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[ CAS No. 864070-44-0 ]

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Chemical Structure| 864070-44-0
Chemical Structure| 864070-44-0
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CAS No. :864070-44-0 MDL No. :MFCD22566222
Formula : C23H27ClO7 Boiling Point : 665°C at 760 mmHg
Linear Structure Formula :- InChI Key :N/A
M.W :450.91 g/mol Pubchem ID :11949646
Synonyms :

Safety of [ 864070-44-0 ]

Signal Word:Warning Class:N/A
Precautionary Statements:P261-P305+P351+P338 UN#:N/A
Hazard Statements:H302-H315-H319-H335 Packing Group:N/A
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Application In Synthesis of [ 864070-44-0 ]

  • Downstream synthetic route of [ 864070-44-0 ]

[ 864070-44-0 ] Synthesis Path-Downstream   1~24

  • 1
  • [ 864070-37-1 ]
  • [ 219823-47-9 ]
  • [ 864070-44-0 ]
YieldReaction ConditionsOperation in experiment
57% With caesium carbonate In N,N-dimethyl-formamide at 75℃; for 21h; Preparation example 1 preparation of according to handkerchief row only Reference Patent document WO2006/117359 A1 preparation prepared by the method of the embodiment of the net according to handkerchief row. In particular to: heating 2.85g the (R) - 3 - (4-methyl phenyl sulfonyl oxy)-tetrahydrofuran to 3.00g of 1-chloro-4 - (β-D-pyran glucose-1-yl) - 2 - (4-hydroxy-benzyl)-benzene and 4.36g cesium carbonate in 38 ml in a mixture of dimethyl formamide. The mixture for 75 °C stirring under 5 hours, then further adding 4.40g of and cesium carbonate 2.87g the (R) - 3 - (4-methyl phenyl sulfonyl oxy)-tetrahydrofuran. In the 75 °C in addition stirring 16 hours after cooling to room temperature after the mixture by adding saline. The obtained mixture is extracted with ethyl acetate, the combined organic extract is dried with anhydrous sodium sulfate. crosses the column purification of the residue (methylene chloride/methanol 1:0 → 5:1). Production of 2.1g, yield 57%. Mass spectrometric (ESI+): m/z=451/453 (Cl) [M+H]+, the net according to handkerchief row.
49% With caesium carbonate In N,N-dimethyl-formamide at 75℃; for 18h; Preparation of the compound A:1-chloro-4-(β-D-qlucopyranos-1-yl)-2-r4-(<fS)-tetrahvdrofuran-3-yloxy)-benzyll- benzene0.19 g (f?)-3-(4-methylphenylsulfonyloxy)-tetrahydrofuran are added to a mixture of 0.20 g 1-chloro-4-(β-D-glucopyranos-1-yl)-2-(4-hydroxybenzyl)-benzene and 0.29 g cesium carbonate in 2.5 ml dimethylformamide. The mixture is stirred at 75 0C for 4 h, before another 0.29 g caesium carbonate and 0.19 g (f?)-3-(4-methylphenyl- sulfonyloxy)-tetrahydrofuran are added. After an additional 14 h stirring at 75 0C the mixture is cooled to ambient temperature and brine is added. The resulting mixture is extracted with ethyl acetate, the combined organic extracts are dried over sodium sulfate, and the solvent is removed. The residue is purified by chromatography on silica gel (dichloromethane/methanol 1 :0 -> 5:1 ). Yield: 0.12 g (49% of theory) Mass spectrum (ESI+): m/z = 451/453 (Cl) [M+H] + EPO Preparation of the crystalline form:Variant 1 :30 mg 1 -chloro-4-(β-D-glucopyranos-1 -yl)-2-[4-((S,)-tetrahydrofuran-3-yloxy)-benzyl]- benzene (obtained as described above) are dissolved in 0.8 ml of ethyl acetate (containing 0.5-3% water) upon heating up to about 50 0C. The solution is allowed to cool slowly (about 1 to 3 h) to about 20 0C. After 48 h the crystalline form is isolated as white crystals by filtration. An excess of the solvent is removed by storing the crystals at elevated temperature (40 to 50 0C) for about 3 to 4 h at reduced pressure.Variant 2:1 g 1 -chloro-4-(β-D-glucopyranos-1 -yl)-2-[4-((S,)-tetrahydrofuran-3-yloxy)-benzyl]- benzene are dissolved in 5 ml of water/ethanol mixture (2 : 3 volume ratio) upon heating up to about 50 0C. 8 ml of water are added and the solution is allowed to cool to about 20 0C in 1 to 3 h. After 16 h the crystalline form is isolated as white crystals by filtration. Excess solvent is removed by storing the crystals at elevated temperature (40 to 50 0C) for about 4 to 6 h.Variant 3:1 g 1 -chloro-4-(β-D-glucopyranos-1 -yl)-2-[4-((S,)-tetrahydrofuran-3-yloxy)-benzyl]- benzene are dissolved in 11 ml of isopropanol upon heating up to about 50 0C. The solution is allowed to cool to about 20 0C in 1 to 3 h. After 16 h the crystalline form is isolated as white crystals by filtration. Residual solvent is removed by storing the crystals at elevated temperature (40 to 50 0C) for about 4 to 6 h.Variant 4:8,9 g 1 -chloro-4-(β-D-glucopyranos-1 -yl)-2-[4-((Sj-tetrahydrofuran-3-yloxy)-benzyl]- benzene are dissolved in 60 ml of water/ethanol mixture (2 : 3 volume ratio) upon heating up to about 50 0C. The solution is allowed to cool to about 20 0C in 3 h and the crystalline compound is isolated by filtration. The separated white solid is dried at 40 0C for 16 h to yield about 6 g of the crystalline form.
