Process for the preparation of a dapagliflozin intermediate

Abstract

The application discloses a preparation method of a dapagliflozin intermediate, and belongs to the technical field of drug chemical synthesis and drug intermediate preparation. Step one, acyl chloride: 5-bromo-2-chlorobenzoic acid and oxalyl chloride are added into dichloromethane containing a catalytic amount of N,N-dimethylformamide, and reaction is carried out at 25-35 DEG C; after the reaction is completed, excess oxalyl chloride and dichloromethane are removed under reduced pressure at a temperature of not more than 35 DEG C; the residue is diluted with 1,2-dichloroethane to obtain a solution containing 5-bromo-2-chlorobenzoyl chloride, and the solution containing 5-bromo-2-chlorobenzoyl chloride is directly used in the next step reaction; the acyl chloride is prepared by using an oxalyl chloride / catalytic amount of N,N-dimethylformamide system, and excess oxalyl chloride and dichloromethane are removed under reduced pressure at low temperature, so that excess acyl chloride reagent is prevented from entering the Friedel-Crafts acylation reaction system, and the exothermic risk and the occurrence rate of side reactions are reduced.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical chemical synthesis and pharmaceutical intermediate preparation technology, specifically relating to a method for preparing dapagliflozin intermediate. Background Technology

[0002] Dapagliflozin is a sodium-glucose cotransporter 2 inhibitor that is clinically used to improve glycemic control. 2-Chloro-5-bromo-4'-ethoxydiphenylmethane is an important aryl bromide intermediate in the synthesis of dapagliflozin. It can usually be metallized and coupled with a protected glycolactone fragment, and then further reduced and deprotected to prepare dapagliflozin or its pharmaceutically acceptable form.

[0003] The existing synthetic route for 2-chloro-5-bromo-4'-ethoxydiphenylmethane generally starts with 5-bromo-2-chlorobenzoic acid, which undergoes acylation and Friedel-Crafts acylation with ethoxybenzene to obtain a diaryl ketone intermediate. The carbonyl group is then reduced to a methylene group to obtain the target diphenylmethane intermediate. This route uses readily available raw materials, has a short procedure time, and possesses potential for industrial scale-up.

[0004] However, in actual production, this type of process still has the following problems: First, if too much acyl chloride reagent remains or is concentrated at high temperature during the acyl chloride step, it will lead to a violently exothermic Friedel-Crafts acylation reaction, an increase in impurities, and may cause partial decomposition or hydrolysis of 5-bromo-2-chlorobenzoyl chloride, affecting the yield and purity of subsequent reactions.

[0005] Second, the Friedel-Crafts acylation reaction is sensitive to temperature, the amount of anhydrous aluminum trichloride used, and the dropping method. If the acyl chloride solution is added to the ethoxybenzene / aluminum trichloride system at a high temperature, polyacylated impurities, positional isomers, and tar-like byproducts are easily generated, leading to a decrease in the purity of crude 4-ethoxyphenyl(5-bromo-2-chlorophenyl) methyl ketone.

[0006] Third, in the carbonyl reduction step, if the ratio of silane reducing agent to acid is inappropriate, or if the triethylsilane dropping speed is too fast, high residual ketone intermediate, deethylation impurities, over-reduction impurities, and other unknown impurities may occur, affecting the quality of the target intermediate.

[0007] Fourth, the target product, 2-chloro-5-bromo-4'-ethoxydiphenylmethane, is a hydrophobic aromatic intermediate. If the crystallization solvent system is not properly selected, problems such as oily precipitation, inclusion of mother liquor, high levels of single unknown impurities, and difficulty in removing diaryl ketone residues may easily occur. Some processes require column chromatography or multiple recrystallizations, which is not conducive to industrial production.

[0008] Fifth, existing technologies typically focus on the chemical purity of the target intermediate, while paying less attention to the reproducible control of its solid-state form. For pharmaceutical intermediates, a stable solid-state form is beneficial for filtration, drying, storage, weighing, and consistency of subsequent feed addition. Therefore, developing a 2-chloro-5-bromo-4'-ethoxydiphenylmethane product that can simultaneously obtain high purity, low residual critical impurities, and a stable crystal form has practical industrial value.

[0009] Therefore, it is necessary to provide a method for preparing 2-chloro-5-bromo-4'-ethoxydiphenylmethane with clearly defined process steps, controllable post-processing, no need for column chromatography, and capable of stably obtaining high-purity crystal form X. Summary of the Invention

[0010] The purpose of this invention is to provide a method for preparing dapagliflozin intermediates, which uses an oxalyl chloride / catalytic N,N-dimethylformamide system for acylation, and removes excess oxalyl chloride and dichloromethane under low temperature and reduced pressure conditions, thereby avoiding the entry of excess acylation reagent into the Friedel-Crafts acylation reaction system, reducing the risk of exothermic reactions and the incidence of side reactions.

[0011] To achieve the above objectives, the present invention provides the following technical solution: a method for preparing a dapagliflozin intermediate, comprising the following steps: Step 1, Acyl chloride: 5-Bromo-2-chlorobenzoic acid and oxalyl chloride are added to dichloromethane containing a catalytic amount of N,N-dimethylformamide and reacted at 25-35°C. After the reaction is completed, the mixture is concentrated under reduced pressure at a temperature not exceeding 35°C to remove excess oxalyl chloride and dichloromethane. The residue is diluted with 1,2-dichloroethane to obtain a solution containing 5-bromo-2-chlorobenzoyl chloride, which is then directly used in the next step of the reaction.

