deprotection reaction is a conventional temperature for such reactions in the art, such as 0±10° C., and preferably 0-5° C. in the present invention.

[0048] In some embodiments, the progress of the deprotection reaction is detected by conventional monitoring methods in the art (such as TLC, HPLC or NMR), and the reaction endpoint is generally when compound 1-16 disappears or no longer reacts. The reaction time can be 10 to 30 hours, or 16 hours.

[0049] In some embodiments, the method for preparing the crude product of Compound 1 further comprises the following steps:

[0050] ;

[0051] In a nitrile solvent, in the presence of an inorganic base, compound 1-14 and compound 1-15 undergo a substitution reaction to obtain compound 1-16.

[0052] In some embodiments, in the substitution reaction, the nitrile solvent may be acetonitrile.

[0053] In some embodiments, in the substitution reaction, the mass volume ratio of the compound 1-14 to the nitrile solvent may be (100-200):1 g / L, or (120-130):1 g / L, for example, 125.23:1.

[0054] In some embodiments, in the substitution reaction, the inorganic base is an alkali metal bicarbonate, such as sodium bicarbonate.

[0055] In some embodiments, in the substitution reaction, the mass ratio of the compound 1-14 to the inorganic base can be 1:(0.5-1.5), or 1:(0.5-1), for example, 1:0.73.

[0056] In some embodiments, in the substitution reaction, the mass ratio of the compound 1-14 to the compound 1-15 may be 1:(1-2), or 1:(1-1.2), for example, 1:1.06.

[0057] In some embodiments, the reaction temperature of the substitution reaction can be a conventional temperature for such reactions in the art, such as 40±15°C, and preferably 40±5°C in the present invention.

[0058] In some embodiments, the progress of the substitution reaction is detected by conventional monitoring methods in the art (such as TLC, HPLC or NMR), and the disappearance or no-reaction of compound 1-14 is generally used as the reaction endpoint. The reaction time can be 10 to 30 hours, or 16 hours.

[0059] The positive improvement effect of the present invention is that the purification method provided by the present invention can reduce the content of impurity A to below the detection limit (0.1%). DETAILED DESCRIPTION

[0060] The present invention is further described below by way of examples, but the present invention is not limited to the scope of the examples. The experimental methods in the following examples without specifying specific conditions are carried out according to conventional methods and conditions, or selected according to the product specifications.

[0061] Abbreviation table:

[0062] .

[0063] The test methods involved in the following embodiments are as follows:

[0064] 1 H-NMR method

[0065] Instrument model: Bruker 400 MHz instrument

[0066] Detailed 1 The H-NMR parameters are as follows:

[0067] .

[0068] HPLC method

[0069] Instrument model: Agilent 1260 series HPLC instrument

[0070] The detailed HPLC parameters are as follows:

[0071] .

[0072] Preparation Example Preparation of Compound 1

[0073] ;

[0074] To a solution of 1-14 (563.5 g) in MeCN (4.5 L) was added 1-15 (599.2 g) and sodium bicarbonate (411 g) at 20±5°C. After addition, the mixture was stirred at 40±5°C for 16 hours. The mixture was cooled to 20±5°C, filtered, and the filter cake was rinsed with MeCN. DCM (9 V) was added to the filter cake. The mixture was cooled to 0~5°C, and TFA (20 eq) was added to the mixture at 0~5°C. After addition, the mixture was stirred at 0~5°C for 16 hours. The reaction mixture was added to an aqueous sodium bicarbonate solution (2.64 kg in 5.6 L of water) at 0±5°C. The mixture was filtered, the filter cake was rinsed with DCM (1.2 L), and MTBE (8.4 L) was added to the filtrate. After stirring and standing, the mixture was separated into two layers, and the upper organic phase was collected. The organic phase was washed with water. The aqueous phases were combined and extracted with DCM (2.8 L). The two organic phases were combined and dried over anhydrous sodium sulfate. The mixture was filtered and concentrated, and then purified by silica gel. The eluent was concentrated to obtain a crude product containing compound 1. MeCN was added to the crude product and concentrated again. The solvent replacement was repeated again. Water (0.56 L) was added to the mixture and the mixture was freeze-dried. Amorphous solid compound 1 (300 g) was obtained with a yield of 39.0% and a purity of 95%, of which the content of impurity A was about 0.17%. LC-MS [M+1] + = 472.1.