49% With caesium carbonate In N,N-dimethyl-formamide at 75℃; for 18h; VI 1-chloro-4-(β-D-glucopyranos-1-yl)-2-[4-((S)-tetrahydrofuran-3-yloxy)-benzyl]-benzene 0.19 g (R)-3-(4-methylphenylsulfonyloxy)-tetrahydrofuran are added to a mixture of 0.20 g 1-chloro-4-(β-D-glucopyranos-1-yl)-2-(4-hydroxybenzyl)-benzene and 0.29 g cesium carbonate in 2.5 ml dimethylformamide. The mixture is stirred at 75° C. for 4 h, before another 0.29 g caesium carbonate and 0.19 g (R)-3-(4-methylphenyl-sulfonyloxy)-tetrahydrofuran are added. After an additional 14 h stirring at 75° C. the mixture is cooled to ambient temperature and brine is added. The resulting mixture is extracted with ethyl acetate, the combined organic extracts are dried over sodium sulfate, and the solvent is removed. The residue is purified by chromatography on silica gel (dichloromethane/methanol 1:0→5:1). Yield: 0.12 g (49% of theory) Mass spectrum (ESI+): m/z=451/453 (Cl) [M+H]+
With caesium carbonate at 25 - 40℃; 9 Preparation of Compound of Formula (I) In a round bottom flask, 1.2 g compound of Formula (II), 1.2 g cesium carbonate, 0.81 (R)-tetrahydrofuran-3-yl-4-methylbenzenesulfonate and 18 mL DMF or DMSO were added at 25° C. to 35° C. The reaction mixture was heated to 35 to 40° C. and stirred for 24-36 hrs. The reaction mixture then cooled to 25° C. to 35° C. 40 mL water and 20 ml toluene were added stirred for 15-20 minutes. Layers were separated. The aqueous layer was extracted with dichloromethane, dried over sodium sulfate. The solvent was distilled out under vacuum. 10 mL ethanol was added and stirred for 30 minutes. The reaction mixture was stirred at 0-5° C. for an hour. The product was filtered and washed with pre-cooled ethanol and dried to obtain empagliflozin.
