Preparation and purification method of Elexacaftor intermediate

Abstract

The invention relates to the technical field of preparation of an Elexacaftor intermediate, in particular to a preparation and purification method of the Elexacaftor intermediate. Comprising the following steps: S1, uniformly stirring a compound 1, a compound 2, DIEA and a solvent, and adding HATU for reaction; s2, adding diluted hydrochloric acid after the reaction, filtering, collecting a filter cake, performing phase separation on filtrate, extracting a water phase with an organic solvent, combining organic phases, washing with diluted hydrochloric acid and saturated salt water in sequence, and drying with anhydrous sodium sulfate; and S3, after drying, carrying out concentration, recrystallization and drying so as to obtain the Elexacaftor intermediate. And adding the Elexacaftor intermediate into a solvent, heating, dissolving, cooling, carrying out suction filtration, rinsing a filter cake with the solvent, drying, purifying the product, and removing monomethyl impurities. The technical scheme provided by the invention is low in cost, simple to operate, high in purity of the obtained product, low in monomethyl impurity content and easy for industrial production.

Description

Technical Field

[0001] The present invention relates to the technical field of the preparation of Elexacaftor intermediates, and in particular to a method for the preparation and purification of Elexacaftor intermediates. Background Art

[0002] The patent document with the publication number WO2018107100A1 of Vertex Pharmaceuticals Incorporated discloses the synthesis of the Elexacaftor intermediate 2-chloro-N-((1,3-dimethyl-1H-pyrazol-4-yl)sulfonyl)-6-(3-(3,3,3-trifluoro-2,2-dimethylpropoxy)-1H-pyrazin-1-yl)nicotinamide.

[0003] The preparation process route is as shown in Formula 1 below:

[0004]

[0005] Specific synthesis steps: Solid carbonyldiimidazole (about 10.49 g, 64.67 mmol) was added in batches to a suspension of 2-chloro-6-[3-(3,3,3-trifluoro-2,2-dimethylpropoxy)pyrazol-1-yl]pyridine-3-carboxylic acid (20.0 g, 53.89 mmol) in THF (78.40 mL), and the mixture was stirred at room temperature (a slight exotherm of 18 - 21 °C was observed). After 1 h, solid 1,3-dimethylpyrazole-4-sulfonamide (about 11.33 g, 64.67 mmol) was added in two equal portions within 1 minute, and then DBU (about 9.845 g, 9.671 mL, 64.67 mmol) (exothermic temperature was 19 to 35 °C) was added. The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with ethyl acetate (118 mL) and HCl (about 107.8 mL 2M, 215.6 mmol). The phases were separated, and the aqueous phase was extracted with ethyl acetate (78 ml). The organic phases were combined, washed with water (39.2 mL), then with brine (40 mL), dried over sodium sulfate and concentrated. The resulting concentrate was crystallized from a mixture of isopropanol:heptane (1:1) (80 mL) to obtain 2-chloro-N-((1,3-dimethyl-1H-pyrazol-4-yl)sulfonyl)-6-(3-(3,3,3-trifluoro-2,2-dimethylpropoxy)-1H-pyrazin-1-yl)nicotinamide as a white solid (26.1 g, 93%).

[0006] The above synthesis method uses expensive CDI (N,N'-carbonyldiimidazole) and DBU (1,8-diazabicycloundec-7-ene), and the post-treatment operation is cumbersome. In particular, ethyl acetate will hydrolyze under acidic conditions, affecting the treatment effect. CDI and DBU cannot be recycled, and the solvents tetrahydrofuran and ethyl acetate are difficult to recycle, generating a large amount of organic waste liquid. During industrial transformation, there are monomethyl impurities in this step, and it is not easy to control, which will affect the quality of the Elexacaftor API obtained in the next step. How to select highly efficient and inexpensive condensing agents and basic reagents, simplify the operation, achieve high-quality, high-yield and low-cost efficient synthesis, and be able to purify and control monomethyl impurities to achieve industrial production is a problem that needs to be solved. Summary of the Invention

[0007] The purpose of the present invention is to provide a method for preparing and purifying an Elexacaftor intermediate, which has low cost, simple operation, high purity of the obtained product, low content of monomethyl impurities, and is easy for industrial production.

