A method for selectively synthesizing an empagliflozin intermediate

Abstract

The present invention discloses a method for selectively synthesizing an empagliflozin intermediate. By selectively hydrogenating and reducing gluconolactone to chiral hemiacetal, and then directly performing a dehydroxy arylation coupling reaction with an aryl halide compound under the action of a catalyst to obtain an intermediate compound Ⅳ of empagliflozin. The beneficial effects of the present invention are as follows: Through the selective synthesis of chiral hemiacetal and the direct dehydroxy arylation coupling reaction, the selectivity of the gluconolactone connection reaction is effectively increased, the reaction steps of the overall route are reduced, and the generation of reaction by-products can be effectively reduced; in addition, the synthesis method of the present invention is simple to operate, the product is easy to process, the product yield and purity are relatively high, the raw materials are easily available, and it is suitable for industrial scale-up production.

Description

Technical Field

[0001] The present invention relates to the technical field of the synthesis of pharmaceutical intermediates, and in particular to a method for selectively synthesizing an empagliflozin intermediate. Background Art

[0002] Empagliflozin (EBI-10773), CAS No.: [864070-43-9], Chinese chemical name: (1S)-1,5-anhydro-1-C-[4-chloro-3-[[4-[[(3S)-tetrahydrofuran-3-yl]oxy]phenyl]methyl]phenyl]-D-glucitol, is jointly developed by Boehringer Ingelheim and Eli Lilly and Company, and obtained the certification of the US Food and Drug Administration (FDA) in August 2014. It is the third new diabetes treatment drug with a new mechanism of inhibiting SGLT2 after the FDA approved canagliflozin (Invokana) of Johnson & Johnson Pharmaceutical Company on March 29, 2013 and dapagliflozin (Farxiga) of AstraZeneca on January 8, 2014. The empagliflozin preparation is a film-coated tablet, with specifications of 10 mg and 25 mg, and the trade name is: Jardiance.

[0003] The molecular structural formula of empagliflozin is shown in Formula I:

[0004]

[0005] Currently, a key step in the synthesis of empagliflozin according to the synthetic route published in the literature lies in the coupling of gluconolactone and a haloaromatic intermediate compound. Currently, the main synthetic methods for the coupling of gluconolactone and haloaromatic compounds in the method for synthesizing empagliflozin are as follows:

[0006] Route 1 (The preparation method of empagliflozin and its key intermediates was publicly reported in PCT patent WO2006120208A)

[0007]

[0008] Currently, most domestic and foreign patents and literature have adopted a method similar to this route. However, the overall route of this method is too long and the process cost is relatively high. This route involves the coupling of the key intermediate (S)-3-(4-(5-bromo-2-chlorobenzyl)phenoxy)tetrahydrofuran and gluconolactone under the action of n-butyllithium (n-BuLi), followed by nucleophilic addition to the sugar, then methylation, reduction and elimination of the hydroxyl group on the anomeric carbon using the Et3SiH / BF3·Et2O system, and finally nucleophilic substitution reaction with (R)-3-tetrahydrofuran tosylate to obtain the final product empagliflozin. The addition reaction of the key intermediate and TMS-protected gluconolactone requires strict low temperature and has a low yield. The stereoselectivity of this reaction is poor. In subsequent reactions, the product needs to be purified by introducing protecting groups such as acetyl groups to improve the crystallinity of the product, which adds additional process steps; the Grignard addition product needs to be reduced with triethylsilane to eliminate the methoxy group at the benzyl position, which further increases the reaction operation and processing difficulty.

[0009] Route Two (CN106905305B discloses a method for synthesizing empagliflozin and its key intermediate)

[0010]

[0011] (wherein, X is bromine or iodine, LG is chlorine, bromine, methanesulfonyloxy or p-toluenesulfonyloxy, and PG is acetyl, tert-butylcarbonyl or benzoyl)

[0012] This method couples the gluconolactone derivative 6 and the key intermediate (S)-3-(4-(5-bromo (iodo)-2-chlorobenzyl)phenoxy)tetrahydrofuran 5 through a format exchange reaction to obtain the protected empagliflozin intermediate compound 7. The compound is deprotected to obtain empagliflozin. In this route, compound 6 needs to be prepared in advance, which increases the reaction steps and makes the operation cumbersome.

