Process for the synthesis of an empagliflozin intermediate

Abstract

This invention discloses a synthetic process for an empagliflozin intermediate, belonging to the technical field of pharmaceutical intermediate synthesis. The synthetic process is as follows: 2-chloro-5-bromobenzoic acid is first mixed with dichloromethane and N,N-dimethylformamide, and thionyl chloride is added dropwise to obtain a dichloromethane solution of acyl chloride. Then, it is reacted with fluorobenzene under anhydrous aluminum trichloride catalysis to obtain intermediate EGAB-3. Then, it is dehydrated by azeotropic reaction with potassium hydroxide aqueous solution in toluene, and then refluxed with 3-hydroxytetrahydrofuran under tetrabutylammonium bromide catalysis to obtain intermediate EGAB-7. Then, it is reacted with 1,1,3,3-tetramethyldisiloxane under anhydrous aluminum trichloride and nitrogen protection, dried, and tested to be qualified to obtain empagliflozin intermediate. This process achieves high purity, high yield, and low isomer impurities in the preparation of empagliflozin intermediate.

Description

Technical Field

[0001] This invention belongs to the technical field of pharmaceutical intermediate synthesis, specifically relating to a synthesis process for an empagliflozin intermediate. Background Technology

[0002] Empagliflozin intermediates are key chemical intermediates in the synthesis of empagliflozin, a sodium-glucose cotransporter 2 inhibitor used to treat diabetes. Their design and preparation directly affect the purity and activity of the final drug. Chemically, the empagliflozin molecule contains a unique C-glycosidic bond connecting a dihydrofuran ring and a glucopyranoside core; the intermediate must precisely match this structural feature.

[0003] Typical intermediates are often glucol derivatives containing chiral centers, such as (1S)-1,5-dehydro-1-C-[substituted phenyl]-D-glucol, or glycosyl fragments that have undergone protection / activation. For example, in synthesis, C-glycosidic bonds are often constructed through the coupling reaction of a glycosyl donor (such as trichloroacetylimine ester) with an aryl acceptor (containing a hydrophobic group with a thiophene / benzene ring). The intermediates generated in this process require strict control of their stereoconfiguration to avoid racemization affecting drug efficacy. The chemical properties of these intermediates directly determine the synthetic efficiency and yield. High-purity intermediates can ensure the proportion of active ingredients in the final drug, reduce impurity interference, and thus guarantee clinical efficacy and safety.

[0004] Chinese invention patent application CN117299223A discloses a synthetic method for preparing intermediates of empagliflozin. The method uses o-chlorotrichlorotoluene and fluorobenzene as starting materials. First, intermediate A is obtained through Friedel-Crafts acylation reaction with rare earth salt La(OTf)3 as a co-catalyst. Then, intermediate B is obtained by reduction in the presence of boron trifluoride ether and triethylsilane. Finally, intermediate B is obtained by etherification reaction with 3-hydroxytetrahydrofuran in the presence of potassium tert-butoxide.

[0005] The background technology of the above scheme points out that the Friedel-Crafts acylation process is prone to generating isomers (such as ortho-substituted fluorine impurities), and the impurities are similar in properties to the products, making separation difficult. Although the existing technology uses rare earth salt La(OTf)3 as a co-catalyst to improve selectivity, the starting material is a trichlorotoluene derivative, which makes the reaction system more complex. Moreover, non-target side reactions may occur in the same system or in continuous operation of multiple steps, which increases the risk of introducing impurities and thus affects the purity of the product. Summary of the Invention

[0006] The purpose of this invention is to provide a synthetic process for empagliflozin intermediates to solve the problems of easy generation of isomer impurities by Friedel-Crafts acylation and the large number of side reactions caused by complex starting materials in the prior art.

[0007] The objective of this invention can be achieved through the following technical solutions: A synthetic process for an empagliflozin intermediate includes the following steps: Step 1: Mix 2-chloro-5-bromobenzoic acid with dichloromethane and N,N-dimethylformamide, add thionyl chloride dropwise to obtain a dichloromethane solution of acyl chloride, then react it with fluorobenzene under the catalysis of anhydrous aluminum trichloride, quench with dilute hydrochloric acid, wash, concentrate and crystallize with isopropanol to obtain the EGAB-3 intermediate.

[0008] Step 2: The EGAB-3 intermediate was dehydrated by azeotropic reaction with potassium hydroxide aqueous solution in toluene, and then refluxed with 3-hydroxytetrahydrofuran under the catalysis of tetrabutylammonium bromide. After washing, concentration and crystallization with ethanol, the EGAB-7 intermediate was obtained.

[0009] Step 3: React the EGAB-7 intermediate with 1,1,3,3-tetramethyldisiloxane under anhydrous aluminum trichloride and nitrogen protection. After quenching with dilute hydrochloric acid, washing, and concentration, crystallize with acetone and isopropanol, dry, and pass the test to obtain the empagliflozin intermediate.

