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CAS No. :1279691-36-9 MDL No. :MFCD28124344
Formula : C24H29ClO8 Boiling Point : -
Linear Structure Formula :- InChI Key :YIVKIDWTTVMRBY-JZTXWIGVSA-N
M.W : 480.94 Pubchem ID :51356674
Synonyms :

Safety of [ 1279691-36-9 ]

Signal Word:Warning Class:N/A
Precautionary Statements:P264-P270-P301+P312-P330 UN#:N/A
Hazard Statements:H302 Packing Group:N/A
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Application In Synthesis of [ 1279691-36-9 ]

* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.

  • Downstream synthetic route of [ 1279691-36-9 ]

[ 1279691-36-9 ] Synthesis Path-Downstream   1~16

  • 1
  • [ 1279691-36-9 ]
  • [ 864070-44-0 ]
YieldReaction ConditionsOperation in experiment
82.5% With triethylsilane; Aluminum Chloride In dichloromethane; acetonitrile 3 (2S,3R,4S,5R,6R)-2-(4-chloro-3- (4-(((S) -tetrahydrofuran-3-yl)oxy)benzyl)phenyl)-6- (hydroxymethyl) tetrahydro-2H-pyran-3,4,5-triol Add acetonitrile: dichloromethane (1: 1,200mL by volume) to a 1L dry reaction flask.Stir down to 0 10 , then add 42g in orderAluminum trichloride and 32.5gTriethylsilane,The reaction was stirred for 30 min.50g(2S, 3R, 4S, 5R, 6R) -2- (4-chloro-3- (4-(((S) -tetrahydrofuran-3-yl) oxy) benzyl) phenyl) -6- (hydroxymethyl ) 2-methoxytetrahydro-2H-pyran-3,4,5-triol in acetonitrile: dichloromethane(Volume ratio 1: 1, 200 mL) The solution was dropped into the above reaction system, and the dropping was completed in 1 to 2 hours;The temperature was controlled at 20 to 30 ° C and the reaction was stirred for 1 to 2 hours. Add 400mL of water,The organic solvent was distilled off under reduced pressure, and the reaction solution was extracted with 200 mL × 2 ethyl acetate.The organic phases were combined, washed once with saturated brine, and concentrated under reduced pressure to give a pale yellow oil.Purity 90.5%.Add 50 mL of ethyl acetate to the concentrate, turn on the stirring, and lower the temperature to -40 ° C to -50 ° C.After precipitation of a large amount of white solid, stirred for 0.5 h, and 250 mL of n-heptane was added dropwise to the reaction.Stir for 0.5h, filter with suction, and place the filter cake in a hot air circulation drying box for 15h.38.7 g of the title compound was obtained, with a molar yield of 82.5% and a purity of 98.3%.
78% With triethylsilane; Aluminum Chloride In dichloromethane; acetonitrile at -5 - 10℃; for 2h; Large scale; 7 Example 7 Preparation of Empagliflozin (VII) 1-Chloro-4-(1-methoxy-D-glucopyranos-1-yl)-2-(4-(S)-tetrahydrofuran-3-yloxy-benzyl)-benzene (100 kg) was used.Dichloromethane 100kg and300kg of acetonitrile was added to the 2000L reactor and stirred well; the reaction solution was cooled to -5 °C, 10kg anhydrous aluminum trichloride was added in batches, the temperature was controlled below -5 °C, stirring was continued for 30min after the addition was completed, and the temperature was kept constant 70kg Et3SiH was added, and the mixture was slowly heated up to 10°C and reacted for 2 hours. After the reaction was completed, the temperature was lowered to -5 °C. Saturated sodium bicarbonate solution was added dropwise, the pH was adjusted to 6-7, and extracted with ethyl acetate (200kgX2). The organic phase was washed successively with water and saturated sodium chloride solution to neutrality, then dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to recover ethyl acetate, and 400 kg of a mixed solution of methanol and dichloromethane (1:1) was added. Stirring, a large amount of solids precipitated, cooling and stirring for 1 h. The solid was filtered, washed with cold ethanol, and dried in vacuum at 50 °C. overnight to obtain 73 kg of a white solid with a yield of 78% and a purity of 99.32%.