[0013] Route Three (CN106117192B discloses a method for synthesizing empagliflozin)

[0014]

[0015] This route uses 2,3,4,6-tetra-O-benzyl-D-glucono-1,5-lactone and p-chloroiodobenzene as raw materials to prepare the intermediate (1-hydroxy-1-p-chlorophenyl-2,3,4,6-tetra-O-benzyl-D-glucopyranose). Then, triethylsilane and aluminum trichloride are used as reducing agents to remove the anomeric carbon. The synthetic route is relatively short, the materials used in the reaction are easily obtained, the intermediate is easy to purify, the whole reaction process is simple to operate, and it has a relatively high overall yield. Moreover, there is no need to use the Et3SiH / BF3·Et2O reduction system (BF3 is highly toxic), which is very beneficial to environmental protection and industrialization. However, there are still problems of insufficient selectivity and more by-products in the connection between gluconolactone and haloarene in this reaction route. Summary of the Invention

[0016] Aiming at the problems in the prior art that there are many reaction steps, poor reaction selectivity, many by-products resulting in low yield and insufficient product purity when synthesizing the coupling product of gluconolactone in the synthesis of empagliflozin, the present invention aims to provide a method for selectively synthesizing an empagliflozin intermediate. By selectively hydrogenating and reducing gluconolactone to chiral hemiacetal, when the reducing agent is DIBAL-H, due to steric hindrance, a larger group is inside during the reaction, and the hydroxyl group is a larger group relative to hydrogen, so the reaction will stereoselectively synthesize the required chiral isomer. Then, it undergoes a direct dehydroxyarylation coupling reaction with an aryl halide compound under the action of a catalyst to obtain an intermediate compound Ⅳ of empagliflozin. Through the selective synthesis of chiral hemiacetal and direct dehydroxyarylation coupling reaction, the selectivity of the reaction is effectively increased, the reaction steps are reduced, and the generation of reaction by-products is reduced. The synthesis method of the present invention is simple to operate, the product is easy to process, the product yield and purity are relatively high, the raw materials are easily obtained, and it is suitable for industrial scale-up production.

[0017] The present invention provides the following technical solutions: A method for selectively synthesizing an empagliflozin intermediate, and the synthetic route is as follows

[0018]

[0019] A method for selectively synthesizing an empagliflozin intermediate, comprising the following steps:

[0020] In the first step of the reaction, dissolve the gluconolactone with protected hydroxyl groups in a solvent, and selectively reduce it with a reducing agent under low-temperature conditions. After the reaction is completed, quench the reaction and separate the product to obtain the chiral alcohol product compound Ⅱ.

[0021] In the second step of the reaction, dissolve the chiral alcohol compound Ⅱ obtained in the first step of the reaction in an organic solvent, gradually add an electrolyte, triphenylphosphine, and a base reagent to the solution, then add the reactant Ⅲ, stir for 5 min, install an electrode, add the ligand solution of the catalyst, and stir the reactants under a constant current for 15 - 18 h, and separate the product to obtain the target intermediate product Ⅳ.

[0022] Furthermore, the reducing agent used in the first-step reaction is DIBAL-H (diisobutylaluminum hydride). Due to steric hindrance, during the reaction, the larger group is on the inside. Since the hydroxyl group is a larger group relative to hydrogen, the reaction will stereoselectively synthesize the desired chiral isomer. The molar ratio of the reducing agent to reactant I is 1:1. The reaction conditions are stirring at -78°C for 2 hours.

[0023] Furthermore, the solvent used in the first-step reaction is dichloromethane.

[0024] Furthermore, the solvent used in the second-step reaction is NMP (N-methylpyrrolidone).