[0010] Furthermore, the general structural formula of the empagliflozin intermediate is shown in Formula 1: Formula 1.

[0011] Furthermore, the specific preparation method of the dichloromethane solution of acyl chloride is as follows: 2-Chloro-5-bromobenzoic acid, dichloromethane, and N,N-dimethylformamide were added to a reaction vessel, stirred and dissolved, and thionyl chloride was added dropwise. The reaction was kept at the temperature until the residual 2-chloro-5-bromobenzoic acid was ≤0.5% as monitored by HPLC. The mixture was then cooled to room temperature to obtain a dichloromethane solution of acyl chloride.

[0012] Furthermore, the mass ratio of 2-chloro-5-bromobenzoic acid, dichloromethane, N,N-dimethylformamide and thionyl chloride is 71.3-71.5:107.1-109.1:3.5-3.7:42.7-42.9.

[0013] Furthermore, the specific preparation method of the EGAB-3 intermediate is as follows: Dichloromethane and anhydrous aluminum trichloride were added to a reaction vessel and stirred for 20-30 min. Fluorobenzene was added, and the mixture was cooled to 0-5℃. A dichloromethane solution of acyl chloride was added dropwise, with the temperature controlled not to exceed 10℃. After the addition was complete, the mixture was heated to room temperature and stirred for 2-4 h until the residual 2-chloro-5-bromo-benzoic acid was ≤0.5% as monitored by HPLC. The mixture was then transferred to 7.2 wt% dilute hydrochloric acid, with the temperature controlled not to exceed 30℃, and stirred for 30-40 min. The mixture was allowed to stand and separate into layers. The organic phase was collected and washed successively with drinking water, 3.2 wt% alkaline solution, and 20 wt% saline solution. The organic phase was then dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain a crude product. Isopropanol was added to the crude product and heated to reflux to dissolve. The mixture was cooled to 0-5℃ and crystallized for 2-3 h. The crystals were filtered, and the filter cake was washed with low-temperature isopropanol and dried under vacuum. After testing, the isopropanol content was ≤0.1% and the moisture content was ≤0.5%. Once the product was deemed qualified, EGAB-3 intermediate was obtained. The reaction process is as follows: Furthermore, the mass ratio of dichloromethane, anhydrous aluminum trichloride, fluorobenzene, dichloromethane solution of acyl chloride, 7.2 wt% dilute hydrochloric acid, drinking water, 3.2 wt% alkaline solution, 20 wt% saline solution, isopropanol, and low-temperature isopropanol is 70.4-72.4: 49.9-50.1: 42.7-42.9: 138-142: 177.4-179.6: 70.4-72.4: 141.7-143.9: 88.2-90.4: 113.2-115.2: 10-30.

[0014] Furthermore, the specific preparation method of the EGAB-7 intermediate is as follows: EGAB-3 intermediate and toluene were added to a reaction vessel and stirred to dissolve. Then, 50 wt% potassium hydroxide solution was added, and the mixture was heated to reflux for azeotropic dehydration. After cooling to room temperature, the lower aqueous phase was removed, and the organic phase was collected. The organic phase was transferred to a new reaction vessel, and tetrabutylammonium bromide and 3-hydroxytetrahydrofuran were added. The mixture was heated to reflux and stirred for 6-8 hours. HPLC monitoring showed that the EGAB-3 intermediate residue was ≤0.5%. The mixture was cooled to room temperature, washed three times with 10 wt% saline solution, stirring for 15 minutes each time. After standing and separating the layers, the organic phase was collected and dried with anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure to recover toluene. Ethanol was added to the concentrated residue, and the mixture was heated to reflux to dissolve. The mixture was cooled to 0-5℃ and crystallized for 2-3 hours. After filtration, the filter cake was washed with low-temperature ethanol and dried under vacuum. The drying loss was ≤0.5% and the moisture content was ≤0.5%, indicating compliance with standards. EGAB-7 intermediate was obtained. The reaction process is shown below: Furthermore, the mass ratio of EGAB-3 intermediate, toluene, 50wt% potassium hydroxide solution, tetrabutylammonium bromide, 3-hydroxytetrahydrofuran, ethanol and low-temperature ethanol is 69.9-70.1:160-162:138.9-141.1:3.4-3.6:20.9-21.1:209-211:15-40.

