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%. |