[0025] Furthermore, the catalyst used in the second-step reaction is NiBr2•2dtbbpy. The amount of the catalyst is 7-15 mmol% of reactant II, preferably 10 mmol%.

[0026] Furthermore, the electrodes used in the second-step reaction are a graphite rod anode and a nickel foam cathode. The depth of the electrodes inserted into the reaction solution is 20-30 mm, preferably 25 mm.

[0027] Furthermore, the electrolyte used in the second-step reaction is lithium bromide. The base reagent used in the second-step reaction is one or more of DIPEA, TEA, and N,N'-tetramethylguanidine, preferably DIPEA.

[0028] Furthermore, the molar ratio of each substance in the second-step reaction is reactant II:reactant III:electrolyte:triphenylphosphine:base reagent = 1:2.5-3.5:0.8-1.2:6-8:1.0-1.5, preferably 1:3:1:7:1.2.

[0029] Furthermore, the constant current used in the second-step reaction is 4 mA.

[0030] Furthermore, the ligand chemical structure of the catalyst NiBr2•2dtbbpy is as follows

[0031] .

[0032] The beneficial effects of the present invention are as follows: Through the selective synthesis of chiral hemiacetals and the direct dehydroxylation arylation coupling reaction, the present invention effectively increases the selectivity of the gluconolactone linkage reaction, reduces the reaction steps of the overall route, and can effectively reduce the generation of reaction by-products. In addition, the synthesis method of the present invention is simple to operate, the product yield and purity are high, the raw materials are easily available, and it is suitable for industrial scale-up production. Description of the Drawings

[0033] Figure 1 It is the reaction route flow chart of the present invention;

[0034] Figure 2 It is the chemical structure schematic diagram of empagliflozin;

[0035] Figure 3 It is the chemical structure schematic diagram of the dtbbpy ligand of the present invention;

[0036] Figure 4 It is the reaction route flow chart of Route 1 of the present invention;

[0037] Figure 5 It is the reaction route flow chart of Route 2 of the present invention;

[0038] Figure 6 It is the reaction route flow chart of Route 3 of the present invention. Specific embodiments

[0039] Next, in combination with the embodiments of the present invention and the accompanying drawings, the technical solutions in the embodiments of the present invention will be clearly and completely described. Obviously, the described embodiments are only a part of the embodiments of the present invention, rather than all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those of ordinary skill in the art without making creative efforts belong to the scope of protection of the present invention.

[0040] Example 1

[0041] In the first step, under nitrogen protection, 5.94 g (0.01 mol) of the reactant Ⅰ protected by benzoyl was added to a three-necked flask, dissolved in 300 ml of dichloromethane, cooled to -78 °C, and 0.01 mol (1 mol / hexane solution) of diisobutylaluminum hydride in dichloromethane was gradually added dropwise. The reaction was carried out at low temperature for 2 h. After the reaction ended, the reaction solution was slowly added to dilute hydrochloric acid at about -10 °C for quenching, and the quenching temperature was kept not exceeding 5 °C. After quenching, the pH value was adjusted to about 6.5, allowed to stand for layering, the upper aqueous layer was extracted with dichloromethane twice, the organic layers were combined, washed successively with water and saturated brine, and the organic layer was evaporated to dryness under reduced pressure. While it was hot, toluene was added for recrystallization, filtered by suction, and dried to obtain 5.6 g of the product, with a yield of 94.3% and a purity of 97.2%