[0015] Furthermore, the specific preparation method of the empagliflozin intermediate is as follows: EGAB-7 intermediate, toluene, and anhydrous aluminum trichloride were added to a reaction vessel and stirred to dissolve. Under nitrogen protection, 1,1,3,3-tetramethyldisiloxane was added dropwise, maintaining the internal temperature at 20-30°C. After the addition was complete, the temperature was raised to 40-50°C and stirred for 4-6 hours. HPLC monitoring showed that the EGAB-7 residue was ≤0.5%. After passing the test, the mixture was cooled to 0-5°C, and 5.15wt% dilute hydrochloric acid was added dropwise, maintaining the temperature below 20°C. The mixture was stirred for 20-30 minutes, allowed to stand for separation, and the organic phase was collected. The organic phase was washed three times with 10wt% saline solution, dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to recover toluene. Acetone and isopropanol were added to the concentrated residue, and the mixture was heated to reflux to dissolve. The temperature was lowered to 0-5°C, and crystallization was allowed for 2-3 hours. The mixture was filtered, and the filter cake was washed with low-temperature isopropanol and dried under vacuum. After passing the test, the drying loss was ≤0.2%, yielding the empagliflozin intermediate. The reaction process is shown below: Furthermore, the mass ratio of EGAB-7 intermediate, toluene, anhydrous aluminum trichloride, 1,1,3,3-tetramethyldisiloxane, 5.15wt% dilute hydrochloric acid, acetone, isopropanol, and low-temperature isopropanol is 108.6-108.8: 243.6-245.6: 49.9-50.1: 43.9-44.1: 286.9-289.1: 7.5-7.7: 169.7-171.7: 15-40.

[0016] The beneficial effects of this invention are: 1. This invention uses 2-chloro-5-bromo-benzoic acid as the starting material. Through low-temperature, precisely controlled acylation and Friedel-Crafts reaction, combined with a multiple washing and recrystallization purification system, the content of isomer impurities is effectively reduced. The safer 1,1,3,3-tetramethyldisiloxane is used to replace the highly corrosive boron trifluoride diethyl ether for reduction. The product quality is ensured by HPLC control throughout the process. The reaction steps are simplified. The etherification step adopts a one-pot operation of azeotropic dehydration and phase transfer catalysis, which helps to improve the stability and ease of operation of the process, making it more suitable for industrial production.

[0017] 2. By strictly controlling the reaction temperature to 0-5℃ and the dropping process not exceeding 10℃, this invention effectively suppresses the formation of fluorine ortho-isomer impurities. Combined with a multi-stage purification process of dilute hydrochloric acid quenching, alkali washing, brine washing, and isopropanol recrystallization, the cleanliness of the EGAB-3 intermediate is ensured as much as possible, creating a foundation for the high purity of the final product.

[0018] 3. This invention introduces tetrabutylammonium bromide as a phase transfer catalyst, which effectively accelerates the reaction rate of the two-phase reaction system, enabling the reaction to achieve complete conversion within 6-8 hours, reducing material loss due to incomplete reaction. At the same time, azeotropic dehydration pretreatment is used to remove moisture from the system, further optimizing the reaction environment and resulting in a high and stable overall process yield.

[0019] 4. This invention uses 1,1,3,3-tetramethyldisiloxane as a reducing agent to replace the traditional corrosive boron trifluoride diethyl ether. This not only provides high reduction selectivity and avoids the impact of boron-containing complex residues on product purity, but also ensures mild reaction conditions and the absence of irritating gases, thus improving the safety and environmental friendliness of the process. Furthermore, by establishing multiple central control systems, strict control is exercised over key quality indicators such as reaction endpoints, intermediate residues, solvent residues, and moisture content at each step, effectively guaranteeing the reproducibility of the process and the stability of product quality. Detailed Implementation

[0020] The technical solutions of the present invention will be clearly and completely described below with reference to the embodiments in the present invention. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those of ordinary skill in the art without creative effort are within the scope of protection of the present invention.

[0021] Example 1: A synthetic process for an empagliflozin intermediate, comprising the following steps: S1: 71.3 kg of 2-chloro-5-bromobenzoic acid, 107.1 kg of dichloromethane and 3.5 kg of N,N-dimethylformamide were added to a reaction vessel and stirred to dissolve. 42.7 kg of thionyl chloride was added dropwise, and the reaction was kept at the temperature until the residual 2-chloro-5-bromobenzoic acid was ≤0.5% as monitored by HPLC. The mixture was then cooled to room temperature to obtain a dichloromethane solution of acyl chloride.

[0022] S2: Add 70.4 kg of dichloromethane and 49.9 kg of anhydrous aluminum trichloride to a reaction vessel and stir for 20 min. Add 42.7 kg of fluorobenzene, cool to 0°C, and add 138 kg of a dichloromethane solution of acyl chloride dropwise, controlling the temperature not to exceed 10°C. After the addition is complete, raise the temperature to room temperature and stir for 2 h until the residual 2-chloro-5-bromo-benzoic acid is ≤0.5% as monitored by HPLC. Transfer to 177.4 kg of 7.2 wt% dilute hydrochloric acid, controlling the temperature not to exceed 30°C, stir for 30 min, allow to stand and separate into layers, collect the organic phase, and then sequentially react the organic phase with 70.4 kg of drinking water, 141.7 kg of 3.2 wt% alkali solution, and 88.2 kg of... Wash with 20wt% brine, then dry with anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure to dryness to obtain crude product, add 113.2 kg isopropanol to crude product, heat to reflux to dissolve, cool to 0℃, crystallize for 2 hours, filter, wash the filter cake with 10 kg low-temperature isopropanol, vacuum dry at 50℃, and after central control testing, the isopropanol content is ≤0.1% and the moisture content is ≤0.5%, and after passing the test, EGAB-3 intermediate is obtained.