78% Stage #1: (2S,3R,4S,5S,6R)-2-(4-chloro-3-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)-6-(hydroxymethyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triol With Aluminum Chloride In dichloromethane; acetonitrile at 5℃; for 0.5h; Large scale; Stage #2: With triethylsilane In dichloromethane; acetonitrile at 10℃; for 2h; Large scale; 7 Example 7 Preparation of Empagliflozin (VII) 1-Chloro-4-(1-methoxy-D-glucopyranosyl-1-yl)-2-(4-(S)-tetrahydrofuran-3-Methoxy-benzyl)-benzene100kg, 100kg of dichloromethane and 300kg of acetonitrile were added to the 2000L reactor and stirred evenly; the reaction solution was cooled. To -5 ° C, add 10 kg of anhydrous aluminum trichloride in batches, control the temperature below -5 degrees, continue to stir for 30 minutes after the addition, keep At this temperature, 70 kg of Et3SiH was added dropwise, and the temperature was slowly raised to 10 ° C for 2 h. After the reaction was completed, the temperature was lowered to -5 ° C, and the mixture was saturated. Sodium bicarbonate solution, adjusted to pH 6-7; extracted with ethyl acetate (200 kg × 2), the organic phase was dissolved with water and saturated sodium chloride. The solution is washed to neutrality, then dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure to recover ethyl acetate. A mixed solution of an alcohol and dichloromethane (1:1) was stirred, and a large amount of solid was precipitated, and the mixture was cooled and stirred for 1 hour. Filtration, cold ethanol washing The mixture was dried under vacuum at 50 ° C overnight to give a white solid (yield: 73 kg), yield 78%, purity 99.32%.
73% With triethylsilane In dichloromethane; acetonitrile at 20 - 30℃; for 1h; 5a Example 5a: Synthesis of the glucoside 11.1To a solution of the iodide V.1 (267kg) in tetrahydrofuran (429kg) is addedTurbogrignard solution (isopropylmagnesium chloride/lithium chloride solution, 14 weight-% iPrMgCI in THF, molar ratio LiCI : iPrMgCI = 0,9 - 1 .1 mol/mol) (472kg) at -21 to -15°C temperature within 1 hr 50 min. On completion of the addition the conversion is determined via HPLC analysis. The reaction is regarded as completed when the area of the peak corresponding to the iodide V.1 is smaller than 5,0% of the total area of both peaks, iodide V.1 and the corresponding desiodo compound of iodide V.1 . If the reaction is not completed, additional Turbogrignard solution is added until the criterion is met. In this particular case the result is 3,45%. Then the lactone IV.1 (320kg) is added at -25 to -18°C temperature within 1 hr 25 min. The resulting mixture is stirred for further 1 hr 30 min at -13 to -18°C. On completion of the addition the conversion is determined via HPLC analysis (for information). On completion, a solution of citric acid in water (938L; concentration: 10 %-weight) is added to the reaction mixture of a volume of about 2500L at -13 to 19°C within 1 hr 25 min. The solvent is partially distilled off from the reaction mixture (residual volume: 1816-1905L) at 20 to 30°C under reduced pressure and 2- methyltetrahydrofuran (532kg) is added. Then the stirrer is switched off and the phases are separated at 29°C. After phase separation the pH value of the organic phase is measured with a pH electrode (Mettler Toledo MT HA 405 DPA SC) or alternatively with pH indicator paper (such as pH-Fix 0-14, Macherey and Nagel). The measured pH value is 2 to 3. Then solvent is distilled off from the organic phase at 30 to 33°C under reduced pressure and methanol (1202kg) is added followed by the addition of a solution of 1 ,25N HCI in methanol (75kg) at 20°C (pH = 0). Full conversion to the acetale 111.1 is achieved by subsequent distillation at 20 to 32°C under reduced pressure and addition of methanol (409kg).Completion of the reaction is obtained when two criteria are fulfilled:1 ) The ratio of the sum of the HPLC-area of the alpha-form + beta-form of intermediate 111.1 relative to the area of intermediate llla.1 is greater or equal to 96,0% : 4,0%.2) The ratio of the HPLC-area of the alpha-form of intermediate 111.1 to the beta-form of 111.1 is greater or equal to 97,0% to 3,0%.In this particular case both criteria are met. Triethylamin (14kg) is added (pH = 7,4) and solvent is distilled off under reduced pressure, acetonitrile (835kg) is added and further distilled under reduced pressure. This procedure is repeated (addition of acetonitrile: 694kg) and methylene chloride (640kg) is added to the resulting mixture to yield a mixture of the acetale 111.1 in acetonitrile and methylene chloride. The water content of the mixture is determined via Karl Fischer titration (result: 0,27%). The reaction mixture is then added within 1 hr 40 min at 10 to 19°C to a preformed mixture of AICI3 (176kg), methylene chloride (474kg), acetonitrile (340kg), and triethylsilane (205kg). The resulting mixture is stirred at 18 to 20°C for 70 min. After completion of the reaction, water (1263L) is added at 20 to 30°C within 1 hr 30 min and the mixture is partially distilled at 30 to 53°C under atmospheric pressure and the phases are separated. Toluene (698kg) is added to the organic phase and solvent is distilled off under reduced pressure at 22 to 33°C. The product is then crystallized by addition of seeding crystals (0,5kg) at 31 °C and water (267kg) added after cooling to 20°C. The reaction mixture is cooled to 5°C within 55 min and stirred at 3 to 5°C for 12 hrs. Finally the product is collected on a centrifuge as colourless, crystalline solid, washed with toluene (348kg) and dried at 22 to 58°C. 21 1 kg (73%) of product are obtained. The identity of the product is determined via the HPLC retention time.
