Improved canagliflozin peroxide preparation method

Abstract

The invention provides a preparation method of a canagliflozin peroxide as shown in a formula I. The method comprises the following steps: (1) heating a canagliflozin compound as shown in a formula II and hydrogen peroxide in a mixture of an organic solvent and water to 50-70 DEG C for reaction, after the reaction is finished, obtaining a mixture containing canagliflozin peroxide as shown in a formula I and canagliflozin alcohol as shown in a formula III; and (2) adding hydrogen peroxide into the mixture obtained in the step (1), and reacting in a reaction solvent under the catalysis of strong acid to obtain the canagliflozin peroxide as shown in the formula I. The substance is a key impurity in the canagliflozin tablet, the preparation method of the canagliflozin peroxide provided by the invention is simple to operate and does not need to use a complex reagent, a by-product generated in the reaction process is converted into the canagliflozin peroxide, the separation difficulty is reduced, the yield is increased, and the preparation method has very obvious technical advantages. # imgabs0 #

Description

[0001] This application is a divisional application of the Chinese patent application with application number CN201911030228.4 filed on October 28, 2019 and invention name “An improved method for preparing canagliflozin peroxide”. Technical Field

[0002] The present invention belongs to the technical field of pharmaceutical chemistry, and particularly relates to a method for preparing canagliflozin peroxide, which is a canagliflozin impurity. Background Art

[0003] Canagliflozin, developed by Mitsubishi Tanabe and Johnson & Johnson, was approved by the U.S. FDA on March 29, 2013. It is the first sodium-glucose co-transporter 2 (SGLT2) inhibitor approved by the FDA for the treatment of type 2 diabetes in adults. Canagliflozin inhibits SGLT2, preventing glucose in the renal tubules from being reabsorbed into the blood and excreted in the urine, thereby reducing blood sugar concentration. In addition to its good blood sugar control effect, the most notable feature of canagliflozin is its weight loss effect and few hypoglycemia events, which give it a very broad application prospect.

[0004] The chemical formula of canagliflozin is (1S)-1,5-dehydro-1-C-[3-[[5-(4-fluorophenyl)-2-thienyl]methyl]-4-methylphenyl]-D-glucitol, and the structural formula is as follows:

[0005]

[0006] Impurity research is a key research area in drug development and commercial production, and runs through the entire drug life cycle research. The presence of impurities directly affects the safety, effectiveness and quality controllability of drugs.

[0007] During the quality study of canagliflozin tablets, we found that canagliflozin may be oxidized in long-term stability samples and accelerated stability samples to produce canagliflozin peroxide, the structural formula of which is shown in Formula I:

[0008]

[0009] This impurity was disclosed as a base-toxic impurity in the EMA review report, and the original research company limited its content to 220 ppm. Therefore, canagliflozin peroxide is an important impurity that has a significant impact on the efficacy and safety of canagliflozin tablets.

[0010] There are two main existing methods for preparing canagliflozin peroxide:

[0011] Method 1 is a method reported in the journal Chemistry Select (2017), 2, P9157-9161, using acetonitrile: water = 4:1 as solvent, 30% peroxide solution as oxidant, and canagliflozin API as raw material for 6-7 days at 40-45°C to synthesize canagliflozin peroxide. Although it is mentioned in the literature that the purity of the target product can reach 10-15% when monitoring the reaction solution, the literature does not report the yield; we repeated the method and found that the yield was only about 1% (see Comparative Example 1). The study found that the sample canagliflozin peroxide is easily decomposed at room temperature in the presence of hydrogen peroxide, especially in the process of heating and distilling to remove the solvent, the decomposition is more serious, resulting in a lower yield. The synthetic route is as follows:

[0012]

[0013] Method 2 is the method adopted in patent CN108530434A, which uses canagliflozin as a raw material, firstly oxidizes the methylene group in the benzyl position of canagliflozin to canagliflozin ketone with an oxidant, then reduces it to canagliflozin alcohol with a reducing agent, and finally replaces the hydroxyl group in canagliflozin alcohol with a peroxy group under acidic conditions with hydrogen peroxide, and finally separates and purifies to obtain canagliflozin peroxide. The specific synthesis route is as follows:

[0014]

[0015] The preparation method has a long synthesis step and the yield is not reported. In addition, in the oxidation step, the process of using oxidants such as 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ) to oxidize canagliflozin to canagliflozin ketone is prone to produce other impurities, resulting in a low yield in the oxidation step. At the same time, column chromatography is required to separate and purify the products of each step of the reaction and separate the by-products, which greatly reduces the product conversion rate. The operation is cumbersome and is not suitable for rapid preparation in the laboratory.