[0023] S3: Add 69.9 kg of EGAB-3 intermediate and 160 kg of toluene to a reactor, stir to dissolve, then add 138.9 kg of 50 wt% potassium hydroxide solution, heat to reflux, azeotropically dehydrate, cool to room temperature, remove the lower aqueous phase, collect the organic phase, transfer the organic phase to a new reactor, add 3.4 kg of tetrabutylammonium bromide and 20.9 kg of... 3-Hydroxytetrahydrofuran was heated to reflux and stirred for 6 hours. HPLC monitoring showed that the EGAB-3 intermediate residue was ≤0.5%. The mixture was cooled to room temperature and washed three times with 10wt% saline solution, stirring for 15 minutes each time. After standing and separating the layers, the organic phase was collected and dried with anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure to recover toluene. 209 kg of ethanol was added to the concentrated residue, and the mixture was heated to reflux to dissolve. The mixture was then cooled to 0°C and crystallized for 2 hours. The residue was filtered, and the filter cake was washed with 15 kg of low-temperature ethanol and dried under vacuum at 50°C. After passing the control test, the drying loss was ≤0.5% and the moisture content was ≤0.5%. The EGAB-7 intermediate was obtained.

[0024] S4: Add 108.6 kg of EGAB-7 intermediate, 243.6 kg of toluene, and 49.9 kg of anhydrous aluminum trichloride to a reaction vessel and stir to dissolve. Under nitrogen protection, add 43.9 kg of 1,1,3,3-tetramethyldisiloxane dropwise, controlling the dropping rate and maintaining the internal temperature at 20°C. After the addition is complete, raise the temperature to 40°C and stir for 4 hours. HPLC monitoring shows that the EGAB-7 residue is ≤0.5%. After passing the test, cool to 0°C and add 286.9 kg of... Add 5.15wt% dilute hydrochloric acid, control the temperature not to exceed 20℃, stir for 20 min, let stand to separate into layers, collect the organic phase, wash the organic phase 3 times with 10wt% saline, dry with anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure to recover toluene, add 7.5kg acetone and 169.7kg isopropanol to the concentrated residue, heat to reflux to dissolve, cool to 0℃, crystallize for 2 h, filter, wash the filter cake with 15kg low-temperature isopropanol, vacuum dry at 50℃, and after the drying loss is ≤0.2% as detected by the central control, the intermediate of empagliflozin is obtained.

[0025] Example 2: A synthetic process for an empagliflozin intermediate, comprising the following steps: S1: 71.4 kg of 2-chloro-5-bromobenzoic acid, 108.1 kg of dichloromethane and 3.6 kg of N,N-dimethylformamide were added to a reaction vessel and stirred to dissolve. 42.8 kg of thionyl chloride was added dropwise, and the reaction was kept at the temperature until the residual 2-chloro-5-bromobenzoic acid was ≤0.5% as monitored by HPLC. The mixture was then cooled to room temperature to obtain a dichloromethane solution of acyl chloride.

[0026] S2: Add 71.4 kg of dichloromethane and 50.0 kg of anhydrous aluminum trichloride to a reaction vessel and stir for 25 min. Add 42.8 kg of fluorobenzene, cool to 2°C, and add 140 kg of a dichloromethane solution of acyl chloride dropwise, controlling the temperature not to exceed 10°C. After the addition is complete, raise the temperature to room temperature and stir for 3 h until the residual 2-chloro-5-bromo-benzoic acid is ≤0.5% as monitored by HPLC. Transfer to 178.5 kg of 7.2 wt% dilute hydrochloric acid, controlling the temperature not to exceed 30°C, stir for 35 min, allow to stand and separate into layers, collect the organic phase, and then sequentially react the organic phase with 71.4 kg of drinking water, 142.8 kg of 3.2 wt% alkaline solution, and 89.3 kg of... Wash with 20wt% brine, then dry with anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure to dryness to obtain crude product, add 114.2 kg isopropanol to crude product, heat to reflux to dissolve, cool to 2℃, crystallize for 2.5 h, filter, wash the filter cake with 20 kg low-temperature isopropanol, vacuum dry at 55℃, and after central control testing, the isopropanol content is ≤0.1% and the moisture content is ≤0.5%, and after passing the test, EGAB-3 intermediate is obtained.