0.55 kg With caesium carbonate In N,N-dimethyl-formamide at 30 - 45℃; for 24h; 36.d Preparation of Empagliflozin Tert-butyl(4-(2-chloro-5-iodobenzyl)phenoxy)dimethylsilane (1 .0 Kg), tetrahydrofuran (6.0 L) and (3R,4S,5R,6R)-3,4,5-tris((trimethylsilyl)oxy)-6-(((trimethylsilyl)oxy)methyl) tetrahydro-2H-pyran-2-one (1 .221 Kg) were charged into a 20 L flask under Nitrogen atmosphere. Toluene (6.0 L) was charged into the flask and the resulted mixture was cooled to -80 °C. n-Butyl Lithium in hexane (1 .6M, 2.8 Kg) was added slowly over a period of 3 hours at -80 °C. The reaction mixture was maintained for 1 hour at -80 °C. A solution of methanesulfonic acid (1 .46 Kg of methanesulfonic acid in 9.0 L of methanol) was added to the reaction mass at -70 °C. The reaction mass was heated to -10 °C and stirred for 30 minutes and heated to 30 °C and stirred for 12 hours at 30 °C. The reaction mass was cooled to 5 °C and sodium bicarbonate solution (2.0 Kg of sodium bicarbonate in 23 L of water) was added slowly. The reaction mass was stirred for 30 minutes at 30 °C. The reaction mass was washed with Toluene (6.0 Lx 3) and the reaction mass was concentrated under vacuum until 20 volumes remains in the flask. The reaction mass was extracted with ethylacetate (10.0 Lx5) and the ethylacetate layer was washed with water (3.0 L). The ethylacetate layer was charged into a 100 L reactor and concentrated under vacuum to 3 volumes remained in the reactor. The concentrated ethylacetate layer was stripped off with acetonitrile (3.0 Lx 3) then dichloromethane (7.0 L) and acetonitrile (1 .2 L) were charged into the reactor and the reaction mass was cooled to -30 °C. Triethylsilane (0.57 Kg) and Borontrifluoride etherate solution (1 .307 Kg) were charged into the reactor and the reaction mass was stirred for 3 hours at -30 °C. Temperature was raised to -5 °C and stirred for 6 hours. A solution of sodium carbonate (2.0 Kg of sodium carbonate in 20.0 L of water) was added to the reaction mass over a period of 30 minutes at 5 °C. The reaction mass was heated to 30 °C and stirred for 30 minutes. The reaction mass was concentrated under vacuum until 25 volumes remained in the reactor. The mass was washed with toluene (4.0 L) and extracted with ethylacetate (8.0 Lx2 and 4.0 Lx4) and the ethylacetate layer washed with water (2.0 Lx2) The organic layer was concentrated under vacuum until 2 volumes remained in the reactor then the crude mass was stripped off with ethylacetate (3.0 l_x2) and with DMF (1 .4 L). Tosyl-THF (0.634 Kg) and DMF (0.20 L) were charged into the reactor and the resulted mass was stirred for 30 minutes at 30 °C. Cesium carbonate lot 1 (0.57 Kg) was added to the reaction mass. Reaction mass was heated to 45 °C and stirred for 2 hours at 45 °C. Cesium carbonate lot 2 (0.57 Kg) was added to the reaction mass and the reaction mass was stirred for 2 hours. Cesium carbonate lot 3 (0.57 Kg) was added to the reaction mass the reaction mass was stirred for 20 hours at 45 °C. The reaction mass was cooled to 30 °C and water (4.0 L) was added to the mass and stirred for 30 minutes. Layers were separated and the aqueous layer was washed with toluene (4.0 L). The aqueous layer was concentrated at 70 °C under vacuum until 1 .0 volume remained in the reactor. The concentrated mass was cooled to 30 °C and water (10.0 L) and acetonitrile 1 .0 L) were charged into the reactor at 30 °C and the resulted mixture was heated to 45 °C and the mixture was stirred for 6 hours at 45 °C. The suspension was cooled to 25 °C and stirred for 7 hours at 25 °C. The precipitation was filtered and the wet solid was washed with water (3.0L) and the solid was suck dried. The wet compound and DMF (1 .0 L) were charged into another reactor and the solution was heated to 45 °C. Acetonitrile (1 .0 L) charged followed by water (10.0 L) into the reactor at 45 °C and stirred for 6 hours. The suspension was cooled to 25 °C and stirred for 6 hours. The precipitation was fileted and the wet cake was washed with water. The wet material was suck dried. The wet material was dried under vacuum at 60 °C for 6 hours to yield 0.55 Kg of crystalline empagliflozin. Purity by HPLC 99%.