[0012] Step 2, Friedel-Crafts acylation: At -5℃ to 0℃, the solution containing 5-bromo-2-chlorobenzoyl chloride obtained in Step 1 is slowly added dropwise to a mixture of ethoxybenzene and anhydrous aluminum trichloride in 1,2-dichloroethane. After the addition is complete, the temperature is raised to 20-30℃ to continue the reaction. The molar ratio of 5-bromo-2-chlorobenzoic acid, ethoxybenzene and anhydrous aluminum trichloride is 1:(1.10-1.20):(1.20-1.40). After the reaction is complete, the reaction solution is slowly added dropwise to 10% hydrochloric acid ice water for quenching, and the quenching temperature is controlled not to exceed 25℃. After standing and separation, the organic phase is taken, washed and concentrated to obtain crude 4-ethoxyphenyl(5-bromo-2-chlorophenyl) methyl ketone.

[0013] Step 3, carbonyl reduction: The crude 4-ethoxyphenyl(5-bromo-2-chlorophenyl) ketone obtained in Step 2 is dissolved in trifluoroacetic acid, and triethylsilane is slowly added dropwise at 15-25℃. After the addition is complete, the reaction is maintained at this temperature. The molar ratio of crude 4-ethoxyphenyl(5-bromo-2-chlorophenyl) ketone, triethylsilane and trifluoroacetic acid is 1:(1.30-1.60):(4.00-5.00). After the reaction is complete, the reaction solution is slowly poured into ice water, neutralized with sodium bicarbonate aqueous solution to pH 7.0-7.5, extracted with dichloromethane, the organic phases are combined and concentrated to obtain crude 2-chloro-5-bromo-4'-ethoxydiphenylmethane.

[0014] Step 4, crystallization purification: The crude 2-chloro-5-bromo-4'-ethoxydiphenylmethane obtained in Step 3 is crystallized using a mixed solvent of isopropanol and water. Water is slowly added as a poor solvent during the crystallization process. After filtration, washing and drying, 2-chloro-5-bromo-4'-ethoxydiphenylmethane is obtained.

[0015] Further, in step one, the molar ratio of 5-bromo-2-chlorobenzoic acid, oxaloyl chloride and N,N-dimethylformamide is 1:(1.10-1.30):(0.008-0.020); the volume ratio of dichloromethane to 5-bromo-2-chlorobenzoic acid is 5-8 mL:1 g.

[0016] Further, in step one, the acyl chloride reaction time is 2-4 hours; the vacuum degree during concentration is -0.080 MPa to -0.095 MPa, and the concentration temperature is 25-35℃; after the residue is diluted with 1,2-dichloroethane, the ratio of 1,2-dichloroethane to 5-bromo-2-chlorobenzoic acid is 4-7 mL: 1 g.

[0017] Further, in step two, ethoxybenzene and anhydrous aluminum trichloride are first added to 1,2-dichloroethane and cooled to -5°C to 0°C, and then the solution containing 5-bromo-2-chlorobenzoyl chloride obtained in step one is added dropwise; the dropwise addition time is 1-2 hours, and the system temperature is maintained at -5°C to 0°C during the dropwise addition; after the dropwise addition is completed, the temperature is raised to 20-30°C and the reaction is maintained at this temperature for 2-4 hours.

[0018] Further, in step two, the ratio of hydrochloric acid ice water to 5-bromo-2-chlorobenzoic acid is 8-12 mL: 1 g; after quenching, the mixture is allowed to stand and separated, the aqueous phase is extracted with dichloromethane 1-2 times, the organic phases are combined, and washed sequentially with water, a 5% sodium bicarbonate aqueous solution, and a 10% sodium chloride aqueous solution.

[0019] Furthermore, in step three, the triethylsilane is added over a period of 30-90 minutes, and the system temperature is maintained at 15-25°C during the addition process. After the addition is complete, the reaction is continued at this temperature for 2-4 hours. The reaction endpoint is determined by the HPLC residue of 4-ethoxyphenyl(5-bromo-2-chlorophenyl) ketone not exceeding 0.50%.

[0020] Further, in step three, after the reaction is complete, the reaction solution is slowly poured into ice water at 0-10℃, and the pouring temperature is controlled not to exceed 20℃; then, sodium bicarbonate aqueous solution is added in batches to neutralize to a pH of 7.0-7.5, and the system temperature during the neutralization process does not exceed 25℃; after neutralization, it is extracted with dichloromethane 2-3 times, the organic phases are combined, dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain crude 2-chloro-5-bromo-4'-ethoxydiphenylmethane.

[0021] Further, in step four, the volume ratio of isopropanol to water in the isopropanol-water mixed solvent is 1:(1.0-2.0); during crystallization, crude 2-chloro-5-bromo-4'-ethoxydiphenylmethane is first added to isopropanol and heated to 45-60℃ to dissolve, then water is slowly added dropwise as a poor solvent. After the addition is complete, the temperature is lowered to 0-10℃ and kept at this temperature for crystallization for 2-6 hours; after filtration, the filter cake is washed with isopropanol-water mixed solvent at 0-10℃ and then vacuum dried at 40-50℃.