[0008] The present invention provides a method for preparing an Elexacaftor intermediate, comprising the following steps:

[0009] S1. Mix compound 1, compound 2, N,N-diisopropylethylamine and an organic solvent, stir evenly, and then add 2-(7-azabenzotriazol)-N,N,N',N'-tetramethyluronium hexafluorophosphate in batches for reaction;

[0010] S2. After the reaction is complete, add dilute hydrochloric acid to adjust the pH value to 5-6, filter, collect the filter cake, separate the phases of the filtrate, extract the aqueous phase with an organic solvent and then combine the organic phases, and then wash with dilute hydrochloric acid and saturated brine in sequence, and then dry with anhydrous sodium sulfate;

[0011] S3. After drying, concentrate, recrystallize the concentrate, dry the precipitated crystals to obtain the Elexacaftor intermediate, namely compound 3;

[0012] The reaction formula is as follows:

[0013]

[0014] Preferably, the organic solvent in step S1 is dichloromethane.

[0015] Preferably, 2-(7-azabenzotriazol)-N,N,N',N'-tetramethyluronium hexafluorophosphate is added in batches under the condition of a temperature of 15-25 °C in step S1.

[0016] Preferably, the concentrate in step S3 is dissolved in ethyl acetate, and then petroleum ether is added for recrystallization, and the precipitated crystals are dried at 40-45 °C.

[0017] Preferably, in the step S1, the molar ratio of compound 1 to compound 2 is 1:(1.1 - 1.5); the molar ratio of N,N-diisopropylethylamine to compound 1 is (3 - 5.5):1.

[0018] Preferably, in the step S1, the molar ratio of 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate to compound 1 is (1 - 1.5):1.

[0019] Preferably, in the step S2, 4 - 4.5 mol / L dilute hydrochloric acid is used to adjust the pH value.

[0020] Preferably, in the step S2, 2 - 2.5 mol / L dilute hydrochloric acid is used for washing.

[0021] The present invention provides a purification method for an Elexacaftor intermediate obtained by the above preparation method. The Elexacaftor intermediate contains a monomethyl impurity, and the structural formula of the monomethyl impurity is as follows:

[0022]

[0023] The purification process is as follows:

[0024] Take the Elexacaftor intermediate, add a solvent, heat to 50 - 60 °C until it is dissolved clearly, then cool to 9 - 11 °C, stir, filter by suction, wash the filter cake with the solvent, and dry it at 30 - 40 °C. If it is unqualified, the above steps can be repeated, and the content of the monomethyl impurity in the Elexacaftor intermediate can be reduced to less than 0.10%.

[0025] Preferably, the solvent used in the purification process is a mixed solution of methanol and water, and the mass ratio of methanol to water in the mixed solution is 4:(3 - 3.2).

[0026] In summary, the present invention has the following advantages:

[0027] The preparation method for the Elexacaftor intermediate provided by the present invention uses a new condensing agent HATU and a basic reagent DIEA for efficient synthesis. The product yield is 97 - 99%, the operation is simple, the product purity reaches more than 99.2%, the content of the monomethyl impurity is less than 0.10%, the cost is low, and the basic reagent DIEA used in the present invention can be recycled and reused, with less organic waste liquid, and it is easy to industrialize.

[0028] The purification method for the Elexacaftor intermediate provided by the present invention is simple and easy to operate, and can effectively control the content of the monomethyl impurity. Description of the Drawings

[0029] To more clearly illustrate the specific embodiments of the present invention or the technical solutions in the prior art, the following will briefly introduce the drawings required for the description of the specific embodiments or the prior art. Obviously, the drawings in the following description are some embodiments of the present invention. For those of ordinary skill in the art, without creative efforts, other drawings can also be obtained based on these drawings.

[0030] Figure 1 HPLC chromatogram of the Elexacaftor intermediate prepared in Example 1 of the present invention;

[0031] Figure 2 Nuclear magnetic spectrum of the Elexacaftor intermediate prepared in Example 1 of the present invention;

[0032] Figure 3 HPLC chromatogram of the unqualified Elexacaftor intermediate before purification in the present invention;

[0033] Figure 4 HPLC chromatogram of the Elexacaftor intermediate after purification in the present invention. Specific Embodiments

[0034] The following will clearly and completely describe the technical solutions of the present invention in combination with the embodiments. Obviously, the described embodiments are some embodiments of the present invention, rather than all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those of ordinary skill in the art without creative efforts belong to the scope of protection of the present invention.

