A synthetic method for an intermediate that can be used to prepare empagliflozin

Abstract

The present invention discloses a synthetic method for an intermediate that can be used to prepare empagliflozin. Using o-chlorobenzotrichloride and fluorobenzene as starting materials, the production cost is reduced. During the reaction process, aluminum trichloride in the system is fully utilized, and a rare earth salt is used as an auxiliary catalyst to improve the selectivity of the reaction, reduce the impurities in the product, and at the same time, the synthetic process of the present invention also improves the product yield.

Description

Technical Field

[0001] The present invention belongs to the field of compound synthesis, and relates to a method for synthesizing a pharmaceutical intermediate, in particular to a method for synthesizing an intermediate that can be used to prepare empagliflozin. Background Art

[0002] Empagliflozin, with the chemical name of (1S)-1,5-anhydro-1-(4-chloro-3-{4-[(3S)-tetrahydrofuran-3-yloxy]benzyl}phenyl)-D-glucitol, is a sodium-glucose cotransporter 2 inhibitor and is clinically used for the treatment of type II diabetes and is widely used globally.

[0003] (S)-3-(4-(5-Bromo-2-chlorobenzyl)phenoxy)tetrahydrofuran is a key intermediate in the preparation of empagliflozin. Therefore, its purity has a direct impact on the impurity situation of empagliflozin, and its production cost also has a significant impact on the production cost of empagliflozin. In the present invention, (S)-3-(4-(5-bromo-2-chlorobenzyl)phenoxy)tetrahydrofuran is simply referred to as the empagliflozin intermediate, and its structure is shown as follows.

[0004]

[0005] Currently, there are many reports on the research of the empagliflozin intermediate. For example, in the Chinese patent application "A Preparation Method of a Key Intermediate of Empagliflozin and an Impurity of Empagliflozin" with the literature number 202210378672.0, using 2-chloro-5-bromobenzoic acid, an acyl chlorination reagent, and fluorobenzene as raw materials, through acyl chlorination and Friedel-Crafts acylation, (5-bromo-2-chlorophenyl)(4-fluorophenyl)methanone is obtained. (5-bromo-2-chlorophenyl)(4-fluorophenyl)methanone then undergoes a substitution reaction with 3-hydroxyfuran under the action of a base and a phase transfer catalyst, and then under the action of a reducing agent, the empagliflozin intermediate is obtained. In this literature, 2-chloro-5-bromobenzoic acid is used as the starting material, which has a relatively high cost, and due to the differences in the processes of raw material producers, the controllability of impurities introduced by the starting material is relatively poor; (S)-3-hydroxytetrahydrofuran is relatively expensive, and using it in the relatively early steps of the reaction will increase the production cost; isomers are easily generated during the Friedel-Crafts acylation process, which will introduce impurities into the product.

[0006] The present invention provides a method for synthesizing an intermediate that can be used to prepare empagliflozin, using o-chlorobenzotrichloride as the starting material, reducing the production cost, and at the same time reducing process impurities and improving the purity of the empagliflozin intermediate through the optimization of the synthesis process. Summary of the Invention

[0007] The purpose of the present invention is to provide a method for synthesizing an intermediate of empagliflozin with low cost and high process controllability.

[0008] To achieve the above object, the technical solution adopted by the present invention is a synthesis method for an intermediate that can be used to prepare empagliflozin. The key lies in the following steps:

[0009] S1: Using o-chlorobenzotrichloride and N-bromosuccinimide as starting materials, successively under the action of ferric chloride and aluminum chloride, and then in a dichloromethane system, under the action of N,N-dimethylformamide and oxalyl chloride, react with fluorobenzene at 0-10°C under the action of a rare earth salt co-catalyst to prepare intermediate A. The structure of intermediate A is as follows:

[0010]

[0011] S2: In a mixed system of acetonitrile and triethylsilane, add boron trifluoride diethyl ether dropwise, and the reaction temperature is less than or equal to 30°C to prepare intermediate B. The structure of intermediate B is as follows:

[0012]