[0016] In view of the fact that this impurity is crucial to controlling the quality of canagliflozin products, and the preparation methods in the prior art have many problems, such as long reaction cycle and low yield; the preparation process is cumbersome and inefficient; therefore, the present invention develops a method for synthesizing canagliflozin peroxide that is easy to operate and has a high yield to carry out in-depth research on this impurity, which is of great significance. Summary of the invention

[0017] The purpose of the present invention is to overcome the shortcomings of the prior art and provide a method for preparing canagliflozin peroxide which is simple to operate, does not require the use of complex reagents, and can quickly and efficiently provide a qualified reference substance for the quality control of canagliflozin finished products.

[0018] The present invention provides a method for preparing canagliflozin peroxide having a structure as shown in Formula I, comprising the following steps:

[0019] (1) heating the canagliflozin compound represented by formula II and hydrogen peroxide to 50-70° C. in a mixture of an organic solvent and water to react, and after the reaction is completed, obtaining a mixture containing the canagliflozin peroxide represented by formula I and the canagliflozin alcohol represented by formula III;

[0020] (2) adding hydrogen peroxide to the mixture obtained in step (1), and reacting in a reaction solvent under the catalysis of a strong acid to obtain canagliflozin peroxide as shown in formula I; the reaction formula is as follows:

[0021]

[0022] More preferably, the organic solvent described in step (1) is selected from acetonitrile, methanol, tetrahydrofuran, N,N-dimethylformamide, N,N-dimethylacetamide, 1,4-dioxane, dimethyl sulfoxide, N-methylpyrrolidone; preferably acetonitrile.

[0023] More preferably, the volume ratio of the organic solvent to water in step (1) is 5:1 to 20:1.

[0024] More preferably, the molar ratio of hydrogen peroxide to canagliflozin in step (1) is 0.5:1 to 100:1, preferably 4:1 to 30:1.

[0025] More preferably, the reaction temperature in step (1) is 50-60° C., and the reaction time is 1-36 hours, preferably 6-18 hours.

[0026] More preferably, the strong acid in step (1) is an inorganic strong acid or an organic strong acid, or any combination thereof, wherein the inorganic strong acid is selected from sulfuric acid, hydrochloric acid, phosphoric acid, perchloric acid, hydrobromic acid, nitric acid, hexafluorophosphoric acid, preferably sulfuric acid and hexafluorophosphoric acid; the organic strong acid is selected from methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, trifluoroacetic acid, tribromoacetic acid, preferably methanesulfonic acid and trifluoroacetic acid.

[0027] More preferably, the reaction solvent in step (2) is acetonitrile, methanol, tetrahydrofuran, N,N-dimethylformamide, N,N-dimethylacetamide, 1,4-dioxane, dimethyl sulfoxide, N-methylpyrrolidone; preferably acetonitrile.

[0028] More preferably, the molar ratio of the strong acid to canagliflozin in step (2) is 0.1:1 to 50:1, preferably 3:1 to 10:1.

[0029] More preferably, the molar ratio of hydrogen peroxide to canagliflozin in step (2) is 0.5:1 to 100:1, preferably 10:1 to 50:1.

[0030] More preferably, the reaction temperature in step (2) is 5 to 35° C., preferably 20 to 30° C.; the reaction time is 1 to 120 hours, preferably 24 to 72 hours.

[0031] More preferably, the canagliflozin peroxide obtained in step (2) can be added with water after the reaction is complete, cooled to 0 to -10°C, stirred and crystallized for 0.5 to 1 hour, filtered to obtain a solid, washed with purified water, and separated by column chromatography to obtain pure canagliflozin peroxide of formula I.

[0032] The inventors have found through research that the temperature control in step (1) is the most critical, and the content of the composition in the reaction solution changes continuously at different reaction temperatures. It is even more gratifying to find that when a reaction solution containing a large amount of byproduct canagliflozin alcohol is first generated, and then a large amount of byproduct canagliflozin alcohol is converted into product canagliflozin peroxide by an effective method, the canagliflozin alcohol generated by the method does not need to be separated and directly proceeds to the next step of reaction, the difficulty of separation is reduced after the reaction is complete, and the yield is greatly improved.

[0033] In addition, the study found that during the post-treatment process, canagliflozin peroxide is easily decomposed at room temperature in the presence of hydrogen peroxide, especially during the heating and distillation process to remove the solvent, the decomposition is more serious; therefore, the inventors used the method of adding water to cool and crystallize in the final post-treatment to greatly reduce the decomposition of canagliflozin peroxide.