[0042] Step 2: Under nitrogen protection, take 5.96 g (0.01 mol) of the chiral alcohol compound II obtained from the first-step reaction and dissolve it in 150 ml of the organic solvent NMP (N-methylpyrrolidone). Gradually add 0.01 mol of electrolyte, 0.07 mol of triphenylphosphine, 0.012 mol of DIPEA to the solution, then add 0.03 mol of reactant III, and stir for 5 min. Install a graphite rod anode and a nickel foam cathode and insert them 25 mm into the liquid surface. Add 0.001 mol of the catalyst NiBr2•2dtbbpy. Stir the reactants at a constant current of 4 mA for 15 - 18 h. After the reaction is completed, wash the electrodes with 50 ml of NMP. Remove the solvent from the reaction solution under reduced pressure to recover NMP. After the solvent removal is completed, add 300 ml of ethyl acetate and 200 ml of water, stir until completely dissolved, let it stand for layer separation. Extract the aqueous layer with 100 ml × 2 of ethyl acetate. Combine the organic layers and wash them once with 200 ml of water and 200 ml of saturated brine respectively. Evaporate the organic layer to dryness under reduced pressure. While it is hot, add isopropanol for recrystallization, filter by suction, and dry to obtain the target intermediate IV. The product weighs 6.20 g, the yield is 89.7%, and the purity is 96.8%.

[0043] Example 2

[0044] Step 2: Under nitrogen protection, take 5.96 g (0.01 mol) of the chiral alcohol compound II obtained from the first-step reaction and dissolve it in 150 ml of the organic solvent NMP (N-methylpyrrolidone). Gradually add 0.08 mol of electrolyte, 0.07 mol of triphenylphosphine, 0.012 mol of DIPEA to the solution, then add 0.03 mol of reactant III, and stir for 5 min. Install a graphite rod anode and a nickel foam cathode and insert them 25 mm into the liquid surface. Add 0.001 mol of the ligand solution of the catalyst NiBr2•2dtbbpy. Stir the reactants at a constant current of 4 mA for 15 - 18 h. After the reaction is completed, wash the electrodes with 50 ml of NMP. Remove the solvent from the reaction solution under reduced pressure to recover NMP. After the solvent removal is completed, add 300 ml of ethyl acetate and 200 ml of water, stir until completely dissolved, let it stand for layer separation. Extract the aqueous layer with 100 ml × 2 of ethyl acetate. Combine the organic layers and wash them once with 200 ml of water and 200 ml of saturated brine respectively. Evaporate the organic layer to dryness under reduced pressure. While it is hot, add isopropanol for recrystallization, filter by suction, and dry to obtain the target intermediate IV. The product weighs 6.11 g, the yield is 88.4%, and the purity is 96.0%.

[0045] Example 3

[0046] Step 2: Under nitrogen protection, take 5.96 g (0.01 mol) of the chiral alcohol compound II obtained from the first-step reaction and dissolve it in 150 ml of the organic solvent NMP (N-methylpyrrolidone). Gradually add 0.012 mol of electrolyte, 0.07 mol of triphenylphosphine, 0.012 mol of DIPEA to the solution, then add 0.03 mol of reactant III, stir for 5 min, install a graphite rod anode and a nickel foam cathode inserted 25 mm below the liquid surface, add 0.001 mol of the ligand solution NiBr2•2dtbbpy as the catalyst, stir the reactants at a constant current of 4 mA for 15 - 18 h. After the reaction is completed, wash the electrodes with 50 ml of NMP, remove the solvent from the reaction solution under reduced pressure to recover NMP. After the solvent removal is completed, add 300 ml of ethyl acetate and 200 ml of water, stir until completely dissolved, let it stand for layer separation. Extract the aqueous layer with 100 ml × 2 of ethyl acetate, combine the organic layers, wash them once with 200 ml of water and 200 ml of saturated brine respectively. Evaporate the organic layer to dryness under reduced pressure, add isopropanol for recrystallization while it is hot, filter by suction, and dry to obtain the target intermediate IV. The weight of the product is 6.10 g, the yield is 88.3%, and the purity is 96.2%.