71% Stage #1: (2S,3R,4S,5S,6R)-2-(4-chloro-3-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)-6-(hydroxymethyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triol With Aluminum Chloride In dichloromethane; acetonitrile at -5℃; for 0.5h; Large scale; Stage #2: With triethylsilane at -5℃; for 2h; Large scale; 8 Example 8 Preparation of Empagliflozin (VIII) Take 1-chloro-4-(1-methoxy-D-glucopyranose-1-yl)-2-(4-(S)-tetrahydrofuran-3-yloxy-benzylBase) - Benzene 208kg,150kg of methylene chloride and 450kg of acetonitrile were added to the 3000L reactor.Stir well;Cool the reaction solution to -5°C, add 15kg anhydrous aluminum trichloride, stir for 30min,125kg of Et3SiH was added dropwise at this temperature.Slowly warm to 10°C and react for 2h. After the reaction is completed, cool down to -5°C and add saturated sodium bicarbonate solution dropwise.Adjust the pH to 6-7.Extract with ethyl acetate (300kg×2) and the organic phase isSaturated sodium chloride solution is washed to neutrality,Then it was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to recover ethyl acetate.400 kg of a mixed solution of methanol and dichloromethane (1:1) is added,With stirring, a large amount of solids precipitated, and the mixture was cooled and stirred for 1 hour. filter,Wash the solid with cold ethanol and vacuum dry at 30°C overnight.White solid 138 kg, yield 71%. Purity 99.32%.
70.8% With triethylsilane; boron trifluoride diethyl ether complex In dichloromethane; acetonitrile at -20 - 0℃; 5 Example 5 To 100mL three-necked flask was added 4.57g of intermediate -3,20ml methylene chloride, 15ml of acetonitrile, stirred to dissolve, cooled to -15 to -20 deg.] C, was added 5.80g of triethylsilane was added dropwise 9.72g three boron bromide in ether dropwise at a rate that the reaction temperature was kept around -10 deg.] C, then warmed to completion of the dropwise addition -5 -0 insulation mixing the reaction, the HPLC monitoring of the reaction is complete, add saturated sodium bicarbonate ph adjusted to about 7, Save pressure distillation, liquor added ethyl acetate, dried over anhydrous sodium sulfate to afford 3.03g Yipa column net yield of 70.8%.
67% With triethylsilane; Aluminum Chloride In dichloromethane; acetonitrile at 20 - 25℃; for 0.5h;
65% Stage #1: (2S,3R,4S,5S,6R)-2-(4-chloro-3-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)-6-(hydroxymethyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triol With triethylsilane In dichloromethane; acetonitrile at -20 - -10℃; for 0.5h; Inert atmosphere; Large scale; Stage #2: With boron trifluoride diethyl ether complex In dichloromethane; acetonitrile at -20 - -10℃; for 2h; Large scale; 4 Example 4 Preparation of Compound 5 Compound 4 (4.18 kg) was dissolved in dichloromethane (22.2 kg)To join the 100L reactor,Acetonitrile (26.3 kg) was added,Stir and nitrogen protection.Cooling below -20 .Temperature control -20 ~ -10 ,Triethylsilane (2.53 kg) was added dropwise.Drop finished,Temperature control -20 ~ -10 ,Stir for 30 minutes.Temperature control -20 ~ -10 ,Samples of boron trifluoride ether (2.63 kg) were slowly added dropwise.Drop finished,Temperature control -20 ~ -10 ,Stir for 2 hours.sampling,HPLC detection.When the compound 4? 1.0%As the reaction is complete.Reaction finished,Temperature control below 0 ,A 10% sodium bicarbonate solution (20 kg) was added dropwise.Plus,And the mixture was stirred at room temperature for 15 minutes.The dichloromethane and acetonitrile were removed by distillation under reduced pressure.No distillate out, stop the distillation,Precipitate a large number of white solid (product)Isopropyl acetate (18.2 kg) and water (18.2 kg) were added (crystallization).Cooling to 15 ~ 20 ,Stirring crystallization 12 hours or more.The quenched reaction system was filtered,Rinse with purified water (20 kg)Filter dry.Collecting filter cake,Dried at 55 to 60 ° C for 8 hours under vacuum,The crude compound of compound 5 was about 3.28 kg.The crude compound of the above compound 5 was charged into a 100 L reactor,Then add methylene chloride (62.2kg) reflux and beaten for 30 minutes.Cooling to 10 ~ 15 ,Stir crystallization for 2 hours.filter,Washed with dichloromethane (5 kg)Filter dry.Dried at 55 to 60 ° C for 8 hours under vacuum,To give compound 5 about 2.36 kg,Sampling detection,HPLC ≥ 97.0%.The product yield of this example was 55-65%.