[0035] In the description of the present invention, it should be understood that the orientation or positional relationships indicated by the terms "center", "longitudinal", "lateral", "length", "width", "thickness", "upper", "lower", "front", "rear", "left", "right", "vertical", "horizontal", "top", "bottom", "inner", "outer", "clockwise", "counterclockwise", etc. are based on the orientation or positional relationships shown in the drawings, and are only for the convenience of describing the present invention and simplifying the description, rather than indicating or implying that the device or element referred to must have a specific orientation, be constructed and operated in a specific orientation, and therefore should not be construed as a limitation to the present invention.

[0036] In addition, the terms "first" and "second" are used for descriptive purposes only and should not be construed as indicating or implying relative importance or implicitly specifying the quantity of the indicated technical features. Thus, features defined with "first" and "second" may explicitly or implicitly include one or more of the said features. In the description of the present invention, the meaning of "a plurality" is two or more unless otherwise specifically defined. In addition, the terms "installed", "connected", and "joined" should be understood in a broad sense. For example, it may be a fixed connection, a detachable connection, or an integral connection; it may be a mechanical connection or an electrical connection; it may be directly connected or indirectly connected through an intermediate medium, and it may be the communication inside two components. For those of ordinary skill in the art, the specific meanings of the above terms in the present invention can be understood according to specific circumstances.

[0037] Example 1

[0038] A preparation method of an Elexacaftor intermediate, and the reaction formula is as follows:

[0039]

[0040] The specific process is as follows:

[0041] S1. Add 2-chloro-6-[3-(3,3,3-trifluoro-2,2-dimethylpropoxy)pyrazol-1-yl]pyridine-3-carboxylic acid (40.0 g, 0.108 mol), dichloromethane (400 mL), 1,3-dimethylpyrazole-4-sulfonamide (24.2 g, 0.138 mol), and N,N-diisopropylethylamine (DIEA) (71.2 g, 0.55 mol) to a 1 L reaction flask and stir evenly; then add 2-(7-azabenzotriazol)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU) (52.4 g, 0.14 mol) in batches at 15 - 25 °C for reaction;

[0042] S2. Detect that the reaction is complete by TLC, then add 4 mol / L dilute hydrochloric acid to adjust the pH value to 5 - 6, filter, and collect the filter cake (recover the basic reagent DIEA, with a recovery rate of 85%); the filtrate is layered, the aqueous phase is extracted with dichloromethane (135 mL) and then the organic phases are combined, washed with 2 mol / L dilute hydrochloric acid (35 g), then washed with saturated brine (50 g), and dried over anhydrous sodium sulfate (20 g);

[0043] S3. After drying and concentration, the concentrate was dissolved in ethyl acetate (50 g), and petroleum ether (100 g) was added for crystallization. The precipitated crystals were dried in a blast dryer at 40 - 45 °C to obtain the Elexacaftor intermediate 2-chloro-N-((1,3-dimethyl-1H-pyrazol-4-yl)sulfonyl)-6-(3-(3,3,3-trifluoro-2,2-dimethylpropoxy)-1H-pyrazin-1-yl)nicotinamide product (55.15 g, molar yield 98.2%), the product purity was 99.5%, and the HPLC spectrum and NMR spectrum of the product were respectively as Figure 1 and Figure 2 shown.

[0044] Example 2

[0045] A preparation method of an Elexacaftor intermediate is as follows:

[0046] S1. Add 2-chloro-6-[3-(3,3,3-trifluoro-2,2-dimethylpropoxy)pyrazol-1-yl]pyridine-3-carboxylic acid (40.0 g, 0.108 mol), dichloromethane (400 mL), 1,3-dimethylpyrazole-4-sulfonamide (20.9 g, 0.119 mol), and N,N-diisopropylethylamine (DIEA) (71.2 g, 0.55 mol) to a 1 L reaction flask and stir evenly; then add 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU) (52.4 g, 0.14 mol) in batches at 15 - 25 °C for reaction;

[0047] S2. TLC detected that the reaction was complete, then add 4 mol / L dilute hydrochloric acid to adjust the pH value to 5 - 6, filter, and collect the filter cake (recover the basic reagent DIEA, recovery rate 85%); the filtrate was separated into layers, the aqueous phase was extracted with dichloromethane (135 mL) and then the organic phases were combined, washed with 2 mol / L dilute hydrochloric acid (35 g), then washed with saturated brine (50 g), and dried over anhydrous sodium sulfate (20 g);

[0048] S3. After drying and concentration, the concentrate was dissolved in ethyl acetate (50 g), and petroleum ether (100 g) was added for crystallization. The precipitated crystals were dried in a blast dryer at 40 - 45 °C to obtain the Elexacaftor intermediate 2-chloro-N-((1,3-dimethyl-1H-pyrazol-4-yl)sulfonyl)-6-(3-(3,3,3-trifluoro-2,2-dimethylpropoxy)-1H-pyrazin-1-yl)nicotinamide product (54.48 g, molar yield 97.0%), and the product purity was 99.3%.