[0027] S3: Add 70.0 kg of EGAB-3 intermediate and 161 kg of toluene into a reaction kettle, stir to dissolve, then add 140.0 kg of 50 wt% potassium hydroxide solution, heat to reflux, perform azeotropic dehydration, cool to room temperature, remove the lower aqueous phase, collect the organic phase, transfer the organic phase to a new reaction kettle, add 3.5 kg of tetrabutylammonium bromide and 21.0 kg of 3-hydroxy tetrahydrofuran, heat to reflux, stir for 7 h, monitor the residual EGAB-3 intermediate by HPLC ≤ 0.5%, cool to room temperature, wash with 10 wt% brine 3 times, stir for 15 min each time, let it stand for phase separation, collect the organic phase, dry the organic phase with anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure to recover toluene, add 210 kg of ethanol to the concentrated residue, heat to reflux to dissolve, cool to 2 °C, crystallize for 2.5 h, filter, wash the filter cake with 27.5 kg of low-temperature ethanol, dry under vacuum at 55 °C, after in-process inspection, the loss on drying ≤ 0.5% and the moisture ≤ 0.5%, after passing the inspection, obtain the EGAB-7 intermediate.

[0028] S4: Add 108.7 kg of EGAB-7 intermediate, 244.6 kg of toluene and 50.0 kg of anhydrous aluminum trichloride into a reaction kettle, stir to dissolve, under nitrogen protection, dropwise add 44.0 kg of 1,1,3,3-tetramethyldisiloxane, control the dropping rate to maintain the internal temperature at 25 °C, after dropping, raise the temperature to 45 °C, stir for 5 h, monitor the residual EGAB-7 by HPLC ≤ 0.5%, after passing the inspection, cool to 2 °C, dropwise add 288.0 kg of 5.15 wt% dilute hydrochloric acid, control the temperature not exceeding 20 °C, stir for 25 min, let it stand for phase separation, collect the organic phase, wash the organic phase with 10 wt% brine 3 times, dry with anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure to recover toluene, add 7.6 kg of acetone and 170.7 kg of isopropanol to the concentrated residue, heat to reflux to dissolve, cool to 2 °C, crystallize for 2.5 h, filter, wash the filter cake with 27.5 kg of low-temperature isopropanol, dry under vacuum at 55 °C, after in-process inspection, the loss on drying ≤ 0.2%, after passing the inspection, obtain the empagliflozin intermediate.

[0029] Example 3: A synthesis process of an empagliflozin intermediate, comprising the following steps: S1: Add 71.5 kg of 2-chloro-5-bromobenzoic acid, 109.1 kg of dichloromethane and 3.7 kg of N,N-dimethylformamide into a reaction kettle, stir to dissolve, dropwise add 42.9 kg of thionyl chloride, keep the temperature for reaction until the residual 2-chloro-5-bromobenzoic acid monitored by HPLC ≤ 0.5%, cool to room temperature to obtain a dichloromethane solution of acyl chloride.

[0030] S2: Add 72.4 kg of dichloromethane and 50.1 kg of anhydrous aluminum trichloride to a reaction vessel and stir for 30 min. Add 42.9 kg of fluorobenzene, cool to 5°C, and add 142 kg of a dichloromethane solution of acyl chloride dropwise, controlling the temperature not to exceed 10°C. After the addition is complete, raise the temperature to room temperature and stir for 4 h until the residual 2-chloro-5-bromo-benzoic acid is ≤0.5% as monitored by HPLC. Transfer to 179.6 kg of 7.2 wt% dilute hydrochloric acid, controlling the temperature not to exceed 30°C, stir for 40 min, allow to stand and separate into layers, collect the organic phase, and then sequentially react the organic phase with 72.4 kg of drinking water, 143.9 kg of 3.2 wt% alkaline solution, and 90.4 kg of... Wash with 20wt% brine, then dry with anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure to dryness to obtain crude product, add 115.2 kg isopropanol to crude product, heat to reflux to dissolve, cool to 5℃, crystallize for 3 hours, filter, wash the filter cake with 30 kg low-temperature isopropanol, vacuum dry at 60℃, and after central control testing, the isopropanol content is ≤0.1% and the moisture content is ≤0.5%, and after passing the test, EGAB-3 intermediate is obtained.

[0031] S3: Add 70.1 kg of EGAB-3 intermediate and 162 kg of toluene to a reactor, stir to dissolve, then add 141.1 kg of 50 wt% potassium hydroxide solution, heat to reflux, azeotropically dehydrate, cool to room temperature, remove the lower aqueous phase, collect the organic phase, transfer the organic phase to a new reactor, add 3.6 kg of tetrabutylammonium bromide and 21.1 kg of... 3-Hydroxytetrahydrofuran was heated to reflux and stirred for 8 hours. HPLC monitoring showed that the EGAB-3 intermediate residue was ≤0.5%. The mixture was cooled to room temperature and washed three times with 10wt% saline solution, stirring for 15 minutes each time. After standing and separating the layers, the organic phase was collected and dried with anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure to recover toluene. 211 kg of ethanol was added to the concentrated residue, and the mixture was heated to reflux to dissolve. The mixture was then cooled to 5°C and crystallized for 3 hours. The residue was filtered, and the filter cake was washed with 40 kg of low-temperature ethanol and dried under vacuum at 60°C. After passing the control test, the drying loss was ≤0.5% and the moisture content was ≤0.5%. The EGAB-7 intermediate was obtained.