[0047] Example 4

[0048] Step 2: Under nitrogen protection, take 5.96 g (0.01 mol) of the chiral alcohol compound II obtained from the first-step reaction and dissolve it in 150 ml of the organic solvent NMP (N-methylpyrrolidone). Gradually add 0.01 mol of electrolyte, 0.06 mol of triphenylphosphine, 0.012 mol of DIPEA to the solution, then add 0.03 mol of reactant III, stir for 5 min, install a graphite rod anode and a nickel foam cathode inserted 25 mm below the liquid surface, add 0.001 mol of the ligand solution NiBr2•2dtbbpy as the catalyst, stir the reactants at a constant current of 4 mA for 15 - 18 h. After the reaction is completed, wash the electrodes with 50 ml of NMP, remove the solvent from the reaction solution under reduced pressure to recover NMP. After the solvent removal is completed, add 300 ml of ethyl acetate and 200 ml of water, stir until completely dissolved, let it stand for layer separation. Extract the aqueous layer with 100 ml × 2 of ethyl acetate, combine the organic layers, wash them once with 200 ml of water and 200 ml of saturated brine respectively. Evaporate the organic layer to dryness under reduced pressure, add isopropanol for recrystallization while it is hot, filter by suction, and dry to obtain the target intermediate IV. The weight of the product is 5.80 g, the yield is 83.9%, and the purity is 96.3%.

[0049] Example 5

[0050] Step 2: Under nitrogen protection, take 5.96 g (0.01 mol) of the chiral alcohol compound II obtained from the first-step reaction and dissolve it in 150 ml of the organic solvent NMP (N-methylpyrrolidone). Gradually add 0.01 mol of electrolyte, 0.05 mol of triphenylphosphine, 0.012 mol of DIPEA to the solution, then add 0.03 mol of reactant III, stir for 5 min, install a graphite rod anode and a nickel foam cathode inserted 25 mm into the liquid surface, add 0.001 mol of the ligand solution NiBr2•2dtbbpy as the catalyst, stir the reactants at a constant current of 4 mA for 15 - 18 h. After the reaction is completed, elute the electrode with 50 ml of NMP, remove the solvent from the reaction solution under reduced pressure to recover NMP. After the solvent removal is completed, add 300 ml of ethyl acetate and 200 ml of water, stir until completely dissolved, let it stand for liquid separation. Extract the aqueous layer with 100 ml × 2 of ethyl acetate, combine the organic layers, wash them once with 200 ml of water and 200 ml of saturated brine in sequence. Concentrate the organic layer under reduced pressure to dryness, add isopropanol for recrystallization while it is hot, filter by suction, and dry to obtain the target intermediate IV. The weight of the product is 5.86 g, the yield is 84.7%, and the purity is 95.8%.

[0051] Example 6

[0052] Step 2: Under nitrogen protection, take 5.96 g (0.01 mol) of the chiral alcohol compound II obtained from the first-step reaction and dissolve it in 150 ml of the organic solvent NMP (N-methylpyrrolidone). Gradually add 0.01 mol of electrolyte, 0.07 mol of triphenylphosphine, 0.010 mol of DIPEA to the solution, then add 0.03 mol of reactant III, stir for 5 min, install a graphite rod anode and a nickel foam cathode inserted 25 mm into the liquid surface, add 0.001 mol of the ligand solution NiBr2•2dtbbpy as the catalyst, stir the reactants at a constant current of 4 mA for 15 - 18 h. After the reaction is completed, elute the electrode with 50 ml of NMP, remove the solvent from the reaction solution under reduced pressure to recover NMP. After the solvent removal is completed, add 300 ml of ethyl acetate and 200 ml of water, stir until completely dissolved, let it stand for liquid separation. Extract the aqueous layer with 100 ml × 2 of ethyl acetate, combine the organic layers, wash them once with 200 ml of water and 200 ml of saturated brine in sequence. Concentrate the organic layer under reduced pressure to dryness, add isopropanol for recrystallization while it is hot, filter by suction, and dry to obtain the target intermediate IV. The weight of the product is 6.05 g, the yield is 87.5%, and the purity is 95.7%.

