Name: 842133-18-0|(2S,3R,4R,5S,6R)-2-(3-((5-(4-Fluorophenyl)thiophen-2-yl)methyl)-4-methylphenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol|95%
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1
[ 842133-18-0 ]
(1S)-1,5-anhydro-1-[3-[[5-(4-fluorophenyl)-2-thienyl]methyl]-4-methylphenyl]-D-glucitol hemihydrate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With water; In acetone; at 20℃; for 18h;Product distribution / selectivity;	Example 2 An amorphous powder of 1-(beta-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienylmethyl]benzene (1.62 g) was dissolved in acetone (15 ml), and thereto were added H2O (30 ml) and a crystalline seed. The mixture was stirred at room temperature for 18 hours, and the precipitate was collected, washed with acetone-H2O (1:4, 30 ml) and dried under reduced pressure at room temperature to give 1-(beta-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienylmethyl]benzene hemihydrate (1.52 g) as colorless crystals. mp 97-100 C.

Reference： [1]Patent: US2008/146515,2008,A1 .Location in patent: Page/Page column 4

Yield	Reaction Conditions	Operation in experiment
	In n-heptane; water; ethyl acetate; at 35℃; for 2 - 2.5h;Purification / work up;	Example 9Crystallization of 1 -(beta-D-Glucopyranosyl)-4-methyl-3-(5-(4-f luorophenyl)-2- thienylmethvPbenzeneOHA 1.0 L three-necked round bottom flask was charged with the compound prepared as in Example 8 above (96.9 g, 217 mmol), water (6.0 ml_, 333 mmol) and ethyl acetate (275 ml_). The resulting solution was heated to 350C, with stirring, under argon. Heptane was added dropwise until the solution became hazy (155 ml_ heptane), followed by the addition of 14.2 g of seed crystals. After stirring for 1.5-2.0 hrs at 350C additional heptane (30 ml_, for a total of 185 ml_) was added. The resulting mixture was stirred for 30 minutes more then filtered. The filter cake was washed with about 56% ethyl acetate/heptane (50 ml_) and dried to yield the title compound as a fluffy, off- white crystalline solid.The procedures as described in Examples 1 through 9 above were run multiple times to yield multiple batches of 1 -(beta-D-glucopyranosyl)-4-methyl-3- (5-(4-fluorophenyl)-2-thienylmethyl)benzene, the compound of formula (I-S). The melting point, mass spec and 1HNMR spectra, as measured for a representative sample of the compound of formula (I-S) (prepared according to the procedures in Example 1 through 9) are as follows:Melting Point: 106-1070C;Mass Spec: m/z (LCMS API-ES) 467 (M+Na); <n="85"/>1H NMR (CD3OD): delta = 2.32 (s, 3H), 3.35-3.53 (m, 4H), 3.71 (d, 1 H1 J = 11.9 Hz), 3.90 (d, 1 H, J = 11.9 Hz), 4.13 (d, 1 H, J = 9.3 Hz), 4.17 (s, 2H), 4.9 (s, 4H), 6.70 (d, 1 H, J = 3.7 Hz), 7.04-7.14 (m, 3H), 7.18 (d, 1 H, J = 7.8 Hz), 7.26 (d, 1 H, J = 7.8 Hz), 7.33 (s, 1 H), 7.52-7.60 (m, 2H).A representative sample of the crystalline form of the compound of formula (I-S), isolated as described in Example 9 above, was characterized as to its x-ray powder diffraction, (a representative example of which is shown in Figure 1 ) utilizing a diffractometer using CuKalpha radiation 3OmA, 40KV; 1/12 divergence slit, 0.2 receiving slit; scanning from 4 to 35 2theta at a scan rate of 0.016 2theta/second; and using an aluminum sample holder.The crystalline form of the compound of formula (I-S) may be characterized by its powder XRD peaks, (preferably, by its powder XRD peaks with a relative intensity of greater than about 10%, more preferably, by its powder XRD peaks with a relative intensity of greater than about 25%, more preferably still, by its powder XRD peaks with a relative intensity of greater than about 35%, more preferably still, by its powder XRD peaks with a relative intensity of greater than about 50%), as listed in Table 1 below.
		, wherein said compound is selected from the group consisting of: ... (2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6-(methylsulfonyl)tetrahydro-2H-pyran-3,4,5-triol; (2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6-(methylthio)tetrahydro-2H-pyran-3,4,5-triol; (2S,3R,4R,5S,6R)-2-(3-(benzo[b]thiophen-2-ylmethyl)-4-fluorophenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol; (2S,3R,4R,5S,6R)-2-(5-(azulen-2-ylmethyl)-2-hydroxyphenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol; (2S,3R,4R,5S,6R)-2-(3-((5-(4-fluorophenyl)thiophen-2-yl)methyl)-4-methylphenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol; (2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-thiopyran-3,4,5-triol; (2S,3R,4R,5S,6R)-2-(3-(benzo[b]thiophen-2-ylmethyl)-4-chlorophenyl)-6-(hydroxymethyl)tetrahydro-2H-thiopyran-3,4,5-triol; and (2S,3R,4R,5S,6R)-2-(5-(4-ethoxybenzyl)-2-methoxy-4-methylphenyl)-6-(hydroxymethyl)tetrahydro-2H-thiopyran-3,4,5-triol.

3
[ 842133-18-0 ]
[ 108-24-7 ]
[ 866607-35-4 ]

Yield	Reaction Conditions	Operation in experiment
78%	With 4-methyl-morpholine; dmap; In tetrahydrofuran; at -10 - 20℃; for 1.25h;	The net Kage column (11.9g, 26.8mmol), 4- methylmorpholine (14.5ml, 130.0mmol),N, N- dimethylaminopyridine (325mg, 2.6mmol) was added to 100ml of tetrahydrofuran, inan ice bath while stirring the pale green mixture was cooled to -10 , and then aceticanhydride (12.5ml, 130mmol) was added dropwise into the control dropping, thetemperature not higher than 0 . After the addition was complete, stirring wascontinued at the following 0 15 minutes and then was slowly warmed to roomtemperature, stirred at 20 1 hour and then concentrated to dryness under reducedpressure at 32 , to the residue was added 10% phosphoric acid 30ml, formed creamy precipitate, to the mixture was added ethyl acetate 80ml, tetrahydrofuran, 30ml, oftoluene 30ml, the solid was dissolved with stirring, layers were separated and theorganic phase was washed with saturated sodium bicarbonate solution and saturated sodiumchloride solution successively, dried dried over anhydrous sodium sulfate, the desiccantwas filtered off, concentrated under reduced pressure to give a syrup which was added30ml methanol, the precipitated white solid was stirred for 30 minutes, filtered, anddried 45 deg.] C in vacuo to give tetra acetylated column Kage net 12.9g, yield 78%.
69.5%	With 4-methyl-morpholine; dmap; In dichloromethane; at -5 - 5℃; for 4h;	Take 2L reaction bottle, install mechanical stirring, thermometer and constant pressure low liquid funnel;Add about 850 ml of the dichloromethane solution of Intermediate 2 to the reaction flask.The temperature was lowered to -5 to 5 C, and 162 g (1.27 mol) of N-methylmorpholine was added under stirring.Add 2.58 g (0.0211 mol) of DMAP; maintain the temperature,Slowly add 129.3 g (1.27 mol) of acetic anhydride;After the addition was completed, the reaction was continued for 4 hours.After completion of the reaction, 425 ml of pure water was added dropwise and stirred for 30 minutes.The organic solvent was evaporated under reduced pressure and filtered to give a white solid.The white solid was added to 1.3 L of ethanol and heated to reflux.Stir for 30 minutes, cool to room temperature, filter, dry,94.0 g of a white solid were obtained. The white solid was added to 752 ml of methyl tert-butyl ether.Heat to reflux to give a clear solution and slowly add 564 ml of n-heptane.Continue heating to reflux to obtain a clear solution, slowly reduce to room temperature and stir overnight;Filter the solution,The filter cake was washed with 50 ml * 2 n-heptane.Get a white solid89.9 g, yield 69.5%.HPLC detection,Intermediate 3 has a purity of 99.81%,No tetraacetyl alpha-isomer was detected.
	With 4-methyl-morpholine;dmap; In tetrahydrofuran; at -10 - 20℃; for 1.25h;	Example 7; OAcA 2.0 L three-necked round bottom flask was charged with the compound prepared as in Example 6 above, (119 g, 0.25 mol), 4- methylmorpholine (145 ml_, 1.30 mol), DMAP (3.25 g, 0.026 mol) and 1.0 L of THF. The resulting light green mixture was cooled to -1 O0C in an ice bath, with stirring, then acetic anhydride (125 ml_, 1.30 mol) was added dropwise, such that the temperature did not exceed O0C. The ice bath was removed 15 minutes after the addition was complete. The resulting mixture was stirred at ambient temperature for 1.0 h, then concentrated under reduced pressure at 30-350C to remove most of the solvent. The resulting mixture was diluted with 10% phosphoric acid (-300 ml_), which resulted in the formation of a cream colored precipitate. The resulting mixture was dissolved in a mix of ethyl acetate (600-800 ml_), THF (200-300 ml_) and toluene (200-300 ml_). Once complete solution was obtained, the layers were separated and the organic layer washed with saturated bicarbonate solution and brine, then dried and concentrated to yield a thick residue. Methanol was added to the residue causing an off-white solid to precipitate out of solution. The slurry was stirred for 30 minutes, then filtered to yield the title compound as an off-white solid.