63% With triethylsilane; Aluminum Chloride In dichloromethane; acetonitrile at 20 - 25℃; for 2.25h; (2S,3R,4R,5S,6R)-2-(4-Chloro-3-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (1) To a stirred slurry of AlCl3 (182.1 g, 1.37 mol based on compound 16) in DCM(350 mL) was slowly added acetonitrile (150 mL, Caution Severe heat evolution duringacetonitrile addition), keeping the internal temperature below 10 C. The mixture wasstirred for 30 min and the AlCl3 dissolved, followed by the addition of Et3SiH (95.3 g,819.4 mmol). The previously prepared solution of 18 (see above) was added to the solutionover 15 min, and the resulting mixture was stirred at 20-25 C for 2 hours. Themixture was cooled to 0-5 C and quenched by slow addition into water (600 mL). Themixture was concentrated to remove the organic solvents. Isopropyl acetate (400 mL)and water (500 mL) were added and then gradually cooled to 20-25 C for an additional5 hours, the solids were collected by filtration, and washed with isopropyl acetate(100 mL). Crude 1 was not dried and was directly recrystallized from ethanol(1000 mL), the mother liquor being reserved for the isolation of compound 9. The filtercake was washed with cool ethanol and vacuum dried to give 1 (157.4 g, yield 63%, purity99.8%, based on compound 16). 1H NMR (600 MHz, DMSO-d6) d (ppm): 7.38 (d,J8.4 Hz, 1H), 7.34 (d, J1.8 Hz, 1H), 7.24 (dd, J1 1.8 Hz, J2 8.4 Hz, 1H), 7.12 (d,J8.4 Hz, 2H), 6.83 (d, J9 Hz, 2H), 4.97 (m, 3H), 4.85 (s, 1H), 4.46 (s, 1H), 4.02-3.95(m, 3H), 3.87 (dd, J1 9.6 Hz, J2 14.4 Hz, 1H), 3.80 (dd, J1 8.4 Hz, J2 15.6 Hz,1H), 3.75-3.69 (m, 3H), 3.45 (q, J6 Hz, 2H), 3.29-3.21 (m, 2H), 3.19-3.15 (m, 1H),3.13-3.09 (m, 1H), 2.22-2.16 (m, 1H), 1.95-1.91 (m, 1H). 13C NMR (150 MHz, CDCl3) d(ppm): 155.95, 140.16, 138.19, 132.38, 132.03, 131.29, 130.13, 129.14, 127.86, 115.64,81.68, 81.15, 78.76, 77.41, 75.17, 72.75, 70.75, 66.86, 61.81, 38.08, 32.91; HRMS (ESI)calcd for C23H27ClO7Na: [MNa] 473.1338, found m/z 473.1346.
60% Stage #1: (2S,3R,4S,5S,6R)-2-(4-chloro-3-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)-6-(hydroxymethyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triol With Aluminum Chloride In dichloromethane; acetonitrile at 0 - 10℃; Inert atmosphere; Stage #2: With triethylsilane In dichloromethane; acetonitrile at 0 - 25℃; Inert atmosphere; 1 Example 1: Preparation of Empagliflozin (compound I) In a dry RBF (round bottom flask) under inert atmosphere, 300 ml of toluene, 100 g (1.0 eq.) of (3S)-3-[4-[(2-Chloro-5-iodophenyl)methyl]phenoxy]-tetrahydrofuran (compound III) were charged at room temperature (RT) and stirred for 20 to 30 min. 135. lg (1.2 eq.) of 2, 3, 4, 6-tetrakis-O-trimethylsilyl-D-glucono- 1,5-lactone (compound II) and 300 ml of tetrahydrofuran were charged at 20°C to 40°C. The reaction mixture was cooled to -80°C to -60°C. 6 ml (0.1 eq.) of boron trifluoride diethyl etherate was charged to the reaction mixture and 188.4 ml (1.25 eq.) of n-BuLi (1.6M in hexane) was added to the reaction mixture at -80°C to -60°C and further maintained for 1 to 2 hrs. The reaction completion for the absence of compound of formula (III) and formation of compound of formula (IV) was ensured by HPLC.To the above reaction mixture, methane sulfonic acid (MTSA) in methanol (3 V) was slowly added at -80°C to -40°C. Then the reaction mass was warmed to -5°C to 5°C and slowly added 2.0 V of methane sulfonic acid in methanol. The reaction mixture was warmed to 30°C to 40°C, maintained for about 6 to 8 hrs. The reaction completion for the formation of compound of formula (V) was ensured by HPLC. It was cooled to 0°C to 15°C, the pH was adjusted between 6.5 to 8.5 using 10% aq. sodium bicarbonate solution. The reaction mixture was concentrated till to arrive a minimum volume of reaction mixture and allowed it to 20°C to 40°C. The 1000 ml (10V) of dichloromethane (DCM) was charged in reaction mixture at room temperature. The aqueous and organic layers were separated. The aqueous layer was extracted with DCM and layers were separated. The combined organic layer was washed with brine and concentrated till to a minimum volume and cooled to room temperature.To the above reaction mixture, 330 ml (3.3 V) of acetonitrile was added. In second RBF, 140 ml (1.4V) of DCM was added at room temperature and cooled at 0°C to 10°C. Further, 67.54 g (2.1 eq.) of aluminum chloride in three equal lots were charged to the reaction mixture at 0°C to 10°C and stirred for 15 to 45 min. Then, to this reaction mixture, 160 ml (1.6V) of acetonitrile (lot-2) at 