  • 2
  • [ 915095-96-4 ]
  • [ 864070-44-0 ]
YieldReaction ConditionsOperation in experiment
With triethylsilane; boron trifluoride diethyl etherate In dichloromethane; acetonitrile at -20 - 10℃; for 2h; XVIIIA.iii; XVIIIB.iii; XVIIIC.iii; XVIII.D.iii; XVIII.E.iii The residue of step ii) was dissolved in 63 mL of MeCN and 43 mL of CH2Cl2 and cooled to -20° C. 7.59 g of triethylsilane is added, followed by addition of 6.95 g of boron trifluoride etherate. The reaction is warmed up gradually from -20 to 10° C. over 2 h. 40 g of 10 weight-% NaHCO3 is added to quench the reaction. The organic solvents are removed under reduced pressure. 50 mL of isopropyl acetate and 12 mL of water are charged and the mixture is stirred at ambient temperature for overnight. The product is filtered and dried. Yield: 13.5 g (55% of theory) Mass spectrum (ESI+): m/z=451/453 (Cl) [M+H]+; The residue of step ii) is dissolved in MeCN (17 mL) and CH2Cl2 (11 mL) and cooled to -20° C. Triethylsilane (2.08 g, 17.9 mmol) is added, followed by addition of boron trifluoride etherate (1.9 g, 13.4 mmol). The reaction is warmed up gradually from -20 to 10° C. over 2 h. 10% NaHCO3 (25 mL) is added to quench the reaction. Organic solvents are removed under reduced pressure. Isopropyl acetate (15 mL) and water (5 ml) are charged and the mixture is stirred at ambient temperature for overnight. The product is filtered and dried. Yield: 0.91 g (27% of theory) Mass spectrum (ESI+): m/z=451/453 (Cl) [M+H]+; The residue of step ii) is dissolved in MeCN (17 mL) and CH2Cl2 (11 mL) and cooled to -20° C. Triethylsilane (2.08 g, 17.9 mmol) is added, followed by addition of boron trifluoride etherate (1.9 g, 13.4 mmol). The reaction is warmed up gradually from -20 to 10° C. over 2 h. 25 ml aqueous 10 weight-% NaHCO3 are added to quench the reaction. Organic solvents are removed under reduced pressure. Isopropyl acetate (15 mL) and water (5 ml) are charged and the mixture is stirred at ambient temperature for overnight. The product is filtered and dried. Yield: 2.2 g (65% of theory) Mass spectrum (ESI+): m/z=451/453 (Cl) [M+H]+
Multi-step reaction with 3 steps 1: trimethylsilan; boron trifluoride diethyl etherate / dichloromethane; acetonitrile / -40 - -30 °C 2: isopropyl alcohol; dichloromethane / 40 - 50 °C 3: ethyl acetate; water / 25 - 50 °C
Multi-step reaction with 3 steps 1: dmap / dichloromethane; pyridine / -5 - 30 °C / Large scale 2: boron trifluoride diethyl etherate; triethylsilane / acetonitrile; water / 0 - 10 °C / Large scale 3: lithium hydroxide / tetrahydrofuran; methanol / 10 - 40 °C
  • 3
  • [ 864070-44-0 ]
  • [ 108-24-7 ]
  • (2R,3R,4R,5S,6S)-2-(acetoxymethyl)-6-(4-chloro-3-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)tetrahydro-2H-pyran-3,4,5-trityl triacetate [ No CAS ]
YieldReaction ConditionsOperation in experiment
91% With pyridine; dmap In dichloromethane at 20℃; for 4h; XIX Example XIX; 1-Chloro-2-r4-((S)-tetrahvdrofuran-3-yloxy)-benzyll-4-(2,3,4,6-tetra-O-acetyl-3-D- glucopyranos-1 -yl)-benzene; To a solution of 2.02 g 1-chloro-4-(β-D-glucopyranos-1-yl)-2-[4-((S)-tetrahydrofuran-3-yloxy)- benzyl]-benzene in 20 mL dichloromethane is added in succession 2.5 mL pyridine, 2.8 mL acetic anhydride and 50 mg 4-dimethylaminopyridine. The reaction solution is stirred at ambient temperature for 4 h. The solution is diluted with 50 mL dichloromethane, washed twice with 50 mL 1 M hydrochloric acid and once with sodium hydrogencarbonate solution. After drying over sodium sulfate, the solvent is evaporated to yield the product. Yield: 2.53 g (91% of theory) Mass spectrum (ESI+): m/z = 642/644 (Cl) [M+Na]+
  • 4
  • [ 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
[12]Current Patent Assignee: SHANGHAI FOSUN PHARMACEUTICAL (GROUP) CO., LTD. - CN109988161, 2019, A Location in patent: Paragraph 0067-0073
[13]Current Patent Assignee: JIANGSU DEYUAN PHARM CO LTD - CN114380775, 2022, A Location in patent: Paragraph 0061-0068
  • 5
  • [ 462-06-6 ]
  • [ 864070-44-0 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 4 steps 1.1: oxalyl dichloride / N,N-dimethyl-formamide / 5 h / 25 - 30 °C 1.2: 6 h / 20 - 30 °C 2.1: potassium <i>tert</i>-butylate / tetrahydrofuran / 4 h / 16 - 25 °C 2.2: 1.83 h / 20 - 21 °C 3.1: aluminum (III) chloride; 1,1,3,3-Tetramethyldisiloxane / toluene / 2.5 h / 18 - 26 °C 4.1: isopropylmagnesium chloride; lithium chloride / tetrahydrofuran / 1.83 h / -21 - -15 °C 4.2: 2.92 h / -25 - -13 °C