7.2 g	With dmap; In acetone; at 0.25 - 0.5℃; for 5h;	Acetic anhydride (19 ml) was added to a solution of <strong>[842133-18-0]canagliflozin</strong> (10 g; Example 5) in acetone (100 mL) at a temperature of about 25C. N,N'-dimethylaminopyridine (275 mg) was added to this mixture at about 25C. The reaction mixture was heated to about 50C for 5 hours. After completion of the reaction, the reaction mixture was concentrated up to the maximum extent at 40C to 45 C. Dichloromethane (100 mL) was added to the reaction mass and then the mixture was stirred for 10 minutes at 25C to 30C. De- ionized water (100 mL) was added to the reaction mixture, the mixture was stirred for 10 minutes at 25C to 30C, and then the layers were separated. The organic layer was concentrated under reduced pressure at 45C to obtain a residue. Methanol (20 mL) was added to the residue, the reaction mixture was stirred for 10 minutes to 30 minutes at 50C to 55C, and then concentrated under vacuum up to the maximum extent. Methanol (100 mL) was added to the residue and the mixture was heated to 55C. The reaction mixture was stirred for 15 minutes at 50C to 55C, then allowed to cool to about 25C, and then stirred for 30 minutes at the same temperature. The solid was filtered under reduced pressure, then washed twice with methanol (10 mL), and then dried under reduced pressure for 20 minutes to 30 minutes. Ethyl acetate (40 mL) was added to the wet solid and the mixture was heated to 60C to 65C until a clear solution was obtained. The solution was stirred for 10 minutes to 15 minutes at the same temperature, and then methanol (100 mL) was added to the clear solution. The solution was stirred for 10 minutes to 15 minutes at 60C to 65C, then cooled slowly to 0C to 5C, and then stirred for 40 minutes to 60 minutes to obtain a solid. The solid was filtered under reduced pressure and then washed with ethyl acetate: methanol (1 :2; 10 mL). The solid obtained was dried under reduced pressure at 40C to 45C to obtain the title compound. Yield: 7.2 g (0.72 w/w) HPLC purity: 97.53%
86 g	With dmap; triethylamine; In tetrahydrofuran; at 5 - 25℃; for 2h;	(3) adding tetrahydrofuran (480 g) to a three-necked flask,After triethylamine (90 g) and 4-dimethylaminopyridine (1.8 g) were stirred and dissolved,Cooling to 5 C is the dropwise addition of acetic anhydride (76 g) within 1 hour.The temperature was raised to 25 C for 2 hours, and the raw material was analyzed by HPLC to be less than 1%.The tetrahydrofuran solvent was removed under reduced pressure, and then dichloromethane (240 g) was added.After washing twice with water, the organic solvent was removed under reduced pressure to give a crude yellow white compound (Comp.After adding dichloromethane (102 g) and stirring and dissolving, methanol (255 g) was added dropwise to precipitate a solid.When the temperature is lowered to 3 C, after filtration and drying, 86 g of the intermediate of formula (Formula III) is obtained.a white solid, which was analyzed by HPLC to give a purity of more than 99%.The alpha isomer is less than 0.1%.Fig. 1 is an HPLC chart of the cardinol intermediate obtained in the present example.

Reference： [1]Patent: WO2017/71813,2017,A1 .Location in patent: Page/Page column 12
[2]Patent: CN103694230,2016,B .Location in patent: Paragraph 0072; 0073
[3]Patent: CN109553609,2019,A .Location in patent: Paragraph 0090; 0100; 0101; 0102; 0105; 0115; 0116; 0117
[4]Patent: WO2009/35969,2009,A1 .Location in patent: Page/Page column 80
[5]Patent: WO2016/16852,2016,A1 .Location in patent: Page/Page column 9; 10
[6]Patent: CN108191841,2018,A .Location in patent: Paragraph 0042; 0047

4
[ 1132832-76-8 ]
[ 842133-18-0 ]

Yield	Reaction Conditions	Operation in experiment
	With triethylsilane; boron trifluoride diethyl etherate; In 1,1-dichloroethane; at -30 - 20℃; for 1.5 - 2h;Product distribution / selectivity;	Example 6; 1-(beta-D-Glucopyranosyl)-4-methyl-3-(5-(4-fluorophenyl)-2- thienylmethvPbenzeneOHA 2.0 L three-necked round bottom flask was charged with the compound prepared as in Example 5 above (232 g, 310 mmol) and dichloroethane (700 ml_). The resulting yellow solution was cooled to -3O0C in an ice bath, with stirring. Thethylsilane (132 ml_, 826 mmol) was added followed by a slow addition (1.75 h) of boron trifluohde diethyl etherate (95.0 ml_, 756 mmol) such that the temperature did not exceed -2O0C. Approximately 30 minutes after the addition was complete the ice bath was removed and the resulting yellow mixture was stirred at ambient temperature, under argon, for 1.0-1.5 hour. Upon complete reaction the resulting mixture was poured into cold water (800 ml_). Ethyl acetate (300 ml_) was added and the layers were separated. The organic layer was washed with a saturated bicarbonate <n="82"/>solution, dried over sodium sulfate and concentrated to yield the title compound as a green foam.

Reference： [1]Patent: WO2009/35969,2009,A1 .Location in patent: Page/Page column 79-80

5
[ 866607-35-4 ]
[ 842133-18-0 ]

Yield	Reaction Conditions	Operation in experiment
94.9%	With methanol; sodium methylate; In tetrahydrofuran; at 0 - 10℃; for 3h;	Take 1L reaction bottle, install mechanical stirring, thermometer and constant pressure dropping funnel; Add 250 ml of methanol, 250 ml of tetrahydrofuran, 50 g (0.0815 mol) Acetyl protecting intermediates, stirring, cooling to 0 ~ 10 C, Slowly add 50 ml of a solution of 13.2 g (0.2445 mol) of sodium methoxide in methanol. After the completion of the dropwise addition, the reaction was continued for 3 hours, and the organic solvent was distilled under reduced pressure. After the distillation, 300 g of water was added, and a solid was gradually precipitated, washed by filtration, and dried under reduced pressure to give a crude white solid (37.2 g). The crude caldazole was added to 180 ml of isopropyl acetate, stirred and dissolved, and 2.0 g of activated carbon was added, and the mixture was decolorized by reflux for 20 minutes. The activated carbon was removed by filtration, and the filtrate was heated to reflux to obtain a clear solution, which was slowly cooled to room temperature, and stirred. The solid was precipitated after standing for 2 hours, filtered, and dried under reduced pressure to give a white solid (34.1 g, yield: 94.9%, HPLC 99.91%
93.5%	With water; sodium methylate; In tetrahydrofuran; methanol; at 20℃; for 4h;	Take 2L reaction bottle, install mechanical stirring, thermometer and constant pressure low liquid funnel;89 g (0.145 mol) of intermediate 3 was added to 445 ml of methanol and 445 mlThe mixed solvent of tetrahydrofuran was stirred to obtain a slurry solution. At room temperature,A pure aqueous solution (100 ml) of 31.3 g (0.58 mol) of sodium methoxide was slowly added dropwise.After the addition was completed, the reaction was continued for 4 hours. The reaction is completed,Add 425 ml of pure water, remove the organic solvent under reduced pressure, and filter under reduced pressure.It was washed with 50 ml of 2 2 pure water and dried to give a white solid.The obtained solid was added to 352 ml of methanol and stirred to dissolve.Add activated carbon (3.2g, 5%) and heat to reflux for 30 minutes.The activated carbon was removed by filtration, and pure water (288 ml) was added and heated to reflux.Obtain a clear solution and slowly drop to room temperature.Stir for more than 12 hours, filter, dry,Obtained 59.8 g of a white solid.The yield is 93.5%.HPLC purity 99.93%,No alpha-isomer impurities were detected.
84.6%	With lithium hydroxide; at 50℃;	Canagliflozin intermediate dimethyl carbonate solution(concentration is 0.1kg/L, 100L)Pumps internal straight 20mm at 300mL/min,In the 20-meter-long first-stage titanium alloy reaction tube,Temperature control to 50 degrees,Lithium hydroxide solution (0.05kg/L)Pumps internal straight 20mm at 100mL/min,In the 200-meter-long second titanium alloy reaction tube,Temperature control to 50 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,6.46 kg of canagliflozin product was obtained through filtration, with a yield of 84.6%.