[0075] Example 1

[0076] Isopropyl ether (21.6 V, "V" represents the volume of isopropyl ether corresponding to 1 g of compound 1, such as "21.6 V" represents the amount of isopropyl ether corresponding to 1 g of compound 1 is 21.6 ml) was added to the crude product of compound 1 (250 mg, purity 95%, impurity A content of about 0.17%, prepared in the preparation example), and then piperazine (0.7 eq) ACN aqueous solution (1.2 V, wherein the volume ratio of ACN to water is 10.9:1.1) was added in batches, and the addition method was as follows: at 0~5°C, 1 / 6, 1 / 3, 1 / 3, 1 / 6wt were added in batches each time, and stirred for 2 hours after each addition. The mixture was stirred at 0±5°C for 2 hours, filtered, and the filter cake was collected. The content of impurity A in the filter cake was detected, and it was reduced to below the detection limit (0.1%).

[0077] The obtained filter cake (250 mg) was mixed with methyl acetate (10.00 V) and stirred at 25±5°C, and then an aqueous formic acid solution (16 V, wherein the mass percentage of formic acid was 1%) was added to the mixture to adjust the pH to 5-6. The mixture was allowed to stand for 20 minutes and filtered, and the organic phase was washed with sodium chloride solution and dried over anhydrous Na2SO4. The mixture was concentrated, and then n-hexane was added and concentrated again. The residue was added to ACN (3.0 V) and stirred until completely dissolved. The obtained mixture was filtered and sterile water was added to the filtrate. The obtained mixture was then lyophilized to obtain compound 1 with a purity of 97.2%.

[0078] Example 2

[0079] 250 mg of compound 1 was dissolved in the solvent (20 V) shown in the following table, and then anhydrous piperazine (0.6 eq) was added thereto. The mixture was treated under the conditions listed in the table, filtered, the filter cake was collected, and the content of impurity A therein was detected.

[0080] The results are shown in the following table:

[0081] ;

[0082] The obtained filter cake (250 mg) and methyl acetate (10.00 V) were mixed and stirred at 25±5°C, and then an aqueous formic acid solution (16 V, wherein the mass percentage of formic acid was 1%) was added to the mixture to adjust the pH to 5-6. The mixture was allowed to stand for 20 minutes and filtered, and the organic phase was washed with sodium chloride solution and dried over anhydrous Na2SO4. The mixture was concentrated, and then n-hexane was added and concentrated again. The residue was added to ACN (3.0 V) and stirred until completely dissolved. The obtained mixture was filtered and sterile water was added to the filtrate. The obtained mixture was then lyophilized to obtain a pure amorphous compound 1.

[0083] Comparative Example 1

[0084] 25 mg of compound 1 was dissolved in 0.5 mL of each solvent shown in the following table, and then an acid or base (0.55~1.1eq) was added to the solution for reaction at room temperature. The salt formation and crystallization of the product, the product morphology and the impurity removal effect are listed in the following table:

[0085] The corresponding situations are as follows:

[0086] ;

[0087] Note: “None” in the table means that the content of impurity A cannot be reduced from 0.17% to below the detection limit (0.1%).

[0088] From the above, it can be seen that although compound 1 can form salts with some acids or bases, these salts are in a free state and are in an oily physical form, and cannot remove impurity A.

[0089] Although the specific embodiments of the present invention are described above, it should be understood by those skilled in the art that this is only for illustration and the protection scope of the present invention is defined by the appended claims. Those skilled in the art may make various changes or modifications to these embodiments without departing from the principles and essence of the present invention, but these changes and modifications all fall within the protection scope of the present invention.

