One-pot method for preparing empagliflozin

Abstract

The present invention belongs to the field of pharmaceutical synthesis technology, and specifically relates to a one-pot method for preparing empagliflozin. The preparation method comprises the following steps: using 4-(5-bromo-2-chlorobenzyl)phenol as a starting material, nucleophilic addition reaction with sugar occurs under the action of a Grignard reagent; then adding a methanolic solution of hydrogen chloride to undergo methyl etherification; then undergoing a nucleophilic substitution reaction with (R)-3-tetrahydrofuryl p-toluenesulfonate; and finally adding Et3SiH3 / AlCl3 to undergo a reduction reaction to obtain a crude product of empagliflozin. The one-pot method for preparing a crude product of empagliflozin provided by the present invention does not require the removal of intermediates during the reaction process, thus avoiding centrifugation and drying operations, and greatly shortening the production cycle. The preparation method is simple to operate, easy to operate in post-processing, and easy to recover the solvent; and it greatly improves production capacity. The purity of the refined finished product is above 99.5%, the total product yield can reach 40%, impurities are easy to control, and it is suitable for industrial production.

Description

Technical Field

[0001] The present invention belongs to the technical field of drug synthesis, and particularly relates to a method for preparing empagliflozin by a one-pot process. Background Art

[0002] Empagliflozin is a sodium-glucose co-transporter 2 (SGLT2) inhibitor that effectively blocks the renal reabsorption of glucose, increases glucose excretion, and lowers blood sugar levels. Empagliflozin is used in combination with diet and exercise to treat adult patients with type 2 diabetes and can improve blood sugar control. The chemical name of empagliflozin is (1S)-1,5-anhydro-1-C-(4-chloro-3-((4-(((3S)-tetrahydro-3-furanyl)oxy)phenyl)methyl)phenyl)-D-glucitol, with a relative molecular mass of 450.91 and a molecular formula of C 23 H 27 ClO7, the structural formula is shown in Formula III.

[0003]

[0004] Currently, the synthesis technology of empagliflozin is relatively mature, but most existing empagliflozin synthesis processes have drawbacks such as long process routes, low yields, and difficulty in industrial production. For example, the original patents for empagliflozin (US7579449B2, US7713938B2, US7745414B2, and US7776830B2) use 2-chloro-5-bromobenzoic acid as the starting material. After chlorination, Friedel-Crafts acylation, carbonyl reduction, and acidic hydrolysis, a phenol derivative is obtained. The phenolic hydroxyl group in the phenol derivative is protected with tert-butyldimethylsilyl chloride (TBDMSCl). In the presence of n-butyl lithium (n-BuLi), the phenol derivative undergoes nucleophilic addition with sugars, followed by methyl etherification, and reduction with the Et3SiH / BF3·Et2O system to eliminate the hydroxyl group on the anomeric carbon. The phenol derivative then undergoes a nucleophilic substitution reaction with (R)-3-tetrahydrofuryl-p-toluenesulfonate to obtain the final product, empagliflozin. This process route is relatively long, and the total yield is only 12%. The simplified synthesis route is as follows:

[0005]

[0006] Patent applications numbered CN201710070415.X and CN201910535608.7 utilize (3S)-3-[4-[(2-halogeno-5-iodophenyl)methyl]phenoxy]tetrahydrofuran as the starting material. In the presence of n-butyl lithium, the product undergoes nucleophilic addition reaction with sugars, followed by methyl etherification and reduction using an Et3SiH / BF3·Et2O system to eliminate the hydroxyl group on the anomeric carbon, yielding the final product, empagliflozin. This process is shorter and yields higher than the original research process, but the key material, (3S)-3-[4-[(2-halogeno-5-iodophenyl)methyl]phenoxy]tetrahydrofuran, is difficult to obtain and is not suitable for industrial production. A simplified synthetic route is as follows:

[0007]

[0008] Therefore, there is an urgent need to optimize the existing preparation process of empagliflozin and explore a new preparation method to overcome the defects of the existing technology. Summary of the Invention

[0009] In view of this, one of the objects of the present invention is to provide a one-pot method for preparing empagliflozin, which directly uses 4-(5-bromo-2-chlorobenzyl)phenol as a raw material, and continuously undergoes nucleophilic addition reaction, methyl etherification, nucleophilic substitution reaction and reduction reaction in a reaction vessel to obtain crude empagliflozin. No intermediates need to be removed during the reaction process, and the method is suitable for large-scale production of empagliflozin.