70.4%	With water; sodium hydroxide; In methanol; at 5 - 60℃; for 30h;	(4) Adding 86 g of the intermediate (formula III) of canagliflozin once in a 500 ml reaction flask,Methanol (225 g), after cooling to 5 C, sodium hydroxide (16.86 g, 3.0 eq) was added dropwise.And a solution of water (60g),The mixture was heated to 60 C for 30 hours, and the reaction was completed for three hours. The complete reaction of the starting material was detected by HPLC. Add 450g of water and 450g of ethyl acetate for extraction. After the liquid separation, the aqueous phase was further extracted with ethyl acetate.After combining the organic phases, the aqueous layer is separated by adjusting the pH of 5 with 1% acetic acid.After adding activated carbon decolorization heat filtration in the organic phase,The organic solvent was evaporated to dryness under reduced vacuo.315 g of toluene was added, and the mixture was heated to 70 C to dissolve, and then 6.5 g of water was added.After cooling, after filtration and drying, 60.2 g of canagliflozin was obtained.The single step yield is 94.5%.The total yield was 70.4%.
	With lithium hydroxide; water; In tetrahydrofuran; methanol; at 20℃;Product distribution / selectivity;	Example 8; 1-(beta-D-Glucopyranosyl)-4-methyl-3-(5-(4-fluorophenyl)-2- thienylmethvPbenzeneOHA flask was charged with the compound prepared as in Example 7 above, (185 g, 302 mmol) in THF (820 ml_) and MeOH (1.23 L). To the stirred suspension was added a solution of lithium hydroxide monohydrate (6.33 g, 147 mmol) in water (410 ml_). After stirring overnight at ambient temperature the volatiles were removed and the resulting residue diluted with ethyl acetate (500-600 ml_). The layers were separated and the aqueous layer extracted with ethyl acetate (3 x 100 ml_). The combined organic layer was washed with brine (250 ml_), dried over sodium sulfate and concentrated under reduced pressure to yield the title compound as a brittle foam.
		Example 5; 2(S)-{3-[5-(4-Fluoro-phenyl)-thiophen-2-ylmethyl]-4-methyl-phenyl}-6(R)-hydroxymethyl-tetrahydro-pyran-3(R),4(R),5(S)-triol To a 3-necked round bottom flask was added methanol (244.80 mL, 3 L/mol-pure-LR), sodium methoxide (15.31 mL, 81.60 mmol) and 3(R),4(R),5(S)-triacetoxy-6(S)-{3-[5-(4-fluoro-phenyl)-thiophen-2-ylmethyl]-4-methyl-phenyl}-tetrahydro-pyran-2(R)-ylmethyl ester acetic acid (prepared as in for example, Example 4 above; 49.99 g, 81.60 mmol) and the resulting thick homogeneous mixture stirred at 20-25 C. for 1 hour. The resulting mixture was then heated to reflux temperature, about 82 mL of solvent distilled off and then cooled to 2 C. over 30 minutes. To the resulting mixture was added acetic acid (4.68 mL, 81.60 mmol). Water (114 mL) was then added with cooling, over about 15 minutes and the resulting mixture warmed to 22 C. The resulting mixture was seeded with previously prepared material (300 mg), then stirred at 22 C. for 19 hours. Additional water (49 mL) was added over 2.5 hours (to a methanol:water ratio of 50:50), the resulting mixture was cooled to 0 C. over 15 minutes, then stirred at 0 C. for 2 hours. The resulting suspension was filtered, the solid washed with 50:50 mixture of methanol:water (20 mL total), then dried at 50 C., under vacuum for 18 hours, to yield the title compound as a solid.
	With lithium hydroxide monohydrate; water; In tetrahydrofuran; methanol; at 20 - 24℃; for 19.5h;	Example 14; (2S,3R,4R,5S,6R)-2-(3-((5-(4-fluorophenyl)thiophen-2-yl)methyl)-4-methylphenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (1S)-2,3,4,6-tetra-O-acetyl-1,5-anhydro-1-(3-[5-(4-fluorophenyl)-2-thienyl]methyl}-4-methylphenyl)-D-glucitol (5 g) was dissolved in methanol (35 mL) and tetrahydrofuran (25 mL) at room temperature. A solution of LiOH hydrate (192 mg) in water (10 mL) was added dropwise to the mixture for 30 minutes at 20-24 C. After the mixture was stirred for 19 hours at room temperature, the solvent was evaporated in vacuo. The residue was partitioned to ethyl acetate (50 mL) and water (25 mL), stirred for 15 minutes, then the layers were separated. The organic layer was washed with water. The organic layer was dried over Na2SO4, filtered using activated carbon pre-coated filter and evaporated. The resulting residue was dissolved in ethyl acetate (11.1 mL) at 40 C., water (241 mL) was added to the mixture at the same temperature. n-Heptane (5.6 mL) was added to the mixture at 40 C., then the mixture was seeded with a slight amount of (1S)-1,5-anhydro-1-(3-[5-(4-fluorophenyl)-2-thienyl]methyl}-4-methylphenyl)-D-glucitol at same temperature. After stirred for 1 hour at 35 C., n-heptane (2.6 mL) was added slowly to the mixture. The resulting mixture was cooled. The precipitate was filtered and washed with ethyl acetate/n-heptane, then dried to give hemihydrate of (1S)-1,5-anhydro-1-(3-[5-(4-fluorophenyl)-2-thienyl]methyl}-4-methylphenyl)-D-glucitol (2.93 g) as white crystals.m/z (APCI) 462 (M++NH4); mp. 106-107 C.
60.94 g	With sodium methylate; In methanol; for 1h;Reflux;	84 gm (0.1372 moles) of compound of Formula-ll of Example 2 in 336 ml methanol and 8.89 gm (0.1647 moles) of sodium methoxide was refluxed for 1 hour. The refluxed mixture was cooled to 30C and then further cooled to 10C to 15C. Dilute acetic acid (8.23 gm in 84 ml water) and 2100 ml of water was charged to the reaction mixture and stirred overnight. The product was filtered and washed with water under nitrogen to obtain 60.94 gm of canagliflozin of formula (I).
4.5g	With lithium hydroxide monohydrate; In tetrahydrofuran; methanol; water; at 20℃; for 12h;	The resulting tetra acetylated net Kage column (12g, 19.6mmol) was added totetrahydrofuran (53 ml) and methanol (80ml) mixed solvent to obtain a suspension,lithium hydroxide monohydrate (410mg, 9.5mmol) dissolved in 26ml of water was added tothe above mixture, stirred at room temperature for 12 hours, the reaction solution wasconcentrated under reduced pressure to almost dry tetrahydrofuran and methanol, to theresidue was added ethyl acetate 39ml, stirring and separation, the aqueous phase with10ml extracted 3 times with ethyl acetate, the organic phases combined, washed with 20mlof saturated sodium chloride solution, dried over anhydrous magnesium sulfate was added,and concentrated to dryness under reduced pressure to give a foamy solid, To this was added 0.6ml foamy solid 27.5ml of water and ethyl acetate, the solidall dissolved, with stirring and heated to 35 , n-heptane was added dropwise to 15.5mlentered, the reaction solution became gradually turbid dropwise addition of n-heptane,stirred at this temperature for 2 hours, the remaining n-heptane was added dropwise toenter, add 3ml supplemented n-heptane, and the reaction was stirred for 30 minutes,filtered, the cake washed with ethyl acetate and 2.5ml 2.5ml of n-heptane washed with amixed solvent, and dried in vacuo to give a white solid 4.5g.
	With lithium hydroxide monohydrate; In tetrahydrofuran; methanol; at 0 - 20℃; for 2h;	Take the above solid (2,3,4,6-tetra-O-acetyl-(1S)-1,5-anhydro-1-[3-[[5-(4-fluorophenyl)-2-thienyl) 1.2 kg of] methyl]-4-methylphenyl]-D-glucitol, dissolved in 8.4 liters of methanol and 6.0 liters of tetrahydrofuran at room temperature, cooled to 0-5 C, and then added dropwise lithium hydroxide monohydrate solution (48 g) Soluble in 480 ml of water) and reacted at room temperature for 2 hours. After diluting the reaction by adding 4.0 liters of water, the solvent was concentrated under reduced pressure, and the reaction solution was extracted with ethyl acetate. The mixture was washed twice with water, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give a crude solid of Caglichynine anhydride (compound represented by Formula 3) in a white foamy solid, yield 95%, liquid purity 99.2. %.
2.93 g	With lithium hydroxide monohydrate; water; In tetrahydrofuran; methanol; at 20 - 24℃; for 19.5h;	10106] (1 S)-2,3,4,6-Tetra-O-acetyl-i ,5-anhydro-i -(3-[5- (4-fluoro-phenyl)-2-thienyl]methyl}-4-methylphenyl)-D- glucitol (5 g) was dissolved in methanol (35 mE) and tetrahydroffiran (25 mE) at room temperature. A solution of EiOH hydrate (192mg) in water (10 mE) was added dropwise to the mixture for 30 minutes at 20-24 C. Afier the mixture was stirred for 19 hours at room temperature, the solvent was evaporated in vacuo. The residue was partitioned to ethyl acetate (50 mE) and water (25 mE), stirred for 15 minutes, then the layers were separated. The organic layer was washed with watet The organic layer was dried over Na2 SO4, filtered using activated carbon pre-coated filter and evaporated. The resulting residue was dissolved in ethyl acetate (11.1 mE) at 40 C., water (241 mE) was added to the mixture at the same temperature. n-Heptane (5.6 mE) was added to the mixture at C., then the mixture was seeded with a slight amount of (1 S)-i ,5-anhydro-1 -(3-{ [5-(4-fluorophenyl)-2-thienyl]me- thyl}-4-methylphenyl)-D-glucitol at same temperature. After
	With sodium hydroxide; In methanol; water; at 30 - 50℃;	Add to a dry 50 mL round bottom flaskSodium hydroxide solid (3.6 mmol, 0.1440 g, 800%),Dissolved in 10 mL of deionized water,Add the system to room temperatureDissolved in 10 mL of anhydrous methanol(2R, 3R, 4R, 5S)-2-(acetoxymethyl)-6-(3 -((5-(4-fluorophenyl))Thiophen-2-yl)methyl)4-methylphenyl) tetrahydro-2H-pyran-3,4,5-triacetic acid triethyl ester(0.45 mmol, 0.2 g, 100 mol %),The oil bath is heated to 30 to 50 degrees Celsius.Stir evenly for 4~ 5 h.After the reaction is completed, the water is removed by azeotropy with excess methanol.Purification by column chromatography(Methanol: ethyl acetate = 1 : 10) gave the white solid drug Canagliflozin.
4.51 kg	With water; lithium hydroxide; In tetrahydrofuran; methanol; at 20℃; for 2h;Large scale;	9.5 kg of CG-5 and 97 L of tetrahydrofuran were added to the reaction kettle, and stirred at room temperature until the solid was dissolved.150 kg of methanol and 24.03 kg of a 1.35% lithium hydroxide aqueous solution were added, and the reaction was stirred for 2 hours.After adding a 5% potassium hydrogen sulfate solution to neutralize, activated carbon was added, and the mixture was stirred at room temperature for 1 hour and then filtered.The filtrate was concentrated under reduced pressure until a large amount of solid precipitated.Refer to the recrystallization method used in patent WO2009035969 for crystallization and purification to obtain 4.51 kg of kanglitide net hemihydrate compound.

Reference： [1]Patent: WO2017/71813,2017,A1 .Location in patent: Page/Page column 14
[2]Journal of the American Chemical Society,2017,vol. 139,p. 10693 - 10701
[3]Patent: CN109180662,2019,A .Location in patent: Page/Page column 8-11
[4]Patent: CN109553609,2019,A .Location in patent: Paragraph 0090; 0103; 0104; 0105; 0118; 0119
[5]Patent: CN107459500,2017,A .Location in patent: Paragraph 0022; 0023
[6]Patent: CN108191841,2018,A .Location in patent: Paragraph 0042; 0048; 0054; 0060
[7]Patent: WO2009/35969,2009,A1 .Location in patent: Page/Page column 81
[8]Patent: US2010/99883,2010,A1 .Location in patent: Page/Page column 39
[9]Patent: US2010/99883,2010,A1 .Location in patent: Page/Page column 43
[10]Patent: WO2016/83790,2016,A1 .Location in patent: Page/Page column 5; 13
[11]Patent: CN103694230,2016,B .Location in patent: Paragraph 0070; 0072; 0074; 0075
[12]Patent: CN107286143,2017,A .Location in patent: Paragraph 0061; 0062
[13]Patent: US2016/228375,2016,A1 .Location in patent: Paragraph 0105; 0106
[14]Patent: CN109456315,2019,A .Location in patent: Paragraph 0022
[15]Patent: CN110698468,2020,A .Location in patent: Paragraph 0024; 0051-0057; 0062-0065

6
[ 1030825-21-8 ]
[ 842133-18-0 ]

Yield	Reaction Conditions	Operation in experiment
81.36%		Take a 2L reaction bottle and install it with mechanical agitation.Thermometer and constant pressure low liquid funnel; add 700 ml of dichloromethane,Add 100 g (0.211 mol) of intermediate 1 and stir to dissolve;Cool down to -25 to -10 C, add 73.5 g (0.632 mol)Triethylsilane; maintaining temperature, slowly adding 89.7g (0.632mol)Boron trifluoride etherate; after the addition was completed, the reaction was continued for 2 hours.The temperature was adjusted to below -10 C, and 800 ml of an aqueous solution of sodium hydrogencarbonate was added dropwise.After the addition is completed, the stirring is stopped, the phase separation is allowed to stand, and the organic phase is separated.Dry over anhydrous sodium sulfate for several hours and filter.A solution of the intermediate 2 in dichloromethane was obtained in ca. 850 ml.HPLC detection,The beta-isomer is 81.36%,The alpha-isomer was 3.22%. The yield is calculated at 100%.
	With triethylsilane; boron trifluoride diethyl etherate; In dichloromethane; at 0 - 5℃;	Triethylsilane (64.43 g) and borontrifloride-diethyletherate (78.61 g) were added (one after another) to a solution of l-(l-methoxyglucopyranosyl)-4-methyl-3-[5-(4- flourophenyl)-2-thienylmethyl]benzene (the whole quantity obtained from Example 4) in dichloromethane (500 mL) at 0C to 5C. The reaction mixture was stirred for 2 hours to 3 hours. After completion of the reaction, an aqueous solution of sodium bicarbonate (25 g of sodium bicarbonate in 500 mL of de-ionized water) was added, and then the reaction mixture was stirred for 30 minutes at 20C to 25 C. The reaction mixture was concentrated under reduced pressure to completely recover the organic layer at 45 C. Ethyl acetate (1000 mL) was added to the reaction mixture, and then the mixture was stirred for 10 minutes to 15 minutes. The reaction mixture was allowed to settle, and then the organic layer was separated. The aqueous layer was washed with ethyl acetate, and the organic layer was separated. The organic layers were combined, and then washed with an aqueous solution of sodium chloride (10 g of sodium chloride in 200 mL of de-ionized water). The organic layer was completely concentrated under reduced pressure at a temperature of about 45C to obtain canagliflozin. HPLC Purity: 80%
		In a round bottom flask equipped with reflux condenser, 1 -(1 -methoxyglucopyranosyl)-4- methyl-3-[5-(4-fluorophenyl)-2-thienylmethylj-benzene (10 gms) was dissolved in mixture ofmethylene chloride (100 ml) and acetonitrile (20 ml) at 25-30C under nitrogen atmosphere. Triethyl silane (7.35 gms) was added and the reaction mass was stined for 10 mm at 25-30C. The reaction mass was cooled to -45 to -40C, added drop wise boron trifluoride ethyl ether complex (8 ml) and the mixture was stined for 1.0 hr at same temperature. Further, thereaction mass was stined at 0-5C for 2 hrs and quenched by adding saturated sodium bicarbonate solution (100 ml). The resulting organic layer was separated, washed with water (50 ml) and the organic solvent was distilled out under vacuum to obtain Canagliflozin (8.5 gms).HPLC purity: 88.249 %,Alpha isomer content by HPLC: 2.76 %.

