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[ CAS No. 864070-44-0 ] {[proInfo.proName]}

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Chemical Structure| 864070-44-0
Chemical Structure| 864070-44-0
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Product Details of [ 864070-44-0 ]

CAS No. :864070-44-0 MDL No. :
Formula : C23H27ClO7 Boiling Point : -
Linear Structure Formula :- InChI Key :OBWASQILIWPZMG-QZMOQZSNSA-N
M.W : 450.91 Pubchem ID :11949646
Synonyms :
BI 10773

Calculated chemistry of [ 864070-44-0 ]

Physicochemical Properties

Num. heavy atoms : 31
Num. arom. heavy atoms : 12
Fraction Csp3 : 0.48
Num. rotatable bonds : 6
Num. H-bond acceptors : 7.0
Num. H-bond donors : 4.0
Molar Refractivity : 113.41
TPSA : 108.61 Ų

Pharmacokinetics

GI absorption : High
BBB permeant : No
P-gp substrate : Yes
CYP1A2 inhibitor : No
CYP2C19 inhibitor : No
CYP2C9 inhibitor : No
CYP2D6 inhibitor : Yes
CYP3A4 inhibitor : No
Log Kp (skin permeation) : -7.61 cm/s

Lipophilicity

Log Po/w (iLOGP) : 3.18
Log Po/w (XLOGP3) : 2.03
Log Po/w (WLOGP) : 1.29
Log Po/w (MLOGP) : 0.7
Log Po/w (SILICOS-IT) : 2.66
Consensus Log Po/w : 1.97

Druglikeness

Lipinski : 0.0
Ghose : None
Veber : 0.0
Egan : 0.0
Muegge : 0.0
Bioavailability Score : 0.55

Water Solubility

Log S (ESOL) : -3.8
Solubility : 0.0706 mg/ml ; 0.000157 mol/l
Class : Soluble
Log S (Ali) : -3.94
Solubility : 0.0519 mg/ml ; 0.000115 mol/l
Class : Soluble
Log S (SILICOS-IT) : -4.25
Solubility : 0.0254 mg/ml ; 0.0000562 mol/l
Class : Moderately soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 0.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 4.87

Safety of [ 864070-44-0 ]

Signal Word:Warning Class:N/A
Precautionary Statements:P201-P202-P281-P308+P313-P405-P501 UN#:N/A
Hazard Statements:H361 Packing Group:N/A
GHS Pictogram:

Application In Synthesis of [ 864070-44-0 ]

* 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 [ 864070-44-0 ]

[ 864070-44-0 ] Synthesis Path-Downstream   1~85

  • 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).
  • 25
  • C36H61ClO9Si4 [ No CAS ]
  • [ 864070-44-0 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: methanesulfonic acid / 20 - 25 °C 2: triethylsilane; boron trifluoride diethyl etherate / dichloromethane; acetonitrile / -40 - 20 °C / Inert atmosphere
  • 26
  • [ 21739-92-4 ]
  • [ 864070-44-0 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 8 steps 1: oxalyl dichloride; N,N-dimethyl-formamide / fluorobenzene / 15 - 25 °C / Inert atmosphere 2: Aluminum Chloride / 25 °C / Inert atmosphere 3: potassium-t-butoxide / tetrahydrofuran / 2 - 10 °C 4: sodium tetrahydridoborate / ethanol / 20 - 25 °C 5: triethylamine / dichloromethane / 0 - 35 °C 6: n-butyllithium / tetrahydrofuran; hexane / -75 - -70 °C / Inert atmosphere 7: methanesulfonic acid / 0 - 35 °C 8: triethylsilane; boron trifluoride diethyl ether complex / dichloromethane; acetonitrile / -40 - 20 °C / Inert atmosphere
Multi-step reaction with 9 steps 1: oxalyl dichloride; N,N-dimethyl-formamide / dichloromethane / 1 h / 0 - 5 °C / Inert atmosphere 2: Aluminum Chloride / dichloromethane / 6 h / 0 - 30 °C 3: titanium(IV) tetrachloride; triethylsilane / dichloromethane / 4.25 h / 0 - 30 °C 4: n-butyllithium / tetrahydrofuran / 3.33 h / -75 - 30 °C / Inert atmosphere 5: triethylsilane; boron trifluoride diethyl ether complex / dichloromethane; acetonitrile / 1 h / 0 - 30 °C 6: dmap / dichloromethane / 4 h / 25 - 30 °C 7: 1-dodecylthiol; Aluminum Chloride / dichloromethane / 3 h / 15 - 30 °C 8: potassium carbonate / acetonitrile / 8 h / 25 - 80 °C 9: sodium hydroxide; water monomer / methanol / 20 h / 25 - 60 °C
Multi-step reaction with 5 steps 1.1: polyphosphoric acid / 50 - 85 °C 2.1: potassium iodide; potassium carbonate / acetonitrile / 50 - 55 °C 3.1: potassium borohydrate; aluminium chloride anhydrous / tetrahydrofuran / 0.5 h / 0 - 20 °C 4.1: isopropylmagnesium chloride lithium chloride complex / tetrahydrofuran / 0.5 h / -10 - 0 °C / Cooling with ice; Inert atmosphere 4.2: 40 - 50 °C / Inert atmosphere 5.1: potassium carbonate / tetrahydrofuran / 40 - 45 °C
Multi-step reaction with 5 steps 1.1: polyphosphoric acid / 50 - 85 °C 2.1: potassium iodide; potassium carbonate / acetonitrile / 50 - 55 °C 3.1: potassium borohydrate; aluminium chloride anhydrous / tetrahydrofuran / 0.5 h / 0 - 20 °C 4.1: isopropylmagnesium chloride lithium chloride complex / tetrahydrofuran / -10 - 0 °C / Cooling with ice; Inert atmosphere 4.3: 40 - 50 °C / Inert atmosphere 5.1: lithium hydroxide monohydrate / ethanol; water monomer / 40 - 45 °C
Multi-step reaction with 10 steps 1.1: N,N-dimethyl-formamide; thionyl chloride / dichloromethane / 10 - 45 °C / Inert atmosphere 2.1: Aluminum Chloride / dichloromethane / 0 - 5 °C / Inert atmosphere 2.2: 1 h / 0 - 5 °C / Inert atmosphere 3.1: triethylsilane / acetonitrile / 10 - 15 °C 3.2: 10 - 45 °C 4.1: boron tribromide / dichloromethane / 0 - 5 °C 5.1: triethylamine / dichloromethane / 0 - 5 °C 6.1: n-butyllithium / tetrahydrofuran / -75 - -70 °C / Inert atmosphere 6.2: 12 h / -75 - 35 °C / Inert atmosphere 7.1: triethylsilane / dichloromethane; acetonitrile / 1 h / 25 - 35 °C / Inert atmosphere 7.2: 0.5 h / -40 - -5 °C / Inert atmosphere 8.1: N-ethyl-N,N-diisopropylamine; dmap / tetrahydrofuran / 0 - 35 °C 9.1: lithium hydroxide monohydrate; water monomer / tetrahydrofuran; methanol / 1 h / 15 - 20 °C 10.1: Cs2CO3 / 25 - 40 °C
Multi-step reaction with 8 steps 1.1: N,N-dimethyl-formamide; thionyl chloride / dichloromethane / 10 - 45 °C / Inert atmosphere 2.1: Aluminum Chloride / dichloromethane / 0 - 5 °C / Inert atmosphere 2.2: 1 h / 0 - 5 °C / Inert atmosphere 3.1: triethylsilane / acetonitrile / 10 - 15 °C 3.2: 10 - 45 °C 4.1: boron tribromide / dichloromethane / 0 - 5 °C 5.1: triethylamine / dichloromethane / 0 - 5 °C 6.1: n-butyllithium / tetrahydrofuran / -75 - -70 °C / Inert atmosphere 6.2: 12 h / -75 - 35 °C / Inert atmosphere 7.1: triethylsilane; boron trifluoride diethyl ether complex / dichloromethane / -70 - 35 °C 8.1: Cs2CO3 / 25 - 40 °C
Multi-step reaction with 7 steps 1: oxalyl dichloride / dichloromethane; N,N-dimethyl-formamide / 2 h / 10 - 20 °C 2: Aluminum Chloride / dichloromethane / 5 h / 0 - 20 °C 3: potassium-t-butoxide / tetrahydrofuran / 2 h / 0 - 10 °C 4: Aluminum Chloride; potassium borohydrate / tetrahydrofuran / 6 h / 20 °C 5: palladium (II) [1,1'-bis(diphenylphosphanyl)ferrocene] dichloride; anhydrous potassium acetate / 1,4-dioxane / 8 h / 8 °C / Inert atmosphere 6: tetrakis-(triphenylphosphine)-palladium; potassium dihydrogen orthophosphate / toluene / 12 h / 105 °C 7: sodium hydroxide / methanol / 1 h / 20 °C
Multi-step reaction with 5 steps 1.1: oxalyl dichloride; N,N-dimethyl-formamide / dichloromethane / 3 h / 25 °C 2.1: Aluminum Chloride / dichloromethane / 5 h / 15 - 20 °C 3.1: potassium-t-butoxide / tetrahydrofuran / 0.5 h / 5 - 10 °C / Inert atmosphere 3.2: 3 h / 5 - 25 °C / Inert atmosphere 4.1: Aluminum Chloride; 1,1,3,3-Tetramethyldisiloxane / 3 h / 5 - 30 °C 5.1: n-butyllithium / tetrahydrofuran; hexane / 0.67 h / Cooling 5.2: 1 h / Cooling 5.3: 15 h / 20 - 25 °C
Multi-step reaction with 6 steps 1.1: oxalyl dichloride; N,N-dimethyl-formamide / dichloromethane / 3 h / 25 °C 2.1: Aluminum Chloride / dichloromethane / 5 h / 15 - 20 °C 3.1: potassium-t-butoxide / tetrahydrofuran / 0.5 h / 5 - 10 °C / Inert atmosphere 3.2: 3 h / 5 - 25 °C / Inert atmosphere 4.1: Aluminum Chloride; 1,1,3,3-Tetramethyldisiloxane / 3 h / 5 - 30 °C 5.1: n-butyllithium / tetrahydrofuran; hexane / 0.67 h / Cooling 5.2: 1 h / Cooling 5.3: 15 h / 20 - 25 °C 6.1: Aluminum Chloride; triethylsilane / dichloromethane; acetonitrile / 2.25 h / 20 - 25 °C