[0034] Beneficial effects of the present invention:

[0035] 1. This method adopts a "one-pot" preparation method, which does not require the separation of intermediate products and is easy to operate. It also greatly shortens the reaction time and can quickly prepare canagliflozin peroxide, thereby improving work efficiency and reducing preparation costs.

[0036] 2. This method cleverly generates a reaction solution containing a large amount of by-product canagliflozin alcohol first, and then effectively converts the large amount of by-product canagliflozin alcohol into the product canagliflozin peroxide, which reduces the difficulty of separation and significantly improves the yield, and has very obvious technical advantages.

[0037] 3. Reasonable post-reaction treatment can minimize the decomposition of canagliflozin peroxide and improve the yield. DETAILED DESCRIPTION

[0038] The present invention is further described below by way of examples, but the present invention is not limited to the scope of the examples. Based on the examples in the present invention, any changes and modifications of the present invention by those skilled in the art without creative work shall fall within the protection scope of the present invention.

[0039] Raw materials and general test methods:

[0040] The canagliflozin compound raw material used in the examples was prepared with reference to Example 8 of CN101801371B.

[0041] General detection method:

[0042] Instrument: High performance liquid chromatograph equipped with UV detector

[0043] Chromatographic column: Agilent ZORBAX SB C18, 150*4.6mm, 5μm

[0044] Mobile phase A: water

[0045] Mobile phase B: acetonitrile

[0046] Detection wavelength: 290nm

[0047] Flow rate: 1.0mL / min

[0048] Column temperature: 45°C

[0049] Running time: 40 minutes

[0050] gradient:

[0051]

[0052] Example 1

[0053] 1.0 g of canagliflozin (2.25 mmol) was added to 20 mL of acetonitrile and 2 mL of water, and 1.1 mL of 30% aqueous hydrogen peroxide solution (10.9 mmol) was added, and the temperature was raised to 55° C. for reaction for 12 hours; then cooled to 20° C., 0.5 mL of concentrated sulfuric acid (9.38 mmol), 20 mL of acetonitrile and 2 mL of 30% aqueous hydrogen peroxide solution (19.8 mmol) were added, and stirring was continued at 20° C. for 48 hours. After the reaction was completed, 80 mL of water was added, stirred for 30 minutes, and then cooled to 0° C., filtered, and the obtained solid was washed twice with purified water, and the remaining solution was freeze-dried with a freeze dryer. The obtained solid was separated by column chromatography [HP-Silica normal phase silica gel, eluent was dichloromethane: methanol = (10:1, V / V)] to separate the target product, and the solvent was dried with nitrogen to finally obtain 0.32 g of canagliflozin peroxide, HPLC purity 98.2%, and yield 30%.

[0054] Example 2

[0055] 1.0 g of canagliflozin (2.25 mmol) was added to 20 mL of acetonitrile and 2 mL of water, and 1.4 mL of 30% aqueous hydrogen peroxide solution (13.6 mmol) was added, and the temperature was raised to 60° C. for reaction for 15 hours; then cooled to 25° C., 0.5 mL of concentrated sulfuric acid (9.38 mmol), 20 mL of acetonitrile and 2 mL of 30% aqueous hydrogen peroxide solution (19.8 mmol) were added, and stirring was continued at 25° C. for 48 hours. After the reaction was completed, 80 mL of water was added, stirred for 30 minutes, and then cooled to -5° C., filtered, and the obtained solid was washed twice with purified water, and the remaining solution was freeze-dried with a freeze dryer. The obtained solid was separated by column chromatography [HP-Silica normal phase silica gel, eluent was dichloromethane: methanol = (15:1, V / V)] for the target product, and the solvent was dried with nitrogen to finally obtain 0.35 g of canagliflozin peroxide, HPLC purity 98.5%, and yield 33%.

[0056] Example 3

[0057] 1.0 g of canagliflozin (2.25 mmol) was added to 20 mL of methanol and 2 mL of water, and 1.5 mL of 30% aqueous hydrogen peroxide solution (14.8 mmol) was added, and the temperature was raised to 50° C. for reaction for 10 hours; then cooled to 20° C., 0.5 mL of concentrated sulfuric acid (9.38 mmol), 20 mL of acetonitrile and 2 mL of 30% aqueous hydrogen peroxide solution (19.8 mmol) were added, and stirring was continued at 20° C. for 48 hours. After the reaction was completed, 80 mL of water was added, stirred for 30 minutes, and then cooled to 0° C. and filtered. The obtained solid was washed twice with purified water, and the remaining solution was freeze-dried with a freeze dryer. The obtained solid was separated from the target product by column chromatography [HP-Silica normal phase silica gel, eluent was dichloromethane: methanol = (12:1, V / V)], and the solvent was dried with nitrogen to finally obtain 0.23 g of canagliflozin peroxide, HPLC purity 98.2%, and yield 21%.