With triethylsilane; boron trifluoride diethyl etherate; In dichloromethane; acetonitrile; at -40 - 5℃; for 2.5h;

(2) Add the organic solvent acetonitrile (51g) to the three-neck bottleStirred with dichloromethane (350g),After adding triethylsilylhydrogen (41 g) to a temperature of -40 C, boron trifluoride diethyl ether (65 g) was added dropwise.The end of the addition within 2 hours;After stirring for 30 minutes, the temperature was raised to 5 C for 2 hours.After the sample was completely analyzed by HPLC analysis, the raw material was completely reacted.Add saturated sodium bicarbonate and adjust the pH to 7-8, then dispense.The aqueous layer was extracted with dichloromethane and ethanol.After combining the organic phases, the organic solvent was distilled off under reduced pressure to give a crude product of carbaryl, as a gray-green solid;

Reference： [1]Patent: CN109553609,2019,A .Location in patent: Paragraph 0090; 0097; 0098; 0099; 0105; 0112; 0113; 0114
[2]Journal of Medicinal Chemistry,2010,vol. 53,p. 6355 - 6360
[3]Patent: WO2016/16852,2016,A1 .Location in patent: Page/Page column 9
[4]Patent: WO2017/46730,2017,A1 .Location in patent: Page/Page column 37; 38
[5]Patent: US2016/228375,2016,A1
[6]Patent: CN108191841,2018,A .Location in patent: Paragraph 0042; 0046; 0052; 0058
[7]Patent: CN110698468,2020,A

Yield	Reaction Conditions	Operation in experiment
	In Isopropyl acetate; water; at 0 - 72.5℃;Purification / work up;	A solution of 1 -(beta-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienylmethyl] benzene hemihydrate (i.e. compound (I)) (317.5 g) in 1 -methylethyl acetate (1400 ml) and water (15.6 ml) was heated till 72.5^ until a clear solution was obtained and filtered. The filter was rinsed with 1 -methyl-ethyl acetate (175 ml) and the reaction mixture was allowed to cool to a temperature of 54 C. The reaction mixture was seeded with compound (I) (1 .59 g) and the mixture was stirred for 2 hours.The reaction mixture was cooled according to a cubic temperature decrease described below : ? to 52.4

8
[ 1283129-18-9 ]
[ 842133-18-0 ]

Yield	Reaction Conditions	Operation in experiment
91%	With hydrogenchloride; In methanol; water; for 2h;Reflux; Large scale;	The pivaloyl ester fine product (3.3 kg), concentrated hydrochloric acid (415 g) and methanol (6.6 kg) were mixed, the mixture was heated to reflux and the solid was gradually dissolved. Sampling HPLC detection, and in about 2 hours reaction was complete. After the reaction was completed, the solution was cooled to 0 to 10 C, aqueous sodium hydroxide solution (6.7 kg, concentration: 5% by weight) was added dropwise and the pH is determined with a pH electrode (Mettler Toledo MTA HA405DPASC) or with pH test strips (eg pH-Fix 0-14, Macherey and Nagel) to ensure that the pH is in the range of 6-7. The solid gradually precipitated, maintaining 0 ~ 10 C and stirred for 2 hours or more, a large number of solid precipitation, the precipitated solid was filtered. The filter cake was washed with water (about 1.0kg), the filter cake was placed in a vacuum oven, dried under reduced pressure at 30 ~ 40 C for 8 hours or more, the moisture content was measured using a rapid moisture analyzer , until the water Canagliflozin crude product. The Canagliflozin crude product dissolved in isopropyl acetate (5.0kg), and at about 55 C the solution was clear. The product was then crystallized by adding seed crystals (19 g) at 43 C, and the mixture was further stirred at 43 C for 15 minutes. The mixture was then cooled to 20 C in 60 minutes and water (91 g) was added at 20 C in 30 minutes. The mixture was cooled to 0 ~ 5 C in 60 minutes and stirred at 3 C for 16 hours. Finally, the product was collected by filtration as colorless crystalline solid, washed with cold isopropyl acetate (120mL) and dried at 40 ~ 45 C, dried to constant weight for about 8 hours to give 1.7kg Canagliflozin fine product, yield 91%. The product was identified via HPLC retention time.
90%	With methanol;sodium methylate; at 60℃; for 16h;Product distribution / selectivity;	Example 1 1(2S.3R.4R.5S.6R)-2-(3-((5-(4-fluorophenyl)thiophen-2-yl)methyl)-4- methylphenyl)-6-(hvdroxymethyl)tetrahvdro-2H-pyran-3,4,5-thol(2S,3S,4R,5R,6R)-2-(3-((5-(4-fluorophenyl)thiophen-2-yl)methyl)-4- methylphenyl)-6-(pivaloyloxymethyl)tetrahydro-2H-pyran-3,4,5-thyl tris(2,2- dimethylpropanoate) (39.0 g, 50.0 mmol)was suspended in methanol (150 mL) at room temperature. Sodium methoxide solution (9.3 mL) was added and the resulting suspension was stirred at room temperature, heated to 60C for 16 hours and then cooled. To the resulting yellow solution was then added water (50 mL) and seeds to the title compound. An additional portion of water (50 mL) was added, and the mixture stirred at 0C for 1 hour, resulting in the formation of a precipitate, which was collected by filtration to yield the title compound. Yield: 20.00 g, 90%.

Reference： [1]Patent: CN104557895,2017,B .Location in patent: Paragraph 0017; 0031; 0041
[2]Patent: WO2012/140120,2012,A1 .Location in patent: Page/Page column 92-93
[3]Patent: US2011/87017,2011,A1

9
[ 898566-17-1 ]
[ 842133-18-0 ]

Reference： [1]Patent: US2011/87017,2011,A1
[2]Patent: US2011/87017,2011,A1
[3]Patent: WO2016/128995,2016,A1
[4]Organic Process Research and Development,2018,vol. 22,p. 27 - 39
[5]Organic Process Research and Development,2018,vol. 22,p. 27 - 39
[6]Patent: US2016/228375,2016,A1
[7]Patent: CN110698468,2020,A

10
C₁₈H₁₄FLiS [ No CAS ]
[ 842133-18-0 ]

Reference： [1]Patent: US2011/87017,2011,A1

11
(2S,3S,4R,5R,6R)-2-(3-((5-(4-fluorophenyl)thiophen-2-yl)methyl)-4-methylphenyl)-6-(pivaloyloxymethyl)tetrahydro-2H-pyran-3,4,5-triyltris(2,2-dimethylpropanoate) [ No CAS ]
[ 842133-18-0 ]

Yield	Reaction Conditions	Operation in experiment
	With water; at 0℃; for 1h;	Example 11 (2S,3R,4R,5S,6R)-2-(3-((5-(4-fluorophenyl)thiophen-2-yl)methyl)-4-methylphenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (2S,3S,4R,5R,6R)-2-(3-((5-(4-fluorophenyl)thiophen-2-yl)methyl)-4-methylphenyl)-6-(pivaloyloxymethyl)tetrahydro-2H-pyran-3,4,5-triyltris(2,2-dimethylpropanoate) (39.0 g, 50.0 mmol) was suspended in methanol (150 mL) at room temperature. Sodium methoxide solution (9.3 mL) was added and the resulting suspension was stirred at room temperature, heated to 60 C. for 16 hours and then cooled. To the resulting yellow solution was then added water (50 mL) and seeds to the title compound. An additional portion of water (50 mL) was added, and the mixture stirred at 0 C. for 1 hour, resulting in the formation of a precipitate, which was collected by filtration to yield the title compound.

Reference： [1]Patent: US2011/87017,2011,A1 .Location in patent: Page/Page column 35

12
[ 1283129-24-7 ]
[ 842133-18-0 ]

Reference： [1]Patent: US2011/87017,2011,A1

13
[ 492-62-6 ]
[ 842133-18-0 ]

Reference： [1]Patent: WO2012/140120,2012,A1
[2]Patent: CN103980263,2016,B
[3]Patent: CN109111490,2019,A

14
[ 898566-17-1 ]
[ 81058-27-7 ]
[ 842133-18-0 ]

Reference： [1]Patent: WO2012/140120,2012,A1

15
[ 1213234-53-7 ]
[ 842133-18-0 ]

Reference： [1]Patent: WO2012/140120,2012,A1
[2]Patent: CN103980263,2016,B

16
[ 842133-18-0 ]
[ 147-85-3 ]
[ 1409936-68-0 ]

Yield	Reaction Conditions	Operation in experiment
93%	In n-heptane; ethyl acetate; at 60 - 65℃; for 5h;Inert atmosphere;	To the 10 cc of Ethyl acetate charged 1.0 mole (2S,3R,4R,5S,6R)-2-{3-[5-[4-Fluoro- phenyl)-thiophen-2-ylmethyl] -4-methyl-phenyl } -6-hydroxymethyl-tetrahydro-pyran- 3,4,5-triolunder argon atmosphere at ambient temperature andstirred for 30.0 mm to get clear solution. Slowly heated the reaction mass to 60 - 65C andstirredfor 1 hr. Slowly addedL-proline at 60 - 65C andmaintained for 1 hr. Slowly added 15 cc n-Heptane to the reaction mass at 60 - 65C andstirred the mass for 2.5 hrs. Cooled the mass to ambient temperature for 3-4 hrs and maintained for 5 hrs.Filteredthe mass under argon atmosphere.Washed the cake with 10 cc n-Heptane.Dried the cake at 50-55C under reduced pressure to get 85-93% titled compound.HPLC purity: 98-99.8%
	In acetone; for 0.166667h;Product distribution / selectivity;	The compound of formula (I-X) (100 mg) was added to a wig-L-bug vial along with L-proline (26.30 mg) (1:1.1 molar equivalent API:CCF), a grinding ball and acetone (20 mul). The wig-L-bug was subjected to 10 minutes of grinding. After milling the recovered solid was confirmed to be the expected crystalline L-proline co-crystal of the compound of formula (I-X) by pXRD.
0.3 g	In ethanol; water;	A solution of <strong>[842133-18-0]canagliflozin</strong> (0.3 g, 0.67 mmol), L-proline (0.17 g, 1.5 mmol), and 5 mL of 95% EtOH aq. was heated and dissolved. The solution was cooled slowly to room temperature. The solution was filtered and the resulting solids were dried under vacuum oven to give 0.3 g of a white solid. The XRPD pattern, IR spectrum, DSC and TGA traces, 1H NMR and 13C NMR spectra of the crystalline complex are shown in FIGS. 5, 6, 7, 8 and 9.