  • 27
  • [ 21900-52-7 ]
  • [ 864070-44-0 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 7 steps 1: Aluminum Chloride / 25 °C / Inert atmosphere 2: potassium-t-butoxide / tetrahydrofuran / 2 - 10 °C 3: sodium tetrahydridoborate / 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 ether complex / dichloromethane; acetonitrile / -40 - 20 °C / Inert atmosphere
Multi-step reaction with 8 steps 1: Aluminum Chloride / dichloromethane / 6 h / 0 - 30 °C 2: titanium(IV) tetrachloride; triethylsilane / dichloromethane / 4.25 h / 0 - 30 °C 3: n-butyllithium / tetrahydrofuran / 3.33 h / -75 - 30 °C / Inert atmosphere 4: triethylsilane; boron trifluoride diethyl ether complex / dichloromethane; acetonitrile / 1 h / 0 - 30 °C 5: dmap / dichloromethane / 4 h / 25 - 30 °C 6: 1-dodecylthiol; Aluminum Chloride / dichloromethane / 3 h / 15 - 30 °C 7: potassium carbonate / acetonitrile / 8 h / 25 - 80 °C 8: sodium hydroxide; water monomer / methanol / 20 h / 25 - 60 °C
Multi-step reaction with 7 steps 1.1: Aluminum Chloride / dichloromethane / 0 - 5 °C / Inert atmosphere 1.2: 1 h / 0 - 5 °C / Inert atmosphere 2.1: triethylsilane / acetonitrile / 10 - 15 °C 2.2: 10 - 45 °C 3.1: boron tribromide / dichloromethane / 0 - 5 °C 4.1: triethylamine / dichloromethane / 0 - 5 °C 5.1: n-butyllithium / tetrahydrofuran / -75 - -70 °C / Inert atmosphere 5.2: 12 h / -75 - 35 °C / Inert atmosphere 6.1: triethylsilane; boron trifluoride diethyl ether complex / dichloromethane / -70 - 35 °C 7.1: Cs2CO3 / 25 - 40 °C
Multi-step reaction with 9 steps 1.1: Aluminum Chloride / dichloromethane / 0 - 5 °C / Inert atmosphere 1.2: 1 h / 0 - 5 °C / Inert atmosphere 2.1: triethylsilane / acetonitrile / 10 - 15 °C 2.2: 10 - 45 °C 3.1: boron tribromide / dichloromethane / 0 - 5 °C 4.1: triethylamine / dichloromethane / 0 - 5 °C 5.1: n-butyllithium / tetrahydrofuran / -75 - -70 °C / Inert atmosphere 5.2: 12 h / -75 - 35 °C / Inert atmosphere 6.1: triethylsilane / dichloromethane; acetonitrile / 1 h / 25 - 35 °C / Inert atmosphere 6.2: 0.5 h / -40 - -5 °C / Inert atmosphere 7.1: N-ethyl-N,N-diisopropylamine; dmap / tetrahydrofuran / 0 - 35 °C 8.1: lithium hydroxide monohydrate; water monomer / tetrahydrofuran; methanol / 1 h / 15 - 20 °C 9.1: Cs2CO3 / 25 - 40 °C
Multi-step reaction with 6 steps 1: Aluminum Chloride / dichloromethane / 5 h / 0 - 20 °C 2: potassium-t-butoxide / tetrahydrofuran / 2 h / 0 - 10 °C 3: Aluminum Chloride; potassium borohydrate / tetrahydrofuran / 6 h / 20 °C 4: palladium (II) [1,1'-bis(diphenylphosphanyl)ferrocene] dichloride; anhydrous potassium acetate / 1,4-dioxane / 8 h / 8 °C / Inert atmosphere 5: tetrakis-(triphenylphosphine)-palladium; potassium dihydrogen orthophosphate / toluene / 12 h / 105 °C 6: sodium hydroxide / methanol / 1 h / 20 °C
Multi-step reaction with 4 steps 1.1: Aluminum Chloride / dichloromethane / 5 h / 15 - 20 °C 2.1: potassium-t-butoxide / tetrahydrofuran / 0.5 h / 5 - 10 °C / Inert atmosphere 2.2: 3 h / 5 - 25 °C / Inert atmosphere 3.1: Aluminum Chloride; 1,1,3,3-Tetramethyldisiloxane / 3 h / 5 - 30 °C 4.1: n-butyllithium / tetrahydrofuran; hexane / 0.67 h / Cooling 4.2: 1 h / Cooling 4.3: 15 h / 20 - 25 °C
Multi-step reaction with 5 steps 1.1: Aluminum Chloride / dichloromethane / 5 h / 15 - 20 °C 2.1: potassium-t-butoxide / tetrahydrofuran / 0.5 h / 5 - 10 °C / Inert atmosphere 2.2: 3 h / 5 - 25 °C / Inert atmosphere 3.1: Aluminum Chloride; 1,1,3,3-Tetramethyldisiloxane / 3 h / 5 - 30 °C 4.1: n-butyllithium / tetrahydrofuran; hexane / 0.67 h / Cooling 4.2: 1 h / Cooling 4.3: 15 h / 20 - 25 °C 5.1: Aluminum Chloride; triethylsilane / dichloromethane; acetonitrile / 2.25 h / 20 - 25 °C