[0058] Example 4

[0059] 1.0 g of canagliflozin (2.25 mmol) was added to 20 mL of acetonitrile and 2 mL of water, and 1.1 mL of 30% aqueous hydrogen peroxide solution (10.9 mmol) was added, and the temperature was raised to 55° C. for reaction for 14 hours; then cooled to 20° C., 1.0 mL of 36% concentrated hydrochloric acid (11.7 mmol), 20 mL of acetonitrile (2.25 mmol) and 3 mL of 30% aqueous hydrogen peroxide solution (29.7 mmol) were added, and stirring was continued at 20° C. for 48 hours. After the reaction was completed, 80 mL of water was added, stirred for 30 minutes, and then cooled to 0° C. and filtered. The obtained solid was washed twice with purified water, and the remaining solution was freeze-dried with a freeze dryer. The obtained solid was separated by column chromatography [HP-Silica normal phase silica gel, eluent was dichloromethane: methanol = (10:1, V / V)] to separate the target product, and the solvent was dried with nitrogen to finally obtain 0.30 g of canagliflozin peroxide, HPLC purity 98.6%, and yield 28%.

[0060] Example 5

[0061] 1.0 g of canagliflozin (2.25 mmol) was added to 20 mL of dimethyl sulfoxide and 2 mL of water, and 1.5 mL of 30% aqueous hydrogen peroxide solution (14.8 mmol) was added, and the temperature was raised to 55° C. for reaction for 12 hours; then cooled to 20° C., 0.5 mL of concentrated sulfuric acid (9.38 mmol), 20 mL of acetonitrile and 3 mL of 30% aqueous hydrogen peroxide solution (29.7 mmol) were added, and stirring was continued at 25° C. for 48 hours. After the reaction was completed, 80 mL of water was added, stirred for 30 minutes, and then cooled to -5° C., filtered, and the obtained solid was washed twice with purified water, and the remaining solution was freeze-dried with a freeze dryer. The obtained solid was separated by column chromatography [HP-Silica normal phase silica gel, eluent was dichloromethane: methanol = (15:1, V / V)] for the target product, and the solvent was dried with nitrogen to finally obtain 0.20 g of canagliflozin peroxide, HPLC purity 97.5%, and yield 19%.

[0062] Example 6

[0063] 1.0 g of canagliflozin (2.25 mmol) was added to 20 mL of acetonitrile and 2 mL of water, and 1.5 mL of 30% aqueous hydrogen peroxide solution (14.8 mmol) was added, and the temperature was heated to 55° C. for reaction for 12 hours; then cooled to 20° C., 1.2 mL of trifluoroacetic acid (16.1 mmol), 20 mL of acetonitrile and 2.5 mL of 30% aqueous hydrogen peroxide solution (24.7 mmol) were added, and stirring was continued at 20° C. for 48 hours. After the reaction was completed, 80 mL of water was added, stirred for 30 minutes, and then cooled to 0° C. and filtered. The obtained solid was washed twice with purified water, and the remaining solution was freeze-dried with a freeze dryer. The obtained solid was separated from the target product by column chromatography [HP-Silica normal phase silica gel, eluent was dichloromethane: methanol = (10:1, V / V)], and the solvent was dried with nitrogen to finally obtain 0.26 g of canagliflozin peroxide, HPLC purity 98.6%, and yield 24%.

[0064] Example 7

[0065] 1.0 g of canagliflozin (2.25 mmol) was added to 20 mL of acetonitrile and 2 mL of water, and 1.2 mL of 30% aqueous hydrogen peroxide solution (10.7 mmol) was added, and the temperature was heated to 60° C. for reaction for 12 hours; then cooled to 25° C., 1.1 mL of hexafluorophosphoric acid (11.8 mmol), 20 mL of acetonitrile and 3 mL of 30% aqueous hydrogen peroxide solution (29.7 mmol) were added, and stirring was continued at 25° C. for 48 hours. After the reaction was completed, 80 mL of water was added, stirred for 30 minutes, and then cooled to -5° C., filtered, and the obtained solid was washed twice with purified water, and the remaining solution was freeze-dried with a freeze dryer. The obtained solid was separated by column chromatography [HP-Silica normal phase silica gel, eluent was dichloromethane: methanol = (12:1, V / V)] to separate the target product, and the solvent was dried with nitrogen to finally obtain 0.38 g of canagliflozin peroxide, HPLC purity 98.9%, and yield 35%.