[0049] Example 3

[0050] A preparation method of an Elexacaftor intermediate is as follows:

[0051] S1. Add 2-chloro-6-[3-(3,3,3-trifluoro-2,2-dimethylpropoxy)pyrazol-1-yl]pyridine-3-carboxylic acid (40.0 g, 0.108 mol), dichloromethane (400 mL), 1,3-dimethylpyrazole-4-sulfonamide (24.2 g, 0.138 mol), and N,N-diisopropylethylamine (DIEA) (55.9 g, 0.432 mol) into a 1 L reaction flask and stir evenly; then add 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU) (52.4 g, 0.14 mol) in batches at 15 - 25 °C and carry out the reaction;

[0052] S2. When the reaction is complete as detected by TLC, then add 4 mol / L dilute hydrochloric acid to adjust the pH value to 5 - 6, filter, and collect the filter cake (recover the basic reagent DIEA with a recovery rate of 85%); separate the layers of the filtrate, extract the aqueous phase with dichloromethane (135 mL), combine the organic phases, wash with 2 mol / L dilute hydrochloric acid (35 g), then wash with saturated brine (50 g), and dry over anhydrous sodium sulfate (20 g);

[0053] S3. After drying and concentrating, dissolve the concentrate in ethyl acetate (50 g), add petroleum ether (100 g) for crystallization, and dry the precipitated crystals by blowing air at 40 - 45 °C to obtain the Elexacaftor intermediate 2-chloro-N-((1,3-dimethyl-1H-pyrazol-4-yl)sulfonyl)-6-(3-(3,3,3-trifluoro-2,2-dimethylpropoxy)-1H-pyrazin-1-yl)nicotinamide product (54.6 g, molar yield 97.2%), and the product purity is 99.5%.

[0054] Example 4

[0055] A preparation method of an Elexacaftor intermediate is as follows:

[0056] S1. Add 2-chloro-6-[3-(3,3,3-trifluoro-2,2-dimethylpropoxy)pyrazol-1-yl]pyridine-3-carboxylic acid (40.0 g, 0.108 mol), dichloromethane (400 mL), 1,3-dimethylpyrazole-4-sulfonamide (24.2 g, 0.138 mol), and N,N-diisopropylethylamine (DIEA) (71.2 g, 0.55 mol) into a 1 L reaction flask and stir evenly; then add 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU) (56.14 g, 0.15 mol) in batches at 15 - 25 °C and carry out the reaction;

[0057] The TLC detection of S2 showed a complete reaction. Then, 4 mol / L dilute hydrochloric acid was added to adjust the pH value to 5 - 6, followed by filtration. The filter cake was collected (the basic reagent DIEA was recovered with a recovery rate of 85%); the filtrate was layered, and the aqueous phase was extracted with dichloromethane (135 mL), and then the organic phases were combined, washed with 2 mol / L dilute hydrochloric acid (35 g), then washed with saturated brine (50 g), and dried over anhydrous sodium sulfate (20 g).

[0058] After drying and concentration, the concentrate was dissolved in ethyl acetate (50 g), and petroleum ether (100 g) was added for crystallization. The precipitated crystals were dried in a blast dryer at 40 - 45 °C to obtain the Elexacaftor intermediate 2-chloro-N-((1,3-dimethyl-1H-pyrazol-4-yl)sulfonyl)-6-(3-(3,3,3-trifluoro-2,2-dimethylpropoxy)-1H-pyrazin-1-yl)nicotinamide product (55.3 g, molar yield 98.5%), and the product purity was 99.6%.