  • 28
  • [ 1198-69-2 ]
  • [ 864070-44-0 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1: 4-methyl-morpholine / tetrahydrofuran / 1 h / -10 - 45 °C 2: n-butyllithium / tetrahydrofuran; toluene; hexane / 2 h / -78 - -65 °C / Inert atmosphere 3: boron trifluoride diethyl etherate; triethylsilane / dichloromethane; acetonitrile / -20 - 0 °C
Multi-step reaction with 3 steps 1: N-ethyl-N,N-diisopropylamine / tetrahydrofuran / 1 h / -10 - 45 °C 2: n-butyllithium / tetrahydrofuran; toluene; hexane / 2 h / -78 - -65 °C / Inert atmosphere 3: boron trifluoride diethyl etherate; triethylsilane / dichloromethane; acetonitrile / -20 - 0 °C
  • 29
  • C30H66O6Si4 [ No CAS ]
  • [ 864070-44-0 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: n-butyllithium / tetrahydrofuran; toluene; hexane / 2 h / -78 - -65 °C / Inert atmosphere 2: boron trifluoride diethyl etherate; triethylsilane / dichloromethane; acetonitrile / -20 - 0 °C
  • 30
  • C25H31ClO8 [ No CAS ]
  • [ 864070-44-0 ]
YieldReaction ConditionsOperation in experiment
71.7% With triethylsilane; boron trifluoride diethyl etherate In dichloromethane; acetonitrile at -20 - 0℃; 6 Example 6 To 100mL three-necked flask was added 4.66g of intermediate -4,20ml methylene chloride, 15ml of acetonitrile, stirred to dissolve, cooled to -15 to -20 deg.] C, was added 6.84g of triethylsilane was added dropwise 8.15g 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 3.04g Yipa column net yield of 71.7%.
  • 31
  • C18H42O6Si4 [ No CAS ]
  • [ 864070-44-0 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: n-butyllithium / tetrahydrofuran; toluene; hexane / 2 h / -78 - -65 °C / Inert atmosphere 2: boron trifluoride diethyl etherate; triethylsilane / dichloromethane; acetonitrile / -20 - 0 °C
Multi-step reaction with 2 steps 1.1: n-butyllithium / tetrahydrofuran; hexane / 0.83 h / -60 - -50 °C / Inert atmosphere 1.2: -50 °C / Inert atmosphere 1.3: 0 - 20 °C 2.1: triethylsilane; boron trifluoride diethyl etherate / acetonitrile / 0 - 25 °C / Inert atmosphere; Large scale
Multi-step reaction with 2 steps 1.1: n-butyllithium / tetrahydrofuran; hexane / 0.83 h / -60 - -50 °C / Inert atmosphere 1.2: -50 °C / Inert atmosphere 1.3: 0 - 20 °C 2.1: triethylsilane; boron trifluoride diethyl etherate / acetonitrile / 0 - 25 °C / Inert atmosphere; Large scale
  • 32
  • [ 864070-44-0 ]
  • [ 147-85-3 ]
  • (1S)-1,5-anhydro-1-C-[4-chloro-3-[[4-[[(3S)-tetrahydro-3-furanyl]oxy]phenyl]methyl]phenyl]-D-glucitol L-proline [ No CAS ]
YieldReaction ConditionsOperation in experiment
5.9 g In ethanol Reflux; 2 Example 2 Preparation of the complex of empagliflozin with proline in ethanol Example 2 Preparation of the complex of empagliflozin with proline in ethanol Empagliflozin (5 g) was stirred up together with (L)-proline (1.3 g) in 40 ml of ethanol. This mixture was heated up to moderate reflux until dissolution. The resulting clear solution was then left to cool down to the laboratory temperature and crystallize overnight in a refrigerator. The solid fraction was filtered. 5.9 g of a white crystalline substance was obtained.
In dichloromethane; isopropyl alcohol at 20 - 40℃; 11 Preparation of crystalline Form A of Empagliflozin L-proline complex To 1.0 gm of L-Proline, 5 mL of isopropyl alcohol was added and heated to 40 °C. To the obtained slurry was added slurry of lgm Empagliflozin in lOmL of dichloromethane at 30 °C to 40 °C. The reaction mixture was stirred for 2 hrs at 20 °C to 30 °C, filtered and dried under vacuum at 50 °C to yield 1.5 gm of crystalline Form A of Empagliflozin L-proline complex.
  • 33
  • 2,3,4,6-tetra-O-benzyl-1-deoxy-1-((S)-(4-chloro-3-(4-(tetrahydrofuran-3-yl)oxy)benzyl)phenyl)-β-D-glucopyranose [ No CAS ]
  • [ 864070-44-0 ]
YieldReaction ConditionsOperation in experiment
80% With palladium 10% on activated carbon; hydrogen In methanol at 20℃; for 18h; 6 Example 6 Preparation of empagliflozin Intermediate IV (19.2 g, 23.6 mmol) obtained in Example 4 was dissolved in 50 mL of methanol, and 1.0 g of 10% Pd-C was added to obtain a mixed solution.The mixture was hydrogenated at room temperature for 18 hours.After the completion of the reaction, the resulting filtrate was concentrated under reduced pressure. To the resulting residue was added isopropyl acetate, the temperature was raised to 45C, and then cooled to 0C. A solid precipitated and was filtered. The resulting cake was washed with isopropyl acetate , And dried to obtain 8.5 g of a white solid product. The yield was 80%, and the purity was 99%.
  • 34
  • [ 108-95-2 ]
  • [ 864070-44-0 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1: caesium carbonate / N,N-dimethyl-formamide / 20 h / 20 °C 2: tetrabutyl ammonium fluoride / chloroform / 15 h / 80 °C 3: palladium 10% on activated carbon; hydrogen / methanol / 18 h / 20 °C
Multi-step reaction with 5 steps 1.1: polyphosphoric acid / 50 - 85 °C 2.1: potassium iodide; potassium carbonate / acetonitrile / 50 - 55 °C 3.1: potassium borohydride; aluminium trichloride / tetrahydrofuran / 0.5 h / 0 - 20 °C 4.1: TurboGrignard / tetrahydrofuran / 0.5 h / -10 - 0 °C / Cooling with ice; Inert atmosphere 4.2: 40 - 50 °C / Inert atmosphere 5.1: potassium carbonate / tetrahydrofuran / 40 - 45 °C
Multi-step reaction with 5 steps 1.1: polyphosphoric acid / 50 - 85 °C 2.1: potassium iodide; potassium carbonate / acetonitrile / 50 - 55 °C 3.1: potassium borohydride; aluminium trichloride / tetrahydrofuran / 0.5 h / 0 - 20 °C 4.1: TurboGrignard / tetrahydrofuran / -10 - 0 °C / Cooling with ice; Inert atmosphere 4.3: 40 - 50 °C / Inert atmosphere 5.1: lithium hydroxide / ethanol; water / 40 - 45 °C
  • 35
  • [ 637-87-6 ]
  • [ 864070-44-0 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 4 steps 1.1: n-butyllithium / tetrahydrofuran; toluene; hexane / 0.5 h / -78 °C 1.2: 2 h / -78 °C 1.3: 5 h / -78 - 20 °C / pH 7.5 2.1: triethylsilane; aluminum (III) chloride / dichloromethane; acetonitrile / 3 h / -10 - 0 °C 3.1: tetrabutyl ammonium fluoride / chloroform / 15 h / 80 °C 4.1: palladium 10% on activated carbon; hydrogen / methanol / 18 h / 20 °C
  • 36
  • [ 13096-62-3 ]
  • [ 864070-44-0 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 4 steps 1.1: n-butyllithium / tetrahydrofuran; toluene; hexane / 0.5 h / -78 °C 1.2: 2 h / -78 °C 1.3: 5 h / -78 - 20 °C / pH 7.5 2.1: triethylsilane; aluminum (III) chloride / dichloromethane; acetonitrile / 3 h / -10 - 0 °C 3.1: tetrabutyl ammonium fluoride / chloroform / 15 h / 80 °C 4.1: palladium 10% on activated carbon; hydrogen / methanol / 18 h / 20 °C
  • 37
  • C40H39ClO6 [ No CAS ]
  • [ 864070-44-0 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1: triethylsilane; aluminum (III) chloride / dichloromethane; acetonitrile / 3 h / -10 - 0 °C 2: tetrabutyl ammonium fluoride / chloroform / 15 h / 80 °C 3: palladium 10% on activated carbon; hydrogen / methanol / 18 h / 20 °C
  • 38
  • [ 90-80-2 ]
  • [ 864070-44-0 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1.1: 4-methyl-morpholine / tetrahydrofuran / 20 °C / Inert atmosphere 2.1: isopropylmagnesium chloride; lithium chloride / tetrahydrofuran / 0.5 h / 20 °C / Inert atmosphere 2.2: 1 h / -25 °C / Inert atmosphere 3.1: aluminum (III) chloride; triethylsilane / dichloromethane; acetonitrile / 20 - 25 °C
Multi-step reaction with 5 steps 1.1: 4-methyl-morpholine / tetrahydrofuran / -5 - 30 °C / Large scale 2.1: n-butyllithium / tetrahydrofuran; toluene; hexane / -80 - -70 °C / Inert atmosphere; Large scale 2.2: -80 - -70 °C / Large scale 2.3: 20 - 30 °C / Large scale 3.1: dmap / dichloromethane; pyridine / -5 - 30 °C / Large scale 4.1: boron trifluoride diethyl etherate; triethylsilane / acetonitrile; water / 0 - 10 °C / Large scale 5.1: lithium hydroxide / tetrahydrofuran; methanol / 10 - 40 °C
Multi-step reaction with 7 steps 1: 4-methyl-morpholine / tetrahydrofuran 2: n-butyllithium / tetrahydrofuran; toluene 3: dmap; N-ethyl-N,N-diisopropylamine / toluene / 6 h / 20 °C / Inert atmosphere 4: triethylsilane; boron trifluoride diethyl etherate / acetonitrile; water / 0.83 h / 15 °C / Inert atmosphere; Cooling with ice 5: aluminum (III) chloride / dichloromethane / 3 h / 5 - 20 °C / Inert atmosphere 6: potassium <i>tert</i>-butylate / tetrahydrofuran / 8 h / Inert atmosphere; Reflux 7: aluminum (III) chloride; sodium tetrahydroborate / tetrahydrofuran / 36 h / 50 °C / Inert atmosphere; Reflux
Multi-step reaction with 8 steps 1: 4-methyl-morpholine / tetrahydrofuran 2: n-butyllithium / tetrahydrofuran; toluene 3: dmap; N-ethyl-N,N-diisopropylamine / toluene / 6 h / 20 °C / Inert atmosphere 4: triethylsilane; boron trifluoride diethyl etherate / acetonitrile; water / 0.83 h / 15 °C / Inert atmosphere; Cooling with ice 5: aluminum (III) chloride / dichloromethane / 3 h / 5 - 20 °C / Inert atmosphere 6: potassium <i>tert</i>-butylate / tetrahydrofuran / 8 h / Inert atmosphere; Reflux 7: sodium hydroxide; methanol / 8 h / 20 °C 8: triethylsilane; boron trifluoride diethyl etherate / acetonitrile; water / 0.83 h / 15 °C / Inert atmosphere; Cooling with ice
Multi-step reaction with 4 steps 1.1: pyridine / dichloromethane / -20 °C / Inert atmosphere; Large scale 1.2: 7 h / 10 °C / Large scale 2.1: lithium chloride; isopropylmagnesium chloride / acetonitrile / 1 h / -20 - -15 °C / Large scale 2.2: 8 h / -10 - 0 °C / Large scale 3.1: trifluoroacetic acid / 5 h / 20 °C / Large scale 4.1: iron(III) chloride; triethylsilane / acetonitrile / 5 h / 20 °C / Large scale
Multi-step reaction with 3 steps 1.1: dmap / tetrahydrofuran / 0 - 20 °C / Inert atmosphere 2.1: n-butyllithium / tetrahydrofuran; hexane / 0.83 h / -60 - -50 °C / Inert atmosphere 2.2: -50 °C / Inert atmosphere 2.3: 0 - 20 °C 3.1: triethylsilane; boron trifluoride diethyl etherate / acetonitrile / 0 - 25 °C / Inert atmosphere; Large scale
Multi-step reaction with 3 steps 1.1: dmap / tetrahydrofuran / 0 - 20 °C / Inert atmosphere 2.1: n-butyllithium / tetrahydrofuran; hexane / 0.83 h / -60 - -50 °C / Inert atmosphere 2.2: -50 °C / Inert atmosphere 2.3: 0 - 20 °C 3.1: triethylsilane; boron trifluoride diethyl etherate / acetonitrile / 0 - 25 °C / Inert atmosphere; Large scale