0°C tol0°C and stirred for 15 to 45 min. 78.49 g (2.8 eq.) of triethyl silane was added to the reaction mixture at 0°C tol0°C and stirred for 30 min. The reaction mixture was allowed to 10°C to 25 °C. To this reaction mixture (in second RBF), the reaction mixture from first RBF was added at 10°C to 25°C and maintained for 2 to 4 hrs. The reaction completion for the absence of compound of formula (V) was ensured by HPLC. 500 ml (5V) of water (lot 1) was added drop wise manner to the reaction mixture at 10°C to 35°C and maintained for 2 to 4 hrs. The solvent was distilled out till 9.5 to 10.5 volume. The upper organic layer was separated at about 40°C to 50°C. 700 ml (7V) of DCM was added in aqueous layer and stirred for 30 to 90 min. The lower organic layer was separated. The organic layers were combined and allowed at room temperature. It was stirred for solid formation and further maintained 3 to 4 hrs. at 0°C to 10°C. The solid was filtered and washed with DCM and suck dry for about 2 to 4 hrs. In RBF, the wet cake and 300 ml (3V) isopropyl alcohol (lot 1) were charged and stirred for about 3 to 4 hrs. The solid was filtered and washed with isopropyl alcohol (lot 2, 200 ml (2V)) and suck dried for 2 to 4 hrs. The wet cake was dried to obtain Empagliflozin (I) (yield - 65.24g, 60 %, purity by HPLC - 99.45%).
With triethylsilane; Aluminum Chloride In dichloromethane; acetonitrile 4 Example 4 (1S) -1,5-anhydro-1-C- [4-chloro-3- [[4 - [[(3S) -tetrahydro-3-furanyl] oxy] phenyl]Methyl] phenyl] -D-glucitol (5) 600.0 g of the compound (4) prepared in Example 3 was dissolved in 1.5 L of acetonitrile,1.5L methylene chloride mixed solvent spare. In a dry reaction kettle was added 1.5 L of acetonitrile,1.5 L dichloromethane,550.0 g of aluminum trichloride was added,445.0 g triethylsilane,The compound (4) solution of acetonitrile and methylene chloride was added dropwise to the above system,Stirring reaction,After completion of the HPLC monitoring reaction, 4.0 L of water was added,Stirring overnight, suction filtration, collecting cake,Obtained white solid (empagliflozin crude),HPLC detection,Purity 98.6%. (Agilent LC, column packed with octadecylsilane bonded silica gel,Using trifluoroacetic acid in water / acetonitrile as mobile phase gradient elution)
7.1 kg With triethylsilane; ferric(III) chloride In acetonitrile at 20℃; for 5h; Large scale; 9; 10 Example 9
Preparation of Compound Y: In an ice salt bath, ferric chloride (8.5 kg, 62 mol) was dissolved in 20 L of acetonitrile solvent.The mixture was stirred to dissolve, and triethylsilane (4.5 kg, 62 mol) and Intermediate II (10 kg, 21 mol) were sequentially added.The reaction was carried out for 5 hours at room temperature.The acetonitrile was concentrated under reduced pressure, and the residual reaction solution was poured into 100 L of cold water.Add 50 L of dichloromethane, extract the layers, and collect the organic layer.The aqueous phase was extracted once with 50 L of dichloromethane and the organic phases were combined.After concentration under reduced pressure to remove 2/3 volume of solvent, 20 L of ethyl acetate was added and stirred for 5 hours.Filtered, the filter cake was washed with 5 L of ethyl acetate and the filter cake was collected.Drying gave 7.1 kg of compound Y.
1.21 kg With triethylsilane; boron trifluoride diethyl ether complex In dichloromethane; acetonitrile at 20 - 30℃; Large scale; 4-5 Example 5: Compound of formula I Empagliflozin (1S)-1,5-anhydro-1-(4-chloro-3-[4-[(3S)-tetrahydrofuran-3yloxy]benzyl]phenyl )-D-glucitol preparation experiment two: Add 7L of acetonitrile, 7L of dichloromethane and 1.9kg of triethylsilane to the 100L reactor, and the control temperature is no more than 30°C,3.88kg of boron trifluoride ether was added to the reaction kettle in batches.After the addition, the acetonitrile solution of the compound of formula II obtained in Example 3 was added to the reaction system under the condition of not exceeding 30° C., the addition was completed, and the reaction was stirred at room temperature.After the reaction was completed, water was added to quench, and after standing, the solution was separated, the organic phase was separated, and the solvent was evaporated by concentration under reduced pressure.Add dichloromethane to make slurry, filter and vacuum dry to obtain 1.21 kg of crude empagliflozin, the yield is 62.7%, and the HPLC purity is 98.34%.The crude empagliflozin was recrystallized from toluene-ethyl acetate to obtain pure empagliflozin with HPLC purity of 99.82%.