[0010] To achieve the above object, the present invention adopts the following technical solutions:

[0011] The one-pot method for preparing empagliflozin comprises the following steps:

[0012] S1: 4-(5-bromo-2-chlorobenzyl)phenol and gluconolactone are used as raw materials, solvent 1 and a catalyst are added to react to obtain a hydroxyl protected product;

[0013] S2: Add a Grignard reagent to the hydroxyl protected product obtained in S1 to undergo a nucleophilic addition reaction, and methyl etherify to obtain a solution of compound I.

[0014] S3: Add (R)-3-tetrahydrofuryl p-toluenesulfonate to the solution of compound I obtained in S2 under alkaline conditions to undergo a nucleophilic substitution reaction to obtain a solution of compound II;

[0015] S4: Add Et3SiH / AlCl3 to the solution of compound II obtained in S3 to cause a reduction reaction to obtain a crude product of Engelhard;

[0016] The structural formulas of Compound I, Compound II, empagliflozin, and the hydroxyl-protected compound are shown in Formula I, Formula II, Formula III, and Formula IV, respectively. The preparation of the crude empagliflozin occurs in a single reaction vessel, and no intermediates need to be removed during the reaction.

[0017]

[0018] The invention uses 4-(5-bromo-2-chlorobenzyl)phenol as a starting material, undergoes nucleophilic addition reaction with sugar under the action of a Grignard reagent, then undergoes methyl etherification, and then undergoes a nucleophilic substitution reaction with (R)-3-tetrahydrofuryl p-toluenesulfonate. Finally, an Et3SiH3 / AlCl3 system is used for reduction to eliminate the hydroxyl group on the anomeric carbon. During the reaction process, no intermediates need to be taken out, centrifugation and drying operations are avoided, centrifugation and drying equipment are reduced, and the production cycle is greatly shortened. The total yield of the product is increased from 12% in the original patent to 40%.

[0019] Furthermore, in S1, the solvent 1 is any one or more of dichloromethane, chloroform, and dichloroethane.

[0020] Preferably, the solvent 1 is dichloromethane. Dichloromethane as a solvent can improve product quality and yield, and is cheap and readily available.

[0021] Furthermore, in S1, the molar ratio of the 4-(5-bromo-2-chlorobenzyl)phenol, the gluconolactone and the catalyst is 1:1-2:0.01-0.5; and the catalyst is any one or more of iodine, sodium iodide and potassium iodide.

[0022] Preferably, the catalyst is iodine, which has the best solubility in the solvent and significantly shortens the reaction time.

[0023] Furthermore, in S2, the Grignard reagent is any one or more of n-butyllithium solution, isopropylmagnesium chloride, and tert-butyllithium; and the molar ratio of the 4-(5-bromo-2-chlorobenzyl)phenol to the Grignard reagent is 1:1.0-1.5.

[0024] Preferably, the Grignard reagent is isopropylmagnesium chloride.

[0025] Preferably, the molar ratio of the 4-(5-bromo-2-chlorobenzyl)phenol to the Grignard reagent is 1:1.1.

[0026] Furthermore, the reaction temperature of the nucleophilic addition reaction is -20°C to -50°C.

[0027] Furthermore, in S2, the Grignard exchange reaction solvent is any one or more of anhydrous ether and tetrahydrofuran.

[0028] Preferably, the Grignard exchange reaction solvent is tetrahydrofuran.

[0029] Furthermore, in S3, the base is any one or more of sodium methoxide, sodium ethoxide, and potassium tert-butoxide; and the molar ratio of the 4-(5-bromo-2-chlorobenzyl)phenol to the base is 1:1.5-2.0.

[0030] Preferably, the base is potassium tert-butoxide.

[0031] Preferably, the molar ratio of 4-(5-bromo-2-chlorobenzyl)phenol to the base is 1:1.6.

[0032] Further, in S4, the solution of compound II reacts with Et3SiH / AlCl3 under the action of solvent 2 and a reducing agent, wherein the solvent 2 is any one or more of dichloromethane, chloroform, and acetonitrile; and the reducing agent is any one or more of sodium borohydride, triethylsilane / aluminum trichloride system, and triethylsilane / boron trifluoride system.

[0033] Preferably, the reducing agent is a triethylsilane / boron trifluoride system, more preferably triethylsilane and boron trifluoride etherate.

[0034] Furthermore, the crude product of Engelijk is dissolved in a solvent at high temperature, filtered, cooled for crystallization, centrifuged, dried, and crushed to obtain the finished product of Engelijk.

[0035] Furthermore, the solvent is any one or more of ethanol, methanol, ethanol water, methanol water, toluene, and xylene.