  • 39
  • [ 1417573-74-0 ]
  • [ 864070-44-0 ]
YieldReaction ConditionsOperation in experiment
57% With triethylsilane; aluminum (III) chloride In dichloromethane; acetonitrile at 20 - 25℃; 1.3 Step 3 to synthesize the Engeli net, the specific method is as follows: (1) Aluminum trichloride (6) was added to the reaction flask, 200 ml of methylene chloride was added, System for the suspension, The reaction system was cooled, And added dropwise acetonitrile 200 ml (2) To the reaction flask was added triethylsilane 36. 2 g. (3) in 10 ~ 15 minutes of time, A solution of compound 3 (l-C- [4-chloro-3 - [[4 - [[(3S) _tetrahydro-3-furanyl] oxy] phenyl] methyl] phenyl] -D-pyran grapes Glycosides, 50 g) in dichloromethane and acetonitrile. (4) control the temperature of the reaction system at 20 ~ 25 ° C under the conditions of reaction, HPLC monitoring reaction. (5) After the reaction is complete, The reaction system is cooled to 0 to 5 ° C, Dropping purified water, Quenching reaction. (6) After the quenching reaction is complete, The organic solvent was removed by concentration under reduced pressure, Ethyl acetate was added, Purified water was washed , And the ethyl acetate was concentrated under reduced pressure to give an oil. (7) To the oil was added ethyl acetate at 35 to 45 ° C with stirring for 1 to 2 hours, And then naturally to 18 ~ 22 ° C stirring 2 ~ 3 hours, filter, Ethyl acetate Wash the filter cake, Take the net weight of 30 grams. The yield was 57% The purity of the liquid was 94%.
  • 40
  • [ 864070-44-0 ]
  • [ 4043-87-2 ]
  • empagliflozin DL-pipecolic acid [ No CAS ]
YieldReaction ConditionsOperation in experiment
12.8 g In butan-1-ol at 80℃; 29 EXAMPLE 29: Preparation of empagliflozin DL-pipecolic acid co-crystals. To a round bottom flask equipped with reflux condenser, Empagliflozin (10 gm), DLpipecolic acid (5.75 gm) and n-butanol (100 ml) were added and raised the temperature to 80°C. DM water (5 ml) was added and stined the reaction mass for 30 mm. The resulted clearsolution was allowed to cool to 25°C and stirred for 30 mm. The suspension was further allowed to cool to 3°C, filtered the product and washed with n-butanol (20 ml). The obtained solid was dried under vacuum for 8 hrs at 40°C to obtain empagliflozin DL-pipecolic acid cocrystals (12.8 gms).The PXRD is set forth in Figure 21, The ‘H NMR is set forth in Figure 22, The DSCthermogram is set forth in Figure 23, The TGA is set forth in Figure 24.
  • 41
  • (2S,3R,4S,5S,6R)-2-(4-chloro-3-(4-methoxybenzyl)phenyl)-6-(hydroxymethyl)-2-hydroxytetrahydro-2H-pyran-3,4,5-triol [ No CAS ]
  • [ 864070-44-0 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 5 steps 1: triethylsilane; boron trifluoride diethyl etherate / dichloromethane; acetonitrile / 1 h / 0 - 30 °C 2: dmap / dichloromethane / 4 h / 25 - 30 °C 3: 1-dodecylthiol; aluminum (III) chloride / dichloromethane / 3 h / 15 - 30 °C 4: potassium carbonate / acetonitrile / 8 h / 25 - 80 °C 5: sodium hydroxide; water / methanol / 20 h / 25 - 60 °C
  • 42
  • [ 333359-90-3 ]
  • [ 864070-44-0 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 4 steps 1: dmap / dichloromethane / 4 h / 25 - 30 °C 2: 1-dodecylthiol; aluminum (III) chloride / dichloromethane / 3 h / 15 - 30 °C 3: potassium carbonate / acetonitrile / 8 h / 25 - 80 °C 4: sodium hydroxide; water / methanol / 20 h / 25 - 60 °C
  • 43
  • (2R,3R,4R,5S,6S)-2-(acetoxymethyl)-6-(4-chloro-3-(4-methoxybenzyl)phenyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate [ No CAS ]
  • [ 864070-44-0 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1: 1-dodecylthiol; aluminum (III) chloride / dichloromethane / 3 h / 15 - 30 °C 2: potassium carbonate / acetonitrile / 8 h / 25 - 80 °C 3: sodium hydroxide; water / methanol / 20 h / 25 - 60 °C
  • 44
  • [ 1079083-63-8 ]
  • [ 864070-44-0 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: potassium carbonate / acetonitrile / 8 h / 25 - 80 °C 2: sodium hydroxide; water / methanol / 20 h / 25 - 60 °C
  • 45
  • (R)-tetrahydrofuran-3-yl 4-nitrobenzenesulfonate [ No CAS ]
  • (((2S,3S,4R,SR,6R)-2-(4-chloro-3-(4-((trimethylsilyl)oxy)benzyl)phenyl)-6-(((trimethylsilyl)oxy)methyl)tetrahydro-2H-pyran-3,4,5-triyl)tris(oxy))tris(trimethylsilane) [ No CAS ]
  • [ 864070-44-0 ]
YieldReaction ConditionsOperation in experiment
9.4 g With potassium carbonate In acetonitrile at 25 - 80℃; 15 Preparation of D-glucitol, i,5-anhydro-i-C-[4-chloro-3- F [4-[ [(3S)-tetrahydro-3-furanylj oxyl phenyl] methyl] phenyi] -, (15) (Empagliflozin (Formula-i)) Add (((2S,38,4R,5R,6R)-2-(4-chloro-3 -(4-((trimethylsilyl)oxy)benzyl)phenyl)-6-(((trimethylsilyl)oxy)methyl)tetrahydro-2H-pyran-3 ,4,5-triyl)tris(oxy))tris(trimethylsilane)(72 gms) to acetonitrile (720 ml) at 25-30°C and stirred for 10 mm. at the same temperature.(R)-Tetrahydrofuran-3-yl 4-nitrobenzenesulfonate (15.9 gms) and K2C03 (67.0 gms) wereadded to the reaction mixture at 25-30°C and stirred for 10 mm. Heated the reaction mixtureto 75-80°C and stirred for 10-11 hrs at same temperature. Filtered the reaction mixture and washed with acetonitrile. Add water (216 ml), 10% aqueous HC1, acetonitrile (360 ml) to the filtrate and separated the organic and aqueous layers. Extracted the aqueous layer using ethyl acetate. Basify the organic layer with 10% Na2CO3 solution and separated the organic andaqueous layers. Extracted the aqueous layer using ethyl acetate. Distilled off the solvent completely from the organic layer under reduced pressure. Add ethyl acetate (72 ml) to the above obtained compound at 55-60°C and stirred for 90 mm at 25-30°. Filtered the solid compound and washed with ethyl acetate followed by dried under reduce pressure to get the title compound. (Yield: 9.4 gms).
  • 46
  • (R)-tetrahydrofuran-3-yl 4-nitrobenzenesulfonate [ No CAS ]
  • 4-(2-chloro-5-((2S,3S,4R,5R,6R)-3,4,5-tris((trimethylsilyl)oxy)-6-(((trimethylsilyl)oxy)methyl)tetrahydro-2H-pyran-2-yl)benzyl)phenol [ No CAS ]
  • [ 864070-44-0 ]
YieldReaction ConditionsOperation in experiment
2 g With potassium carbonate In acetonitrile at 25 - 80℃; 16 Preparation of D-glucitol, 1,5-anhydro-1 -C-[4-chloro-3- [[4- [[(38)- tetrahydro-3-furanyl]oxy] phenyl] methyl] phenyl] -, (18) (Empagliflozin (Formula-1)) Add 4-(2-chloro-5 -((2S,3S,4R,5R,6R)-3 ,4,5-tris((trimethylsilyl)oxy)-6- (((trimethylsilyl)oxy)methyl)tetrahydro-2H-pyran-2-yl)benzyl)phenol (17 gms) to acetonitrile(170 ml) at 25-30°C and stirred to 10 mm. at the same temperature. (R)-Tetrahydrofuran-3-yl4-nitrobenzenesulfonate (4.2 gms) and K2C03 (17.5 gms) were added to the reaction mixture at 25-30°C. Heated the reaction mixture to 75-80°C and stirred for 9-10 his at the same temperature. Cooled the reaction mixture to 55-60°C and stirred for 3 his at same temperate. Filtered the reaction mixture and washed with hot acetonitrile. Distilled off the solvent fromthe filtrate under reduced pressure. Add water (51 ml), 10% aqueous HC1, ethyl acetate (85 ml) to the distillate and separated the organic and aqueous layers. Extracted the aqueous layer using ethyl acetate. Basify the organic layer with 10% Na2CO3 solution and separated the organic and aqueous layers. Extracted the aqueous layer using ethyl acetate. Distilled off the solvent completely from the organic layer under reduced pressure. Add ethyl acetate (72 ml) to the above obtained compound at 55-60°C and stirred for 90 mm at 25-30°. Filtered the solidcompound and washed with ethyl acetate followed by dried under reduce pressure to get the title compound. (Yield: 2 gms).
  • 47
  • (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 ]
  • [ 864070-44-0 ]
YieldReaction ConditionsOperation in experiment
99% With water; sodium methylate In methanol at 20℃; for 0.166667h; 16-19 Preparation of the final product, Enpagliflozin: Compound 5 (6.2 g, 10 mmol) and methanol (50 mL) were added to a three-necked flask, and after all was dissolved, 1 mol/L methanol/sodium methoxide solution (20 mL) was added, and the reaction was carried out at room temperature for 10 minutes. The pH of the reaction solution was adjusted to 7 with a cation exchange resin (H+ type), the reaction solution was concentrated and recrystallized with a mixed solvent of toluene and ethanol to obtain the final product, Enpagliflozin (4.5 g, 99%), with a purity of 99.69%.
93% With potassium carbonate In tetrahydrofuran at 40 - 45℃; 10 Example 10 The compound 7a (61.91 g, 100 mmol) was added to the three-necked flask, tetrahydrofuran (301 mL) was added, stirred and dissolved, and potassium carbonate (55.28 g, 400 mmol)Plus heating after heating to 40 ~ 45 reaction 2 to 3 hours.The reaction was terminated by removing part of the tetrahydrofuran,Cool to room temperature and add water (301 mL)Ethyl acetate (301 mL) was added twice,The organic phase saturated brine was washed twice (301 mL)Sodium sulfate,filter,After concentration, the product was recrystallized from a mixed solvent of toluene and ethanol Engelie net 8 (41.93g, 93%).
91.7% With sodium hydroxide In methanol at 20℃; for 1h; 6 Example 6. Synthesis of empagliflozin 31 g of a compound of formula 9 was added to the reaction flask,50 ml of methanol, after stirring and dissolving, 50 g of 20% sodium hydroxide solution was added dropwise below 20 ° C. After the dropwise addition, the reaction solution was reacted below 20 ° C for 60 minutes. After the reaction was detected by HPLC, pH = 7 was adjusted with dilute hydrochloric acid and concentrated Methanol, the residue was extracted twice with dichloromethane, the organic layers were combined and concentrated,The residue was purified by adding ethyl acetate and water to obtain 20.7 g. The yield in this step was 91.7%, and HPLC = 99.1%.
89.2% With lithium hydroxide In methanol; water at 0 - 5℃; 5 To a 250 mL three-neck flask was added Compound III (10.0 g, 16.2 mmol), 50 mL of THF, and 40 mL of methanol.After stirring and cooling to 0 to 5°C, 20 mL of an aqueous solution of LiOH (0.21 g, 8.4 mmol) was added dropwise.The reaction was maintained at this temperature, and the reaction was completed by HPLC. Most of the organic solvent was removed under reduced pressure.The aqueous layer was extracted with ethyl acetate (50 mL x 3) and the organic phases were combined and washed sequentially with saturated NH4Cl and NaCl.Dry over anhydrous MgSO4, filter, and concentrate the filtrate under reduced pressure. Stir with EA and toluene.The solid was precipitated, cooled, filtered, and dried under reduced pressure at 30C to give a white or off-white solid (6.5 g) in 89.2% yield. HPLC purity 99.430%.
73.5% With water; potassium hydroxide In ethyl acetate at 30℃; 2 Example 2 Preparation of Egliflozin Erigic acid intermediate ethyl acetate solution(concentration is 0.03kg/L, 500L)Pump 10 mm straight inside at 40 mL/minIn the first Teflon tube reaction tube with a length of 20 meters,Temperature control to 30 degrees,Potassium hydroxide aqueous solution (0.1kg/L)Pump 10 mm straight inside at 20 mL/minIn the second-stage PTFE tube reaction tube 150 meters long,Temperature control to 30 degrees,The reaction solution flows into the vertical reservoir and is stationary.Separate the organic phase,The organic layer was washed once with a 5% aqueous potassium hydrogensulfate solution.After the activated carbon is bleached and filtered,The filtrate is concentrated to a large amount of solids,8.27 kg of Eglegide product was filtered, yield 73.5%.
68.8% With lithium hydroxide In tetrahydrofuran; methanol at 10 - 40℃; 5 Embodiment 5: (1S) - 1, 5 - dehydration -1 - (4 - chloro -3 - {4 - [(3S) - tetrahydrofuran -3 - yloxy] benzyl} phenyl) - D - glucitol To 50L in the reactor by adding 12L tetrahydrofuran, 18L water-free methanol, 6L purified water and embodiment 4 the resulting compound, added under mixing a hydrated hydrogen lithia 195g, temperature control 10 - 40 °C reaction 2.5 - 3 hours. Concentrated under reduced pressure to dry, the residue dissolved in 50L ethyl acetate, for sequentially 10L purified water and 10L 20% sodium chloride aqueous solution washing, and collecting the organic phase with anhydrous sodium sulfate drying, filtering, the filtrate is concentrated under reduced pressure to dry.For residue 18L dichloromethane/methanol mixed solvent heating and dissolving (5/1, v/v), adding dichloromethane 75L, stirring at room temperature for 2 hours, filtered, the filter cake 50 °C vacuum drying 12 hours to obtain title compound 1.25 kg, molar yield 68.8%, HPLC purity 99.8%.
56.5 g With water; sodium hydroxide In methanol at 25 - 60℃; for 20h; 11 Preparation of D-glucitol, l,5-anhydro-i-C-[4-chloro-3-[[4-[ [(38)- tetrahydro-3furanyl] oxy] phenyl] methyl] phenyl] -, (18) (Empagliflozin (Formula-1)) The product of example- 10 (100 gms) and methanol (800 ml) were charged into a RBF at 25-30°C. Added aqueous sodium hydroxide solution (154 gms dissolved in 100 ml ofwater) to the resulted reaction mixture and raised reaction mixture temperature to 65°C and stirred for 20 his at same temperature. Filter the formed reaction mixture with methanol Cooled the reaction mixture to 25-30°C and added water (1000 ml), ethyl acetate (1000 ml). Raised the reaction mixture temperature to 45-50°C and stirred for 45 mins at same temperature. Organic and aqueous layers were separated and distilled off the solventcompletely from theorganic. layer under reduced pressure. Filtered and dried the obtained material to get the title compound. (Yield: 56.5 gms, MR: 147-150°C).
8.6 kg With methanol; lithium hydroxide monohydrate In tetrahydrofuran; water at 30℃; for 2h; Large scale; 1.4; 2.4; 3.4 Step (4): Preparation of empagliflozin Compound (I-1) was dissolved in 30.0Kg of tetrahydrofuran and 13.0Kg of methanol,Add 2.7Kg of purified water and 5.5Kg of lithium hydroxide monohydrate,The reaction was stirred at 30 ° C for 2h.After the reaction, the solution was concentrated to dryness under reduced pressure at 50 ° C.The residue was dissolved in ethyl acetate / water (volume ratio 5: 3) to 50 ° C, and extracted and washed.The organic phase was concentrated to dryness under reduced pressure to give crude empagliflozin.Dissolve the crude englitazone with isopropanol / isopropyl acetate under reflux,Gradient cooling and crystallization.After crystallization, centrifugation and drying yielded empagliflozin 8.60Kg, purity 99.88%.