[0013] S3: In a dimethylacetamide system, at a reaction temperature of 0°C - 5°C, under the action of potassium tert-butoxide, react with 3-hydroxy tetrahydrofuran to prepare the intermediate of empagliflozin. The prepared intermediate of empagliflozin, (S)-3-(4-(5-bromo-2-chlorobenzyl)phenoxy)tetrahydrofuran, has the following structure:

[0014]

[0015] Furthermore, the specific operation steps of the above S1 step are as follows:

[0016] S11: Add o-chlorobenzotrichloride to the reaction kettle, then add N-bromosuccinimide and ferric chloride, heat to 40°C - 50°C, react for 2 - 3 h, then add aluminum chloride, heat to 60°C - 80°C, and carry out hydrolysis reaction for 4 - 6 h, and cool to 15°C - 20°C;

[0017] S12: Add dichloromethane to the reaction kettle after step S11 for the first time. After adding N,N-dimethylformamide, control the temperature at 0°C - 10°C and dropwise add oxalyl chloride. After the reaction is completed, concentrate the reaction solution until there is no distillate, and add dichloromethane for the second time;

[0018] S13: Add rare earth salt to the reaction kettle after step S12, and dropwise add fluorobenzene, control the reaction temperature at 0°C - 10°C. When the reaction is completed, quench the system with water, separate the layers, and retain the organic phase; The organic phase is successively washed with water, washed with alkali, concentrated, dried, then add methanol, dissolve the material and crystallize, and filter by suction to obtain intermediate A.

[0019] Furthermore, the specific operation steps of the above S2 step are as follows:

[0020] Add a mixed solvent of triethylsilane and acetonitrile to the reaction kettle, add intermediate A, control the temperature at 20°C to 25°C, dropwise add boron trifluoride diethyl ether, adjust the pH value to 6 - 7 with sodium hydroxide, and concentrate under reduced pressure until there is no distillate; continue to add water and ethyl acetate, stir, let stand for liquid separation, take the organic phase and concentrate until there is no distillate, add isopropanol and wait for crystallization, then obtain intermediate compound B through suction filtration and drying.

[0021] Furthermore, the specific operation steps of the above S3 step are as follows:

[0022] Add dimethylacetamide to the reaction kettle, add intermediate compound B, control the temperature of the reaction kettle at 0°C to 5°C, add potassium tert-butoxide, continue to control the temperature at 0°C to 5°C, dropwise add 3-hydroxy tetrahydrofuran, after the reaction is completed, add it to water, and centrifuge at 0°C to 5°C to obtain the wet product of the intermediate of empagliflozin, add it to isopropanol for crystallization, and obtain the intermediate of empagliflozin through suction filtration and drying.

[0023] Furthermore, in the above S1 step, the mass ratio of o-chlorobenzotrichloride, N-bromosuccinimide, N,N-dimethylformamide, oxalyl chloride, fluorobenzene, ferric chloride, aluminum trichloride, and rare earth salt is 230:180 - 215:4 - 5:390 - 470:485 - 580:65 - 100:190 - 350:50 - 65;

[0024] Preferably, the mass of methanol is 0.5 - 0.8 times the mass of fluorobenzene;

[0025] Preferably, the rare earth salt is La(OTf)3.

[0026] Furthermore, in the above S2 step, the mass ratio of intermediate A, boron trifluoride diethyl ether, and triethylsilane is 320:380 - 445:715 - 830; the mass of acetonitrile is 5.0 - 5.5 times the mass of the triethylsilane;

[0027] Preferably, the mass of water is 4 - 4.5 times the mass of intermediate A;

[0028] Preferably, the mass of ethyl acetate is 7 - 7.5 times the mass of intermediate A;

[0029] Preferably, the mass of isopropanol is 2.5 - 3 times the mass of intermediate A.

[0030] Furthermore, in the above S3 step, the mass ratio of intermediate B, dimethylacetamide, potassium tert-butoxide, and 3-hydroxy tetrahydrofuran is 330:975 - 990:165 - 170:88 - 90;

[0031] Preferably, the mass of water is 5 - 5.5 times the mass of dimethylacetamide;

[0032] Preferably, the isopropanol is 1.5 to 2 times the mass of intermediate B.