Multi-step reaction with 4 steps 1.1: oxalyl dichloride; aluminum (III) chloride / N,N-dimethyl-formamide / 25 - 45 °C / Industry scale 2.1: potassium <i>tert</i>-butylate / tetrahydrofuran / 4 h / 16 - 25 °C / Industry scale 3.1: aluminum (III) chloride; 1,1,3,3-Tetramethyldisiloxane / toluene / 2.5 h / 18 - 26 °C / Industry scale 3.2: 20 - 51 °C / Industry scale 4.1: isopropylmagnesium chloride; lithium chloride / tetrahydrofuran / 1.83 h / -21 - -15 °C / Industry scale 4.2: 2.92 h / -25 - -18 °C / Industry scale 4.3: -13 - 19 °C / Industry scale
Multi-step reaction with 4 steps 1.1: potassium <i>tert</i>-butylate / tetrahydrofuran; <i>tert</i>-butyl alcohol / 1.5 h / 0 - 10 °C / Inert atmosphere; Large scale 2.1: aluminum (III) chloride / ethyl acetate / 9 h / 78 °C / Cooling with ice; Large scale 3.1: n-butyllithium / tetrahydrofuran; toluene; hexane / 3 h / -78 °C / Inert atmosphere; Large scale 3.2: 10 h / 0 - 40 °C / Inert atmosphere; Large scale 4.1: aluminum (III) chloride; triethylsilane / dichloromethane; acetonitrile / 2 h / -5 - 10 °C / Large scale
Multi-step reaction with 4 steps 1.1: potassium <i>tert</i>-butylate / tetrahydrofuran / 1 h / 0 - 10 °C / Inert atmosphere; Large scale 2.1: ethyl acetate / 0.5 h / Cooling with ice; Large scale 2.2: 8.5 h / 78 °C / Cooling with ice; Large scale 3.1: n-butyllithium / tetrahydrofuran; toluene / 1 h / -78 °C / Large scale 3.2: 3 h / -78 °C / Large scale 3.3: 10 h / 0 - 40 °C / Large scale 4.1: aluminum (III) chloride / dichloromethane; acetonitrile / 0.5 h / 5 °C / Large scale 4.2: 2 h / 10 °C / Large scale

  • 7
  • [ 915095-94-2 ]
  • [ 32469-28-6 ]
  • [ 864070-44-0 ]
YieldReaction ConditionsOperation in experiment
73% To a solution of the iodide V.1 (267 kg) in tetrahydrofuran (429 kg) is added Turbogrignard solution (isopropylmagnesium chloride/lithium chloride solution, 14 weight-% iPrMgCl in THF, molar ratio LiCl:iPrMgCl=0.9-1.1 mol/mol) (472 kg) 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 (320 kg) 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 the conversion is determined via HPLC analysis (for information). On completion, a solution of citric acid in water (938 L; concentration: 10%-weight) is added to the reaction mixture of a volume of about 2500 L at -13 to 19 C. within 1 hr 25 min.The solvent is partially distilled off from the reaction mixture (residual volume: 1816-1905 L) at 20 to 30 C. under reduced pressure and 2-methyltetrahydrofuran (532 kg) 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 (1202 kg) is added followed by the addition of a solution of 1.25N HCl in methanol (75 kg) at 20 C. (pH=0). Full conversion to the acetale III.1 is achieved by subsequent distillation at 20 to 32 C. under reduced pressure and addition of methanol (409 kg).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 III.1 relative to the area of intermediate IIIa.1 is greater or equal to 96.0%:4.0%. 2) The ratio of the HPLC-area of the alpha-form of intermediate III.1 to the beta-form of III.1 is greater or equal to 97.0% to 3.0%. In this particular case both criteria are met. Triethylamin (14 kg) is added (pH=7.4) and solvent is distilled off under reduced pressure, acetonitrile (835 kg) is added and further distilled under reduced pressure. This procedure is repeated (addition of acetonitrile: 694 kg) and methylene chloride (640 kg) is added to the resulting mixture to yield a mixture of the acetale III.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 AlCl3 (176 kg), methylene chloride (474 kg), acetonitrile (340 kg), and triethylsilane (205 kg). The resulting mixture is stirred at 18 to 20 C. for 70 min. After completion of the reaction, water (1263 L) 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 (698 kg) 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 (0.5 kg) at 31 C. and water (267 kg) 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 (348 kg) and dried at 22 to 58 C. 211 kg (73%) of product are obtained. The identity of the product is determined via the HPLC retention time.