  • 48
  • [ 864070-44-0 ]
  • [ 147-85-3 ]
  • empagliflozin-L-proline [ No CAS ]
YieldReaction ConditionsOperation in experiment
380 mg In tetrahydrofuran; dichloromethane; chlorobenzene; isopropyl alcohol at 25 - 65℃; for 1h; 22 Preparation of crystalline Form-I of Empagliflozin-L-proline Empagliflozin (500 mg) and L-proline (20 mg), isopropanol (5 ml), dichloromethane (5 ml), chlorobenzene (5 ml) and tetrahydrofuran (5 ml) mixture were charged into a cleanand dry RBF at 25-30°C. Raised the resulting reaction mixture temperature to 60-65°C and stirred for 60 mm at same temperature. Slowly cooled the reaction mixture to 25-30°C and stirred for 5 hrs at same temperature. Filtered the obtained precipitated solid and dried to get the title compound (Yield: 380 mg). .The obtained crystalline Form-I of Empagliflozin-L-proline is characterized by PXRD havingpeaks at about 4.2, 15.6, 18.7, 19.9, 22.3, 31.9, 33.8 ± 0.2 degrees of two-theta as illustrated infigure-4.
  • 49
  • [ 864070-37-1 ]
  • [ 864070-44-0 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: 4-methyl-morpholine / tetrahydrofuran / 0 - 50 °C 2: potassium carbonate / acetonitrile / 25 - 80 °C
  • 50
  • [ 461432-25-7 ]
  • [ 864070-44-0 ]
  • 51
  • [ 333361-49-2 ]
  • [ 864070-44-0 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 7 steps 1: titanium tetrachloride; triethylsilane / dichloromethane / 4.25 h / 0 - 30 °C 2: n-butyllithium / tetrahydrofuran / 3.33 h / -75 - 30 °C / Inert atmosphere 3: triethylsilane; boron trifluoride diethyl etherate / dichloromethane; acetonitrile / 1 h / 0 - 30 °C 4: dmap / dichloromethane / 4 h / 25 - 30 °C 5: 1-dodecylthiol; aluminum (III) chloride / dichloromethane / 3 h / 15 - 30 °C 6: potassium carbonate / acetonitrile / 8 h / 25 - 80 °C 7: sodium hydroxide; water / methanol / 20 h / 25 - 60 °C
  • 52
  • 4-bromo-1-chloro-2-(4-methoxybenzyl)benzene [ No CAS ]
  • [ 864070-44-0 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 6 steps 1: n-butyllithium / tetrahydrofuran / 3.33 h / -75 - 30 °C / Inert atmosphere 2: triethylsilane; boron trifluoride diethyl etherate / dichloromethane; acetonitrile / 1 h / 0 - 30 °C 3: dmap / dichloromethane / 4 h / 25 - 30 °C 4: 1-dodecylthiol; aluminum (III) chloride / dichloromethane / 3 h / 15 - 30 °C 5: potassium carbonate / acetonitrile / 8 h / 25 - 80 °C 6: sodium hydroxide; water / methanol / 20 h / 25 - 60 °C
  • 53
  • [ 864070-44-0 ]
  • [ 73-22-3 ]
  • (1S)-1,5-anhydro-1-C-[4-chloro-3-[[4-[[(3S)-tetrahydro-3-furanyl]oxy]phenyl]methyl]phenyl]-D-glucitol tryptophan [ No CAS ]
YieldReaction ConditionsOperation in experiment
19.6 g In isopropyl alcohol at 50 - 55℃; for 1h; 6 Preparation of crystalline Empagliflozin Tryptophan complex To 10.0 gm of Empagliflozin in 60 mL of isopropyl alcohol was added 9gm of tryptophan. The obtained slurry was heated to 50 °C to 55 °C and stirred for lhr. Thereafter the reaction mixture was cooled to 20 °C to 30 °C, filtered and dried under vacuum at 45 °C to yield 19.6 gm of crystalline Empagliflozin tryptophan complex.
  • 54
  • (1S)-1,5-anhydro-1-C-[4-chloro-3-[[4-[[(3S)-tetrahydro-3-furanyl]oxy]phenyl]methyl]phenyl]-D-glucitol L-proline [ No CAS ]
  • [ 864070-44-0 ]
YieldReaction ConditionsOperation in experiment
9 mg In water; ethyl acetate at 25 - 50℃; 4 Preparation of pure crystalline Empagliflozin A mixture of 20 gm of crystalline Form A of Empagliflozin L-proline complex in 120 mL ethylacetate and 100 mL water was stirred at 25 °C to 50°C for 45 to 60 min. Thereafter the layers were separated and the aqueous layer was extracted with 25 mL ethylacetate. The combined organic layer was washed with 25 mL water and concentrated to afford 10.2 gm solid. The solid thus obtained was mixed with 70 mL ethylacetate and 10 mL water and was heated to 60°C to 70°C to obtain a clear solution. Thereafter the solution was cooled to 20°C to 30°C, followed by filtration and drying under vacuum to afford 9 gm of pure crystalline Empagliflozin.
  • 56
  • (3R,4S,5R,6R)-3,4,5-tris((trimethylsilyl)oxy)-6-(((trimethylsilyl)oxy)methyl)tetrahydro-2H-pyran-2-one [ No CAS ]
  • [ 864070-44-0 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 4 steps 1.1: n-hexyllithium / tetrahydrofuran; toluene / -100 - -90 °C 1.2: -100 - -90 °C 1.3: -90 - 15 °C 2.1: trimethylsilane; boron trifluoride diethyl ether complex / dichloromethane; acetonitrile / -40 - -30 °C 3.1: isopropanol; dichloromethane / 40 - 50 °C 4.1: ethyl acetate; lithium hydroxide monohydrate / 25 - 50 °C
Multi-step reaction with 3 steps 1.1: n-butyllithium / 2-methyltetrahydrofuran; hexane / 2 h / -78 °C 1.2: 20 h / 20 - 45 °C 2.1: triethylsilane; boron trifluoride diethyl ether complex / dichloromethane; acetonitrile / 2 h / -15 - 5 °C 3.1: sodium tetrahydridoborate / tetrahydrofuran / 1.5 h / 0 - 20 °C 3.2: 0 °C 3.3: 0 - 5 °C
Multi-step reaction with 4 steps 1.1: n-butyllithium / tetrahydrofuran; toluene; hexane / -80 - -70 °C / Inert atmosphere; Large scale 1.2: -80 - -70 °C / Large scale 1.3: 20 - 30 °C / Large scale 2.1: 4-dimethylaminopyridine / dichloromethane; pyridine / -5 - 30 °C / Large scale 3.1: boron trifluoride diethyl ether complex; triethylsilane / acetonitrile; lithium hydroxide monohydrate / 0 - 10 °C / Large scale 4.1: lithium hydroxide monohydrate / tetrahydrofuran; methanol / 10 - 40 °C
Multi-step reaction with 6 steps 1: n-butyllithium / tetrahydrofuran; toluene 2: 4-dimethylaminopyridine; N-ethyl-N,N-diisopropylamine / toluene / 6 h / 20 °C / Inert atmosphere 3: triethylsilane; boron trifluoride diethyl ether complex / acetonitrile; lithium hydroxide monohydrate / 0.83 h / 15 °C / Inert atmosphere; Cooling with ice 4: Aluminum Chloride / dichloromethane / 3 h / 5 - 20 °C / Inert atmosphere 5: potassium-t-butoxide / tetrahydrofuran / 8 h / Inert atmosphere; Reflux 6: Aluminum Chloride; sodium tetrahydridoborate / tetrahydrofuran / 36 h / 50 °C / Inert atmosphere; Reflux
Multi-step reaction with 7 steps 1: n-butyllithium / tetrahydrofuran; toluene 2: 4-dimethylaminopyridine; N-ethyl-N,N-diisopropylamine / toluene / 6 h / 20 °C / Inert atmosphere 3: triethylsilane; boron trifluoride diethyl ether complex / acetonitrile; lithium hydroxide monohydrate / 0.83 h / 15 °C / Inert atmosphere; Cooling with ice 4: Aluminum Chloride / dichloromethane / 3 h / 5 - 20 °C / Inert atmosphere 5: potassium-t-butoxide / tetrahydrofuran / 8 h / Inert atmosphere; Reflux 6: sodium hydroxide; methanol / 8 h / 20 °C 7: triethylsilane; boron trifluoride diethyl ether complex / acetonitrile; lithium hydroxide monohydrate / 0.83 h / 15 °C / Inert atmosphere; Cooling with ice
Multi-step reaction with 3 steps 1.1: lithium chloride; isopropylmagnesium chloride lithium chloride / acetonitrile / 1 h / -20 - -15 °C / Large scale 1.2: 8 h / -10 - 0 °C / Large scale 2.1: trifluoroacetic acid / 5 h / 20 °C / Large scale 3.1: ferric(III) chloride; triethylsilane / acetonitrile / 5 h / 20 °C / Large scale
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; 4-dimethylaminopyridine / 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; lithium hydroxide monohydrate / 2 h / 30 °C / Large scale
Multi-step reaction with 3 steps 1.1: isopropylmagnesium chloride lithium chloride complex / tetrahydrofuran / 1 h / -30 - -20 °C / Inert atmosphere 1.2: 0.5 h / Inert atmosphere 2.1: hydrogenchloride / lithium hydroxide monohydrate / 1 h / 20 - 30 °C 3.1: Aluminum Chloride; triethylsilane / dichloromethane; acetonitrile
Multi-step reaction with 3 steps 1.1: boron trifluoride diethyl ether complex; n-butyllithium / toluene; hexane / -80 - 40 °C / Inert atmosphere 2.1: methanol / -80 - 40 °C / Inert atmosphere 3.1: Aluminum Chloride / acetonitrile; dichloromethane / 0 - 10 °C / Inert atmosphere 3.2: 0 - 25 °C / Inert atmosphere
Multi-step reaction with 3 steps 1.1: n-butyllithium / tetrahydrofuran; toluene; hexane / 1 h / -80 - -70 °C / Inert atmosphere; Large scale 1.2: 1 h / -80 - 70 °C / Large scale 1.3: 2 h / 20 °C / Large scale 2.1: methanesulfonic acid / 3 h / Large scale 3.1: triethylsilane; boron trifluoride diethyl ether complex / acetonitrile; dichloromethane / 20 - 30 °C / Large scale