Reference: [1]Current Patent Assignee: YANGTZE RIVER PHARMACEUTICAL GROUP CO LTD - CN110407891, 2019, A Location in patent: Paragraph 0043-0048
[2]Current Patent Assignee: JIANGSU COLLEGE OF ENGINEERING AND TECHNOLOGY - CN107652276, 2018, A Location in patent: Paragraph 0015; 0021
[3]Current Patent Assignee: JIANGSU COLLEGE OF ENGINEERING AND TECHNOLOGY - CN107652277, 2018, A Location in patent: Paragraph 0022
[4]Current Patent Assignee: C.H. Boehringer Sohn AG & Co. KG - WO2011/39107, 2011, A1 Location in patent: Page/Page column 21-23
[5]Current Patent Assignee: JIANGSU COLLEGE OF ENGINEERING AND TECHNOLOGY - CN107652278, 2018, A Location in patent: Paragraph 0022
[6]Current Patent Assignee: BEIJING WINSUNNY PHARMACEUTICAL - CN105481915, 2016, A Location in patent: Paragraph 0035; 0036
[7]Wang, Xiao-Jun; Zhang, Li; Byrne, Denis; Nummy, Larry; Weber, Dirk; Krishnamurthy, Dhileep; Yee, Nathan; Senanayake, Chris H. [Organic Letters, 2014, vol. 16, # 16, p. 4090 - 4093]
[8]Current Patent Assignee: ANHUI JIUHUA HUAYUAN PHARMACEUTICAL - CN106632288, 2017, A Location in patent: Paragraph 0076; 0077; 0078; 0079; 0080
[9]Peng, Peng; Zhao, Chuanmeng; Yang, Jiangtao; Liu, Xiao; Yu, Jun; Zhang, Fuli [Organic Preparations and Procedures International, 2022, vol. 54, # 3, p. 203 - 219]
[10]Current Patent Assignee: THE KALYANI GROUP - WO2021/250565, 2021, A1 Location in patent: Page/Page column 4; 9-11
[11]Current Patent Assignee: YANGTZE RIVER PHARMACEUTICAL GROUP CO LTD - CN107163033, 2017, A Location in patent: Paragraph 0035; 0036
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  • 2
  • [ 915095-87-3 ]
  • [ 1279691-36-9 ]
  • 4
  • [ 19094-56-5 ]
  • [ 1279691-36-9 ]
  • 5
  • [ 281652-58-2 ]
  • [ 1279691-36-9 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 6 steps 1: aluminum (III) chloride / 1 h / 0 - 25 °C 2: potassium <i>tert</i>-butylate / tetrahydrofuran / 0.5 h / 7 - 10 °C 3: aluminum (III) chloride; 1,1,3,3-Tetramethyldisiloxane / toluene / 2.5 h / 0 - 23 °C 4: isopropylmagnesium chloride; lithium chloride / tetrahydrofuran / 1.5 h / -20 - 10 °C 5: hydrogenchloride / isopropyl alcohol / 5 h / 38 - 42 °C / pH 2 6: hydrogenchloride / isopropyl alcohol; methanol
  • 6
  • [ 915095-86-2 ]
  • [ 1279691-36-9 ]
  • 7
  • [ 1198-69-2 ]
  • [ 1279691-36-9 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: 4-methyl-morpholine / tetrahydrofuran / 1 h / -10 - 45 °C 2: n-butyllithium / tetrahydrofuran; toluene; hexane / 2 h / -78 - -65 °C / Inert atmosphere
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  • [ 915095-94-2 ]
  • C18H42O6Si4 [ No CAS ]
  • [ 1279691-36-9 ]
YieldReaction ConditionsOperation in experiment
77.6% With n-butyllithium; In tetrahydrofuran; hexane; toluene; at -78 - -65℃; for 2h;Inert atmosphere; Under helium gas protection, to a 50mL three-necked flask were successively added 5.08g (S) -3- (4- (5- iodo-2-chlorobenzyl) phenoxy) in tetrahydrofuran, 10ml of tetrahydrofuran and 20ml of toluene, and dissolved with stirring, cooled to -78 , 2.4M n-hexane solution of n-butyllithium was added dropwise 5.46ml, dropping the temperature was kept below -70 deg.] C, after the addition was complete the reaction was complete to give (S) -3- (4- ( 5- lithium 2-chlorobenzyl) phenoxy) tetrahydrofuran. Under helium gas protection, to a 250mL three-necked flask was added 6.20g Compound B-1 and 30ml of toluene, followed by stirring to dissolve, cooled to -78 deg.] C, the (S) -3- (4- (5- lithium-2-chlorobenzyl yl) phenoxy) in tetrahydrofuran was added dropwise, the dropping rate to keep the temperature below -65 deg.] C, after the addition was complete the reaction was kept 2 hours, methanol was added dropwise a solution of 8.5g of acetic acid (acetic acid containing 3.5g), after the addition was complete , the reaction mixture was stirred at room temperature, the HPLC monitoring of the reaction is complete, add saturated NaHCO3 solution to a pH of about 7.5, the organic layer was separated and the aqueous layer extracted with ethyl acetate, the combined organic phase was washed with saturated brine, evaporated under reduced pressure, supplemented with 20ml toluene, evaporated under reduced pressure rotary evaporation to give 4.57g of intermediate -3, yield: 77.6%.