Claims

1. A method for purifying compound 1, characterized in that: The purification method comprises the following steps: Step S1, in a solvent, reacting a crude product of compound 1 with piperazine to generate an intermediate; Step S2, in a solvent, reacting the intermediate with an acid to obtain compound 1; ； The crude product of compound 1 includes compound 1 and impurity A; impurity A is a compound whose relative retention time in HPLC is 1.03 times that of the main peak, LC-MS [M+1] = 483; the parameters of HPLC are as follows: Instrument model: Agilent 1260 series HPLC instrument; chromatographic column: ACE Ultracore SUPER C18, 4.6×150mm, 2.5 μm; mobile phase: A: 0.02% trifluoroacetic acid in water; B: 0.02% trifluoroacetic acid in acetonitrile; gradient: 0 / 10%, 3 / 30%, 28 / 45%, 40 / 95%, 45 / 95%, 45.1 / 10%, 50 / 10%; the gradient is expressed as T / B%, T is the number of minutes, and B% is the volume percentage of mobile phase B in the total mobile phase; column temperature: 40℃; detector: DAD; 210 nm; flow rate: 1 mL / min; injection volume: 5 μL; running time: 50 min; equilibrium time: 0 min; diluent: acetonitrile; In the step S1, the molar ratio of the compound 1 to the piperazine is 1:(0.5-1.5); In the step S1, the mass volume ratio of the compound 1 to the solvent is 1: (15-40) g / mL; In the step S1, the solvent is: a mixed solvent of isopropyl ether and water, a mixed solvent of isopropyl ether, water and acetonitrile, or methyl tert-butyl ether; In the step S1, when the solvent is a mixed solvent of isopropyl ether and water, the volume ratio of the isopropyl ether to water is (100-230):1; In step S1, when the solvent is a mixed solvent of isopropyl ether, water and acetonitrile, the volume ratio of isopropyl ether: water: acetonitrile is (10-200): 1: (0.1-15).

2. The purification method according to claim 1, characterized in that It meets one or more of the following conditions: (1) In the crude product of the compound 1, the purity of the compound 1 is 70-99%; (2) In the step S1, the piperazine is reacted in the form of a solution or added in the form of anhydrous piperazine; (3) In step S1, the piperazine is added in batches; (4) In step S1, the temperature for reacting the crude compound 1 with piperazine is 0±15°C; (5) In the step S1, the reaction time of the crude product of compound 1 and piperazine is 1 to 10 hours; (6) The reaction material of step S1 is composed of the following: the solvent, the crude product of compound 1 and the piperazine; (7) The step S1 further comprises the following post-treatment step: after the reaction is completed, filtering and collecting the filter cake to obtain the intermediate; (8) In step S2, the solvent is an ester solvent; (9) In step S2, the mass volume ratio of the intermediate to the solvent is 1:(1-30) g / mL; (10) In step S2, the acid is an organic acid; (11) In the step S2, the mass volume ratio of the intermediate to the acid is 1:(5-30) g / mL; (12) In step S2, the reaction temperature of the intermediate and the acid is 25±15°C; (13) In step S2, the reaction time of the intermediate and the acid is 10 to 80 minutes; (14) The reaction material of step S2 is composed of the following: the intermediate, the solvent and the acid; (15) The step S2 also includes post-treatment, and the post-treatment operation includes the following steps: after the reaction is completed, filtering, washing, drying, first concentration, second concentration, dissolving, second filtration, and freeze-drying.

3. The purification method according to claim 2, characterized in that It meets one or more of the following conditions: (1) In the crude product of the compound 1, the purity of the compound 1 is 95%; (2) In step S1, the solvent is a mixed solvent of isopropyl ether, water and acetonitrile; (3) In step S1, the piperazine participates in the reaction in the form of a solution, and the solvent of the solution is a mixed solvent of acetonitrile and water; (4) In the step S1, the piperazine is added in batches; the batch addition is performed in 2 to 7 times; (5) In step S1, the temperature for the reaction of the crude compound 1 and piperazine is 0±5°C; (6) In step S1, the reaction time of the crude product of compound 1 and piperazine is 2 hours; (7) In step S2, the ester solvent is selected from one or more of methyl formate, ethyl acetate, ethyl formate and methyl acetate; (8) In the step S2, the mass volume ratio of the intermediate to the solvent is 1:(5-15) g / mL; (9) In step S2, the acid is formic acid and / or acetic acid, (10) In the step S2, the mass volume ratio of the intermediate to the acid is 1:(10-30) g / mL; (11) In step S2, the reaction temperature of the intermediate and the acid is 25±5°C; (12) In step S2, the reaction time of the intermediate and the acid is 20 minutes; (13) In the post-treatment of step S2, the washing is performed using a sodium chloride solution; (14) In the post-treatment of step S2, the drying is performed using anhydrous Na2SO4; (15) In the post-treatment of step S2, n-hexane is added between the first concentration and the second concentration; (16) In the post-treatment of step S2, the dissolving is performed using acetonitrile; (17) In the post-treatment of step S2, after the second filtration, water is added to the filtrate; (18) The purification method can reduce the content of impurity A from more than 0.15% to below the detection limit.