73% To a solution of the iodide V.1 (267 kg) in tetrahydrofuran (429 kg) is added Turbogrignard solution (isopropylmagnesium chloride/lithium chloride solution, 14 weight-% iPrMgCl in THF, molar ratio LiCl:iPrMgCl=0.9-1.1 mol/mol) (472 kg) 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 (320 kg) 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 (938 L; concentration:10%-weight) is added to the reaction mixture of a volume of about 2500 L at -13 to 19 C. within 1 hr 25 min. The solvent is partially distilled off from the reaction mixture (residual volume: 1816-1905 L) at 20 to 30 C. under reduced pressure and 2-methyltetrahydrofuran (532 kg) 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 (1202 kg) is added followed by the addition of a solution of 1.25N HCl in methanol (75 kg) at 20 C. (pH=0). Full conversion to the acetale III.1 is achieved by subsequent distillation at 20 to 32 C. under reduced pressure and addition of methanol (409 kg).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 III.1 relative to the area of intermediate IIIa.1 is greater or equal to 96.0%:4.0%.2) The ratio of the HPLC-area of the alpha-form of intermediate III.1 to the beta-form of III.1 is greater or equal to 97.0% to 3.0%.In this particular case both criteria are met. Triethylamin (14 kg) is added (pH=7.4) and solvent is distilled off under reduced pressure, acetonitrile (835 kg) is added and further distilled under reduced pressure. This procedure is repeated (addition of acetonitrile: 694 kg) and methylene chloride (640 kg) is added to the resulting mixture to yield a mixture of the acetale III.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 AlCl3 (176 kg), methylene chloride (474 kg), acetonitrile (340 kg), and triethylsilane (205 kg). The resulting mixture is stirred at 18 to 20 C. for 70 min. After completion of the reaction, water (1263 L) 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 (698 kg) 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 (0.5 kg) at 31 C. and water (267 kg) 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 (348 kg) and dried at 22 to 58 C. 211 kg (73%) of product are obtained. The identity of the product is determined via the HPLC retention time.
  • 11
  • C35H59ClO8Si4 [ No CAS ]
  • [ 864070-44-0 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1: hydrogenchloride / isopropyl alcohol / 5 h / 38 - 42 °C / pH 2 2: hydrogenchloride / isopropyl alcohol; methanol 3: aluminum (III) chloride; triethylsilane / dichloromethane; acetonitrile / 0.5 h / 20 - 25 °C
  • 12
  • C24H29ClO8 [ No CAS ]
  • [ 864070-44-0 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: hydrogenchloride / isopropyl alcohol; methanol 2: aluminum (III) chloride; triethylsilane / dichloromethane; acetonitrile / 0.5 h / 20 - 25 °C
  • 13
  • [ 281652-58-2 ]
  • [ 864070-44-0 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 7 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 7: aluminum (III) chloride; triethylsilane / dichloromethane; acetonitrile / 0.5 h / 20 - 25 °C
Multi-step reaction with 7 steps 1: aluminum (III) chloride / 25 °C / Inert atmosphere 2: potassium <i>tert</i>-butylate / tetrahydrofuran / 2 - 10 °C 3: sodium tetrahydroborate / ethanol / 20 - 25 °C 4: methanesulfonic acid / 20 - 30 °C 5: n-butyllithium / tetrahydrofuran; hexane / -75 - -70 °C / Inert atmosphere 6: methanesulfonic acid / 20 - 25 °C 7: triethylsilane; boron trifluoride diethyl etherate / dichloromethane; acetonitrile / -40 - 20 °C / Inert atmosphere
Multi-step reaction with 7 steps 1: aluminum (III) chloride / 25 °C / Inert atmosphere 2: potassium <i>tert</i>-butylate / tetrahydrofuran / 2 - 10 °C 3: sodium tetrahydroborate / ethanol / 20 - 25 °C 4: triethylamine / dichloromethane / 0 - 35 °C 5: n-butyllithium / tetrahydrofuran; hexane / -75 - -70 °C / Inert atmosphere 6: methanesulfonic acid / 0 - 35 °C 7: triethylsilane; boron trifluoride diethyl etherate / dichloromethane; acetonitrile / -40 - 20 °C / Inert atmosphere