[0033] The beneficial effects of the present invention are as follows: The present invention uses o-chlorobenzotrichloride and fluorobenzene, which are relatively low in price, as starting materials to prepare the intermediate of empagliflozin, namely (S)-3-(4-(5-bromo-2-chlorobenzyl)phenoxy)tetrahydrofuran, saving production costs; and reducing unknown impurities introduced by purchasing starting materials externally.

[0034] In the last step of the synthesis process of the present invention, (S)-3-hydroxytetrahydrofuran, which is relatively expensive in raw material price, is introduced, not only further reducing the production cost, but also greatly improving the product yield.

[0035] In the synthesis process of the present invention, aluminum trichloride in the system is fully utilized, and rare earth salts are used as co-catalysts, improving the reaction selectivity, reducing product impurities and increasing product purity. The purity of the product of the present invention can reach 99.5%.

[0036] In addition, the synthesis method of the present invention improves the reaction yield, and the average total yield can reach 80.6%. Description of the Drawings

[0037] Figure 1 It is the synthesis reaction formula of the intermediate of empagliflozin. Detailed Embodiments

[0038] To make the objectives, technical solutions and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments of the present invention will be clearly and completely described below. Those not specified in the embodiments are carried out according to conventional conditions; those reagents or instruments not specified in the manufacturer are all conventional products that can be obtained through commercial purchase.

[0039] Example 1

[0040] (1) Add 230 kg of o-chlorobenzotrichloride to the reaction kettle, then add 180 kg of N-bromosuccinimide and 65 kg of catalyst ferric trichloride. Heat the reaction kettle to 40 °C and keep the temperature for 2 h. Then add 190 kg of aluminum trichloride, heat to 70 °C, start the hydrolysis reaction, and after 6 h of reaction, lower the temperature of the reaction kettle to 20 °C to obtain 2-chloro-5-bromotrichlorobenzoic acid.

[0041] (2) Continue to lower the temperature of the reaction kettle. At the same time, add 880 kg of dichloromethane to the reaction kettle for the first time after step (1). After stirring evenly, add 5 kg of N,N-dimethylformamide, control the temperature at 10 °C, keep the low temperature and dropwise add 390 kg of oxalyl chloride, stir for 0.5 h for the acylation reaction. After the reaction is completed, concentrate the reaction solution until there is no distillate, and add 300 kg of dichloromethane for the second time.

[0042] (3) Using aluminum trichloride present in the system after step (2) as a catalyst, 50 kg of rare earth salt La(OTf)3 was added to the reaction kettle as a co-catalyst, and 485 kg of fluorobenzene was added dropwise. The reaction temperature was controlled at 10 °C, and stirring was carried out for 0.5 h. When the reaction ended, the system was quenched into 1200 kg of water. After standing and separating the liquid, the organic phase was retained, washed with water, washed with alkali, concentrated, dried, and then 690 kg of methanol was added. After dissolving the material and crystallizing, filtration was carried out to obtain intermediate A, with the chemical name: (5-bromo-2-chlorophenyl)(4-fluorophenyl)methanone.

[0043] (4) 715 kg of triethylsilane and 3930 kg of acetonitrile were added to the reaction kettle. After stirring evenly, 320 kg of intermediate A was added. The temperature of the reaction kettle was controlled at 20 °C, 380 kg of boron trifluoride diethyl etherate was added dropwise, and the pH value was adjusted to 6.5 with 30% mass concentration of sodium hydroxide. It was concentrated under reduced pressure until there was no distillate; then 1280 kg of water and 2240 kg of ethyl acetate were added, stirred, and left to stand for liquid separation. The organic phase was retained, concentrated until there was no distillate, 800 kg of isopropanol was added for crystallization, and after filtration and drying, intermediate compound B was obtained.