[0036] Furthermore, the crude empagliflozin product was prepared in a glass-lined reaction tank; in the glass-lined reaction tank, the 4-(5-bromo-2-chlorobenzyl)phenol first underwent a nucleophilic addition reaction with the gluconolactone, and then methylated to obtain the compound I solution; the compound I solution underwent a nucleophilic substitution reaction with the (R)-3-tetrahydrofuran p-toluenesulfonate to obtain the compound II solution; the compound II solution was further added with the Et3SiH / AlCl3 to undergo a reduction reaction to obtain the crude empagliflozin product.

[0037] The beneficial effects of the present invention are:

[0038] 1. The preparation method of empagliflozin provided by the present invention directly uses 4-(5-bromo-2-chlorobenzyl)phenol as a raw material to prepare the crude empagliflozin in a one-pot process. During the reaction, it is not necessary to remove the intermediates, which reduces the purification and drying process of the intermediates, improves the yield, and shortens the manufacturing cycle.

[0039] 2. The process of the present invention has a single-step reaction solvent, which is easy to recycle and reuse.

[0040] 3. The process of the present invention requires less equipment, has lower equipment requirements, is simple to process and takes a short time, and is convenient for large-scale production.

[0041] 4. The product obtained by the process of the present invention has high purity and yield. The total yield of the product is increased from 12% of the original patent to 40%. The product purity is above 99.5%, which meets the requirements for medication. BRIEF DESCRIPTION OF THE DRAWINGS

[0042] Figure 1 is the reaction scheme of the present invention;

[0043] Figure 2 It is a production flow chart of the present invention. DETAILED DESCRIPTION

[0044] The technical solutions of the present invention will be further described in detail below with reference to specific embodiments. Obviously, the embodiments described are only some of the embodiments of the present invention, not all of them. Therefore, all other embodiments derived by those skilled in the art based on the embodiments of the present invention without inventive effort are intended to fall within the scope of protection of the present invention.

[0045] Example 1. One-pot preparation of crude Engelite

[0046] Add 29.8g of 4-(5-bromo-2-chlorobenzyl)phenol, 19.6g of glucose lactone, 500ml of dichloromethane, 2.6g of iodine, and 87.1g of hexamethyldisilazane to a three-necked flask. Reflux for 24-36h. Cool to 0-5°C, wash with a 1% aqueous sodium thiosulfate solution, and concentrate the dichloromethane to obtain a colorless to pale yellow oily liquid. Dilute with 300ml of tetrahydrofuran, cool to -40 to -50°C with stirring, and add 32.8g of isopropylmagnesium chloride and lithium chloride solution dropwise. Maintain the temperature at -40°C with stirring for 1h. Then raise the temperature to -10 to -20°C, add 25g of a 10% methanolic hydrogen chloride solution dropwise, and stir and react for 6-10h while maintaining the temperature below 0°C. After the reaction was completed, 15 g of sodium carbonate was added, the pH was adjusted to 7-8, the temperature was controlled below 30° C., and the mixture was concentrated under reduced pressure to obtain 110 g of a light yellow suspension of Compound I with a liquid phase purity of 90%.

[0047] Dilute 110g of Compound I suspension with 500ml of tetrahydrofuran to control the moisture content to below 0.5%. Add 26.6g of (R)-3-toluenesulfonic acid tetrahydrofuran ester, stir, and cool to -5 to 0°C. Add 123g of a 10% potassium tert-butoxide solution in tetrahydrofuran dropwise. After the addition is complete, warm to 30-40°C and stir for 3-5 hours. Distill under reduced pressure to constant weight to obtain a pale yellow solid. Add 300ml of dichloromethane and stir to dissolve. Wash the mixture twice with 100ml of water (2x), then wash once with 100ml of saturated brine. Control the moisture content of the organic phase to below 0.3% to obtain Compound II.

[0048] The dichloromethane organic phase of compound II was cooled to -10 to 0°C, 12 g of boron trifluoride etherate was added, and the mixture was stirred for 30 min. Triethylsilane was added dropwise. After the addition was complete, the mixture was stirred for 10 min at room temperature. 200 ml of water was added to quench the reaction. The dichloromethane was distilled under reduced pressure to precipitate a solid. Ethanol was added and stirred for 30 min. The filter cake was filtered, washed with ethanol, and dried to obtain 25 g of an off-white crude product of Engelhardt with a molar yield of 55% and a purity of 98.0%.