Reference： [1]Patent: WO2016/142950,2016,A1 .Location in patent: Page/Page column 19
[2]Patent: US2012/289694,2012,A1 .Location in patent: Page/Page column 9
[3]Patent: US2013/237487,2013,A1 .Location in patent: Paragraph 0070-0071

17
[ 842133-18-0 ]
[ 77-92-9 ]
[ 1409936-69-1 ]

Yield	Reaction Conditions	Operation in experiment
	In Isopropyl acetate; for 0.166667h;Product distribution / selectivity;	The compound of formula (I-X) (100 mg) was added to a wig-L-bug vial along with citric acid (43.83 mg) (1:1.1 molar equivalent API:CCF), a grinding ball and isopropyl acetate (20 mul). The wig-L-bug was subjected to 10 minutes of grinding. After milling the recovered solid was confirmed to be the expected crystalline citric acid co-crystal of the compound of formula (I-X) by pXRD.

Reference： [1]Patent: US2012/289694,2012,A1 .Location in patent: Page/Page column 9

18
[ 842133-18-0 ]
[ 344-25-2 ]
[ 1432187-89-7 ]

Yield	Reaction Conditions	Operation in experiment
0.32 g	In ethanol; water;	<strong>[842133-18-0]Canagliflozin</strong> (0.3 g, 0.67 mmol) and D-proline (0.09 g, 0.8 mmol) were dissolved in 5 mL of 95% aqueous EtOH by heating. The solution was cooled slowly to room temperature and the mixture was filtered and the resulting solids were dried in a vacuum oven to give 0.32 g of the crystalline complex as a white solid. The XRPD pattern, IR spectrum, DSC and TGA traces, 1H NMR and 13C NMR spectra of the crystalline complex are shown in FIGS. 10, 11, 12, 13 and 14.

Reference： [1]Patent: US2013/237487,2013,A1 .Location in patent: Paragraph 0072-0073

19
[ 842133-18-0 ]
[ 63-91-2 ]
[ 1432187-87-5 ]

Yield	Reaction Conditions	Operation in experiment
0.52 g	In ethanol; water;	<strong>[842133-18-0]Canagliflozin</strong> (0.4 g, 0.9 mmol) and L-phenylalanine (0.33 g, 2 mmol) were dissolved in a mixture of 3.2 mL of absolute EtOH and 3.2 mL of H2O with heating. The solution was cooled slowly to room temperature and the resulting mixture was filtered. The resulting solids were dried in a vacuum oven to give 0.52 g of the complex as a white solid. The XRPD pattern, IR spectrum, DSC and TGA traces, 1H NMR and 13C NMR spectra of the crystalline complex are shown in FIGS. 15, 16, 17, 18 and 19.

Reference： [1]Patent: US2013/237487,2013,A1 .Location in patent: Paragraph 0074-0075

20
[ 1432591-75-7 ]
[ 842133-18-0 ]

Reference： [1]Patent: US2014/128595,2014,A1
[2]Journal of Organic Chemistry,2015,vol. 80,p. 2295 - 2309

21
[ 498-07-7 ]
[ 842133-18-0 ]

Reference： [1]Patent: US2014/128595,2014,A1
[2]Journal of Organic Chemistry,2015,vol. 80,p. 2295 - 2309

22
[ 1432591-84-8 ]
[ 842133-18-0 ]

Yield	Reaction Conditions	Operation in experiment
73%	With tetrabutyl ammonium fluoride; In tetrahydrofuran; at 20℃; for 4h;	A mixture of the 2,4-di-O-tert-butyldiphenylsilyl-1-C-(3-((5-(4-fluorophenyl)thiophen-2-yl)methyl)-4-methylphenyl)-beta-D-glucopyranoside (408 mg, 0.44 mmol) and TBAF (3.5 mL, 3.5 mmol, 1.0 M in THF) was stirred at ambient temperature for 4 hours. CaCO3 (0.73 g), Dowex 50WX8-400 ion exchange resin (2.2 g) and MeOH (5 mL) were added to the product mixture and the suspension was stirred at ambient temperature for 1 hour and then the mixture was filtered through a pad of diatomaceous earth. The filter cake was rinsed with MeOH and the combined filtrates was evaporated under vacuum and the resulting residue was purified by column chromatography (eluting with 1:20 MeOH/DCM) affording canagliflozin (143 mg, 73%). 1H NMR (400 MHz, DMSO-d6) delta 7.63-7.57 (m, 2H), 7.28 (d, J=3.6 Hz, 1H), 7.23-7.18 (m, 3H), 7.17-7.12 (m, 2H), 6.80 (d, J=3.6 Hz, 1H), 4.93 (br, 2H, OH), 4.73 (br, 1H, OH), 4.44 (br, 1H, OH), 4.16 (d, J=16 Hz, 1H), 4.10 (d, J=16 Hz, 1H), 3.97 (d, J=9.2 Hz, 1H), 3.71 (d, J=11.6 Hz, 1H), 3.47-3.43 (m, 1H), 3.30-3.15 (m, 4H), 2.27 (s, 3H); 13C NMR (100 MHz, DMSO-d6) delta 161.8 (d, J=243 Hz, C), 144.1 (C), 140.7 (C), 138.7 (C), 137.8 (C), 135.4 (C), 131.0 (d, J=3.1 Hz, C), 130.1 (CH), 129.5 (CH), 127.4 (d, J=8.1 Hz, CH×2), 126.8 (CH), 126.7 (CH), 123.9 (CH), 116.4 (d, J=21.6 Hz, CH×2), 81.8 (CH), 81.7 (CH), 79.0 (CH), 75.2 (CH), 70.9 (CH), 61.9 (CH2), 33.9 (CH2), 19.3 (CH3); LCMS (ESI) m/z 462 (100, [M+NH4]+), 467 (3, [M+Na]+).

Reference： [1]Patent: US2014/128595,2014,A1 .Location in patent: Paragraph 0274; 0275
[2]Journal of Organic Chemistry,2015,vol. 80,p. 2295 - 2309

23
[ 842133-18-0 ]
1-(β-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienylmethyl]benzene hydrate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
4.8 g	With water; at 15 - 25℃; for 18h;	A suspension of 5.0 g amorphous 1-(f3-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2- thienylmethyl]benzene (for example prepared in accordance with the procedures described in WO 2005/012326 Al) in 500 mL water was stirred at room temperature for 18 hours usinga magnetic stirrer. Thereafter the solid material was collected by filtration and dried at 40 C under vacuum ( 30 mbar) for about 24 hours (<30% relative humidity) to obtain 4.8 g (96% of theory) of 1 -(f3-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienyl methyl]benzene form HxA.

Reference： [1]Patent: WO2014/180872,2014,A1 .Location in patent: Page/Page column 21; 22

24
[ 32741-93-8 ]
[ 842133-18-0 ]

Reference： [1]Journal of Organic Chemistry,2015,vol. 80,p. 5189 - 5195

25
bis(3-[[5-(4-fluorophenyl)-2-thienyl]methyl]-4-methylphenyl)chloroalane [ No CAS ]
[ 498-07-7 ]
[ 842133-18-0 ]

Reference： [1]Journal of Organic Chemistry,2015,vol. 80,p. 5189 - 5195

26
[ 1030825-20-7 ]
[ 842133-18-0 ]

Reference： [1]Journal of Organic Chemistry,2015,vol. 80,p. 5189 - 5195
[2]Patent: WO2016/16852,2016,A1
[3]Patent: CN105440025,2016,A
[4]Patent: CN106866645,2017,A
[5]Patent: US2016/228375,2016,A1

27
[ 1030825-20-7 ]
[ 74372-90-0 ]
[ 842133-18-0 ]

Reference： [1]Patent: WO2015/177083,2015,A1
[2]Patent: WO2015/177083,2015,A1

28
(2S,3S,4R,5R,6R)-4,5-bis(benzyloxy)-6-((benzyloxy)methyl)-2-(3-((5-(4-fluorophenyl)thiophen-2-yl)methyl)-4-methylphenyl)tetrahydro-2H-pyran-3-ol [ No CAS ]
[ 842133-18-0 ]

Yield	Reaction Conditions	Operation in experiment
0.31 g	With chloro-trimethyl-silane; sodium iodide; In acetonitrile; at 0 - 20℃; for 1h;	0.52 g (2R,3S,4R,5R,6R)-4,5-bis(benzyloxy)-6-((benzyloxy)methyl)-2-(3-((5-(4-fluoro- phenyl)thiophen-2-yl)methyl)-4-methylphenyl)tetrahydro-2H-pyran-3-ol (3A) was dissolved in absolute acetonitrile (4 ml). 0.65 g of sodium iodide was added, solution was cooled to 0C and 0.55 ml of trimethylsilyl chloride was slowly (10 min) added. Suspension was left to warm up to ambient temperature, stirred from another 60 min then quenched with saturated sodium thiosulfate (20 ml), extracted with ethyl acetate (3x30 ml) washed with thiosulfate and brine, then dried and concentrated. Hexane (20 ml) was added to the oily residue and stirred until white precipitate formed. The latter was collected with filtration to give canagliflozin (0.31 g).