  • 9
  • [ 67-56-1 ]
  • [ 915095-89-5 ]
  • [ 32469-28-6 ]
  • [ 1279691-36-9 ]
YieldReaction ConditionsOperation in experiment
87% Take (S)-3-(4-(5-bromo-2-chlorobenzyl)phenoxy) tetrahydrofuran 183kg,400kg anhydrous THF/toluene (1:4) was added to the nitrogen-dried 3000 litre reactor.The liquid nitrogen was cooled to -78, and hexane solution of 1. 6 mol·L-1 n-butyllithium was slowly added dropwise.Stirring was continued at this temperature for 1 h; 600 kg of a 2,3,4,6-tetra-O-trimethylsilyl-D-glucono-lactone (256 kg) in toluene solution cooled to -78C was slowly added dropwise to the above 600 kg. In the reaction solution,-78 reaction for 3 h, after the basic reaction of TLC detection is completed,At this temperature is added 500kg of methanesulfonic acid in methanol solution (methanesulfonic acid 225kg + methanol 275kg);The reaction was stirred at 0 C 4h, and then warmed to 40 C stirred reaction 6h;5 mol?L-1 sodium hydroxide aqueous solution was added to the reaction solution, and the pH was adjusted to 7-8; stirring for 30 min,Extract with ethyl acetate (300kg×2)The organic phase is washed with saturated aqueous sodium chloride solution until neutral, then dried over anhydrous sodium sulfate and filtered.The filtrate was concentrated to dryness to give 208 kg of a light yellow viscous oil with a yield of 87%.
84% Take (5)-3-(4-(5-bromo-2-chlorobenzyl)phenoxy) tetrahydrofuran (91 kg), anhydrous tetrahydrofuran/toluene (200 kg (1:4)), and add it to a nitrogen-dried 2000-liter reactor. , Liquid nitrogen was cooled to -78 C, was slowly added dropwise 1. 6 mol-L" 1 n-butyllithium hexane solution 120L, maintaining the temperature stirred for 1h;A 300 kg toluene solution of 2,3,4,6-tetra-O-trimethylsilyl-D-glucono lactone (130 kg) cooled to -78C was slowly added dropwise to the above reaction solution, -78 C reaction 3 h, TLC test after the completion of the basic reaction, at this temperature was added 300kg of methanol solution of methanesulfonic acid (methanesulfonic acid 115kg + methanol 185kg); stirred at 0 C reaction 4.0h, and then heated to 40 C The reaction was stirred for 6 h. After the reaction was completed, 5 mol.I/1 aqueous sodium hydroxide solution was added to the reaction solution to adjust the pH to 7 - 8; stirred for 30 min, extracted with ethyl acetate (200 kg X 2), and the organic phase was washed with a saturated aqueous solution of sodium chloride. Neutral, then dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness to give 100 kg of pale yellow viscous oil in a yield of 84%.
  • 10
  • [ 54932-72-8 ]
  • [ 1279691-36-9 ]
  • 11
  • [ 149965-41-3 ]
  • [ 1279691-36-9 ]
  • 12
  • [ 915095-89-5 ]
  • [ 32469-28-6 ]
  • [ 1279691-36-9 ]
YieldReaction ConditionsOperation in experiment
84% Take <strong>[915095-89-5](S)-<strong>[915095-89-5]3-(4-(5-bromo-2-chlorobenzyl)phenoxy)tetrahydrofuran</strong></strong> 91kg,Anhydrous tetrahydrofuran/toluene 200 kg (1:4) mixed solvent was added to a nitrogen-dried 2000 liter reactor, liquid nitrogen was cooled to -78 C, and 1. 6 mol?L-1 n-butyl lithium was slowly added dropwise. 120L of the alkane solution, stirring at this temperature for 1h;300 kg of a toluene solution of 2,3,4,6-tetra-O-trimethylsilyl-D-gluconolactone (130 kg) cooled to -78 C was slowly added dropwise to the above reaction solution, -78 C Reaction for 3 h,After the basic reaction of TLC was detected, 300 kg of methanesulfonic acid in methanol (methanolsulfonic acid 115 kg + methanol) was added at this temperature.185 kg); The reaction was stirred at 0 C for 4. 0 h, then the temperature was raised to 40 C and the reaction was stirred for 6 h.After the reaction, 5 mol?L-1 sodium hydroxide aqueous solution was added to the reaction solution.Adjust to pH 7 - 8; stir for 30 min, extract with ethyl acetate (200 kg×2).The organic phase is washed with a saturated aqueous solution of sodium chloride until neutral, then dried over anhydrous sodium sulfate.Filtration and concentration of the filtrate to dryness afforded a pale yellow viscous oil, 100 g, yield 84%.