[0022] Furthermore, the HPLC purity of the high-purity crystal form X of 2-chloro-5-bromo-4'-ethoxydiphenylmethane is not less than 99.50%, the content of a single unknown impurity is not more than 0.10%, the residual amount of 4-ethoxyphenyl(5-bromo-2-chlorophenyl) methyl ketone is not more than 0.15%, and the moisture content is not more than 0.30%; the product is prepared by the preparation method described in this invention.

[0023] The present invention also provides the use of the high-purity crystal form X of 2-chloro-5-bromo-4'-ethoxydiphenylmethane in the preparation of dapagliflozin, pharmaceutically acceptable salts of dapagliflozin, dapagliflozin solvates or pharmaceutical compositions containing dapagliflozin.

[0024] Compared with the prior art, the present invention provides a method for preparing dapagliflozin intermediate, which has the following advantages: acyl chloride is carried out using an oxalyl chloride / catalytic amount N,N-dimethylformamide system, and excess oxalyl chloride and dichloromethane are removed under low temperature and reduced pressure conditions, avoiding excess acyl chloride reagent from entering the Friedel-Crafts acylation reaction system, reducing the risk of exothermic reaction and the incidence of side reactions.

[0025] This invention allows the residue obtained from acyl chloride to be diluted with 1,2-dichloroethane and used directly in the next reaction step. This avoids the hydrolysis risk caused by the separation of acyl chloride intermediates and makes the solvent system of the Friedel-Crafts acylation reaction more stable, which is conducive to industrial scale-up.

[0026] This invention employs a low-temperature dropwise addition method at -5°C to 0°C in the Friedel-Crafts acylation step and controls the ratio of ethoxybenzene to anhydrous aluminum trichloride, which can significantly reduce polyacylation impurities and positional isomers, thereby improving the quality of crude ketone.

[0027] In this invention, a trifluoroacetic acid / triethylsilane system is used in the carbonyl reduction step, and the dropping rate of triethylsilane, reaction temperature and post-treatment neutralization pH are controlled to effectively control ketone intermediate residues and over-reduction impurities.

[0028] This invention employs an isopropanol-water system for crystallization and purification, with water added slowly as a poor solvent. This avoids the oily precipitation of the target product and the inclusion of mother liquor, resulting in a high-purity 2-chloro-5-bromo-4'-ethoxydiphenylmethane product with an HPLC purity of not less than 99.50% and a single unknown impurity content of not more than 0.10% at a relatively high yield.

[0029] This invention provides a stable method for obtaining 2-chloro-5-bromo-4'-ethoxydiphenylmethane product with crystal form X via an isopropanol-water crystallization system. The X-ray powder diffraction pattern of the product exhibits stable and identifiable characteristic peaks, indicating that the method of this invention can not only improve chemical purity but also stably control the solid state of the product, which is beneficial for subsequent storage, transportation, and use. Attached Figure Description

[0030] Figure 1 This is a superimposed X-ray powder diffraction pattern of 2-chloro-5-bromo-4'-ethoxydiphenylmethane crystal form X obtained in Examples 1, 2, 3 and 4 of this invention; Figure 2 This is a comparison of HPLC related substance chromatograms of crude 4-ethoxyphenyl(5-bromo-2-chlorophenyl) methyl ketone obtained in Example 2 and Comparative Example 2 of the present invention; Figure 3 This is a schematic diagram (chemical reaction formula) of the overall synthetic route of the present invention. Figure 4 This is a biaxial curve showing the effect of the crystallization solvent ratio (isopropanol / water) on the product purity and yield of this invention. Detailed Implementation

[0031] The technical solutions of the present invention will be clearly and completely described below with reference to the embodiments of 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.

[0032] Please see Figures 1-4This invention provides a technical solution for preparing a dapagliflozin intermediate: In the following examples, 5-bromo-2-chlorobenzoic acid is referred to as raw material A; 5-bromo-2-chlorobenzoyl chloride is referred to as acyl chloride intermediate; 4-ethoxyphenyl(5-bromo-2-chlorophenyl) methyl ketone is referred to as ketone intermediate; and 2-chloro-5-bromo-4'-ethoxydiphenylmethane is referred to as target intermediate.

[0033] Unless otherwise specified, all raw materials and reagents used are commercially available industrial-grade or pharmaceutical-grade synthetic reagents, and the water used is purified water.

[0034] Test methods 1. HPLC purity and related substance determination The determination was performed in accordance with the General Rules for High Performance Liquid Chromatography in the current Chinese Pharmacopoeia, and the specificity, linearity, precision, repeatability and limit of quantitation were confirmed in accordance with the requirements for validation of relevant substances in drug quality research.

[0035] The chromatographic conditions are as follows: Chromatographic column: Octadecylsilane-bonded silica column, 250 mm × 4.6 mm, 5 μm; Mobile phase A: 0.02 mol / L potassium dihydrogen phosphate aqueous solution, adjusted to pH 3.0 with phosphoric acid; Mobile phase B: Acetonitrile; Detection wavelength: 225nm; Column temperature: 35℃; Flow rate: 1.0 mL / min; Injection volume: 10 μL; Gradient elution program: 0-10 min, mobile phase B is 55%; 10-35 min, mobile phase B increases from 55% to 85%; 35-45 min, mobile phase B is maintained at 85%; 45-50 min, mobile phase B decreases to 55%; 50-60 min, mobile phase B is maintained at 55%.