[0059] If the Elexacaftor intermediate obtained by the preparation method of the present invention contains a monomethyl impurity, the structural formula of the monomethyl impurity is as follows:

[0060]

[0061] The prepared Elexacaftor intermediate was detected. If the content of the above monomethyl impurity was too large (greater than >0.1%), the following method could be used for purification:

[0062] Take the unqualified Elexacaftor intermediate prepared (20 g, product purity 98.23%, content of monomethyl impurity 0.27%) and add it to a mixed solution of methanol and water (100 g of methanol and 75 g of water in the mixed solution), heat to 50 - 60 °C until it is completely dissolved, then slowly cool to about 10 °C and stir for 1 - 2 hours, and then filter; the filter cake was rinsed with a methanol / water = 2 / 1.5 mixed solution and dried at 30 - 40 °C. If it was unqualified, the recrystallization was repeated once. The refined yield was 95%, the product purity was 99.73%, and the content of monomethyl impurity was 0.086%. The HPLC chromatogram of the product before purification was as Figure 3 shown, and the HPLC chromatogram of the purified product was as Figure 4 shown.

[0063] Comparative Example 1

[0064] A preparation method of an Elexacaftor intermediate, the technical solution is basically the same as that in Example 1, except that: in step S1 of this comparative example, the organic solvent used was dimethyl sulfoxide (DMSO).

[0065] Comparative Example 2

[0066] A preparation method of an Elexacaftor intermediate, the technical solution is basically the same as that of Example 1, except that: the organic solvent used in step S1 of this comparative example is methyl tert-butyl ether.

[0067] Comparative Example 3

[0068] A preparation method of an Elexacaftor intermediate, the technical solution is basically the same as that of Example 1, except that: the organic solvent used in step S1 of this comparative example is tetrahydrofuran (THF).

[0069] Comparative Example 4

[0070] A preparation method of an Elexacaftor intermediate, the technical solution is basically the same as that of Example 1, except that: the organic solvent used in step S1 of this comparative example is N,N-dimethylformamide (DMF).

[0071] The reaction, post-treatment, yield, and product purity of the Elexacaftor intermediates obtained in Comparative Examples 1-4 and Example 1 are shown in Table 1.

[0072] Table 1 Comparison of the effects of reactions using different organic solvents

[0073] Group Reaction solvent Reaction and post-treatment conditions Yield (%) Product purity (%) Example 1 Dichloromethane Normal 98.2 99.5 Comparative Example 1 DMSO Complicated post-treatment 78 98 Comparative Example 2 Methyl tert-butyl ether Incomplete reaction 65 97 Comparative Example 3 THF Large amount of waste liquid 86 98.5 Comparative Example 4 DMF Complicated post-treatment, large amount of waste liquid 70 98

[0074] It can be clearly seen from Table 1 that the reaction solvent dichloromethane used in the present invention has normal reaction and post-treatment conditions, and the highest yield and purity.

[0075] Comparative Example 5

[0076] A preparation method of an Elexacaftor intermediate, the technical solution is basically the same as that of Example 1, except that: the condensing agent used in this comparative example is HBTU.

[0077] Comparative Example 6

[0078] A preparation method of an Elexacaftor intermediate, the technical solution is basically the same as that of Example 1, except that: the condensing agent used in this comparative example is HCTU.

[0079] Comparative Example 7

[0080] A preparation method of an Elexacaftor intermediate, the technical solution is basically the same as that of Example 1, except that: the condensing agent used in this comparative example is EDCI·HCl.

[0081] The reaction conditions, yield, and product purity of the Elexacaftor intermediates obtained in Comparative Examples 5-7 and Example 1 are shown in Table 2.

[0082] Table 2 Comparison of the effects of reactions using different condensing agents

[0083]

[0084] It can be clearly seen from Table 2 that the condensing agent used in the present invention has the highest yield and purity compared with several other condensing agents.

[0085] Comparative Example 8

[0086] A preparation method of an Elexacaftor intermediate, the technical solution is basically the same as that of Example 1, except that: the basic reagent used in this comparative example is triethylamine.

[0087] Comparative Example 9

[0088] A preparation method of an Elexacaftor intermediate, the technical solution is basically the same as that of Example 1, except that: the basic reagent used in this comparative example is pyridine.

[0089] Comparative Example 10

[0090] A preparation method of an Elexacaftor intermediate, the technical solution is basically the same as that of Example 1, except that: the basic reagent used in this comparative example is imidazole.

[0091] The reaction conditions, yields, and product purities of the Elexacaftor intermediates obtained in Comparative Examples 8 - 10 and Example 1 are shown in Table 3.