  • 13
  • [ 189628-37-3 ]
  • [ 1279691-36-9 ]
  • 14
  • [ 67-56-1 ]
  • [ 915095-94-2 ]
  • [ 32469-28-6 ]
  • [ 1279691-36-9 ]
YieldReaction ConditionsOperation in experiment
In a dry 20L four-necked flask, add SM1 (2000g) and THF (3575ml) under the protection of nitrogen, install an exhaust gas absorption device, stir it at 20-25 C and completely dissolve it, and then cool the internal temperature to -16 C.4410 ml of (1.3N) isopropylmagnesium chloride-lithium chloride THF solution was added dropwise. During the dropwise addition, the internal temperature was controlled at -14 ± 2 C. After 1.5 hours of dripping, the reaction was continued for 0.5 hours. 2251.5g SM2 was added dropwise, and the addition was completed after 50 minutes.The reaction was almost complete by TLC (developing solvent: petroleum ether / ethyl acetate = 3/1).Control the internal temperature below 5 C and add 6000ml of 10% citric acid aqueous solution dropwise. After 20min, the stirring is continued for 5min.The upper organic phase was separated, and the aqueous phase was extracted once more with 2000 ml of tetrahydrofuran. The combined organic phases were concentrated under reduced pressure to an oil at 30-32 C.Add 9000ml of methanol to the residue, stir to dissolve, and put it into a 20L four-necked flask.270 g of 2.5N HCl / methanol solution was added under stirring, and the temperature was controlled at 13 to 17 C. and the reaction was stirred for 15 hours.Adjust the pH to about 8 ~ 9 with triethylamine between 5 10 , then control the temperature to 32 ± 2 and concentrate to dryness under reduced pressure.The residue was dissolved by stirring with 3925 ml of acetonitrile and 2190 ml of dichloromethane (to be used in the next step).
  • 15
  • [ 915095-84-0 ]
  • [ 1279691-36-9 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1.1: Aluminum Chloride; 1,1,3,3-Tetramethyldisiloxane / 3 h / 5 - 30 °C 2.1: n-butyllithium / tetrahydrofuran; hexane / 0.67 h / Cooling 2.2: 1 h / Cooling 2.3: 15 h / 20 - 25 °C
  • 16
  • [ 67-56-1 ]
  • [ 915095-89-5 ]
  • (3R,4S,5R,6R)-3,4,5-tris((trimethylsilyl)oxy)-6-(((trimethylsilyl)oxy)methyl)tetrahydro-2H-pyran-2-one [ No CAS ]
  • [ 864070-44-0 ]
  • [ 1279691-36-9 ]
  • (S)-3-(4-(2-chlorobenzyl)phenoxy)tetrahydrofuran [ No CAS ]
YieldReaction ConditionsOperation in experiment
1: 73.1% 2: 9% 3: 5.5% Stage #1: (S)-4-bromo-1-chloro-2-(4-tetrahydrofuran-3-yloxy-benzyl)benzene With n-butyllithium In tetrahydrofuran; hexane for 0.666667h; Cooling; Stage #2: (3R,4S,5R,6R)-3,4,5-tris((trimethylsilyl)oxy)-6-(((trimethylsilyl)oxy)methyl)tetrahydro-2H-pyran-2-one In tetrahydrofuran; hexane for 1h; Cooling; Stage #3: methanol at 20 - 25℃; for 15h; (2S,3R,4S,5S,6R)-2-(4-Chloro-3-(4-(((S)-tetrahydronfuran-3-yl)oxy)benzyl)phenyl)-6-(hydroxymethyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triol (18) General procedure: To a solution of 16 (200 g, 546.4 mmol) in THF (600 mL) was slowly added 1.1 eq n-BuLi (240 ml, 2.5 mol/L hexane solution, 600.0 mol) at -75 C over 40 min. Compound17 (280.1g, 1.1 eq) in THF (560 mL) was then slowly added at -78 C over 1 hour. Afterthe reaction was completed, the reaction mass was quenched with 4N HCl in methanol and the pH was brought to 0-1. Then, the reaction mixture was concentrated to removeTHF, and then MeOH (500 mL) was added. The mixture was stirred at 20-25 C for15 hours. Next, saturated NaHCO3 solution was slowly added to adjust the pH to 7-8.The mixture was concentrated to remove methanol. The residue was extracted intoDCM (1500 mL) and the organic layer was washed with water. The separated DCM wasdried with anhydrous magnesium sulfate, then filtered. The dried phase was used forthe next step without purification.
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