[0066] Example 8

[0067] 1.0 g of canagliflozin (2.25 mmol) was added to 20 mL of N-methylpyrrolidone and 2 mL of water, and 1.1 mL of 30% aqueous hydrogen peroxide solution (10.7 mmol) was added, and the mixture was heated to 55° C. for reaction for 12 hours; then cooled to 20° C., 0.5 mL of concentrated sulfuric acid (9.38 mmol), 20 mL of acetonitrile and 2 mL of 30% aqueous hydrogen peroxide solution (19.8 mmol) were added, and stirring was continued at 30° C. for 36 hours. After the reaction was completed, 80 mL of water was added, stirred for 30 minutes, and then cooled to 0° C. and filtered. The obtained solid was washed twice with purified water, and the remaining solution was freeze-dried with a freeze dryer. The obtained solid was separated from the target product by column chromatography [HP-Silica normal phase silica gel, eluent was dichloromethane: methanol = (15:1, V / V)], and the solvent was dried with nitrogen to finally obtain 0.18 g of canagliflozin peroxide, with an HPLC purity of 97.4% and a yield of 17%.

[0068] Example 9

[0069] 1.0 g of canagliflozin (2.25 mmol) was added to 20 mL of acetonitrile and 2 mL of water, and 1.1 mL of 30% aqueous hydrogen peroxide solution (10.7 mmol) was added, and the temperature was heated to 50° C. for reaction for 12 hours; then cooled to 20° C., 1.0 mL of methanesulfonic acid (15.4 mmol), 20 mL of acetonitrile and 3 mL of 30% aqueous hydrogen peroxide solution (29.7 mmol) were added, and stirring was continued at 20° C. for 48 hours. After the reaction was completed, 80 mL of water was added, stirred for 30 minutes, and then cooled to -5° C., filtered, and the obtained solid was washed twice with purified water, and the remaining solution was freeze-dried with a freeze dryer. The obtained solid was separated by column chromatography [HP-Silica normal phase silica gel, eluent was dichloromethane: methanol = (10:1, V / V)] to separate the target product, and the solvent was dried with nitrogen to finally obtain 0.17 g of canagliflozin peroxide, HPLC purity 97.3%, and yield 16%.

[0070] Example 10

[0071] 1.0 g of canagliflozin (2.25 mmol) was added to 20 mL of 1,4-dioxane and 2 mL of water, and 1.5 mL of 30% aqueous hydrogen peroxide solution (14.8 mmol) was added, and the temperature was raised to 55° C. for reaction for 16 hours; then cooled to 20° C., 0.5 mL of concentrated sulfuric acid (9.38 mmol), 20 mL of acetonitrile and 3 mL of 30% aqueous hydrogen peroxide solution (29.7 mmol) were added, and stirring was continued at 30° C. for 42 hours. After the reaction was completed, 80 mL of water was added, stirred for 30 minutes, and then cooled to -5° C., filtered, and the obtained solid was washed twice with purified water, and the remaining solution was freeze-dried with a freeze dryer. The obtained solid was separated from the target product by column chromatography [HP-Silica normal phase silica gel, eluent was dichloromethane: methanol = (10:1, V / V)], and the solvent was dried with nitrogen to finally obtain 0.27 g of canagliflozin peroxide, HPLC purity 98.5%, and yield 25%.

[0072] Comparative Example 1

[0073] 1.0 g of canagliflozin (2.25 mmol) was dissolved in 80 mL of acetonitrile and 20 mL of water, and then 1.0 mL of 30% hydrogen peroxide solution (9.90 mmol) was added, and the mixture was reacted at 45° C. for 7 days. The reaction solution was monitored by HPLC. The canagliflozin peroxide content in the reaction solution was 11%, the canagliflozin alcohol content was 18.5%, and the canagliflozin ketone content was 17.3%; the obtained reaction solution was evaporated in a rotary evaporator at 30-40° C. to remove acetonitrile, and the remaining solution was freeze-dried with a freeze dryer. The obtained solid was separated from the target product by column chromatography [HP-Silica normal phase silica gel, eluent was dichloromethane: methanol = (10:1, V / V)], and the solvent was dried with nitrogen to finally obtain 10.5 mg of canagliflozin peroxide, HPLC purity was 97.1%, and the yield was 1.0%.