[0092] Table 3 Comparison of the effects of reactions using different basic reagents

[0093] Group Basic reagent Reaction conditions Yield (%) Product purity (%) Example 1 DIEA Normal 98.2 99.5 Comparative Example 8 Triethylamine Will change chirality 80 98.0 Comparative Example 9 Pyridine High toxicity 85 98.5 Comparative Example 10 Imidazole Weak basicity, poor reaction effect 60 98

[0094] It can be clearly seen from Table 3 that the basic reagent DIEA used in the present invention has the highest yield and purity compared with several other basic reagents.

[0095] The Elexacaftor intermediate provided by the present invention is efficiently synthesized using a new condensing agent, basic reagent, and organic solvent. The operation is simple, the product yield is 97 - 99%, the product purity is high (above 99.2%), the control of monomethyl impurities is low (below 0.10%). Compared with the preparation method in the background technology, the cost is reduced by 35%, and the product yield is increased by more than 4%. Moreover, the dichloromethane solvent used in the preparation method of the present invention can be recycled and reused, with a recovery rate of 85%; the basic reagent DIEA used can be recycled and reused, with a recovery rate of 50%. There is less organic waste liquid and it is easy to industrialize. The monomethyl impurity purification method provided by the present invention can effectively reduce the impurity content and improve the product purity.

[0096] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, rather than to limit them; although the present invention has been described in detail with reference to the foregoing embodiments, those of ordinary skill in the art should understand that they can still modify the technical solutions described in the foregoing embodiments, or perform equivalent replacements on some or all of the technical features; and these modifications or replacements do not cause the essence of the corresponding technical solutions to deviate from the scope of the technical solutions of the various embodiments of the present invention.

Claims

1. A preparation method of an Elexacaftor intermediate, characterized in that, It includes the following steps: S1. Mix compound 1, compound 2, N,N-diisopropylethylamine and an organic solvent, stir evenly, and then add 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate in batches for reaction; S2. After the reaction is complete, add dilute hydrochloric acid to adjust the pH value to 5-6, filter, collect the filter cake, separate the phases of the filtrate, extract the aqueous phase with an organic solvent and then combine the organic phases, and then wash successively with dilute hydrochloric acid and saturated brine, and then dry with anhydrous sodium sulfate; S3. After drying, concentrate, recrystallize the concentrate, dry the precipitated crystals to obtain the Elexacaftor intermediate, that is, compound 3; The reaction formula is as follows:

2. The preparation method according to claim 1, wherein, The organic solvent in step S1 is dichloromethane.

3. The preparation method according to claim 1, wherein In step S1, 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate is added in batches under the condition that the temperature is 15-25 °C.

4. The preparation method according to claim 1, wherein, The concentrate in step S3 is dissolved in ethyl acetate, and then petroleum ether is added for recrystallization, and the precipitated crystals are dried at 40-45 °C.

5. The preparation method according to claim 1, characterized in that, In step S1, the molar ratio of compound 1 to compound 2 is 1:(1.1-1.5); the molar ratio of N,N-diisopropylethylamine to compound 1 is (3-5.5):

1.

6. The preparation method according to claim 1, characterized in that, In step S1, the molar ratio of 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate to compound 1 is (1-1.5):

1.

7. The preparation method according to claim 1, characterized in that In step S2, 4-4.5 mol / L dilute hydrochloric acid is used to adjust the pH value.

8. The preparation method according to claim 1, wherein In step S2, 2-2.5 mol / L dilute hydrochloric acid is used for washing.

9. A purification method for the Elexacaftor intermediate obtained by using the preparation method according to any one of claims 1-8, characterized in that, The Elexacaftor intermediate contains a monomethyl impurity, and the structural formula of the monomethyl impurity is as follows: The purification process is as follows: Take the Elexacaftor intermediate, add a solvent, heat to 50-60 °C until it is clear, then cool to 9-11 °C and stir, filter by suction, rinse the filter cake with the solvent and dry at 30-40 °C. If it is unqualified, the above steps can be repeated to reduce the content of the monomethyl impurity in the Elexacaftor intermediate to less than 0.10%.

10. The purification method according to claim 9, characterized in that, The solvent used in the purification process is a mixed solution of methanol and water, and the mass ratio of methanol to water in the mixed solution is 4:(3-3.2).

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