[0036] Test solution: Take an appropriate amount of sample, dissolve and dilute it with acetonitrile to a solution of about 0.5 mg / mL.

[0037] Calculation method: The HPLC purity of the target intermediate, the residual amount of the ketone intermediate, the single unknown impurity, and the total impurities were calculated by the area normalization method.

[0038] 2. X-ray powder diffraction determination The determination was performed in accordance with the general rules of X-ray powder diffraction in the current valid Chinese Pharmacopoeia.

[0039] The test conditions are as follows: Radiation source: Cu-Kα radiation; Tube voltage: 40kV; Tube current: 40mA; Scanning range: 3°-40°; Step size: 0.02°; Scanning speed: 2° per minute; Sample preparation method: Take an appropriate amount of the crystalline powder sample obtained in the example, press it lightly and spread it evenly in the sample trough to avoid the influence of preferred orientation.

[0040] Crystal form determination method: The position of characteristic peaks is the primary criterion, with an allowable error of ±0.2° for peak position. The product obtained in the example exhibits characteristic peaks at reflection angles 2θ of 7.82°±0.2°, 10.26°±0.2°, 12.48°±0.2°, 15.64°±0.2°, 18.36°±0.2°, 20.72°±0.2°, 22.84°±0.2°, 25.18°±0.2°, and 27.46°±0.2°, and is therefore determined to be crystal form X.

[0041] 3. Residual solvent determination According to the general rules for residual solvent determination in the current effective Chinese Pharmacopoeia, headspace gas chromatography was used to determine the residues of dichloromethane, 1,2-dichloroethane and isopropanol.

[0042] The gas chromatography conditions are as follows: Chromatographic column: 6% cyanopropylphenyl-94% dimethyl polysiloxane capillary column, 30m × 0.32mm × 1.8μm; Detector: FID; Carrier gas: Nitrogen; Headspace equilibrium temperature: 80℃; Headspace equilibration time: 30 min; Inlet temperature: 200℃; Detector temperature: 250℃.

[0043] 4. Moisture content determination The water content was determined by the Karl Fischer method as specified in the General Rules for Water Determination in the current valid Chinese Pharmacopoeia.

[0044] 5. Structural Confirmation The structure was confirmed using proton nuclear magnetic resonance spectroscopy (¹H NMR) with CDCl₃ as the solvent and a test frequency of 400 MHz. Characteristic signals of the target intermediate included aromatic hydrogen signals, benzylic methylene signals, ethoxymethylene signals, and methyl signals.

[0045] Example 1 Step 1, Acyl Chlorination: Using 1.00 mol of raw material A as the feed basis, raw material A was added to dichloromethane at a ratio of 5 mL:1 g. 0.008 mol of N,N-dimethylformamide was added, and 1.10 mol of oxalyl chloride was added dropwise with stirring. The reaction was carried out at 25 °C for 2 h. After the reaction was completed, the mixture was concentrated under reduced pressure at 25 °C and a vacuum of -0.080 MPa to remove excess oxalyl chloride and dichloromethane. The residue was diluted with 1,2-dichloroethane at a ratio of 4 mL:1 g to obtain a solution containing the acyl chloride intermediate, which was directly used in the next reaction step.

[0046] Step 2, Friedel-Crafts acylation: 1.10 mol of ethoxybenzene and 1.20 mol of anhydrous aluminum trichloride were added to 1,2-dichloroethane, and the mixture was cooled to -5°C. At a temperature between -5°C and 0°C, the solution containing the acyl chloride intermediate obtained in Step 1 was slowly added dropwise to the system over a period of 1 hour. After the addition was complete, the temperature was raised to 20°C, and the reaction was maintained at this temperature for 2 hours. After the reaction was complete, the reaction solution was slowly added dropwise to a 10% hydrochloric acid-ice water solution for quenching. The ratio of hydrochloric acid-ice water solution to raw material A was 8 mL:1 g, and the quenching temperature was controlled to not exceed 25°C. The mixture was allowed to stand and separated. The aqueous phase was extracted once with dichloromethane. The organic phases were combined and washed successively with water, a 5% sodium bicarbonate aqueous solution, and a 10% sodium chloride aqueous solution. The mixture was then concentrated to obtain the crude ketone intermediate.

[0047] Step 3, carbonyl reduction: The crude ketone intermediate obtained in Step 2 was dissolved in trifluoroacetic acid, and triethylsilane was slowly added dropwise at 15°C. The molar ratio of crude ketone intermediate, triethylsilane, and trifluoroacetic acid was 1:1.30:4.00, and the addition time of triethylsilane was 90 min. After the addition was complete, the reaction was maintained at 15°C for 2 h. HPLC analysis showed that the residual amount of the ketone intermediate was 0.46%. After the reaction was completed, the reaction solution was slowly poured into ice water at 0°C, controlling the pouring temperature to not exceed 20°C. Then, sodium bicarbonate aqueous solution was added in batches to neutralize to pH 7.0, and the system temperature did not exceed 25°C during the neutralization process. After neutralization, the solution was extracted twice with dichloromethane, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude target intermediate.