[0032] S4: Add 108.8 kg of EGAB-7 intermediate, 245.6 kg of toluene, and 50.1 kg of anhydrous aluminum trichloride to a reaction vessel and stir to dissolve. Under nitrogen protection, add 44.1 kg of 1,1,3,3-tetramethyldisiloxane dropwise, controlling the dropping rate and maintaining the internal temperature at 30°C. After the addition is complete, raise the temperature to 50°C and stir for 6 hours. HPLC monitoring shows that the EGAB-7 residue is ≤0.5%. After passing the test, cool to 5°C and add 289.1 kg of... Add 5.15wt% dilute hydrochloric acid, control the temperature not to exceed 20℃, stir for 30 min, let stand to separate into layers, collect the organic phase, wash the organic phase 3 times with 10wt% saline, dry with anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure to recover toluene, add 7.7kg acetone and 171.7kg isopropanol to the concentrated residue, heat to reflux to dissolve, cool to 5℃, crystallize for 3 h, filter, wash the filter cake with 40kg low-temperature isopropanol, vacuum dry at 60℃, and after the drying loss is ≤0.2% as detected by the central control, the intermediate of empagliflozin is obtained.

[0033] In Examples 1-3, 2-chloro-5-bromo-benzoic acid was selected from Wuhan Jixin Yibang Biotechnology Co., Ltd., CAS No. 21739-92-4; dichloromethane was selected from Shandong Huijun Chemical Co., Ltd., CAS No. 75-09-2; N,N-dimethylformamide was selected from Shandong Haocheng Chemical New Materials Co., Ltd., CAS No. 68-12-2; thionyl chloride was selected from Shandong Xuxiang Chemical Co., Ltd., CAS No. 7719-09-7; anhydrous aluminum trichloride was selected from Shandong Wenhui Chemical Co., Ltd., CAS No. 7446-70-0; fluorobenzene was selected from Jiangsu Bosite Chemical Technology Co., Ltd., CAS No. 462-06-6; and anhydrous sodium sulfate was selected from Suzhou Lanyu Chemical Co., Ltd. The CAS number is 7757-82-6; isopropanol is from Jinan Xinjiuyao Chemical Co., Ltd., CAS number 67-63-0; toluene is from Wuxi Jiaxi Chemical Co., Ltd.; tetrabutylammonium bromide is from Jinan Yuansu Chemical Co., Ltd., CAS number 1643-19-2; 3-hydroxytetrahydrofuran is from Wuhan Kemike Biomedical Technology Co., Ltd., CAS number 84976-47-6; ethanol is from Jinan Junyi Chemical Materials Co., Ltd., CAS number 64-17-5; 1,1,3,3-tetramethyldisiloxane is from Hubei Langbowan Biomedical Co., Ltd., CAS number 3277-26-7; acetone is from Nanjing Kaiyan Environmental Protection Technology Co., Ltd.; the remaining raw materials are all commercially available products.

[0034] Comparative Example 1: The difference from Example 1 is that in step S2, the reaction temperature was changed from 0-5℃ low temperature control to room temperature (20-25℃), and the temperature of the dropping process was not strictly controlled. The remaining steps remained unchanged to prepare the empagliflozin intermediate.

[0035] Comparative Example 2: The difference from Example 1 is that in step S3, 3.4 kg of tetrabutylammonium bromide is not added, while the other steps remain unchanged to prepare the empagliflozin intermediate.

[0036] Comparative Example 3: The difference from Example 1 is that in step S4, 43.9 kg of 1,1,3,3-tetramethyldisiloxane was replaced with an equimolar amount of 56.8 kg of boron trifluoride diethyl ether, while the other steps remained unchanged, to prepare the empagliflozin intermediate.

[0037] The empagliflozin intermediates obtained in Examples 1-3 and Comparative Examples 1-3 were subjected to high-performance liquid chromatography (HPLC) to determine their chemical purity and isomer impurity content, respectively, in accordance with the General Chapter of Part IV of the 2025 edition of the Chinese Pharmacopoeia. The overall yield of the process was calculated, and the results are shown in Table 1. Table 1 Performance test results of empagliflozin intermediates As can be seen from Table 1, the empagliflozin intermediates prepared in Examples 1-3 show significant advantages in product purity, isomer impurity control, and overall process yield compared to the process routes of Comparative Examples 1-3, which use room temperature reaction, phase transfer-free catalysis, and boron trifluoride diethyl ether reduction.