  • 57
  • C43H59ClO11 [ No CAS ]
  • [ 864070-44-0 ]
YieldReaction ConditionsOperation in experiment
87% With lithium hydroxide In ethanol; water at 40 - 45℃; 11 Example 11 The three-necked flask was added with the compound7b (78.74 g, 100 mmol),Anhydrous ethanol (236 mL) was added,After stirring, 20% aqueous lithium hydroxide solution (96 g, 800 mmol) was added,Plus heating after heating to 40 ~ 45 reaction 2 to 3 hours.Reaction end part of the spin,Cool to room temperature and add water (236 mL)Ethyl acetate (236 mL) was added twice,The organic phase saturated brine was washed twice (236 mL)Sodium sulfate,filter,After concentrating, the product was recrystallized with a mixed solvent of toluene and ethanol to give the product nigrine net 8 (39.23 g, 87%).
  • 58
  • C51H43ClO11 [ No CAS ]
  • [ 864070-44-0 ]
YieldReaction ConditionsOperation in experiment
90% With sodium methylate In tetrahydrofuran at 40 - 45℃; 12 Example 12 The compound 7c (86.73 g, 100 mmol) was added to the three-necked flask, tetrahydrofuran (433 mL) was added, and the mixture was stirred and dissolved Sodium methoxide (54 g, 1000 mmol) was added,Plus heating after heating to 40 ~ 45 reaction 2 to 3 hours.After completion of the reaction, tetrahydrofuran was removed, and the mixture was cooled to room temperature and water (433 mL) was added. The mixture was extracted with ethyl acetate (433 mL) and extracted twice. Washed twice (433 mL), dried over sodium sulfate, filtered, concentrated and recrystallized from a mixed solvent of toluene and ethanol. Net 8 (40.58g, 90%).
  • 59
  • [ 1360568-68-8 ]
  • [ 864070-44-0 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 4 steps 1.1: potassium iodide; potassium carbonate / acetonitrile / 50 - 55 °C 2.1: potassium borohydride; aluminium trichloride / tetrahydrofuran / 0.5 h / 0 - 20 °C 3.1: TurboGrignard / tetrahydrofuran / 0.5 h / -10 - 0 °C / Cooling with ice; Inert atmosphere 3.2: 40 - 50 °C / Inert atmosphere 4.1: potassium carbonate / tetrahydrofuran / 40 - 45 °C
Multi-step reaction with 4 steps 1.1: potassium iodide; potassium carbonate / acetonitrile / 50 - 55 °C 2.1: potassium borohydride; aluminium trichloride / tetrahydrofuran / 0.5 h / 0 - 20 °C 3.1: TurboGrignard / tetrahydrofuran / -10 - 0 °C / Cooling with ice; Inert atmosphere 3.3: 40 - 50 °C / Inert atmosphere 4.1: lithium hydroxide / ethanol; water / 40 - 45 °C
  • 60
  • [2-chloro-5-[(3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)-2 methoxy-tetrahydropyran-2-yl]phenyl]-[4-[(3S)-tetrahydrofuran-3-yl]oxyphenyl]methanone [ No CAS ]
  • [ 864070-44-0 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1.1: triethylsilane; boron trifluoride diethyl etherate / dichloromethane; acetonitrile / 2 h / -15 - 5 °C 2.1: sodium tetrahydroborate / tetrahydrofuran / 1.5 h / 0 - 20 °C 2.2: 0 °C 2.3: 0 - 5 °C
Multi-step reaction with 3 steps 1: 4-methyl-morpholine; dmap / ethyl acetate / 4 h / 5 - 30 °C / Inert atmosphere; Large scale 2: phenylsilane; aluminum (III) chloride / acetonitrile / 6 h / 45 °C / Inert atmosphere; Large scale 3: lithium hydroxide monohydrate; methanol / tetrahydrofuran; water / 2 h / 30 °C / Large scale
  • 61
  • (2-chloro-5-((2S,3R,4R,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)phenyl) (4-(((S)-tetrahydrofuran-3-yl)oxy)phenyl)methanone [ No CAS ]
  • [ 864070-44-0 ]
YieldReaction ConditionsOperation in experiment
81 mg Stage #1: (2-chloro-5-((2S,3R,4R,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)phenyl) (4-(((S)-tetrahydrofuran-3-yl)oxy)phenyl)methanone With sodium tetrahydroborate In tetrahydrofuran at 0 - 20℃; for 1.5h; Stage #2: With water In tetrahydrofuran at 0℃; Stage #3: With triethylsilane; boron trifluoride diethyl etherate In dichloromethane; acetonitrile at 0 - 5℃; 4 Preparation of (2S,3R,4R,5S,6R)-2-[4-chloro-3-[[4-[(3S)-tetrahydrofuran-3-yl]oxyphenyl]methyl]phenyl]-6-(hydroxymethyl)tetrahydropyran-3,4,5-triol Example 4 Preparation of (2S,3R,4R,5S,6R)-2-[4-chloro-3-[[4-[(3S)-tetrahydrofuran-3-yl]oxyphenyl]methyl]phenyl]-6-(hydroxymethyl)tetrahydropyran-3,4,5-triol To a suspension of (2S,3R,4R,5S,6R)-2-[4-chloro-3-[[4-[(3S)-tetrahydrofuran-3-yl]oxyphenyl]methyl]phenyl]-6-(hydroxymethyl)tetrahydropyran-3,4,5-triol (100 mg, 0.215 mmol, 1.0 equiv.) in THF (2 mL) at 0° C. was slowly added NaBH4 (16.3 mg, 0.431 mmol, 2.0 equiv.). The reaction mixture was stirred at 0° C. for 0.5 h and at RT for 1 h, and then quenched with H2O at 0° C. The resultants were extracted 2 * with EtOAc. The combined organic layers were washed with brine and dried over Na2SO4. After concentration the obtained crude white solid was dissolved in DCM (1 mL) and ACN (1 mL) and added Et3SiH (80 μL, 0.501 mmol, 2.34 equiv.) and followed by BF3Et2O (66 μL, 0.535 mmol, 2.50 equiv.) at 0-5° C. When HPLC analysis indicated the reaction was complete, the reaction was quenched by addition of EtOAc and sat'd aq NaHCO3. The resultants were concentrated to remove the organic solvents prior to being extracted 3 * with EtOAc. The combined organic layers were washed with brine and dried over Na2SO4. After concentration the crude oil was crystallization from IPAc to yield 81 mg of the title compound as a white solid.
With triethylsilane; boron trifluoride diethyl etherate In water; acetonitrile at 15℃; for 0.833333h; Inert atmosphere; Cooling with ice; 7 General Procedure B (Carbonyl Reduction) to Prepare Empagliflozin (VIII) General procedure: A solution of (2-chloro-5-((2S,3R,4R,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetra hydro-2H-pyran-2-yl) phenyl) (4-(((S)-tetrahydrofuran-3-yl) oxy) phenyl) methanone from example 5 (10 mmol) in CH3CN (60 mL) was prepared at room temperature under nitrogen atmosphere and 1 mol equivalent of water was added. The solution was cooled in an ice bath and Et3SiH (36 mmol) was added. To this solution was added BF3.Et2O (28 mmol) over 30 min, and the mixture was allowed to warm to 15° C. over 20 min. Upon completion, the reaction was quenched with aqueous saturated NaHCO3 (35 mL); the pH of the aqueous layer was 7. The organic layer was washed with brine (60 mL) and the solution was dried (Na2SO4). The mixture was filtered and the solvent was evaporated to obtain the crude product which was chromatographed on silica gel (60-120 mesh) beginning 5% acetonitrile in dichloromethane and gradually increased the polarity to 50% acetonitrile in dichloromethane. The product fractions were distilled off under vacuum at 45° C. to obtain empagliflozin in amorphous form.
  • 62
  • 2-(2-chloro-5-iodo-phenyl)-2-[4-[(3S)-tetrahydrofuran-3-yl]oxyphenyl]-1,3-dioxolane [ No CAS ]
  • [ 864070-44-0 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1.1: n-butyllithium / 2-methyltetrahydrofuran; hexane / 2 h / -78 °C 1.2: 20 h / 20 - 45 °C 2.1: triethylsilane; boron trifluoride diethyl etherate / dichloromethane; acetonitrile / 2 h / -15 - 5 °C 3.1: sodium tetrahydroborate / tetrahydrofuran / 1.5 h / 0 - 20 °C 3.2: 0 °C 3.3: 0 - 5 °C
  • 63
  • [ 461432-22-4 ]
  • [ 864070-44-0 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 6 steps 1.1: triethylsilane / acetonitrile / 10 - 15 °C 1.2: 10 - 45 °C 2.1: boron tribromide / dichloromethane / 0 - 5 °C 3.1: triethylamine / dichloromethane / 0 - 5 °C 4.1: n-butyllithium / tetrahydrofuran / -75 - -70 °C / Inert atmosphere 4.2: 12 h / -75 - 35 °C / Inert atmosphere 5.1: triethylsilane; boron trifluoride diethyl etherate / dichloromethane / -70 - 35 °C 6.1: caesium carbonate / 25 - 40 °C
Multi-step reaction with 8 steps 1.1: triethylsilane / acetonitrile / 10 - 15 °C 1.2: 10 - 45 °C 2.1: boron tribromide / dichloromethane / 0 - 5 °C 3.1: triethylamine / dichloromethane / 0 - 5 °C 4.1: n-butyllithium / tetrahydrofuran / -75 - -70 °C / Inert atmosphere 4.2: 12 h / -75 - 35 °C / Inert atmosphere 5.1: triethylsilane / dichloromethane; acetonitrile / 1 h / 25 - 35 °C / Inert atmosphere 5.2: 0.5 h / -40 - -5 °C / Inert atmosphere 6.1: N-ethyl-N,N-diisopropylamine; dmap / tetrahydrofuran / 0 - 35 °C 7.1: lithium hydroxide; water / tetrahydrofuran; methanol / 1 h / 15 - 20 °C 8.1: caesium carbonate / 25 - 40 °C
  • 64
  • C32H24BrClO [ No CAS ]
  • [ 864070-44-0 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1.1: n-butyllithium / tetrahydrofuran / -75 - -70 °C / Inert atmosphere 1.2: 12 h / -75 - 35 °C / Inert atmosphere 2.1: triethylsilane; boron trifluoride diethyl etherate / dichloromethane / -70 - 35 °C 3.1: caesium carbonate / 25 - 40 °C