[0044] (5) 990 kg of dimethylacetamide was added to the reaction kettle, 330 kg of intermediate B was added, the temperature of the reaction kettle was controlled at 5 °C, 165 kg of potassium tert-butoxide was added, and the temperature was still controlled at 5 °C. 88 kg of 3-hydroxytetrahydrofuran was added dropwise, and stirring was carried out for 0.5 h. After the reaction ended, 4950 kg of water was added, and the wet product of the intermediate of empagliflozin was centrifuged at 5 °C, added to 660 kg of isopropanol for crystallization, and after filtration and drying, the intermediate of empagliflozin was obtained. The name of the obtained sample was empagliflozin intermediate sample 1.

[0045] Example 2

[0046] The operations of each step were the same as those in Example 1, except that the masses of each material used and the specific process parameters were different. The masses of each material in each step were as follows:

[0047] In step (1), the masses of the materials used were: 250 kg of o-chlorobenzotrichloride, 234 kg of N-bromosuccinimide, 109 kg of catalyst ferric trichloride, and 380 kg of aluminum trichloride; the specific process parameters were: heated to 45 °C, the temperature was maintained for reaction for 2.5 h, then heated to 75 °C after adding ferric trichloride, and after hydrolysis reaction for 5 h, the temperature of the reaction kettle was reduced to 15 °C.

[0048] In step (2), the masses of the materials used were: 793 kg of dichloromethane added for the first time, 5.0 kg of N,N-dimethylformamide, 467 kg of oxalyl chloride, and 266 kg of dichloromethane added for the second time; the specific process parameters were: the reaction temperature was 10 °C.

[0049] The masses of the materials used in step (3) are as follows: 60 kg of rare earth salt, 576 kg of fluorobenzene, 1440 kg of quenching water, and 200 kg of methanol; the specific process parameters are: the reaction temperature is 10°C.

[0050] The masses of the materials used in step (4) are as follows: 310 kg of intermediate A, 804 kg of triethylsilane, 4020 kg of acetonitrile, 431 kg of boron trifluoride diethyl etherate, 1395 kg of water, and 2325 kg of ethyl acetate, 930 kg of isopropanol; the specific process parameters are: control the temperature at 22°C and adjust the pH value to 7.

[0051] The masses of the materials used in step (5) are as follows: 320 kg of intermediate B, 1005 kg of dimethylacetamide, 175 kg of potassium tert-butoxide, 93 kg of 3-hydroxytetrahydrofuran, 5530 kg of water, and 480 kg of isopropanol; the specific process parameters are: the reaction temperature is 1°C, and the name of the obtained sample is Empagliflozin intermediate sample 2.

[0052] Example 3

[0053] The operations of each step are the same as those in Example 1, except that the masses of each material used and the specific process parameters are different. The specific masses of the materials in each step are as follows:

[0054] The masses of the materials used in step (1) are as follows: 245 kg of o-chlorobenzotrichloride, 208 kg of N-bromosuccinimide, 91 kg of catalyst ferric chloride, and 298 kg of aluminum trichloride; the specific process parameters are: heat to 48°C, maintain the temperature for 3 h, then add ferric chloride and heat to 78°C, after the hydrolysis reaction for 4.5 h, the temperature of the reaction kettle drops to 18°C.

[0055] The masses of the materials used in step (2) are as follows: 873 kg of dichloromethane added for the first time, 5.1 kg of N,N-dimethylformamide, 501 kg of oxalyl chloride, and 298 kg of dichloromethane added for the second time; the specific process parameters are: the reaction temperature is 0°C.

[0056] The masses of the materials used in step (3) are as follows: 69 kg of rare earth salt, 618 kg of fluorobenzene, 1545 kg of quenching water, and 147 kg of methanol; the specific process parameters are: the reaction temperature is 0°C.

[0057] The masses of the materials used in step (4) are as follows: 320 kg of intermediate A, 804 kg of triethylsilane, 4183 kg of acetonitrile, 433 kg of boron trifluoride diethyl etherate, 1320 kg of water, 2376 kg of ethyl acetate, and 990 kg of isopropanol; the specific process parameters are: control the temperature at 25°C and adjust the pH value to 6.7.