[0053] Example 7

[0054] Step 2: Under nitrogen protection, take 5.96 g (0.01 mol) of the chiral alcohol compound II obtained from the first-step reaction and dissolve it in 150 ml of the organic solvent NMP (N-methylpyrrolidone). Gradually add 0.01 mol of electrolyte, 0.07 mol of triphenylphosphine, 0.015 mol of DIPEA to the solution, then add 0.03 mol of reactant III, stir for 5 min, install a graphite rod anode and a nickel foam cathode inserted 25 mm below the liquid surface, add 0.001 mol of the ligand solution NiBr2•2dtbbpy as the catalyst, stir the reactants at a constant current of 4 mA for 15 - 18 h. After the reaction is completed, wash the electrodes with 50 ml of NMP, remove the solvent from the reaction solution under reduced pressure to recover NMP. After the solvent removal is completed, add 300 ml of ethyl acetate and 200 ml of water, stir until completely dissolved, let it stand for layer separation. Extract the aqueous layer with 100 ml × 2 of ethyl acetate, combine the organic layers, wash them once with 200 ml of water and 200 ml of saturated brine in sequence. Evaporate the organic layer to dryness under reduced pressure, add isopropanol for recrystallization while it is hot, filter by suction, and dry to obtain the target intermediate IV. The product weighs 6.26 g, the yield is 90.5%, and the purity is 96.1%.

[0055] Example 8

[0056] Step 2: Under nitrogen protection, take 5.96 g (0.01 mol) of the chiral alcohol compound II obtained from the first-step reaction and dissolve it in 150 ml of the organic solvent NMP (N-methylpyrrolidone). Gradually add 0.01 mol of electrolyte, 0.07 mol of triphenylphosphine, 0.012 mol of DIPEA to the solution, then add 0.025 mol of reactant III, stir for 5 min, install a graphite rod anode and a nickel foam cathode inserted 25 mm below the liquid surface, add 0.001 mol of the ligand solution NiBr2•2dtbbpy as the catalyst, stir the reactants at a constant current of 4 mA for 15 - 18 h. After the reaction is completed, wash the electrodes with 50 ml of NMP, remove the solvent from the reaction solution under reduced pressure to recover NMP. After the solvent removal is completed, add 300 ml of ethyl acetate and 200 ml of water, stir until completely dissolved, let it stand for layer separation. Extract the aqueous layer with 100 ml × 2 of ethyl acetate, combine the organic layers, wash them once with 200 ml of water and 200 ml of saturated brine in sequence. Evaporate the organic layer to dryness under reduced pressure, add isopropanol for recrystallization while it is hot, filter by suction, and dry to obtain the target intermediate IV. The product weighs 6.14 g, the yield is 88.8%, and the purity is 96.5%.

[0057] Example 9

[0058] Step 2: Under nitrogen protection, take 5.96 g (0.01 mol) of the chiral alcohol compound II obtained from the first-step reaction and dissolve it in 150 ml of the organic solvent NMP (N-methylpyrrolidone). Gradually add 0.01 mol of electrolyte, 0.07 mol of triphenylphosphine, 0.012 mol of DIPEA to the solution, then add 0.035 mol of reactant III, stir for 5 min, install a graphite rod anode and a nickel foam cathode inserted 25 mm below the liquid surface, add 0.001 mol of the catalyst ligand solution NiBr2•2dtbbpy, stir the reactants at a constant current of 4 mA for 15 - 18 h. After the reaction is completed, wash the electrodes with 50 ml of NMP, remove the solvent from the reaction solution under reduced pressure to recover NMP. After the solvent removal is completed, add 300 ml of ethyl acetate and 200 ml of water, stir until completely dissolved, let it stand for layer separation. Extract the aqueous layer with 100 ml × 2 of ethyl acetate, combine the organic layers, wash them once with 200 ml of water and 200 ml of saturated brine in sequence. Evaporate the organic layer to dryness under reduced pressure, add isopropanol for recrystallization while it is hot, filter by suction, dry, to obtain the target intermediate IV. The product weighs 6.11 g, the yield is 88.4%, and the purity is 96.5%.