Reference： [1]Patent: WO2015/177083,2015,A1 .Location in patent: Page/Page column 25

29
[ 32469-28-6 ]
[ 842133-18-0 ]

Reference： [1]Patent: WO2015/181692,2015,A1
[2]Patent: WO2016/142950,2016,A1
[3]Patent: CN106866645,2017,A
[4]Patent: CN107286143,2017,A
[5]Patent: CN110698468,2020,A

30
[ 90-80-2 ]
[ 842133-18-0 ]

Reference： [1]Patent: WO2015/181692,2015,A1
[2]Patent: WO2016/83790,2016,A1
[3]Patent: WO2016/83790,2016,A1
[4]Patent: CN107286143,2017,A

31
1-(1-methoxyglucopyranosyl)-4-methyl-3-(5-(4-fluorophenyl)-2-thienylhydroxymethyl)benzene [ No CAS ]
[ 842133-18-0 ]

Yield	Reaction Conditions	Operation in experiment
		Example 6: Preparation of canagliflozin (I): A mixture of l-(l-methoxyglucopyranosyl)-4-methyl-3-(5-(4-fluorophenyl)-2- thienylhydroxymethyl) benzene (lOg) and methylene chloride (100ml) was cooled to a temperature of about -70 to about -75C. To the reaction mass triethylsilane (8ml) was added slowly. The reaction mass was maintained for a period of about 15 to 30 min. To the reaction mass boron trifluoride diethyl etherate (10ml) was added. The temp of the reaction mass was raised to 0C. The reaction mass was maintained for a period of about 2-3hrs. To the reaction mass saturated sodium bicarbonate solution was added. The reaction mass was maintained for a period of about 30 to 90 min. The reaction mass was distilled under vacuum. To the reaction mass ethyl acetate and water were added. The ethyl acetate layer was separated, washed with water and brine solution. Ethyl acetate layer was dried on sodium sulphate, treated with activated carbon and filtered. The filtrate was distilled under vacuum to obtain a foamy solid.

Reference： [1]Patent: WO2015/181692,2015,A1 .Location in patent: Paragraph 0196

32
(5-(4-fluorophenyl)thiophen-2-yl)(5-iodo-2-methylphenyl)methanone [ No CAS ]
[ 842133-18-0 ]

Reference： [1]Patent: WO2015/181692,2015,A1
[2]Patent: WO2016/83790,2016,A1
[3]Patent: WO2016/83790,2016,A1
[4]Organic Process Research and Development,2018,vol. 22,p. 27 - 39
[5]Organic Process Research and Development,2018,vol. 22,p. 27 - 39

33
[ 108440-70-6 ]
[ 842133-18-0 ]

Reference： [1]Patent: WO2015/181692,2015,A1
[2]Patent: CN103980263,2016,B
[3]Organic Process Research and Development,2018,vol. 22,p. 27 - 39
[4]Organic Process Research and Development,2018,vol. 22,p. 27 - 39

34
[ 54811-38-0 ]
[ 842133-18-0 ]

Reference： [1]Patent: WO2015/181692,2015,A1
[2]Patent: WO2016/83790,2016,A1
[3]Patent: WO2016/83790,2016,A1
[4]Patent: CN103980263,2016,B
[5]Organic Process Research and Development,2018,vol. 22,p. 27 - 39
[6]Organic Process Research and Development,2018,vol. 22,p. 27 - 39

35
[5-(4-fluorophenyl)thiophen-2-yl](5-iodo-2-methylphenyl)methanol [ No CAS ]
[ 842133-18-0 ]

Reference： [1]Patent: WO2015/181692,2015,A1
[2]Patent: WO2016/83790,2016,A1

36
[ 1765-93-1 ]
[ 842133-18-0 ]

Reference： [1]Patent: WO2016/16852,2016,A1
[2]Patent: CN109336874,2019,A

37
[ 58861-48-6 ]
[ 842133-18-0 ]

Reference： [1]Patent: WO2016/16852,2016,A1
[2]Patent: WO2016/83790,2016,A1
[3]Patent: WO2016/83790,2016,A1

38
[ 1132832-75-7 ]
[ 842133-18-0 ]

Reference： [1]Patent: WO2016/16852,2016,A1
[2]Patent: US2017/73336,2017,A1

39
[ 842133-18-0 ]
[ 7585-39-9 ]
canagliflozin β-cyclodextrin complex [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
370 mg	In water; at 100℃; for 0.0833333h;	beta-Cyclodextrin (300 mg, 0.225 mmol) was added to 4 ml of water and the resulting suspension was heated up to 100C until dissolution. Crystalline <strong>[842133-18-0]canagliflozin</strong> hemihydrate (102 mg, 0.225 mmol) was gradually added to the resulting clear solution; then it got dissolved and subsequently began to be yielded in the form of the complex with beta-cyclodextrin. After adding of all the <strong>[842133-18-0]canagliflozin</strong> the reaction mixture was agitated at 100C for another about 5 minutes. Then it was left to slowly cool down to the room temperature and after that it was agitated in an ice bath for 30 minutes. The resulting crystalline substance was filtered, washed with 1 ml of icy water and dried in a vacuum drier at 25 C overnight. 370 mg of a purely white substance was obtained with the chemical purity of 100.0% (HPLC).

Reference： [1]Patent: WO2016/41530,2016,A1 .Location in patent: Page/Page column 9

40
[ 842133-18-0 ]
[ 7585-39-9 ]
canagliflozin β-cyclodextrin complex [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
11.4 mg	In water; at 100℃; for 0.25h;	beta-Cyclodextrin (9.26 g, 6.95 mmol) was added to 55 ml of water and the resulting suspension was heated up to 100C until dissolution. Amorphous <strong>[842133-18-0]canagliflozin</strong> (3.00 g, 6.75 mmol) was gradually added to the resulting clear solution. After adding of all the amorphous <strong>[842133-18-0]canagliflozin</strong> the reaction mixture was agitated at 100C for another about 15 minutes. Then it was left to slowly cool down to the room temperature and after that it was agitated in an ice bath for 60 minutes. The resulting crystalline substance was filtered, washed with 2 x 10 ml of icy water and dried in a vacuum drier at 25C overnight. The amount of 11.4 mg of a purely white substance was obtained with the chemical purity of 99.9% (HPLC).

Reference： [1]Patent: WO2016/41530,2016,A1 .Location in patent: Page/Page column 9

41
[ 842133-18-0 ]
[ 17465-86-0 ]
canagliflozin γ-cyclodextrin complex [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
350 mg	In water; at 100℃; for 0.0833333h;	gamma-Cyclodextrin (286 mg, 0.22 mmol) was added to 2 ml of water and the resulting solution was heated up to 100 C. Amorphous <strong>[842133-18-0]canagliflozin</strong> (100 mg, 0.22 mmol) was gradually added. After adding of all the amorphous <strong>[842133-18-0]canagliflozin</strong> the reaction mixture was agitated at 100oC for another about 5 minutes. Then it was left to slowly cool down to the room temperature and after that it was agitated in an ice bath for 30 minutes. The resulting crystalline substance was filtered, washed with 1 ml of icy water and dried in a vacuum drier at 25C overnight. 350 mg of a purely white substance was obtained with the chemical purity of 99.85% (HPLC).

Reference： [1]Patent: WO2016/41530,2016,A1 .Location in patent: Page/Page column 9

42
[ 842133-18-0 ]
[ 55216-11-0 ]
canagliflozin heptakis(2,3,6-tri-O-methyl)-β-cyclodextrin complex [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
275 mg	In water; at 25 - 100℃; for 0.0833333h;	Hep1akis(2,3J6-tri-0-methyl)-p-cyclodextrin (347 mg5 0.24 mmol) was added to 2 ml of water and it got dissolved after about 5 min of agitation at 25C. This solution was heated up to 100C and at an elevated temperature the modified cyclodextrin started to be yielded. <strong>[842133-18-0]Canagliflozin</strong> (100 mg, 0.22 mmol) was added at 100C and the suspension was agitated at this temperature for another 5 min. Then it was left to slowly cool down to the room temperature and after that it was agitated for 30 minutes in an ice bath and put in a fridge for 72 hours. The resulting crystalline substance was filtered, washed with 1 ml of icy water and dried in a vacuum drier at 25C overnight. 275 mg of a purely white substance was obtained with the chemical purity of 99.92% (HPLC).

Reference： [1]Patent: WO2016/41530,2016,A1 .Location in patent: Page/Page column 11

43
[ 842133-18-0 ]
[ 51166-71-3 ]
canagliflozin heptakis(2,6-di-O-methyl)-β-cyclodextrin complex [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
260 mg	In water; at 25 - 100℃; for 0.0833333h;	Heptakis(2,6-di-0-memyI)-p-cyclodextrin (345 mg, 0.24 mmol) was added to 2 ml of water I and it got dissolved after approx. 5 min of agitation at 25C. This solution was heated up to 100C and at an elevated temperature the modified cyclodextrin started to be yielded. <strong>[842133-18-0]Canagliflozin</strong> (100 mg, 0.22 mmol) was added at 100C and the suspension was agitated at this temperature for another 5 min. Then it was left to slowly cool down to the room temperature and after that it was agitated in an ice bath for 30 minutes and put in a fridge for i 72 hours. The resulting crystalline substance was filtered, washed with 1 ml of icy water and dried in a vacuum drier at 25C overnight. 260 mg of a purely white substance was obtained with the chemical purity of 99.90% (HPLC).

Reference： [1]Patent: WO2016/41530,2016,A1 .Location in patent: Page/Page column 11

44
[ 1358581-37-9 ]
[ 842133-18-0 ]

Yield	Reaction Conditions	Operation in experiment
90%	With triethylsilane; boron trifluoride diethyl etherate; In dichloromethane; at -40 - 0℃; for 3h;	Into a 2L 4 necked RB flask were added (3R,4S,5S,6R)-2-[3-[[5-(4-fluorophenyl)-2- thienylj methylj -4-methyl-phenylj -6-(hydroxymethyl)-2-methyl-tetrahydropyran-3 ,4,5-triol of formula (5) (bOg, 0.21 moles), triethylsilane (77.Og, 0.63 moles) in dichloromethane (1300 ml). The resulting solution was cooled to 0C, and was added BF3-O(Et)2 (91.8 0.63 moles) drop wise at -40 to -30 C. The reaction mixture was warmed to 0C and stirred for 3 hrs. The reaction mixture was then quenched with satd.NaHCO3 solution (1.5 L) at 0C and the layers were separated. The organic layer was washed with DM water (650 ml) and aq. saturated sodium chloride solution (650 ml). The solvent distilled off completely under reduced pressure to yield (97.lg, > 90%) titled compound of formula (1) as a foamy solid.
79%		Take 1-(1-O-methyl-beta-D-glucopyranose-1-yl)-4-methyl-3-[[5-(4-fluorophenyl)-2-thienyl]methyl]benzene 23g, dichloromethane 40ml and acetonitrile 120ml were added to a 500ml reaction flask, stirred evenly; the reaction solution was cooled to -5C, 2g anhydrous aluminum trichloride was added, stirred for 30min, and 33g Et3SiH was added dropwise at this temperature. Slowly warm to 10 C, the reaction is 2h; the reaction is completed, the temperature is lowered to -5 C, the saturated sodium bicarbonate solution is added dropwise, the pH is adjusted to 6-7; extracted with ethyl acetate (200 g × 2), The organic phase was washed successively with water and a saturated sodium chloride solution until neutral, then dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure to recover ethyl acetate, and 100 g of a mixed solution of methanol and dichloromethane (1:1) was added. After stirring, a large amount of solid was precipitated, and the mixture was cooled and stirred for 1 hour; filtered, and the solid was washed with cold ethanol, and dried under vacuum at 50 C overnight to obtain 17 g of a white solid, yield 79%, purity 99.14%.
77.5%	With triethylsilane; acetonitrile boron trifluoride complex; In n-heptane; at -5 - 5℃; for 5h;	300 ml of methanol and 100 ml of methanesulfonic acid were added to a 500 ml three-necked flask, and the mixture was stirred and stirred to room temperature. After the reaction solution was discharged from the B unit, the methanol solution of methanesulfonic acid was flowed together at a flow rate of 20 ml / min Unit, the residence time of the reaction unit was 6.9 seconds, the reaction temperature controlled by the reaction unit was 0 C, After the reaction liquid was withdrawn from the C unit, boron trifluoride acetonitrile was simultaneously supplied at a flow rate of 15 ml / min, The flow rate of triethylsilane 20 ml / min flows into the D unit together, the residence time of the reaction unit is 5.9 seconds, the reaction temperature controlled by the reaction unit is -5 C, The raw material discharged from the unit was added to a three-necked flask equipped with 300 ml of n-heptane and stirred to crystallize. After incubation at 0-5 C for 5 hours, the crude product of Canagliflozin.After weighing the column-triazine obtained in Step Cango crude 20g, the dissolved 50ml of ethyl acetate, was slowly added dropwise to 300ml with purified water, the feed solution temperature is controlled at 10-20 deg.] C, until crystallization incubated for 16 hours pumping by filtration and drying to obtain the finished Cango column piperazine, the product content of 99.97%, total yield of 77.5%.