[0048] Step 4, Crystallization and Purification: The crude target intermediate obtained in Step 3 was added to isopropanol and heated to 45°C to dissolve. Water was then slowly added dropwise as a poor solvent, with a volume ratio of isopropanol to water of 1:1.0. After the addition was complete, the temperature was lowered to 0°C and kept at this temperature for 2 hours to allow crystals to crystallize. The mixture was then filtered, and the filter cake was washed with a 0°C isopropanol-water mixed solvent. Finally, it was vacuum dried at 40°C to obtain 2-chloro-5-bromo-4'-ethoxydiphenylmethane of crystal form X.

[0049] Example 2 Step 1, Acyl Chlorination: Using 1.00 mol of raw material A as the feed basis, raw material A was added to dichloromethane at a ratio of 6.5 mL:1 g. 0.014 mol of N,N-dimethylformamide was added, and 1.20 mol of oxalyl chloride was added dropwise with stirring. The reaction was carried out at 30 °C for 3 h. After the reaction was completed, the mixture was concentrated under reduced pressure at 30 °C and a vacuum of -0.090 MPa to remove excess oxalyl chloride and dichloromethane. The residue was diluted with 1,2-dichloroethane at a ratio of 5.5 mL:1 g to obtain a solution containing the acyl chloride intermediate, which was directly used in the next reaction step.

[0050] Step 2, Friedel-Crafts acylation: 1.15 mol of ethoxybenzene and 1.30 mol of anhydrous aluminum trichloride were added to 1,2-dichloroethane, and the mixture was cooled to -3°C. At -5°C to 0°C, the solution containing the acyl chloride intermediate obtained in Step 1 was slowly added dropwise to the system over 1.5 h. After the addition was complete, the temperature was raised to 25°C, and the reaction was maintained for 3 h. After the reaction was complete, the reaction solution was slowly added dropwise to a 10% hydrochloric acid-ice water solution for quenching. The ratio of hydrochloric acid-ice water solution to raw material A was 10 mL: 1 g, and the quenching temperature was controlled to not exceed 25°C. The mixture was allowed to stand and separated. The aqueous phase was extracted twice with dichloromethane. The organic phases were combined and washed successively with water, a 5% sodium bicarbonate aqueous solution, and a 10% sodium chloride aqueous solution. The mixture was then concentrated to obtain the crude ketone intermediate.

[0051] Step 3, carbonyl reduction: The crude ketone intermediate obtained in Step 2 was dissolved in trifluoroacetic acid, and triethylsilane was slowly added dropwise at 20°C. The molar ratio of crude ketone intermediate, triethylsilane, and trifluoroacetic acid was 1:1.45:4.50, and the addition time of triethylsilane was 60 min. After the addition was complete, the reaction was maintained at 20°C for 3 h. HPLC analysis showed that the residual amount of the ketone intermediate was 0.18%. After the reaction was completed, the reaction solution was slowly poured into ice water at 5°C, controlling the pouring temperature to not exceed 20°C. Sodium bicarbonate aqueous solution was then added in batches to neutralize to pH 7.2, with the system temperature not exceeding 25°C during neutralization. After neutralization, the solution was extracted three times with dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude target intermediate.

[0052] Step 4, Crystallization and Purification: The crude target intermediate obtained in Step 3 was added to isopropanol and heated to 52°C to dissolve. Water was then slowly added dropwise as a poor solvent, with a volume ratio of isopropanol to water of 1:1.5. After the addition was complete, the temperature was lowered to 5°C and maintained at this temperature for 4 hours to allow crystals to crystallize. The mixture was then filtered, and the filter cake was washed with a 5°C isopropanol-water mixed solvent. Finally, it was vacuum dried at 45°C to obtain 2-chloro-5-bromo-4'-ethoxydiphenylmethane of crystal form X.

[0053] Example 3 Step 1, Acyl Chlorination: Using 1.00 mol of raw material A as the feed basis, raw material A was added to dichloromethane at a ratio of 8 mL:1 g. 0.020 mol of N,N-dimethylformamide was added, and 1.30 mol of oxalyl chloride was added dropwise with stirring. The reaction was carried out at 35 °C for 4 h. After the reaction was completed, the mixture was concentrated under reduced pressure at 35 °C and a vacuum of -0.095 MPa to remove excess oxalyl chloride and dichloromethane. The residue was diluted with 1,2-dichloroethane at a ratio of 7 mL:1 g to raw material A to obtain a solution containing the acyl chloride intermediate, which was directly used in the next reaction step.

[0054] Step 2, Friedel-Crafts acylation: 1.20 mol of ethoxybenzene and 1.40 mol of anhydrous aluminum trichloride were added to 1,2-dichloroethane, and the mixture was cooled to 0°C. At -5°C to 0°C, the solution containing the acyl chloride intermediate obtained in Step 1 was slowly added dropwise to the system over 2 hours. After the addition was complete, the temperature was raised to 30°C and maintained for 4 hours. After the reaction was complete, the reaction solution was slowly quenched by adding dropwise to 10% hydrochloric acid-ice water at a ratio of 12 mL:1 g of raw material A, and the quenching temperature was controlled to not exceed 25°C. The mixture was allowed to stand and separated. The aqueous phase was extracted twice with dichloromethane. The organic phases were combined and washed successively with water, a 5% sodium bicarbonate aqueous solution, and a 10% sodium chloride aqueous solution. The mixture was then concentrated to obtain the crude ketone intermediate.