[0049] Example 2. One-pot preparation of crude Engelite

[0050] To a three-necked flask, add 29.8g of 4-(5-bromo-2-chlorobenzyl)phenol, 19.6g of glucose lactone, 500ml of dichloromethane, 2.6g of iodine, and 87.1g of hexamethyldisilazane. Reflux for 24-36h. Cool to 0-5°C, wash with a 1% aqueous sodium thiosulfate solution, and concentrate the dichloromethane to obtain a colorless to pale yellow oily liquid. Dilute with 500ml of anhydrous ether, cool to -60 to -70°C with stirring, and add 32g of a 20% n-butyllithium solution dropwise. Maintain at -60°C with stirring for 1h. Then, warm to -10 to -20°C, add 100ml of a 1% aqueous ammonium chloride solution dropwise to quench the reaction. Concentrate the ether layer by layer to obtain a yellow oily substance. Add 200ml of methanol, cool to 0-5°C, and add 25g of a 10% methanolic hydrogen chloride solution dropwise. Stir and react at below 0°C for 6-10h. After the reaction is complete, add 15g of sodium carbonate, adjust the pH to 7-8, filter, and add 23g of (R)-3-tetrahydrofuryl toluenesulfonate to the liquid. Stir and cool to -5 to 0°C. Add 18g of 30% sodium methoxide solution dropwise. Maintain stirring for 3-5 hours, and distill under reduced pressure to constant weight to obtain a pale yellow solid. Add 300ml of dichloromethane and stir to dissolve. Add 100ml of water*2 and wash the mixture twice, then wash once with 100ml of saturated brine. The organic phase moisture content is controlled to below 0.3%, yielding Compound II.

[0051] The dichloromethane organic phase of compound II was cooled to -10 to 0°C, 12 g of boron trifluoride etherate was added, and the mixture was stirred for 30 min. Triethylsilane was added dropwise. After the addition was complete, the mixture was stirred for 10 min at room temperature. 200 ml of water was added to quench the reaction. Dichloromethane was distilled under reduced pressure to precipitate a solid. Ethanol was added and stirred for 30 min. The filter cake was filtered, washed with ethanol, and dried to obtain 23 g of an off-white crude product of Engelhardt with a molar yield of 50.9% and a purity of 95.0%.

[0052] Example 3. Preparation of Ngoli finished product

[0053] The crude product of Engelijk was prepared by the method of Example 1. 20 g of the crude product of Engelijk was added to a reaction flask, 80 g of ethanol was added, the temperature was raised to 70 ° C for dissolution, and then the temperature was lowered to 50 ° C to precipitate a solid. The mixture was stirred for 1 h, then cooled to 10-20 ° C, filtered, and the filter cake was washed with ethanol and dried to obtain 16.1 g of a white solid with a purity of 99.8%.

[0054] Example 4. Preparation of Engelite Finished Product

[0055] The crude product of Engelijk was prepared by the method of Example 1. 20 g of the crude product of Engelijk was added to a reaction flask, 80 g of ethanol was added, the temperature was raised to 70 ° C for dissolution, and then the temperature was lowered to 50 ° C to precipitate a solid. The mixture was stirred for 1 h, then cooled to 10-20 ° C, 10 g of water was added dropwise, filtered, and the filter cake was washed with ethanol and dried to obtain 17.5 g of a white solid with a purity of 99.0%.

[0056] Example 5. Preparation of Ngoli Finished Product

[0057] The crude product of Engelijk was prepared by the method of Example 1. 20 g of the crude product of Engelijk was added to a reaction flask, 80 g of 95% ethanol was added, refluxed to dissolve the clear solution, and then cooled to precipitate the solid. The mixture was stirred for 1 h, then cooled to 10-20 ° C, filtered, and the filter cake was washed with 95% ethanol and dried to obtain 18.2 g of a white solid with a purity of 99.5%.

[0058] Example 6. Preparation of Ngoli Finished Product

[0059] The crude product of Engelijk was prepared by the method of Example 1. 20 g of the crude product of Engelijk was added to a reaction flask, 80 g of toluene was added, refluxed to dissolve the clear solution, and then cooled to precipitate a solid. The mixture was stirred for 1 h, then cooled to 10-20 ° C, filtered, and the filter cake was washed with toluene and dried to obtain 17.9 g of a white solid with a purity of 98.8%.