Multi-step reaction with 8 steps 1: aluminum (III) chloride / chlorobenzene / 1.5 h / 5 °C / Inert atmosphere 2: aluminum (III) chloride / chlorobenzene / 5 - 60 °C / Inert atmosphere 3: 1,1,3,3-tetramethyldisilazane / chlorobenzene / 5.5 h / 5 - 25 °C 4: dmap; triethylamine / dichloromethane / 3 h / 5 - 28 °C 5: n-butyllithium / tetrahydrofuran; toluene; hexane / 4 h / -80 °C / Inert atmosphere; Large scale 6: methanesulfonic acid / tetrahydrofuran; toluene; hexane / 12.5 h / -70 - 30 °C / Inert atmosphere 7: triethylsilane; boron trifluoride diethyl etherate / dichloromethane; acetonitrile / 9 h / -30 - -5 °C 8: caesium carbonate / N,N-dimethyl-formamide / 24 h / 30 - 45 °C

  • 15
  • [ 915095-84-0 ]
  • [ 864070-44-0 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 5 steps 1: sodium tetrahydridoborate / ethanol / 20 - 25 °C 2: triethylamine / dichloromethane / 0 - 35 °C 3: n-butyllithium / tetrahydrofuran; hexane / -75 - -70 °C / Inert atmosphere 4: methanesulfonic acid / 0 - 35 °C 5: triethylsilane; boron trifluoride diethyl ether complex / dichloromethane; acetonitrile / -40 - 20 °C / Inert atmosphere
Multi-step reaction with 3 steps 1.1: potassium borohydrate; aluminium chloride anhydrous / tetrahydrofuran / 0.5 h / 0 - 20 °C 2.1: isopropylmagnesium chloride lithium chloride complex / tetrahydrofuran / -10 - 0 °C / Cooling with ice; Inert atmosphere 2.3: 40 - 50 °C / Inert atmosphere 3.1: lithium hydroxide monohydrate / ethanol; water monomer / 40 - 45 °C
Multi-step reaction with 3 steps 1.1: potassium borohydrate; aluminium chloride anhydrous / tetrahydrofuran / 0.5 h / 0 - 20 °C 2.1: isopropylmagnesium chloride lithium chloride complex / tetrahydrofuran / 0.5 h / -10 - 0 °C / Cooling with ice; Inert atmosphere 2.2: 40 - 50 °C / Inert atmosphere 3.1: potassium carbonate / tetrahydrofuran / 40 - 45 °C
Multi-step reaction with 6 steps 1.1: Aluminum Chloride; sodium tetrahydridoborate / tetrahydrofuran / 24.5 h / 0 - 60 °C 2.1: n-butyllithium / tetrahydrofuran / 1 h / -80 - -70 °C 2.2: -80 - 0 °C 3.1: sodium tetrahydridoborate; cerium(III) trichloride heptahydrate / methanol / 2 h / -80 - 70 °C 4.1: acetic acid / water monomer / 100 °C 4.2: 5 h / 0 - 30 °C 5.1: potassium fluoride; trimethylsilyl trifluoropmethanesulfonate / acetonitrile / -80 - -70 °C 6.1: potassium hydroxide; water monomer / acetonitrile / 50 - 60 °C
Multi-step reaction with 4 steps 1.1: n-butyllithium / toluene; tetrahydrofuran; hexane / 0.5 h / -80 °C / Inert atmosphere 1.2: 2 h / Inert atmosphere 1.3: 12 h / 30 °C / Inert atmosphere 2.1: 4-methyl-morpholine; dmap / ethyl acetate / 4 h / 5 - 30 °C / Inert atmosphere; Large scale 3.1: phenylsilane; Aluminum Chloride / acetonitrile / 6 h / 45 °C / Inert atmosphere; Large scale 4.1: lithium hydroxyde monohydrate; methanol / tetrahydrofuran; water monomer / 2 h / 30 °C / Large scale
Multi-step reaction with 4 steps 1: Aluminum Chloride; potassium borohydrate / tetrahydrofuran / 6 h / 20 °C 2: palladium (II) [1,1'-bis(diphenylphosphanyl)ferrocene] dichloride; anhydrous potassium acetate / 1,4-dioxane / 8 h / 8 °C / Inert atmosphere 3: tetrakis-(triphenylphosphine)-palladium; potassium dihydrogen orthophosphate / toluene / 12 h / 105 °C 4: sodium hydroxide / methanol / 1 h / 20 °C
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
Multi-step reaction with 3 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 3.1: Aluminum Chloride; triethylsilane / dichloromethane; acetonitrile / 2.25 h / 20 - 25 °C

  • 16
  • C17H16BrClO3 [ No CAS ]
  • [ 864070-44-0 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 4 steps 1: triethylamine / dichloromethane / 0 - 35 °C 2: n-butyllithium / tetrahydrofuran; hexane / -75 - -70 °C / Inert atmosphere 3: methanesulfonic acid / 0 - 35 °C 4: triethylsilane; boron trifluoride diethyl etherate / dichloromethane; acetonitrile / -40 - 20 °C / Inert atmosphere
  • 17
  • [ 189628-37-3 ]
  • [ 864070-44-0 ]
  • 18
  • [ 857854-82-1 ]