[0055] Step 3, carbonyl reduction: The crude ketone intermediate obtained in Step 2 was dissolved in trifluoroacetic acid, and triethylsilane was slowly added dropwise at 25°C. The molar ratio of crude ketone intermediate, triethylsilane, and trifluoroacetic acid was 1:1.60:5.00, and the addition time of triethylsilane was 30 min. After the addition was complete, the reaction was maintained at 25°C for 4 h. HPLC analysis showed that the residual amount of the ketone intermediate was 0.12%. After the reaction was completed, the reaction solution was slowly poured into ice water at 10°C, controlling the pouring temperature to not exceed 20°C. Then, sodium bicarbonate aqueous solution was added in batches to neutralize to pH 7.5, and the system temperature did not exceed 25°C during the neutralization process. After neutralization, the solution was extracted three times with dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude target intermediate.

[0056] Step 4, Crystallization and Purification: The crude target intermediate obtained in Step 3 was added to isopropanol and heated to 60°C to dissolve. Water was then slowly added dropwise as a poor solvent, with a volume ratio of isopropanol to water of 1:2.0. After the addition was complete, the temperature was lowered to 10°C and maintained at this temperature for 6 hours to allow crystals to crystallize. The crystals were then filtered, and the filter cake was washed with a 10°C isopropanol-water mixed solvent. Finally, the crystals were dried under vacuum at 50°C to obtain 2-chloro-5-bromo-4'-ethoxydiphenylmethane of crystal form X.

[0057] Example 4: Step 1, Acyl Chlorination: Using 10.00 mol of raw material A as the feed basis, raw material A was added to dichloromethane at a ratio of 6.5 mL:1 g. 0.14 mol of N,N-dimethylformamide was added, and 12.00 mol of oxalyl chloride was added dropwise with stirring. The reaction was carried out at 30 °C for 3 h. After the reaction was completed, the mixture was concentrated under reduced pressure at 30 °C and a vacuum of -0.090 MPa to remove excess oxalyl chloride and dichloromethane. The residue was diluted with 1,2-dichloroethane to obtain a solution containing the acyl chloride intermediate, which was directly used in the next reaction step.

[0058] Steps two through four were performed according to the method of Example 2 to obtain 2-chloro-5-bromo-4'-ethoxydiphenylmethane of crystal form X.

[0059] In Comparative Example 1, after the reaction was completed, excess oxalyl chloride and dichloromethane were removed by vacuum concentration at 50°C. All other conditions were the same as in Example 2.

[0060] In Comparative Example 2, in step two, when the solution containing the acyl chloride intermediate was added dropwise to the system of ethoxybenzene and anhydrous aluminum trichloride, the dropping temperature was adjusted from -5°C to 0°C to 15-20°C, and the other conditions were the same as in Example 2.

[0061] In Comparative Example 3, the amount of anhydrous aluminum trichloride in step two was adjusted from 1.30 mol to 1.00 mol, and all other conditions were the same as in Example 2.

[0062] In Comparative Example 4, the amount of triethylsilane used in step three was adjusted from 1.45 mol to 1.00 mol, and all other conditions were the same as in Example 2.

[0063] In Comparative Example 5, in step three, after the reaction solution was poured into ice water, it was neutralized to pH 8.5 with sodium bicarbonate aqueous solution. All other conditions were the same as in Example 2.

[0064] In Comparative Example 6, in step four, the volume ratio of isopropanol to water was adjusted from 1:1.5 to 1:0.5, meaning that the amount of the undesirable solvent water was insufficient. All other conditions were the same as in Example 2.

[0065] In Comparative Example 7, in step four, water was added dropwise as a poor solvent and the temperature was directly and rapidly reduced to 0°C for 10 minutes. All other conditions were the same as in Example 2.

[0066] Summary of test results.

[0067] Table 1. Quality results of 2-chloro-5-bromo-4'-ethoxydiphenylmethane products obtained from the examples and comparative examples.

[0068] As shown in Table 1, Examples 1-3 respectively cover the lower end, middle region, and upper end of the key numerical range in the claims, and all can obtain high-purity 2-chloro-5-bromo-4'-ethoxydiphenylmethane products with HPLC purity not less than 99.50%, single unknown impurity content not more than 0.10%, ketone intermediate residue not more than 0.15%, and moisture content not more than 0.30%. Example 4 shows that the method can still maintain good yield and quality under 10mol scale-up conditions, and has industrial applicability.

[0069] Comparative Examples 1-7 are all single-factor variable comparisons. Comparative Example 1 shows that low-temperature concentration after acyl chlorination plays an important role in controlling impurities in acyl chloride degradation; Comparative Example 2 shows that low-temperature dropwise addition of Friedel-Crafts acylation can significantly reduce positional isomers and polyacylation byproducts; Comparative Example 3 shows that limiting the amount of anhydrous aluminum trichloride is necessary for reaction conversion and impurity control; Comparative Example 4 shows that insufficient triethylsilane will lead to excessive residue of ketone intermediates; Comparative Example 5 shows that a high neutralization pH will cause an increase in impurities; Comparative Example 6 shows that the proportion of water, a poor solvent, in the isopropanol-water crystallization system has a key impact on the purification effect; Comparative Example 7 shows that slow cooling crystallization helps reduce mother liquor entrainment and high water content.

[0070] Table 2 shows the XRPD characteristic peak test results of the products obtained in the examples.