4. The purification method according to claim 3, characterized in that It meets one or more of the following conditions: (1) In the step S1, the mass volume ratio of the compound 1 to the solvent is 1:20 g / mL or 1:22.8 g / mL; (2) In the step S1, the molar ratio of the compound 1 to the piperazine is 1:0.6 or 1:0.7; (3) In the step S1, the piperazine is added in batches; the batch addition is added in 4 times; (4) In step S2, the solvent is methyl acetate; (5) In step S2, the mass volume ratio of the intermediate to the solvent is 1:10 g / mL; (6) In step S2, the acid is formic acid; (7) In step S2, the mass volume ratio of the intermediate to the acid is 1:16 g / mL; (8) The purification method can reduce the content of impurity A from 0.17% to below the detection limit.

5. The purification method according to claim 4, characterized in that It meets one or more of the following conditions: (1) The content of impurity A in the crude product of compound 1 is 0.17%; (2) In the step S1, when the piperazine participates in the reaction in the form of a solution; the solvent of the solution is a mixed solvent of acetonitrile and water; the volume ratio of acetonitrile to water in the solvent of the solution is (5-15): 1; (3) In step S2, the formic acid is added in the form of a formic acid aqueous solution.

6. The purification method according to claim 1, characterized in that It meets one or more of the following conditions: (1) In step S1, when the solvent is a mixed solvent of isopropyl ether and water, the volume ratio of isopropyl ether to water is 199:1; (2) In step S1, when the solvent is a mixed solvent of isopropyl ether, water and acetonitrile, the volume ratio of isopropyl ether: water: acetonitrile is 21.6: 1.09: 0.11; (3) In the step S1, the piperazine participates in the reaction in the form of a solution; the solvent of the solution is a mixed solvent of acetonitrile and water; the volume ratio of acetonitrile to water in the solvent of the solution is 10.9:1.

1.

7. The purification method according to claim 1, characterized in that The crude compound 1 is prepared by the following method, which comprises the following steps: ； In a halogenated hydrocarbon solvent, in the presence of an organic acid, compound 1-16 undergoes a deprotection reaction to obtain a crude product of compound 1.

8. The purification method according to claim 7, characterized in that The deprotection reaction satisfies one or more of the following conditions: (1) In the deprotection reaction, the halogenated hydrocarbon solvent is dichloromethane; (2) In the deprotection reaction, the mass volume ratio of the compound 1-16 to the halogenated hydrocarbon solvent is 1:(5-30); (3) In the deprotection reaction, the organic acid is trifluoroacetic acid; (4) In the deprotection reaction, the molar ratio of the compound 1-16 to the organic acid is 1:(10-40); (5) The reaction temperature of the deprotection reaction is 0±10°C; (6) The reaction time of the deprotection reaction is 10 to 30 hours.

9. The purification method according to claim 7, characterized in that The method for preparing the crude product of compound 1 further comprises the following steps: ； In a nitrile solvent, in the presence of an inorganic base, compound 1-14 and compound 1-15 undergo a substitution reaction to obtain compound 1-16.

10. The purification method according to claim 9, characterized in that The substitution reaction satisfies one or more of the following conditions: (1) In the substitution reaction, the nitrile solvent is acetonitrile; (2) In the substitution reaction, the mass volume ratio of the compound 1-14 to the nitrile solvent is (100-200): 1 g / L; (3) In the substitution reaction, the inorganic base is an alkali metal bicarbonate; (4) In the substitution reaction, the mass ratio of the compound 1-14 to the inorganic base is 1:(0.5-1.5); (5) In the substitution reaction, the mass ratio of the compound 1-14 to the compound 1-15 is 1:(1~2); (6) The reaction temperature of the substitution reaction is 40±15°C; (7) The reaction time of the substitution reaction is 10 to 30 hours.

11. The purification method according to claim 1, characterized in that The content of impurity A in the crude product of compound 1 is greater than 0.1%.

12. The purification method according to claim 1, characterized in that The content of impurity A in the crude product of compound 1 is 0.1-0.2%.

13. The purification method according to claim 5, characterized in that In step S2, the mass percentage of formic acid in the formic acid aqueous solution is 1%.

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