[0058] The masses of the materials used in step (5) are as follows: 340 kg of intermediate B, 951 kg of dimethylacetamide, 170 kg of potassium tert-butoxide, 87 kg of 3-hydroxy tetrahydrofuran, 5231 kg of water, and 612 kg of isopropanol; the specific process parameters are: reaction temperature 0 °C, and the name of the obtained sample is Empagliflozin intermediate sample 3.

[0059] Example 4

[0060] The operations of each step are the same as those in Example 1, except that the masses of the materials used and the specific process parameters are different. The masses of the materials in each step are as follows:

[0061] The masses of the materials used in step (1) are as follows: 220 kg of o-chlorobenzotrichloride, 191 kg of N-bromosuccinimide, 86 kg of the catalyst ferric chloride, and 220 kg of aluminum trichloride; the specific process parameters are: heating to 50 °C, maintaining the temperature for reaction for 3 h, adding ferric chloride and then heating to 80 °C, and after hydrolysis reaction for 5.5 h, the temperature of the reaction kettle is reduced to 20 °C.

[0062] The masses of the materials used in step (2) are as follows: 746 kg of dichloromethane added for the first time, 3.8 kg of N,N-dimethylformamide, 430 kg of oxalyl chloride, and 210 kg of dichloromethane added for the second time; the specific process parameters are: reaction temperature 2 °C.

[0063] The masses of the materials used in step (3) are as follows: 58 kg of rare earth salt, 478 kg of fluorobenzene, 1196 kg of quenching water, and 154 kg of methanol; the specific process parameters are: reaction temperature 2 °C.

[0064] The masses of the materials used in step (4) are as follows: 340 kg of intermediate A, 850 kg of triethylsilane, 4675 kg of acetonitrile, 425 kg of boron trifluoride diethyl etherate, 1428 kg of water, 2448 kg of ethyl acetate, and 952 kg of isopropanol; the specific process parameters are: controlling the temperature at 20 °C and adjusting the pH value to 6.9.

[0065] The masses of the materials used in step (5) are as follows: 350 kg of intermediate B, 1045 kg of dimethylacetamide, 180 kg of potassium tert-butoxide, 94 kg of 3-hydroxy tetrahydrofuran, 5223 kg of water, and 700 kg of isopropanol; the specific process parameters are: reaction temperature 3 °C, and the name of the obtained sample is Empagliflozin intermediate sample 4.

[0066] Comparative Example 1: Using commercially available 2-chloro-5-bromobenzoic acid as the starting material

[0067] 880 kg of dichloromethane was first added to the reaction kettle, and 238 kg of commercially available 2-chloro-5-bromobenzoic acid (with the requirement that the content of 2-chloro-5-bromobenzoic acid ≥ 99.0%) was added. After stirring evenly, 5 kg of N,N-dimethylformamide was added. The temperature was controlled at 10 °C, and while maintaining a low temperature, 390 kg of oxalyl chloride was added dropwise. After stirring for 0.5 h, an acyl chlorination reaction occurred. After the reaction ended, the reaction solution was concentrated until there was no distillate, and 300 kg of dichloromethane was added for the second time.

[0068] The subsequent steps were the same as steps (2) to (5) of Example 1, and the name of the obtained sample was Empagliflozin Intermediate Control 1.

[0069] The manufacturers of 2-chloro-5-bromobenzoic acid used were Suzhou Xinyi Chemical Industry, Shanghai Yijing Industry, and Chongqing Ruiya Biology, corresponding to Control 1-1, Control 1-2, and Control 1-3 respectively.

[0070] Control Example Two: Without using rare earth salts

[0071] The operation steps were the same as those of Example 1. The main difference was that 50 kg of rare earth salt La(OTf)3 was not used as a co-catalyst in step (3). The name of the obtained sample was Empagliflozin Intermediate Control 2.