[0071] As shown in Table 2, the products obtained in Examples 1-4 all exhibit essentially consistent XRPD characteristic peaks, indicating that the present invention, through an isopropanol-water crystallization system, especially with the slow addition of water as a poor solvent and temperature-controlled crystallization, can stably obtain crystal form X. This crystal form X has good batch-to-batch reproducibility and can serve as an important structural feature distinguishing the high-purity 2-chloro-5-bromo-4'-ethoxydiphenylmethane product of the present invention from conventional products with undefined solid forms.

[0072] Table 3 Results of residual solvent in the products obtained from the examples

[0073] As shown in Table 3, the residual solvents of the target intermediates obtained in the examples were at low levels after isopropanol-water crystallization and vacuum drying. In particular, the residual 1,2-dichloroethane was effectively controlled, indicating that the post-processing and drying process of the present invention is suitable for preparing pharmaceutical intermediates.

[0074] Table 4. Comparison of the mass of crude ketone products obtained in Example 2 and some comparative examples.

[0075] Table 4 shows that the quality of the Friedel-Crafts acylation step has a significant transfer effect on the final target intermediate. Example 2, through low-temperature dropwise addition and appropriate control with anhydrous aluminum trichloride, achieved higher purity in the crude ketone product, resulting in a higher purity target intermediate after subsequent carbonyl reduction and crystallization.

[0076] Table 5. Quality comparison of the carbonyl reduction stage between Example 2 and some comparative examples.

[0077] As shown in Table 5, the amount of triethylsilane used in the carbonyl reduction stage and the neutralization pH in the post-treatment significantly affect the quality of the final product. In Example 2, the synergistic effect of the triethylsilane dosage and pH control resulted in low levels of ketone intermediate residue and unknown impurities.

[0078] Structural confirmation The target intermediate obtained in Example 2 was tested by ¹H-NMR, and the results are as follows: ¹H-NMR, 400MHz, CDCl3, δ: 7.38–7.12, m, 6H, aromatic hydrogen; 4.02, q, 2H, OCH2CH3; 3.98, s, 2H, Ar-CH2-Ar; 1.41, t, 3H, OCH2CH3.

[0079] The above NMR signal is consistent with the structure of 2-chloro-5-bromo-4'-ethoxydiphenylmethane, indicating that the product obtained in Example 2 is the target intermediate.

[0080] in conclusion A comparison of Examples 1-4 with Comparative Examples 1-7 shows that the present invention is not a simple combination of existing acyl chloride, Friedel-Crafts acylation, and carbonyl reduction steps. Instead, it achieves synergistic effects of impurity source control, reaction process control, solid state control, and crystallization purification control through the overall process control of "oxalyl chloride / DMF acyl chloride—low-temperature concentration to remove oxalyl chloride—direct Friedel-Crafts acylation after dilution with 1,2-dichloroethane—low-temperature dropwise addition of acyl chloride solution—mild reduction with trifluoroacetic acid / triethylsilane—neutralization at pH 7.0-7.5—isopropanol-water crystallization purification, with water added slowly as a poor solvent".

[0081] In particular, all four examples consistently yielded crystal form X, demonstrating that the isopropanol-water crystallization system of the present invention is not only used for impurity removal but also for stable control of the solid morphology of the target intermediate. Comparative Examples 2 and 4 show that the Friedel-Crafts acylation dropping temperature and the amount of triethylsilane have a significant impact on the quality of the final product; Comparative Examples 6 and 7 further demonstrate that the proportion of water as a poor solvent and the cooling method in the isopropanol-water crystallization system not only affect the yield but also directly affect individual unknown impurities, ketone residues, and moisture content.

[0082] In particular, the results of Comparative Examples 2 and 4-7 unexpectedly demonstrate that the present invention, through low-temperature dropwise addition and precise crystallization control, specifically solves the problem that regioisomeric impurities and ketone residues in this route are difficult to completely remove by conventional methods. This is something that those skilled in the art could not foresee in conventional process optimization. The above results prove that the technical solution of the present invention can stably obtain a high-purity 2-chloro-5-bromo-4'-ethoxydiphenylmethane product with an HPLC purity of not less than 99.50%, a single unknown impurity content of not more than 0.10%, a ketone intermediate residue of not more than 0.15%, a moisture content of not more than 0.30%, and crystal form X characteristics.

[0083] Therefore, compared with conventional processes, the present invention has higher product purity, lower residue of key impurities, more stable solid state, better controllability of post-processing, and stronger industrial applicability, and has substantial features and significant progress.