[0038] In Comparative Example 1, the chemical purity of the final product decreased, the content of isomer impurities increased significantly, and the overall yield of the process decreased. This may be because in step S2, the strictly controlled low-temperature reaction conditions were replaced with a room-temperature reaction. Friedel-Crafts acylation is extremely sensitive to temperature; at room temperature, non-selective substitution easily occurs, promoting the formation of fluorine ortho-isomer impurities. These isomers have structures similar to the target product and are difficult to separate, leading to a decrease in product purity. This also increases the difficulty of purification and material loss, thus reducing the overall yield.

[0039] The chemical purity of the final product in Comparative Example 2 was close to that of the Example, but the overall yield of the process was significantly lower. This may be because the phase transfer catalyst tetrabutylammonium bromide was not added in step S3. Etherification is a two-phase reaction system, and the absence of a phase transfer catalyst leads to a slower reaction rate and incomplete reaction. Extending the reaction time or increasing the temperature is necessary to achieve the same conversion rate, increasing the risk of side reactions and energy consumption. Furthermore, incomplete reaction may result in some EGAB-3 intermediates not being fully converted, easily causing yield loss.

[0040] In Comparative Example 3, the chemical purity of the final product decreased slightly, and the overall process yield decreased. This may be because in step S4, the mild and safe 1,1,3,3-tetramethyldisiloxane reducing agent was replaced with the conventionally corrosive boron trifluoride diethyl ether. Boron trifluoride diethyl ether has slightly poor reduction selectivity, which may introduce a small amount of boron-containing complex residue, affecting the purity of the final product. Furthermore, its strong corrosiveness places high demands on equipment, easily generates irritating gases during operation, has poor safety, and requires additional post-processing steps to remove boron-containing impurities, leading to a decrease in yield.

[0041] Although embodiments of the invention have been shown and described, it will be understood by those skilled in the art that various changes, modifications, substitutions and variations can be made to these embodiments without departing from the principles and spirit of the invention.

Claims

1. A synthetic process for an empagliflozin intermediate, characterized in that, The steps include the following: Step 1: Mix 2-chloro-5-bromobenzoic acid with dichloromethane and N,N-dimethylformamide, add thionyl chloride dropwise to obtain a dichloromethane solution of acyl chloride, then react it with fluorobenzene under the catalysis of anhydrous aluminum trichloride, quench with dilute hydrochloric acid, wash, concentrate and crystallize with isopropanol to obtain EGAB-3 intermediate; Step 2: The EGAB-3 intermediate was dehydrated by azeotropic reaction with potassium hydroxide aqueous solution in toluene, and then refluxed with 3-hydroxytetrahydrofuran under the catalysis of tetrabutylammonium bromide. After washing, concentration and crystallization with ethanol, the EGAB-7 intermediate was obtained. Step 3: React the EGAB-7 intermediate with 1,1,3,3-tetramethyldisiloxane under anhydrous aluminum trichloride and nitrogen protection. After quenching with dilute hydrochloric acid, washing, and concentration, crystallize with acetone and isopropanol, dry, and pass the test to obtain the empagliflozin intermediate. The structural formula of the engaliplatin intermediate is shown in Formula 1: Formula 1.

2. The synthetic process for an empagliflozin intermediate according to claim 1, characterized in that, The specific preparation method of the dichloromethane solution of the acyl chloride is as follows: 2-Chloro-5-bromobenzoic acid, dichloromethane, and N,N-dimethylformamide were added to a reaction vessel, stirred and dissolved, and thionyl chloride was added dropwise. The reaction was kept at the temperature until the residual 2-chloro-5-bromobenzoic acid was ≤0.5% as monitored by HPLC. The mixture was then cooled to room temperature to obtain a dichloromethane solution of acyl chloride.

3. The synthetic process for an empagliflozin intermediate according to claim 2, characterized in that, The mass ratio of 2-chloro-5-bromobenzoic acid, dichloromethane, N,N-dimethylformamide and thionyl chloride is 71.3-71.5:107.1-109.1:3.5-3.7:42.7-42.

9.