  • [ 864070-44-0 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 5 steps 1: n-butyllithium / tetrahydrofuran; hexane / -75 - -70 °C / Inert atmosphere 2: triethylamine / dichloromethane / 0 - 35 °C 3: n-butyllithium / tetrahydrofuran; hexane / -75 - -70 °C / Inert atmosphere 4: methanesulfonic acid / 0 - 35 °C 5: triethylsilane; boron trifluoride diethyl etherate / dichloromethane; acetonitrile / -40 - 20 °C / Inert atmosphere
  • 19
  • C20H24BrClO3Si [ No CAS ]
  • [ 864070-44-0 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1: n-butyllithium / tetrahydrofuran; hexane / -75 - -70 °C / Inert atmosphere 2: methanesulfonic acid / 0 - 35 °C 3: triethylsilane; boron trifluoride diethyl etherate / dichloromethane; acetonitrile / -40 - 20 °C / Inert atmosphere
  • 20
  • C17H16ClIO3 [ No CAS ]
  • [ 864070-44-0 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 4 steps 1: triethylamine / dichloromethane / 0 - 35 °C 2: n-butyllithium / tetrahydrofuran; hexane / -75 - -70 °C / Inert atmosphere 3: methanesulfonic acid / 0 - 35 °C 4: triethylsilane; boron trifluoride diethyl etherate / dichloromethane; acetonitrile / -40 - 20 °C / Inert atmosphere
Multi-step reaction with 4 steps 1: methanesulfonic acid / 20 - 30 °C 2: n-butyllithium / tetrahydrofuran; hexane / -75 - -70 °C / Inert atmosphere 3: methanesulfonic acid / 20 - 25 °C 4: triethylsilane; boron trifluoride diethyl etherate / dichloromethane; acetonitrile / -40 - 20 °C / Inert atmosphere
  • 21
  • C20H24ClIO3Si [ No CAS ]
  • [ 864070-44-0 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1: n-butyllithium / tetrahydrofuran; hexane / -75 - -70 °C / Inert atmosphere 2: methanesulfonic acid / 0 - 35 °C 3: triethylsilane; boron trifluoride diethyl etherate / dichloromethane; acetonitrile / -40 - 20 °C / Inert atmosphere
  • 22
  • C18H18ClIO3 [ No CAS ]
  • [ 864070-44-0 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1: n-butyllithium / tetrahydrofuran; hexane / -75 - -70 °C / Inert atmosphere 2: methanesulfonic acid / 20 - 25 °C 3: triethylsilane; boron trifluoride diethyl etherate / dichloromethane; acetonitrile / -40 - 20 °C / Inert atmosphere
  • 23
  • C38H67ClO9Si5 [ No CAS ]
  • [ 864070-44-0 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: methanesulfonic acid / 0 - 35 °C 2: triethylsilane; boron trifluoride diethyl etherate / dichloromethane; acetonitrile / -40 - 20 °C / Inert atmosphere
  • 24
  • C25H31ClO9 [ No CAS ]
  • [ 864070-44-0 ]
YieldReaction ConditionsOperation in experiment
0.2 g With triethylsilane; boron trifluoride diethyl etherate In dichloromethane; acetonitrile at -40 - 20℃; Inert atmosphere; 19 Example 19: Preparation of empagliflozin of formula I from formula 14a Formula 14a (lg, 1.96 mole) was dissolved in a mixture of dichloromethane (10 mL) and acetonitrile (10 mL) at 25-35 °C and then cooled to -40 to -38 °C under dry nitrogen atmosphere. Triethylsilane (0.85 g, 7.3 mmole) was added then added over the course of 5-10 minutes, followed by boron trifluoride diethyl etherate (0.6 g, 4.2 mmole) while maintaining the temperature between -40 and -38 °C. Next, the reaction mixture temperature was raised to 10 to 20 °C and stirred at same temperature until the reaction completed. After completion of the reaction, the reaction mixture was quenched with saturated aqueous sodium bicarbonate solution (20 rriL) and diluted with ethyl acetate (20 rriL). The organic layer was washed with saturated aqueous sodium bicarbonate solution (20 mL) and aqueous sodium chloride solution (10%, 20 mL). The organic layer was then concentrated under reduced pressure maintaining the temperature below 45 °C. Isopropyl acetate (10 mL) was added to the residue and the mixture was heated to 45-50 °C. The contents were then cooled to 25-30 °C and stirred over night at same temperature. The product was filtered and washed with isopropyl acetate (2mL) to yield empagliflozin (0.2 g).
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