Multi-step reaction with 5 steps 1.1: n-butyllithium / tetrahydrofuran / -75 - -70 °C / Inert atmosphere 1.2: 12 h / -75 - 35 °C / Inert atmosphere 2.1: triethylsilane / dichloromethane; acetonitrile / 1 h / 25 - 35 °C / Inert atmosphere 2.2: 0.5 h / -40 - -5 °C / Inert atmosphere 3.1: N-ethyl-N,N-diisopropylamine; dmap / tetrahydrofuran / 0 - 35 °C 4.1: lithium hydroxide; water / tetrahydrofuran; methanol / 1 h / 15 - 20 °C 5.1: caesium carbonate / 25 - 40 °C
  • 65
  • [ 461432-23-5 ]
  • [ 864070-44-0 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 5 steps 1.1: boron tribromide / dichloromethane / 0 - 5 °C 2.1: triethylamine / dichloromethane / 0 - 5 °C 3.1: n-butyllithium / tetrahydrofuran / -75 - -70 °C / Inert atmosphere 3.2: 12 h / -75 - 35 °C / Inert atmosphere 4.1: triethylsilane; boron trifluoride diethyl etherate / dichloromethane / -70 - 35 °C 5.1: caesium carbonate / 25 - 40 °C
Multi-step reaction with 7 steps 1.1: boron tribromide / dichloromethane / 0 - 5 °C 2.1: triethylamine / dichloromethane / 0 - 5 °C 3.1: n-butyllithium / tetrahydrofuran / -75 - -70 °C / Inert atmosphere 3.2: 12 h / -75 - 35 °C / Inert atmosphere 4.1: triethylsilane / dichloromethane; acetonitrile / 1 h / 25 - 35 °C / Inert atmosphere 4.2: 0.5 h / -40 - -5 °C / Inert atmosphere 5.1: N-ethyl-N,N-diisopropylamine; dmap / tetrahydrofuran / 0 - 35 °C 6.1: lithium hydroxide; water / tetrahydrofuran; methanol / 1 h / 15 - 20 °C 7.1: caesium carbonate / 25 - 40 °C
  • 66
  • [ 864070-18-8 ]
  • [ 864070-44-0 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 4 steps 1.1: triethylamine / dichloromethane / 0 - 5 °C 2.1: n-butyllithium / tetrahydrofuran / -75 - -70 °C / Inert atmosphere 2.2: 12 h / -75 - 35 °C / Inert atmosphere 3.1: triethylsilane; boron trifluoride diethyl etherate / dichloromethane / -70 - 35 °C 4.1: caesium carbonate / 25 - 40 °C
Multi-step reaction with 6 steps 1.1: triethylamine / dichloromethane / 0 - 5 °C 2.1: n-butyllithium / tetrahydrofuran / -75 - -70 °C / Inert atmosphere 2.2: 12 h / -75 - 35 °C / Inert atmosphere 3.1: triethylsilane / dichloromethane; acetonitrile / 1 h / 25 - 35 °C / Inert atmosphere 3.2: 0.5 h / -40 - -5 °C / Inert atmosphere 4.1: N-ethyl-N,N-diisopropylamine; dmap / tetrahydrofuran / 0 - 35 °C 5.1: lithium hydroxide; water / tetrahydrofuran; methanol / 1 h / 15 - 20 °C 6.1: caesium carbonate / 25 - 40 °C
  • 67
  • [ 912917-83-0 ]
  • [ 864070-44-0 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: triethylsilane; boron trifluoride diethyl etherate / dichloromethane / -70 - 35 °C 2: caesium carbonate / 25 - 40 °C
Multi-step reaction with 4 steps 1.1: triethylsilane / dichloromethane; acetonitrile / 1 h / 25 - 35 °C / Inert atmosphere 1.2: 0.5 h / -40 - -5 °C / Inert atmosphere 2.1: N-ethyl-N,N-diisopropylamine; dmap / tetrahydrofuran / 0 - 35 °C 3.1: lithium hydroxide; water / tetrahydrofuran; methanol / 1 h / 15 - 20 °C 4.1: caesium carbonate / 25 - 40 °C
Multi-step reaction with 2 steps 1: triethylsilane; boron trifluoride diethyl etherate / dichloromethane; acetonitrile / 9 h / -30 - -5 °C 2: caesium carbonate / N,N-dimethyl-formamide / 24 h / 30 - 45 °C
  • 68
  • [ 864070-44-0 ]
  • C23H28O7 [ No CAS ]
YieldReaction ConditionsOperation in experiment
90% With ethanol for 0.5h; Reflux; Large scale; 5 Example 5 Preparation of Compound 6 The compound 5 (2.36 kg)Ethanol (18.62kg) into the 50L reactor,Stir to warm up and dissolve.After dissolving,Activated charcoal (0.24 kg)Refluxing and decolorizing for 30 minutes.Hot filter,A small amount of ethanol leaching,Collect the filtrate.The filtrate was transferred to another clean 50 L reactor,Heating up 55-60 ,Add a small amount of seed,Cooling 45-50 .After the precipitation of a large amount of white solid,Starch crystallization for 1 hour.Slow down 10-15 ,Starch crystallization for 1 hour.filter,The filter cake was rinsed with cooled ethanol (5 kg).Filter dry,A white solid.Filter cake at 55 ~ 60 ,Dried in vacuo for 8 hours.Finished product EMPA about 2kg.Sampling full inspection.The product yield of this example was 80-90%.
  • 69
  • [ 864070-44-0 ]
  • [ 147-85-3 ]
  • 1-chloro-4-(beta-D-glucopyranos-1-yl)-2-[4-((S)-tetrahydrofuran-3-yloxy)benzyl]benzene di-L-proline [ No CAS ]
YieldReaction ConditionsOperation in experiment
1.12 g In water; isopropyl alcohol at 82℃; for 1h; 13 Preparation of empagliflozin L-proline complex Isopropanol (4 mL) and L-proline (0.459 g) were charged into 50 mL 2 neck round bottom flask. Water (0.5 mL) was added to the mass at 30°C. The mixture was heated to 82°C and stirred for 30 minutes at 82°C. A solution of empagliflozin (purity: 95%) (1 g of empagliflozin in 4 mL of isopropanol) was added to the reaction mixture at 82°C and resulted mixture was stirred for 1 hour at 82°C. Reaction mixture was cooled to 30°C and MTBE (16 mL) was added to the mixture and the reaction mixture was stirred for 2 hours at 33°C. The precipitation was filtered and the wet cake was washed with MTBE (4 mL) and suck dried under vacuum for 1 hour to get the 1 .12 gm of title complex as white solid. Purity: 98.57% by HPLC. (0281) PXRD pattern: Fig. 5.
  • 70
  • 1-chloro-4-(beta-D-glucopyranos-1-yl)-2-[4-((S)-tetrahydrofuran-3-yloxy)benzyl]benzene di-L-proline [ No CAS ]
  • [ 864070-44-0 ]
YieldReaction ConditionsOperation in experiment
0.47 g In water; ethyl acetate at 27℃; for 0.333333h; 12.b Conversion of empagliflozin L-proline complex to empagliflozin Empagliflozin and L-proline complex prepared in example 12 was dissolved in water (10 mL) and ethylacetate (10 mL) and the resulted solution was stirred for 20 minutes at 27°C. Separated the layers and the aqueous layer was extracted with ethylacetate (10 mL). The ethylacetate layers were combined and washed with saturated NaCI solution (5 mL). The organic layer was dried over sodium sulphate and was concentrated under vacuum at 40°C to yield 0.470 g of empagliflozin. Purity: 98.15 by HPLC.
  • 71
  • [ 864070-44-0 ]
  • [ 63-91-2 ]
  • 1-chloro-4-(beta-D-glucopyranos-1-yl)-2-[4-((S)-tetrahydrofuran-3-yloxy)benzyl]benzene L-phenylalanine [ No CAS ]
YieldReaction ConditionsOperation in experiment
In ethanol; water at 5 - 50℃; for 336h; 32 Preparation of Empagliflozin L-phenylalanine complex Empagliflozin (300 mg) and L-phenylalanine (143 mg) were added to water ethanol mixture (1 :1 , 14 mL) at 25°C and the mixture was heated to 50 °C using a hot air gun to form clear solution. The solution was kept idle for 14 days at 5 ° C. The precipitation was filtered to obtain the title compound. PXRD pattern: Figure 31 .
  • 72
  • C32H37ClO10 [ No CAS ]
  • [ 864070-44-0 ]
YieldReaction ConditionsOperation in experiment
1.20 kg With water; sodium hydroxide In acetonitrile at 60℃; for 1h; 1.1; 1.2 (2) operation process In 50L reactor, the acetyl protection product 3.4kg (5.5mol) was dissolved in 17L of acetonitrile, stirred at room temperature as a milk (yellow) white suspension, constant pressure dropping funnel was added with a good 10% NaOH 1.1kg of aqueous solution.Heated to 60 ° C for about 1h, the system gradually clear, HPLC monitoring reaction was completed, cooled to room temperature.Add about 5L concentrated HCl adjusted pH to neutral, stirring crystallization overnight.About 1.20kg of light yellowish white product can be filtered, about 98% of purity by HPLC.
  • 73
  • (S)-3-phenoxytetrahydrofuran [ No CAS ]
  • [ 864070-44-0 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1.1: aluminum (III) chloride / ethyl acetate / 9 h / 78 °C / Cooling with ice; Large scale 2.1: n-butyllithium / tetrahydrofuran; toluene; hexane / 3 h / -78 °C / Inert atmosphere; Large scale 2.2: 10 h / 0 - 40 °C / Inert atmosphere; Large scale 3.1: aluminum (III) chloride; triethylsilane / dichloromethane; acetonitrile / 2 h / -5 - 10 °C / Large scale
Multi-step reaction with 3 steps 1.1: ethyl acetate / 0.5 h / Cooling with ice; Large scale 1.2: 8.5 h / 78 °C / Cooling with ice; Large scale 2.1: n-butyllithium / tetrahydrofuran; toluene / 1 h / -78 °C / Large scale 2.2: 3 h / -78 °C / Large scale 2.3: 10 h / 0 - 40 °C / Large scale 3.1: aluminum (III) chloride / dichloromethane; acetonitrile / 0.5 h / 5 °C / Large scale 3.2: 2 h / 10 °C / Large scale
  • 74
  • [ 54932-72-8 ]
  • [ 864070-44-0 ]
  • 75
  • [ 149965-41-3 ]