[0074] Comparative Example 2

[0075] 1.0 g of canagliflozin (2.25 μmol) was added to 20 mL of acetonitrile and 2 mL of water, and 1.4 mL of 30% aqueous hydrogen peroxide solution (13.9 mmol) was added, and the temperature was raised to 55° C. for reaction for 15 hours; then cooled to 25° C., 0.5 mL of concentrated sulfuric acid (9.38 mmol), 20 mL of acetonitrile and 2 mL of 30% aqueous hydrogen peroxide solution (19.8 mmol) were added, and stirring was continued at 25° C. for 48 hours. After the reaction was completed, the obtained reaction solution was evaporated in a rotary evaporator at 30-40° C. to remove acetonitrile, and the remaining solution was lyophilized by a freeze dryer. The obtained solid was separated by column chromatography [HP-Silica normal phase silica gel, eluent was dichloromethane: methanol = (15:1, V / V)] to separate the target product, and the solvent was dried with nitrogen to finally obtain 42.9 mg of canagliflozin peroxide, HPLC purity 97.4%, and yield 4%.

Claims

1. A method for preparing canagliflozin peroxide having a structure as shown in Formula I, comprising the following steps: (1) heating the canagliflozin compound represented by formula II and hydrogen peroxide to 50-70° C. in a mixture of an organic solvent and water to react, and after the reaction is completed, obtaining a mixture containing the canagliflozin peroxide represented by formula I and the canagliflozin alcohol represented by formula III; (2) adding hydrogen peroxide to the mixture obtained in step (1), and reacting in a reaction solvent under the catalysis of a strong acid to obtain canagliflozin peroxide as shown in formula I; the reaction formula is as follows:

2. The preparation method according to claim 1, characterized in that: The organic solvent described in step (1) is selected from acetonitrile, methanol, tetrahydrofuran, N,N-dimethylformamide, N,N-dimethylacetamide, 1,4-dioxane, dimethyl sulfoxide, N-methylpyrrolidone; preferably acetonitrile.

3. The preparation method according to claim 1, characterized in that: The volume ratio of the organic solvent to water in step (1) is 5:1 to 20:

1.

4. The preparation method according to claim 1, characterized in that: The molar ratio of hydrogen peroxide to canagliflozin in step (1) is 0.5:1 to 100:1, preferably 4:1 to 30:

1.

5. The preparation method according to claim 1, characterized in that: The reaction temperature in step (1) is 50-60°C; The reaction time is 1 to 36 hours, preferably 6 to 18 hours.

6. The preparation method according to claim 1, characterized in that: The strong acid in step (2) is selected from an inorganic strong acid or an organic strong acid or any combination thereof, wherein the inorganic strong acid is sulfuric acid, hydrochloric acid, phosphoric acid, perchloric acid, hydrobromic acid, nitric acid, hexafluorophosphoric acid, preferably sulfuric acid and hexafluorophosphoric acid; the organic strong acid is selected from methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, trifluoroacetic acid, tribromoacetic acid, preferably methanesulfonic acid and trifluoroacetic acid.

7. The preparation method according to claim 1, characterized in that: The reaction solvent in step (2) is acetonitrile, methanol, tetrahydrofuran, N,N-dimethylformamide, N,N-dimethylacetamide, 1,4-dioxane, dimethyl sulfoxide, N-methylpyrrolidone; preferably acetonitrile.

8. The preparation method according to claim 1, characterized in that: The molar ratio of the strong acid to canagliflozin in step (2) is 0.1:1 to 50:1, preferably 3:1 to 10:

1.

9. The preparation method according to claim 1, characterized in that: The molar ratio of hydrogen peroxide to canagliflozin in step (2) is 0.5:1 to 100:1, preferably 10:1 to 50:

1.

10. The preparation method according to claim 1, characterized in that: The reaction temperature in step (2) is 5 to 35° C., preferably 20 to 30° C.; the reaction time is 1 to 120 hours, preferably 24 to 72 hours.

11. The preparation method according to claim 1, characterized in that: The canagliflozin peroxide obtained in step (2) can be added with water after the reaction is complete, cooled to 0-10°C, stirred and crystallized for 0.5-1 hour, filtered to obtain a solid, washed with purified water, and separated by column chromatography to obtain pure canagliflozin peroxide of formula I.

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