[0072] Control Example Three: Changing the reaction steps

[0073] Steps (1) to (3) were the same as those of Example 1. The main differences were in steps (4) and (5):

[0074] (4) 990 kg of dimethylacetamide was added to the reaction kettle, 320 kg of Intermediate A was added, the temperature of the reaction kettle was controlled at 5 °C, 165 kg of potassium tert-butoxide was added, the temperature was continuously controlled at 5 °C, 88 kg of 3-hydroxytetrahydrofuran was added dropwise, and after stirring for 0.5 h, after the reaction ended, 4950 kg of water was added, and the wet product of the Empagliflozin intermediate was centrifuged at 5 °C and added to 660 kg of isopropanol for crystallization, filtration, and drying to obtain the compound (S)-(5-bromo-2-chlorophenyl)(4-((tetrahydrofuran-3-yl)oxy)phenyl)methanone, simply referred to as Intermediate C.

[0075] (5) 715 kg of triethylsilane and 3930 kg of acetonitrile were added to the reaction kettle. After stirring evenly, 398 kg of Intermediate C was added. The temperature of the reaction kettle was controlled at 20 °C, 380 kg of boron trifluoride diethyl etherate was added dropwise, the pH value was adjusted to 6.5 with 30% mass concentration of sodium hydroxide, and it was concentrated under reduced pressure until there was no distillate; then 1280 kg of water and 2240 kg of ethyl acetate were added, stirred and allowed to stand for liquid separation, and the organic phase was retained, concentrated until there was no distillate, and 800 kg of isopropanol was added and waited for crystallization. After filtration and drying, the Empagliflozin intermediate was obtained, and the name of the obtained sample was Empagliflozin Intermediate Control 3.

[0076] Analysis and Detection:

[0077] 1. Yield Analysis:

[0078] Total yield = (Actual weight of the intermediate of empagliflozin obtained, kg / Theoretical amount of the intermediate of empagliflozin obtained, kg) × 100%.

[0079] Among them, except for Comparative Example 1, the theoretical amount of the intermediate of empagliflozin is calculated based on the mass of o-chlorobenzotrichloride input, and in Comparative Example 1, it is calculated based on the mass of 2-chloro-5-bromobenzoic acid input.

[0080] The results are shown in Table 1. The average total yield of the present invention can reach 80.6%.

[0081] Table 1: Summary Table of Yield Results

[0082]

[0083]

[0084] 2. Purity and Impurity Analysis:

[0085] The intermediate of empagliflozin was tested by high performance liquid chromatography, and the method is as follows:

[0086] Instrument: High performance liquid chromatograph, ultraviolet detector

[0087] Chromatographic conditions:

[0088] C8 chromatographic column (250 mm × 4.6 mm, 5 μm); Mobile phase A is phosphoric acid aqueous solution (pH 3.5), and mobile phase B is methanol - acetonitrile (50:50) solution, with gradient elution; Flow rate is 1.0 mL / min, detection wavelength is 224 nm, column temperature is 25 °C, and injection volume is 20 μL.

[0089] The external standard method was used to locate each peak according to the retention time. The test results are shown in Table 2.

[0090] Table 2: Summary Table of Purity and Impurity Analysis Results of the Intermediate of Empagliflozin

[0091]

[0092] It can be seen from the results in Table 2 that the purity of the examples of the present invention can reach more than 99.6% at the highest, and the content of unknown impurities is less than 0.4%. The unknown impurities of 2-chloro-5-bromobenzoic acid purchased from different manufacturers are higher than those of the synthesis method of the present invention.