70.5%	With triethylsilane; boron trifluoride diethyl etherate; In dichloromethane; acetonitrile; at -20 - 0℃;	To 100mL three-necked flask was added 4.45g of intermediate -2,22ml of methylene chloride, 20ml of acetonitrile, stirred to dissolve, cooled to -15 to -20 deg.] C, was added 6.96g of triethylsilane was added dropwise 6.34g three boron trifluoride diethyl, dropping the reaction temperature is kept at -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 2.94g Kage column net yield: 70.5%.
15.2 g	With triethylsilane; aluminum (III) chloride; In dichloromethane; at -5 - 22℃; for 2h;	In a round bottom flask dichloromethane (25 ml) and aluminiumchloride (14.5 gm) were added and cooled to -5C and then acetonitrile (61 ml) was added for about 20 minutes. Now triethylsilane (10.8 gm) was added for about 30 minutes at the same temperature. Now dichloromethane (37 ml) and 2S,3R,4S,5S,6R)-2-(3-((5-(4- fI uorophenyl)thiophen-2-yl)methyl)-4-methyl phenyl)-6-(hydroxymethyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triol (25 mg) were added and maintained for about 1 hour. Now temperature raised to 22C and maintained for about 1 hour and cooled to - 5C. Water (125 ml) was added for about 30 minutes and the temperature of the reaction raised to room temperature. Now the reaction mass was charged into a separating funnel and the organic layer was separated and distilled under vacuum at 40C for about 20 minutes. Now chased with dichloromethane (125 ml) and cooled to room temperature. Methyltertiarybutylether (150 ml), water (2 ml) and canagliflozin hemihydrate (0.25 gm) seed were added and maintained for about 6 hours. Again water (0.5 ml) was added and maintained for about 6 hours. Now Methyltertiarybutylether (150 ml) was added and distilled under vacuum for about 40 minutes at 40C. To this Methyltertiarybutylether (150 ml) was added and distilled under vacuum for about 30 minutes and cooled to room temperature. At this temperature water (2 ml) was added and maintained for about 6 hours and filtered and washed with methyltertiarybutylether (25 ml) to give canagliflozin crude (16 gm) compound.The above wet compound was charged into a round bottom flask and isopropylacetate (100 ml) was added and heated to 55C. Maintained for about 10 minutes and cooled to room temperature and dichloromethane (12.5 ml), canagliflozin hemihydrate (0.25 gm) seed, water (1 ml) were added and maintained for about 5 hours. Filtered and washed with isopropylacetate (25 ml) to give canagliflozin (15.2 gm). HPLC purity: 99.58%.The above wet compound was charged into a round bottom flask and charged isopropylacetate (100 ml) and heated to 55C. Maintained for about 15 minutes and cooled to room temperature and dichloromethane (12.5 ml), canagliflozin hemihydrate (0.25 gm) seed, water (1 ml) were added and maintained for about 18 hours. Filtered and washed with isopropylacetate (25 ml) and dried under vacuum for about 6 hours at 55C to give canagliflozin hemihydrate (12.5 gm). HPLC purity: 99.77%.

Reference： [1]Patent: WO2018/20506,2018,A1 .Location in patent: Page/Page column 13
[2]Patent: CN109336874,2019,A .Location in patent: Paragraph 0019
[3]Patent: CN106866645,2017,A .Location in patent: Paragraph 0025; 0052; 0055
[4]Patent: CN105481915,2016,A .Location in patent: Paragraph 0029; 0030
[5]Patent: WO2017/71813,2017,A1 .Location in patent: Page/Page column 11; 12
[6]Patent: WO2017/93949,2017,A1 .Location in patent: Page/Page column 13; 14
[7]Organic Process Research and Development,2018,vol. 22,p. 27 - 39

45
[ 1198-69-2 ]
[ 842133-18-0 ]

Reference： [1]Patent: CN105481915,2016,A

46
C₁₉H₁₆FIOS [ No CAS ]
[ 842133-18-0 ]

Reference： [1]Patent: WO2016/83790,2016,A1

47
[ 61259-48-1 ]
[ 842133-18-0 ]

Reference： [1]Patent: WO2016/83790,2016,A1
[2]Patent: WO2016/83790,2016,A1

48
C₃₂H₃₁FO₁₁S [ No CAS ]
[ 842133-18-0 ]

Reference： [1]Patent: WO2016/83790,2016,A1

49
(2R,3R,4R,5S,6S)-3,4,5-tris(benzyloxy)-2-((benzyloxy)methyl)-6-(3-((5-(4-fluorophenyl)-thiophen-2-yl)methyl)-4-methylphenyl)tetrahydro-2H-pyran [ No CAS ]
[ 842133-18-0 ]

Yield	Reaction Conditions	Operation in experiment
90%	With palladium 10% on activated carbon; In dichloromethane;Inert atmosphere;	178.1 g (221 mmol) of the resulting off-white solid was placed in a 2 L round bottom flask, washed with 890 mL24 wt.% Of hydrogen bromide in acetic acid was added and the mixture was stirred at room temperature for 3 hours until the starting material reacted completely. Reaction junctionAfter the beam, the reaction product solution was added dropwise to 10 L of ice water, a large amount of oil was precipitated, and centrifugedThe supernatant was removed and the organic phase was washed sequentially with dichloromethane, saturated sodium bicarbonate and saturated chlorinatedSodium solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a light yellow foamy solid, which foamThe solid was recrystallized from 360 mL of ethyl acetate and 180 mL of n-heptane, And then solid-liquid separation,88.3 g of an off-white solid was obtained.The white solid was detected and the yield was calculated, The results show that such whiteColor solid for the Kage column net,The purity was 99.5% and the yield was 90%.
90%	With trimethylsilyl iodide; In dichloromethane; at 0 - 30℃;	In 250 ml RBF charged (3R,4R,5R,6R)-3,4,5-tris (benzyloxy)-6- (benzyloxymethyl)-2-(3 -[(5 -(4-fluorophenyl)thiophen-2-yl)-4-methylphenyl]tetrahydro-2H-pyran (10 gm, 0.0124 moles) and dichloromethane (100 ml). The reaction mixture was cooled under stirring to 0C, and charged iodotrimethylsilane (8.83 ml, 0.062 moles). Raised the temp to 25C - 30C and maintained for 5 - 6 hours. The reaction was monitored on TLC. The reaction mixture was concentrated under reduced pressure, charged cyclohexane to the residual mass and stirred. Filtered the precipitated compound and dried to isolate (2 S,3R,4R, 5 S,6R)-2-(3 -((5 -(4-fluorophenyl)thiophen-2-yl)methyl)-4-methylphenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3 ,4, 5 -triol as a solid (5.0 gm, 90%).

Reference： [1]Patent: CN105440025,2016,A .Location in patent: Paragraph 0079
[2]Patent: WO2016/128995,2016,A1 .Location in patent: Page/Page column 20

50
[ 13096-62-3 ]
[ 842133-18-0 ]

Reference： [1]Patent: CN105440025,2016,A

51
1-[2,3,4,6-tetra-O-(trimethylsilyl)-β-D-glucopyranosyl]-4-methyl-3-[[5-(4-fluorophenyl)-2-thienyl]methyl]benzene [ No CAS ]
[ 842133-18-0 ]

Yield	Reaction Conditions	Operation in experiment
42 g	With hydrogenchloride; In tetrahydrofuran; methanol; water; at 30℃; for 3h;	The intermediate 1Pi obtained in the previous step was dissolved in 200 ml of THF and 100 ml of methanol, and then 12 g of hydrochloric acid (mass fraction30%). The reaction temperature was 30 C and the reaction mixture was stirred for 3 hours. After completion of the TLC reaction, 100 ml of water was added to quench the reaction. After adding BEthyl acetate, and the phases were separated and dried (anhydrous sodium sulphate). Filtered and concentrated to give 42 g of Compound I as a light yellow solid.The yield of three steps was 81.2%, the purity was 99.95%

Reference： [1]Patent: CN105541815,2016,A .Location in patent: Paragraph 0053

52
methyl 1-C-(3-[5-(4-fluorophenyl)-2-thienyl]methyl}-4-methylphenyl)-D-glucopyranoside [ No CAS ]
[ 842133-18-0 ]

Yield	Reaction Conditions	Operation in experiment
3.98kg	With triethylsilane; boron trifluoride diethyl etherate; In dichloromethane; at 0℃; for 2h;Large scale;	Compound 1 (6.3kg, 13.2mol) was added to 60L of methylene chloride, was addedtriethylsilane (4.6kg, 39.9mol) was cooled with a dry ice-acetone, boron trifluorideether solution (5L, 39.5mmol) was added dropwise entered, then the reaction mixture waswarmed to 0 deg.] C, stirred for 2 hours, a saturated aqueous sodium bicarbonatesolution (80L) was added slowly to the reaction kettle, the reaction was quenched. Thelayers were separated and the organic phase was concentrated to dryness under reducedpressure, and ethyl acetate was added water 100L 70L, extracted after stirring, theaqueous phase was further extracted with ethyl acetate 70L, and the combined organicphases, washed with 50L water, and then saturated with chlorine 50L washed with asolution of sodium, anhydrous magnesium sulfate, the desiccant was filtered off, theactivated carbon was added, followed by stirring for 30 minutes, the activated carbonwas filtered, and the filtrate was concentrated to dryness under reduced pressure, theresidue was dissolved in ethyl acetate (30L), the ether (60L) was added slowly, solidprecipitation, the Kage column net total of 3.98kg.