Claims

1. A method for preparing a dapagliflozin intermediate, characterized in that, Includes the following steps: Step 1, Acyl chloride: 5-Bromo-2-chlorobenzoic acid and oxalyl chloride are added to dichloromethane containing N,N-dimethylformamide as a catalyst and reacted at 25-35°C. After the reaction is completed, the mixture is concentrated under reduced pressure at a temperature not exceeding 35°C to remove excess oxalyl chloride and dichloromethane. The residue is diluted with 1,2-dichloroethane to obtain a solution containing 5-bromo-2-chlorobenzoyl chloride, which is then used directly in the next step of the reaction. Step 2, Friedel-Crafts acylation: At -5°C to 0°C, the solution containing 5-bromo-2-chlorobenzoyl chloride obtained in Step 1 is slowly added dropwise to a mixture of ethoxybenzene and anhydrous aluminum trichloride in 1,2-dichloroethane. After the addition is complete, the temperature is raised to 20-30°C to continue the reaction. The molar ratio of 5-bromo-2-chlorobenzoic acid, ethoxybenzene and anhydrous aluminum trichloride is 1:(1.10-1.20):(1.20-1.40). After the reaction was completed, the reaction solution was slowly added dropwise to 10% hydrochloric acid ice water to quench it, and the quenching temperature was controlled not to exceed 25°C. After standing and separating the liquid, the organic phase was taken, washed and concentrated to obtain crude 4-ethoxyphenyl(5-bromo-2-chlorophenyl) methyl ketone. Step 3, carbonyl reduction: Dissolve the crude 4-ethoxyphenyl(5-bromo-2-chlorophenyl) methyl ketone obtained in step 2 in trifluoroacetic acid, and slowly add triethylsilane dropwise at 15-25℃. After the addition is complete, keep the temperature for reaction. The molar ratio of crude 4-ethoxyphenyl(5-bromo-2-chlorophenyl) ketone, triethylsilane, and trifluoroacetic acid is 1:(1.30-1.60):(4.00-5.00). After the reaction was completed, the reaction solution was slowly poured into ice water, neutralized with sodium bicarbonate aqueous solution to pH 7.0-7.5, extracted with dichloromethane, the organic phases were combined and concentrated to obtain crude 2-chloro-5-bromo-4'-ethoxydiphenylmethane. Step 4, crystallization and purification: The crude 2-chloro-5-bromo-4'-ethoxydiphenylmethane obtained in Step 3 is crystallized using a mixed solvent of isopropanol and water, filtered, washed and dried to obtain 2-chloro-5-bromo-4'-ethoxydiphenylmethane.

2. The method for preparing a dapagliflozin intermediate according to claim 1, characterized in that, In step one, the molar ratio of 5-bromo-2-chlorobenzoic acid, oxaloyl chloride, and N,N-dimethylformamide is 1:(1.10-1.30):(0.008-0.020). The ratio of dichloromethane to 5-bromo-2-chlorobenzoic acid is 5-8 mL: 1 g.

3. The method for preparing a dapagliflozin intermediate according to claim 1, characterized in that, In step one, the acyl chloride reaction time is 2-4 hours; The vacuum degree during vacuum concentration is -0.080MPa to -0.095MPa, and the concentration temperature is 25-35℃. The residue was diluted with 1,2-dichloroethane, with the ratio of 1,2-dichloroethane to 5-bromo-2-chlorobenzoic acid being 4-7 mL: 1 g.

4. The method for preparing a dapagliflozin intermediate according to claim 1, characterized in that, In step two, the ethoxybenzene and anhydrous aluminum trichloride are first added to 1,2-dichloroethane and cooled to -5°C to 0°C, and then the solution containing 5-bromo-2-chlorobenzoyl chloride obtained in step one is added dropwise. The dropping time is 1-2 hours, and the system temperature is maintained between -5℃ and 0℃ during the dropping process; After the addition is complete, raise the temperature to 20-30℃ and keep it at that temperature for 2-4 hours.

5. The method for preparing a dapagliflozin intermediate according to claim 1, characterized in that, In step two, after the Friedel-Crafts acylation reaction is completed, the reaction solution is slowly added dropwise to a 10% hydrochloric acid solution in ice water for quenching. The ratio of hydrochloric acid ice water to 5-bromo-2-chlorobenzoic acid is 8-12 mL: 1 g; After quenching, allow the mixture to stand and separate. Extract the aqueous phase with dichloromethane 1-2 times, combine the organic phases, and wash them sequentially with water, a 5% sodium bicarbonate aqueous solution, and a 10% sodium chloride aqueous solution.

6. The method for preparing a dapagliflozin intermediate according to claim 1, characterized in that, In step three, the triethylsilane is added over a period of 30-90 minutes, and the system temperature is maintained at 15-25°C during the addition process. After the addition is complete, continue to keep the reaction at the desired temperature for 2-4 hours; The reaction endpoint was determined by the HPLC residue of 4-ethoxyphenyl(5-bromo-2-chlorophenyl) ketone not exceeding 0.50%.

7. The method for preparing a dapagliflozin intermediate according to claim 1, characterized in that, In step three, after the reaction is complete, slowly pour the reaction solution into ice water at 0-10℃, and control the pouring temperature to not exceed 20℃; Add sodium bicarbonate solution in batches to neutralize to a pH of 7.0-7.5, and the system temperature should not exceed 25°C during the neutralization process; After neutralization, the product was extracted 2-3 times with dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain crude 2-chloro-5-bromo-4'-ethoxydiphenylmethane.

8. The method for preparing a dapagliflozin intermediate according to claim 1, characterized in that, In step four, the volume ratio of isopropanol to water in the isopropanol-water mixed solvent is 1:(1.0-2.0); During crystallization, crude 2-chloro-5-bromo-4'-ethoxydiphenylmethane is first added to isopropanol and heated to 45-60℃ to dissolve. Then, water is slowly added dropwise as a poor solvent. After the addition is complete, the temperature is lowered to 0-10℃ and kept at this temperature for 2-6 hours to allow crystals to precipitate. After filtration, the filter cake is washed with a mixed solvent of isopropanol and water at 0-10℃ and then vacuum dried at 40-50℃.

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