[0059] Example 10

[0060] Step 2: Under nitrogen protection, take 5.96 g (0.01 mol) of the chiral alcohol compound II obtained from the first-step reaction and dissolve it in 150 ml of the organic solvent NMP (N-methylpyrrolidone). Gradually add 0.01 mol of electrolyte, 0.07 mol of triphenylphosphine, 0.012 mol of TEA to the solution, then add 0.03 mol of reactant III, stir for 5 min, install a graphite rod anode and a nickel foam cathode inserted 25 mm below the liquid surface, add 0.001 mol of the catalyst NiBr2•2dtbbpy, stir the reactants at a constant current of 4 mA for 15 - 18 h. After the reaction is completed, wash the electrodes with 50 ml of NMP, remove the solvent from the reaction solution under reduced pressure to recover NMP. After the solvent removal is completed, add 300 ml of ethyl acetate and 200 ml of water, stir until completely dissolved, let it stand for layer separation. Extract the aqueous layer with 100 ml × 2 of ethyl acetate, combine the organic layers, wash them once with 200 ml of water and 200 ml of saturated brine in sequence. Evaporate the organic layer to dryness under reduced pressure, add isopropanol for recrystallization while it is hot, filter by suction, dry, to obtain the target intermediate IV. The product weighs 6.01 g, the yield is 87.0%, and the purity is 95.6%.

[0061] Examples of Comparative Document (CN106117192B)

[0062] Example 1 (Preparation of Intermediate II)

[0063] p-Chloroiodobenzene (12.8 g, 54 mmol) and a tetrahydrofuran-toluene mixed solvent (volume ratio 1:2, total amount 120 mL) were added to a 500 mL three-necked flask. It was cooled to -78 °C, and a 2.2 mol / L n-butyllithium hexane solution (36 mL, 80 mmol) was added dropwise. After stirring for 30 min, a mixed solution was obtained. Then, the mixed solution was slowly added dropwise to a toluene (120 mL) solution of 2,3,4,6-tetra-O-benzyl-D-glucopyranuronic acid-1,5-lactone (43.0 g, 80 mmol) pre-cooled to -78 °C. After stirring for 2 h, a saturated citric acid solution was added, the pH value was adjusted to 7.5, the temperature was raised to room temperature, and the reaction was continued with stirring for 5 h. After the reaction was completed, the organic phase of the system was separated, the aqueous phase was extracted with ethyl acetate (80 mL × 3 times), the organic phases were combined, washed with saturated brine (120 mL), dried over anhydrous sodium sulfate and filtered. The obtained filtrate was evaporated under reduced pressure to remove the solvent, and 40 g of a yellow viscous crude product was obtained. This crude product was dissolved in hot toluene, and then added dropwise to ice-cold n-hexane. After a pale yellow solid appeared, it was immediately filtered, washed several times with n-hexane, and dried to obtain 29.8 g of a pale yellow pure intermediate II, with a purity of 95% and a yield of 85%.

[0064] Example 2 (Preparation of Intermediate III)

[0065] Intermediate II (29.8 g, 49.3 mmol) was dissolved in a dichloromethane-acetonitrile mixed solvent (volume ratio 1:1, total amount 100 mL), cooled to -10 °C, triethylsilane (14 mL, 88 mmol) was added, and then aluminum trichloride (8.5 g, 64 mmol) was added in batches. After addition, the reaction was carried out at 0 °C for 3 h. After the reaction was completed, saturated sodium bicarbonate solution (80 mL) was added, the solvent was evaporated under reduced pressure, 80 mL of ethyl acetate and 80 mL of water were added to the obtained residue, and after stirring and standing, the organic phase was separated. The aqueous phase was extracted with ethyl acetate (80 mL × 2 times), the organic phases were combined, washed successively with water (120 mL) and saturated brine (120 mL), dried over anhydrous sodium sulfate and filtered. The obtained filtrate was evaporated under reduced pressure to remove the solvent, and the obtained residue was recrystallized from ethanol to obtain 25.1 g of intermediate III, with a purity of 96% and a yield of 80%.