Claims

1. A one-pot method for preparing empagliflozin, characterized in that: The following steps are involved: (1) Add 29.8g of 4-(5-bromo-2-chlorobenzyl)phenol to a three-necked flask. 19.6 g of glucose lactone, 500 ml of dichloromethane, 2.6 g of iodine, and 87.1 g of hexamethyldisilazane were refluxed for 24-36 h, cooled to 0-5 ° C, washed with a 1% sodium thiosulfate aqueous solution, and the dichloromethane was concentrated to obtain a colorless to light yellow oily liquid; 300 ml of tetrahydrofuran was added to dilute, and the temperature was stirred and cooled to -40 to -50 ° C. 32.8 g of isopropylmagnesium chloride and lithium chloride solution was added dropwise, and the temperature was kept at -40 ° C and stirred for 1 h; then the temperature was raised to -10 to -20 ° C, 25 g of 10% methanolic hydrogen chloride solution was added dropwise, and the temperature was kept below 0 ° C and stirred for 6-10 h; after the reaction was completed, 15 g of sodium carbonate was added, the pH was adjusted to 7-8, and the temperature was kept below 30 ° C and concentrated under reduced pressure to obtain a light yellow suspension of Compound I; (2) Dilute 110 g of compound I suspension with 500 ml of tetrahydrofuran, control the water content to below 0.5%, add 26.6 g of (R)-3-toluenesulfonic acid tetrahydrofuran ester, stir and cool to -5 to 0 ° C, add 123 g of 10% potassium tert-butoxide tetrahydrofuran solution dropwise, raise the temperature to 30-40 ° C after the addition is complete, keep stirring for 3-5 hours, and distill under reduced pressure to constant weight to obtain a light yellow solid; add 300 ml of dichloromethane and stir to dissolve, add 100 ml of water * 2, wash and layer twice, and then wash once with 100 ml of saturated brine; control the moisture content of the organic phase to below 0.3% to obtain the organic phase of compound II; (3) The dichloromethane organic phase of compound II was cooled to -10 to 0°C, 12 g of boron trifluoride ether was added, and the mixture was stirred for 30 min. Triethylsilane was added dropwise, and after the addition was complete, the mixture was kept warm and stirred for 10 min. 200 ml of water was added to quench the reaction, and the dichloromethane was distilled under reduced pressure to precipitate a solid. Ethanol was added and stirred for 30 min. The filter cake was washed with ethanol and dried to obtain an off-white crude product of Engelijk. Or the method comprises the following steps: 1) Add 29.8g of 4-(5-bromo-2-chlorobenzyl)phenol to a three-necked flask. 19.6g glucose lactone, 500ml dichloromethane, 2.6g iodine, 87.1g hexamethyldisilazane, reflux reaction for 24-36h, cool to 0-5℃, wash with 1% sodium thiosulfate aqueous solution, concentrate dichloromethane to obtain a colorless to light yellow oily liquid; add 500ml anhydrous ether to dilute, stir and cool to -60 to -70℃, add 32g 20% n-butyl lithium solution, -60 ° C, stirring for 1 hour; then warm to -10 to -20 ° C, add 100 ml of 1% ammonium chloride aqueous solution dropwise to quench the reaction, and concentrate the ether layer by layer to obtain a yellow oil; add 200 ml of methanol, cool to 0-5 ° C, add 25 g of 10% hydrogen chloride methanol solution dropwise, control the temperature below 0 ° C, and stir for 6-10 hours; after the reaction is completed, add 15 g of sodium carbonate, adjust the pH to 7-8, filter, add 23 g of (R)-3-tetrahydrofuran toluenesulfonate to the feed solution, stir and cool to -5 to 0 ° C, add 18 g of 30% sodium methoxide solution dropwise, stir for 3-5 hours, and distill under reduced pressure to constant weight to obtain a light yellow solid; add 300 ml of dichloromethane and stir to dissolve, add 100 ml of water * 2, wash the layer twice, and then wash once with 100 ml of saturated brine; the moisture content of the organic phase is controlled below 0.3% to obtain the organic phase of compound II; 2) Cool the dichloromethane organic phase of Compound II to -10 to 0°C, add 12g of boron trifluoride etherate, stir for 30 minutes, add triethylsilane dropwise, and after the addition is complete, stir for 10 minutes at this temperature. Add 200ml of water to quench the reaction, dichloromethane is distilled under reduced pressure to precipitate a solid, add ethanol and stir for 30 minutes, filter, wash the filter cake with ethanol, and dry to obtain an off-white crude product of Engelijk. The structural formulas of Compound I, Compound II, Empagliflozin, and the hydroxyl-protected compound are shown in Formula I, Formula II, Formula III, and Formula IV, respectively. The preparation of the crude Empagliflozin occurs in a single reaction vessel, and no intermediates need to be removed during the reaction.

2. The method according to claim 1, characterized in that The crude product of Engelijk is dissolved in solvent 3 at high temperature, filtered, cooled for crystallization, centrifuged, dried, and crushed to obtain the finished product of Engelijk; the solvent 3 is any one or more of ethanol, methanol, ethanol water, methanol water, toluene, and xylene.

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