  • [ 864070-44-0 ]
  • 76
  • [ 864070-37-1 ]
  • (R)-tetrahydrofuran-3-yl 4-nitrobenzenesulfonate [ No CAS ]
  • [ 864070-44-0 ]
YieldReaction ConditionsOperation in experiment
55 g With potassium carbonate In butan-1-ol at 25 - 80℃; for 2h; 6 £xample-6: D-glucitol, 1 ,5-anhydro-i -C-14-chloro-3-I 14-I (3S)-tetrahydro-3furanylI oxyl phenylJmethylphenylJ-, (18) (Empagliflozin (Formula-i)) (2R ,3 R,4R,58,6S)-2-(Acttoxymethyi)-6-(4-chloro-3-(4-hydroxybenzyl)phenyl)tetra hydro-2H-pyran-3 ,4,5-triyl triacetate (100 gms), (R)-tetrahydrofuran-3 -yl 4-nitrobenzene sulfonate (54.7 gms) and n-butanol (1000 ml) were mixed in a clean and dry round bottom flask at 25-30°C. To this reaction mixture, potassium carbonate (125.8 gms) was added and heated the reaction mixture to 80°C and stirred for 2 hrs. Filtered the reaction mixture and washed with n-butanol and distilled off the solvent completely from the filtrate under reduced pressure. Cooled the reaction mixture to 25-30°C and then added ethyl acetate and water. Heated the reaction mixture to 45-50°C and stirred for 45 mins at same temperature. Separated the organic and aqueous layers. Extracted the aqueous layer with ethyL acetate and combined the total organic layers. Distilled off the solvent completely from the organic layer under reduced pressure. Ethyl acetate (500 ml) was added to the above obtained residue compound at 25-30°C. Heated the reaction mixture to 70°C and stirred for 60 mm at same temperature. Cooled the reaction mixture to 25-30°C and stirred for 2 hours at same temperature. Filtered the obtained material and washed with ethyl acetate and then dried to get the solid compound. Dissolved the obtained solid in the mixture of methanol (100 ml) and toluene (100 ml) at 65-70°C. Cooled the reaction mixture to 25-30°C and fUrther to 0-5°C and stirred for 2 hrs at 0-5°C. Filtered the obtained solid, washed with methanol and toluene mixture and then dried to get title compound. (Yield: 55 gms, M.R: 165-170)
  • 77
  • [ 1103738-17-5 ]
  • [ 864070-44-0 ]
  • 78
  • [ 1103738-19-7 ]
  • [ 864070-44-0 ]
  • 79
  • C29H32BrClO9 [ No CAS ]
  • [ 864070-44-0 ]
YieldReaction ConditionsOperation in experiment
93.8% With water; potassium hydroxide In acetonitrile at 50 - 60℃; 18 Example 18: Synthesis of empagliflozin Compound I-2 (5.0 g, 7.82 mmol) was added to a 150 mL three-necked flask, acetonitrile (15 mL) and 5NAqueous KOH (45 mL) was added and the mixture was heated to 50-60 ° C for 7-8 hours. TLC detection reaction is complete, the reaction solutionAfter cooling to room temperature, the resulting suspension was stirred at room temperature for 1 hour and filtered. The obtained white solid was added to 20 mL of methanol and heated to 40-50The solution was stirred and stirred at ° C, and further stirred by adding 30 mL of water for 1 hour, and then gradually cooled to 0 to 10 ° C and stirred for 1-2 hours. Filter, getGleevec dry product 3.30g, yield 93.8%, HPLC purity 99.9%.
  • 80
  • (3R,4S,5S,6R)-2-(4-chlorophenyl)-6-(hydroxymethyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triol [ No CAS ]
  • [ 864070-44-0 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 5 steps 1: dmap; N-ethyl-N,N-diisopropylamine / toluene / 6 h / 20 °C / Inert atmosphere 2: triethylsilane; boron trifluoride diethyl etherate / acetonitrile; water / 0.83 h / 15 °C / Inert atmosphere; Cooling with ice 3: aluminum (III) chloride / dichloromethane / 3 h / 5 - 20 °C / Inert atmosphere 4: potassium <i>tert</i>-butylate / tetrahydrofuran / 8 h / Inert atmosphere; Reflux 5: aluminum (III) chloride; sodium tetrahydroborate / tetrahydrofuran / 36 h / 50 °C / Inert atmosphere; Reflux
Multi-step reaction with 6 steps 1: dmap; N-ethyl-N,N-diisopropylamine / toluene / 6 h / 20 °C / Inert atmosphere 2: triethylsilane; boron trifluoride diethyl etherate / acetonitrile; water / 0.83 h / 15 °C / Inert atmosphere; Cooling with ice 3: aluminum (III) chloride / dichloromethane / 3 h / 5 - 20 °C / Inert atmosphere 4: potassium <i>tert</i>-butylate / tetrahydrofuran / 8 h / Inert atmosphere; Reflux 5: sodium hydroxide; methanol / 8 h / 20 °C 6: triethylsilane; boron trifluoride diethyl etherate / acetonitrile; water / 0.83 h / 15 °C / Inert atmosphere; Cooling with ice
  • 81
  • methyl 1-C-(4-chlorophenyl)-2,3,4,6-tetra-O-acetyl-α-D-glucopyranoside [ No CAS ]
  • [ 864070-44-0 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 4 steps 1: triethylsilane; boron trifluoride diethyl etherate / acetonitrile; water / 0.83 h / 15 °C / Inert atmosphere; Cooling with ice 2: aluminum (III) chloride / dichloromethane / 3 h / 5 - 20 °C / Inert atmosphere 3: potassium <i>tert</i>-butylate / tetrahydrofuran / 8 h / Inert atmosphere; Reflux 4: aluminum (III) chloride; sodium tetrahydroborate / tetrahydrofuran / 36 h / 50 °C / Inert atmosphere; Reflux
Multi-step reaction with 5 steps 1: triethylsilane; boron trifluoride diethyl etherate / acetonitrile; water / 0.83 h / 15 °C / Inert atmosphere; Cooling with ice 2: aluminum (III) chloride / dichloromethane / 3 h / 5 - 20 °C / Inert atmosphere 3: potassium <i>tert</i>-butylate / tetrahydrofuran / 8 h / Inert atmosphere; Reflux 4: sodium hydroxide; methanol / 8 h / 20 °C 5: triethylsilane; boron trifluoride diethyl etherate / acetonitrile; water / 0.83 h / 15 °C / Inert atmosphere; Cooling with ice
  • 82
  • [ 135700-53-7 ]
  • [ 864070-44-0 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1: aluminum (III) chloride / dichloromethane / 3 h / 5 - 20 °C / Inert atmosphere 2: potassium <i>tert</i>-butylate / tetrahydrofuran / 8 h / Inert atmosphere; Reflux 3: aluminum (III) chloride; sodium tetrahydroborate / tetrahydrofuran / 36 h / 50 °C / Inert atmosphere; Reflux
Multi-step reaction with 4 steps 1: aluminum (III) chloride / dichloromethane / 3 h / 5 - 20 °C / Inert atmosphere 2: potassium <i>tert</i>-butylate / tetrahydrofuran / 8 h / Inert atmosphere; Reflux 3: sodium hydroxide; methanol / 8 h / 20 °C 4: triethylsilane; boron trifluoride diethyl etherate / acetonitrile; water / 0.83 h / 15 °C / Inert atmosphere; Cooling with ice
  • 83
  • [ 456-22-4 ]
  • [ 864070-44-0 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 4 steps 1: thionyl chloride / dichloromethane / 3 h / Reflux 2: aluminum (III) chloride / dichloromethane / 3 h / 5 - 20 °C / Inert atmosphere 3: potassium <i>tert</i>-butylate / tetrahydrofuran / 8 h / Inert atmosphere; Reflux 4: aluminum (III) chloride; sodium tetrahydroborate / tetrahydrofuran / 36 h / 50 °C / Inert atmosphere; Reflux
Multi-step reaction with 5 steps 1: thionyl chloride / dichloromethane / 3 h / Reflux 2: aluminum (III) chloride / dichloromethane / 3 h / 5 - 20 °C / Inert atmosphere 3: potassium <i>tert</i>-butylate / tetrahydrofuran / 8 h / Inert atmosphere; Reflux 4: sodium hydroxide; methanol / 8 h / 20 °C 5: triethylsilane; boron trifluoride diethyl etherate / acetonitrile; water / 0.83 h / 15 °C / Inert atmosphere; Cooling with ice
  • 84
  • [ 403-43-0 ]
  • [ 864070-44-0 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1: aluminum (III) chloride / dichloromethane / 3 h / 5 - 20 °C / Inert atmosphere 2: potassium <i>tert</i>-butylate / tetrahydrofuran / 8 h / Inert atmosphere; Reflux 3: aluminum (III) chloride; sodium tetrahydroborate / tetrahydrofuran / 36 h / 50 °C / Inert atmosphere; Reflux
Multi-step reaction with 4 steps 1: aluminum (III) chloride / dichloromethane / 3 h / 5 - 20 °C / Inert atmosphere 2: potassium <i>tert</i>-butylate / tetrahydrofuran / 8 h / Inert atmosphere; Reflux 3: sodium hydroxide; methanol / 8 h / 20 °C 4: triethylsilane; boron trifluoride diethyl etherate / acetonitrile; water / 0.83 h / 15 °C / Inert atmosphere; Cooling with ice
  • 85
  • C27H26ClFO10 [ No CAS ]
  • [ 864070-44-0 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: potassium <i>tert</i>-butylate / tetrahydrofuran / 8 h / Inert atmosphere; Reflux 2: aluminum (III) chloride; sodium tetrahydroborate / tetrahydrofuran / 36 h / 50 °C / Inert atmosphere; Reflux
Multi-step reaction with 3 steps 1: potassium <i>tert</i>-butylate / tetrahydrofuran / 8 h / Inert atmosphere; Reflux 2: sodium hydroxide; methanol / 8 h / 20 °C 3: triethylsilane; boron trifluoride diethyl etherate / acetonitrile; water / 0.83 h / 15 °C / Inert atmosphere; Cooling with ice
Same Skeleton Products
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