4. The synthetic process for an empagliflozin intermediate according to claim 1, characterized in that, The specific preparation method of the EGAB-3 intermediate is as follows: Dichloromethane and anhydrous aluminum trichloride were added to a reaction vessel and stirred for 20-30 min. Fluorobenzene was added, and the mixture was cooled to 0-5℃. A dichloromethane solution of acyl chloride was added dropwise, with the temperature controlled not to exceed 10℃. After the addition was complete, the mixture was heated to room temperature and stirred for 2-4 h until the residual 2-chloro-5-bromo-benzoic acid was ≤0.5% as monitored by HPLC. The mixture was then transferred to 7.2 wt% dilute hydrochloric acid, with the temperature controlled not to exceed 30℃, and stirred for 30-40 min. The mixture was allowed to stand and separate into layers. The organic phase was collected and washed successively with drinking water, 3.2 wt% alkaline solution, and 20 wt% saline solution. The organic phase was then dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain a crude product. Isopropanol was added to the crude product and heated to reflux to dissolve. The mixture was cooled to 0-5℃ and crystallized for 2-3 h. The crystals were filtered, and the filter cake was washed with low-temperature isopropanol and dried under vacuum. After testing, the isopropanol content was ≤0.1% and the moisture content was ≤0.5%. Once the product was deemed qualified, EGAB-3 intermediate was obtained.

5. The synthetic process for an empagliflozin intermediate according to claim 4, characterized in that, The mass ratio of dichloromethane, anhydrous aluminum trichloride, fluorobenzene, dichloromethane solution of acyl chloride, 7.2 wt% dilute hydrochloric acid, drinking water, 3.2 wt% alkaline solution, 20 wt% saline solution, isopropanol, and low-temperature isopropanol is 70.4-72.4: 49.9-50.1: 42.7-42.9: 138-142: 177.4-179.6: 70.4-72.4: 141.7-143.9: 88.2-90.4: 113.2-115.2: 10-30.

6. The synthetic process for an empagliflozin intermediate according to claim 1, characterized in that, The specific preparation method of the EGAB-7 intermediate is as follows: EGAB-3 intermediate and toluene were added to a reaction vessel and stirred to dissolve. Then, 50 wt% potassium hydroxide solution was added, and the mixture was heated to reflux for azeotropic dehydration. After cooling to room temperature, the lower aqueous phase was removed, and the organic phase was collected. The organic phase was transferred to a new reaction vessel, and tetrabutylammonium bromide and 3-hydroxytetrahydrofuran were added. The mixture was heated to reflux and stirred for 6-8 h. HPLC monitoring showed that the EGAB-3 intermediate residue was ≤0.5%. The mixture was cooled to room temperature, washed three times with 10 wt% saline solution, stirring for 15 min each time. After standing and separating the layers, the organic phase was collected and dried with anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure to recover toluene. Ethanol was added to the concentrated residue, and the mixture was heated to reflux to dissolve. The mixture was cooled to 0-5 °C and crystallized for 2-3 h. After filtration, the filter cake was washed with low-temperature ethanol and dried under vacuum. After passing the control test, the drying loss was ≤0.5% and the moisture content was ≤0.5%. After passing the test, EGAB-7 intermediate was obtained.

7. The synthetic process for an empagliflozin intermediate according to claim 6, characterized in that, The mass ratio of the EGAB-3 intermediate, toluene, 50wt% potassium hydroxide solution, tetrabutylammonium bromide, 3-hydroxytetrahydrofuran, ethanol, and low-temperature ethanol is 69.9-70.1:160-162:138.9-141.1:3.4-3.6:20.9-21.1:209-211:15-40.

8. The synthetic process for an empagliflozin intermediate according to claim 1, characterized in that, The specific preparation method of the empagliflozin intermediate is as follows: EGAB-7 intermediate, toluene, and anhydrous aluminum trichloride were added to a reaction vessel and stirred to dissolve. Under nitrogen protection, 1,1,3,3-tetramethyldisiloxane was added dropwise, controlling the dropping rate and maintaining the internal temperature at 20-30℃. After the addition was complete, the temperature was raised to 40-50℃ and stirred for 4-6 hours. HPLC monitoring showed that the EGAB-7 residue was ≤0.5%. After passing the test, the mixture was cooled to 0-5℃, and 5.15wt% dilute hydrochloric acid was added dropwise, controlling the temperature not to exceed 20℃. The mixture was stirred for 20-30 minutes, allowed to stand for separation, and the organic phase was collected. The organic phase was washed three times with 10wt% saline solution, dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to recover toluene. Acetone and isopropanol were added to the concentrated residue, and the mixture was heated to reflux to dissolve. The temperature was lowered to 0-5℃, and crystals were precipitated for 2-3 hours. The mixture was filtered, and the filter cake was washed with low-temperature isopropanol and dried under vacuum. After passing the test, the drying loss was ≤0.2%, and the intermediate empagliflozin was obtained.

9. The synthetic process for an empagliflozin intermediate according to claim 8, characterized in that, The mass ratio of the EGAB-7 intermediate, toluene, anhydrous aluminum trichloride, 1,1,3,3-tetramethyldisiloxane, 5.15wt% dilute hydrochloric acid, acetone, isopropanol, and low-temperature isopropanol is 108.6-108.8: 243.6-245.6: 49.9-50.1: 43.9-44.1: 286.9-289.1: 7.5-7.7: 169.7-171.7: 15-40.

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