Claims

1. A synthetic method for an intermediate that can be used to prepare empagliflozin, characterized in that, Comprising the following steps: S1: Using o-chlorobenzotrichloride and N-bromosuccinimide as starting materials, successively reacting under the action of iron(III) chloride and aluminum chloride respectively, then in a dichloromethane system, reacting with fluorobenzene at 0 - 10 °C under the action of N,N-dimethylformamide and oxalyl chloride with the co-catalyst of rare earth salt La(OTf)3 to prepare intermediate A, and the structure of intermediate A is as follows: ； S2: Intermediate A is in a mixed system of acetonitrile and triethylsilane, and boron trifluoride diethyl etherate is added dropwise, with the reaction temperature less than or equal to 30 °C, to prepare intermediate B, and the structure of intermediate B is as follows: ; S3: Intermediate B is in a dimethylacetamide system, with the reaction temperature at 0 °C - 5 °C, reacting with 3-hydroxytetrahydrofuran under the action of potassium tert-butoxide to prepare the intermediate of empagliflozin. The prepared intermediate of empagliflozin, (S)-3-(4-(5-bromo-2-chlorobenzyl)phenoxy)tetrahydrofuran, has the following structure: ； The specific operation steps of step S2 are as follows: Add the mixed solvent of triethylsilane and acetonitrile to the reaction kettle, add intermediate A, control the temperature at 20 °C - 25 °C, add dropwise boron trifluoride diethyl etherate, adjust the pH value to 6 - 7 with sodium hydroxide, and concentrate under reduced pressure until there is no distillate; continue to add water and ethyl acetate, stir, stand for liquid separation, take the organic phase and concentrate until there is no distillate, add isopropanol and wait for crystallization, and then obtain intermediate compound B through suction filtration and drying; The specific operation steps of step S3 are as follows: Add dimethylacetamide to the reaction kettle, add intermediate compound B, control the temperature of the reaction kettle at 0 °C - 5 °C, add potassium tert-butoxide, continue to control the temperature at 0 °C - 5 °C, add dropwise 3-hydroxytetrahydrofuran. After the reaction is completed, add it to water, and centrifuge at 0 °C - 5 °C to obtain the wet product of the intermediate of empagliflozin, add it to isopropanol for crystallization, and obtain the intermediate of empagliflozin through suction filtration and drying.

2. The synthetic method of an intermediate for preparing empagliflozin according to claim 1, characterized in that, The specific operation steps of step S1 are as follows: S11: Add o-chlorobenzotrichloride to the reaction kettle, then add N-bromosuccinimide, add iron(III) chloride, heat to 40 °C - 50 °C, react for 2 - 3 h, then add aluminum chloride, heat to 60 °C - 80 °C, and carry out hydrolysis reaction for 4 - 6 h, and cool to 15 °C - 20 °C; S12: First add dichloromethane to the reaction kettle after step S11, add N,N-dimethylformamide, control the temperature at 0 °C - 10 °C and add dropwise oxalyl chloride. After the reaction is completed, concentrate the reaction solution until there is no distillate, and add dichloromethane for the second time; S13: Add rare earth salt to the reaction kettle after step S12, and add dropwise fluorobenzene, control the reaction temperature at 0 °C - 10 °C. When the reaction is completed, quench the system into water, carry out liquid separation, and retain the organic phase; the organic phase is successively washed with water, washed with alkali, concentrated, dried, then add methanol, dissolve the material for crystallization, and obtain intermediate A through suction filtration.

3. A synthetic method of an intermediate for preparing empagliflozin according to claim 1, characterized in that, In the step S1, the mass ratio of o-chlorobenzotrichloride, N-bromosuccinimide, N,N-dimethylformamide, oxalyl chloride, fluorobenzene, ferric chloride, aluminum chloride and rare earth salt is 230: 180-215: 4-5: 390-470: 485-580: 65-100: 190-350: 50-65; the mass of methanol is 0.5-0.8 times that of fluorobenzene.

4. A synthetic method of an intermediate for preparing empagliflozin according to claim 1, characterized in that, In the step S2, the mass ratio of intermediate A, boron trifluoride diethyl etherate, triethylsilane is 320: 380-445: 715-830; the mass of acetonitrile is 5.0-5.5 times that of triethylsilane; the mass of water is 4-4.5 times that of intermediate A; the mass of ethyl acetate is 7-7.5 times that of intermediate A; the mass of isopropanol is 2.5-3 times that of intermediate A.

5. A synthetic method for an intermediate that can be used to prepare empagliflozin according to claim 1, characterized in that, In the step S3, the mass ratio of intermediate B, dimethylacetamide, potassium tert-butoxide and 3-hydroxytetrahydrofuran is 330: 975-990: 165-170: 88-90; the mass of water is 5-5.5 times that of dimethylacetamide; the isopropanol is 1.5-2 times that of intermediate B.

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