[0066] As can be seen from the above, the technical solution of the present invention has higher selectivity and yield compared with the prior art. The technical solution of the present invention shortens the reaction steps of the overall synthesis route of empagliflozin, and can effectively reduce the generation of reaction by-products; in addition, the synthesis method of the present invention is simple to operate, the product yield and purity are relatively high, the raw materials are easily available, and it is suitable for industrial scale-up production.

[0067] For those skilled in the art, it is obvious that the present invention is not limited to the details of the above-described exemplary embodiments, and the present invention can be implemented in other specific forms without departing from the spirit or basic characteristics of the present invention. Therefore, in any aspect, the embodiments should be regarded as exemplary and non-limiting. The scope of the present invention is defined by the appended claims rather than the above description. Therefore, all changes falling within the meaning and scope of the equivalent elements of the claims are intended to be embraced within the present invention. Any reference signs in the claims should not be construed as limiting the claims involved.

[0068] In addition, it should be understood that although this specification is described in terms of embodiments, not every embodiment only contains an independent technical solution. This narrative manner of the specification is only for clarity. Those skilled in the art should regard the specification as a whole, and the technical solutions in each embodiment can also be appropriately combined to form other embodiments that can be understood by those skilled in the art.

Claims

1. A method for the selective synthesis of an empagliflozin intermediate, characterized in that, It includes the following steps: The first-step reaction: Dissolve the glucuronic acid lactone Ⅰ with the hydroxyl group protected by a protecting group in a solvent, and selectively reduce it with a reducing agent under low-temperature conditions. After the reaction ends, quench the reaction and separate the product to obtain the chiral alcohol product compound Ⅱ; The second-step reaction: Dissolve the chiral alcohol compound Ⅱ obtained from the first-step reaction in an organic solvent, gradually add an electrolyte, triphenylphosphine, and a base reagent to the solution, then add the reactant Ⅲ, stir for 5 min, install electrodes, add the ligand solution of the catalyst, and stir the reactants under a constant current for 15 - 18 h. Separate the product to obtain the target intermediate product Ⅳ; The reducing agent used in the first-step reaction is DIBAL-H (diisobutylaluminum hydride), the molar ratio of the amount of the reducing agent to the amount of the glucuronic acid lactone Ⅰ with the hydroxyl group protected by a protecting group is 1:1, and the reaction conditions of the reaction are stirring and reacting at -78 °C for 2 h; The solvent used in the second-step reaction is NMP (N-methylpyrrolidone); The catalyst used in the second-step reaction is NiBr2•2dtbbpy; The electrolyte used in the second-step reaction is lithium bromide, and the base reagent used in the second-step reaction is one or more of DIPEA, TEA, and N,N'-tetramethylguanidine.

2. The method for the selective synthesis of an empagliflozin intermediate according to claim 1, characterized in that: The solvent used in the first-step reaction is dichloromethane.

3. The method for the selective synthesis of an empagliflozin intermediate according to claim 1, characterized in that: The electrodes used in the second-step reaction are a graphite rod anode and a nickel foam cathode, and the depth of the electrodes inserted into the reaction solution is 20 - 30 mm.

4. The method for the selective synthesis of an empagliflozin intermediate according to claim 1, characterized in that: The molar ratio of each substance in the second-step reaction is compound Ⅱ: reactant Ⅲ: electrolyte: triphenylphosphine: base reagent = 1:2.5 - 3.5:0.8 - 1.2:6 - 8:1.0 - 1.

5.

5. The method for the selective synthesis of an empagliflozin intermediate according to claim 1, characterized in that: The constant current used in the second-step reaction is 4 mA.

6. The method for the selective synthesis of an empagliflozin intermediate according to claim 1, characterized in that: The chemical structure of the ligand of the catalyst NiBr2•2dtbbpy is as follows 。

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