Reference： [1]Patent: CN103694230,2016,B .Location in patent: Paragraph 0065; 0066

53
[ 4291-69-4 ]
[ 842133-18-0 ]

Reference： [1]Patent: WO2016/128995,2016,A1

54
C₄₄H₅₇FO₉S [ No CAS ]
[ 842133-18-0 ]

Yield	Reaction Conditions	Operation in experiment
85%	With methanol;	The target product is further subjected to removal of the pivaloyl group under acidic conditions,To give the title compound,Reaction completed,The first atmospheric pressure is not easy to remove the characteristics of impurities,Concentrated to give the crude product,And then repeatedly beat the method of methanol to remove a variety of impurities,To obtain the target product with purity higher than 98%The yield was over 85%.

Reference： [1]Patent: CN103980263,2016,B .Location in patent: Paragraph 0038

55
[ 118-90-1 ]
[ 842133-18-0 ]

Reference： [1]Patent: CN103980263,2016,B

56
3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-one [ No CAS ]
[ 842133-18-0 ]

Reference： [1]Patent: WO2016/142950,2016,A1

57
2-allyloxy-2-{3-[5-(4-fluoro-phenyl)-thiophen-2-ylmethyl]-4-methyl-phenyl}-3,4,5-tris-trimethylsilanyloxy-6-trimethylsilanyloxymethyl-tetrahydro-pyran [ No CAS ]
[ 842133-18-0 ]

Yield	Reaction Conditions	Operation in experiment
		To themixture of 20 cc(1:1 MDC + ACN) added 0.11 mole 2-Allyloxy-2-{3-[5-(4-fluoro- phenyl)-thiophen-2-ylmethyl] -4-methyl-phenyl } -3 ,4,5-tris-trimethylsilanyloxy-6-trimethylsilanyloxymethyl-tetrahydro-pyran under argon atmosphere. Stirred the reaction mass for 30.0 min.Cooled the reaction mass to -40 to -55C in a dry ice/acetone bath under argon atmosphere. Charged 3 mole Triethylsilane at -40 to -55Candstirred the reaction mass for 30.0 mm at -50 to -55C. Slowly addedBorontrifloride in diethyl ether solution at -40 to -55C and stirred the reaction mass for 2 hrs. Quenched the reaction mass with 50 cc sat. sodium bicarbonate solution at -40 to -55C . andStirred the reaction mass for 30.0 mm. Slowly raised the temperature to 25 to 30C. Settled downthe reaction mass and separated the layers, extracted the aqueous layer with 100 cc of MDC. Combined the organic layer and washed with 500 cc water. Washed the organic layer with 500 cc of sat.Brinesolution.Distilled out the MDC under reduced pressure below 40C.to get 85-87% titled compound as light yellow solid.HPLC purity: 90-95%

Reference： [1]Patent: WO2016/142950,2016,A1 .Location in patent: Page/Page column 17; 18

58
2-allyloxy-2-{3-[5-(4-fluoro-phenyl)-thiophen-2-ylmethyl]-4-methyl-phenyl}-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol [ No CAS ]
[ 842133-18-0 ]

Reference： [1]Patent: WO2016/142950,2016,A1

59
C₂₇H₂₇FO₆S [ No CAS ]
[ 842133-18-0 ]

Yield	Reaction Conditions	Operation in experiment
		To themixture of 20 cc(1:1 MDC + ACN) added 0.11 mole 2- prop-2ynyl -2-{3-[5-(4- fluoro-phenyl)-thiophen-2-ylmethylj-4-methyl-phenyl } -6- hydroxymethyl-tetrahydropyran-3,4,5-triolunder argon atmosphere. Stirred the reaction mass for 30.0 min.Cooled the reaction mass to -40 to -55C in a dry ice/acetone bath under argon atmosphere. Charged 3 mole Triethylsilane at -40 to -55Candstirred the reaction mass for 30.0 mm at-50 to -55C. Slowly addedBorontrifloride in diethyl ether solution at -40 to -55C and stirred the reaction mass for 2 hrs. Quenched the reaction mass with 50 cc sat. sodium bicarbonate solution at -40 to -55C . andstirred the reaction mass for 30.0 mm. Slowly raised the temperature to 25 to 30C. Settled downthe reaction mass and separated ,the layers, extracted the aqueous layer with 100 cc of MDC. Combined the organic layers and washed with 500 cc water. Washed the organic layer with 500 cc of sat.Brinesolution.Distilled out the MDC under reduced pressure below 40C.to get85- 87% titled compound aslight yellow solid. HPLC purity: 90-95%

Reference： [1]Patent: WO2016/142950,2016,A1 .Location in patent: Page/Page column 18

60
(2S,3S,4R,5R,6R)-6-(benzoylmethyl)-3,4,5-tribenzoyl-2-{3-[(5-(4-fluorophenyl)-2-thienyl)methyl]-4-methylphenyl}-2H-glucopyranoside [ No CAS ]
[ 842133-18-0 ]

Yield	Reaction Conditions	Operation in experiment
96%	With sodium methylate; In tetrahydrofuran; methanol; at 40℃; for 2h;	The intermediate II obtained above was dissolved in 40 ml of tetrahydrofuran and 80 ml of methanol. 7. 7 g of sodium methoxide (molar ratio of 4: 1) was added and the temperature was raised to 40 C. After 2 hours, the plate was started. After the completion of the reaction, 100 ml of acetic acid Ethyl acetate and 150 ml of water. The layers were separated and the aqueous layer was extracted once more with 70 ml of ethyl acetate. The organic phase was separated and the organic phase was washed once with 100 ml of saturated aqueous sodium chloride. Dried, and then dissolved in isopropyl acetate to make the total weight of the liquid 60g, the liquid slowly dropping to 1. 1L of water, stirring crystallization for 10 hours, filter to get the net finished products Kagel 15. 2g. The yield was 96% and the content was 99.93%.

Reference： [1]Patent: CN104119324,2016,B .Location in patent: Paragraph 0050

61
[ 842133-18-0 ]
[ 4043-87-2 ]
(2S,3R,4R,5S,6R)-2-{3-[5-[4-fluorophenyl]thiophen-2-ylmethyl]-4-methylphenyl}-6-hydroxymethyl tetrahydropyran-3,4,5-triol pipecolic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	In ethanol; n-heptane; at 20℃; for 3h;Reflux;	Charged 100gms <strong>[842133-18-0]canagliflozin</strong> crude to a clean, dry round bottom flask fitted with reflux condenser in a water bath. Charged ethanol 7.5 vol. stirred to get clear solution. Slowly heated the reaction mass to reflux and maintained the reflux for 30 mins. Added pipecolic acid 15 mmolein a single lot. Stirred for 1 hr at reflux, material slowly precipitates stirred for another 1 hr at reflux. Slowly added heptanes 7.5 vol. maintained for another 1 hr at reflux. Slowly cooled the reaction mass to room temperature and stirred for 5- 6 hrs at room temperature. Filtered the mass and washed the cake with heptanes 2 vol. suck dried the cake and dried the wet cake i n ai r dri er f or 8 " 10 hrs.
4 g	In ethanol; ethyl acetate; for 0.5h;Reflux;	To a round bottom flask equipped with reflux condenser, ethanol (10 ml) and ethyl acetate (50ml) was added followed by <strong>[842133-18-0]canagliflozin</strong> (5 gm) and stined for 10 mm at 25-30C. DLPipecolic acid (1.74 gm) was added; the contents were heated to reflux and stined for 30 mm.Then the reaction mass was cooled to 25-30C and the solid was filtered. The wet solid thusobtained was added into the mixture of ethanol (10 ml) and ethyl acetate (50 ml) and heated toreflux. The reaction mass was further allowed to cool to 25-30C and the solids were filtered to get <strong>[842133-18-0]Canagliflozin</strong> DL-pipecolic acid co-crystal (4gms). HPLC purity: 99.5%.

Reference： [1]Patent: WO2017/60924,2017,A1 .Location in patent: Page/Page column 24; 25
[2]Patent: WO2017/46730,2017,A1 .Location in patent: Page/Page column 38

62
2-[(5-bromo-2-methylphenyl)(dimethoxy)methyl]-5-(4-fluorophenyl)thiophene [ No CAS ]
[ 842133-18-0 ]

Reference： [1]Patent: US2017/73336,2017,A1

63
[5-(4-fluorophenyl)-thiophen-2-yl]-[2-methyl-5-(3,4,5-trihydroxy-6-hydroxymethyl-2-methoxy-tetrahydropyran-2-yl)-phenyl]methanone [ No CAS ]
[ 842133-18-0 ]

Yield	Reaction Conditions	Operation in experiment
		In a clean and dry four neck R B Flask, charge acetonitrile (150 ml) and dichloromethane (150 ml) at room temperature, charge [5-(4-Fluoro-phenyl)-thiophen-2-yl]-[2-methyl-5-(3,4,5-trihydroxy-6-hydroxymethyl-2-methoxy-tetrahydro-pyran-2-yl)-phenyl]-methanone prepared in Example-2 or Example-3 (30 gm, 0.0614 moles). The reaction mass was cooled to 0-5 C. under nitrogen atmosphere, slowly added triethylsilane (18.2 gm, 0.246 moles) and stirred the reaction mass for 15 minutes at 0-5 C., followed by slowly addition of boron trifluoride diethyl etharate 46% solution (72.7 gm, 0.246 moles) at 0-5 C. and stirred for 30 minutes at same temperature. The resultant mixture was allowed to raise the temperature at 25-30 C. and stirred at same temperature for 3-5 hours till completion of reaction. After completion, the reaction mixture was quenched with 5% sodium bicarbonate solution (300 ml) and stir for 15 minutes at 25-30 C. The organic layer was separated and washed with water, distilled out solvent under reduced pressure at below 50 C. to get a residue, further it was charge with ethyl acetate (150 ml), n-heptane (300 ml) and water (3 ml) and stirred for overnight at room temperature to form precipitated solid. The obtain solid was filtered and dried at 40-45 C. to get a title compound of Canagliflozin hemihydrate.

Reference： [1]Patent: US2017/73336,2017,A1 .Location in patent: Paragraph 0028; 0045

64
[5-(4-fluorophenyl)thiophen-2-yl]-[2-methyl-5-(3,4,5-trihydroxy-6-hydroxymethyl-2-methoxytetrahydropyran-2-yl)phenyl]methanone [ No CAS ]
[ 842133-18-0 ]

Reference： [1]Patent: US2017/73336,2017,A1

65
[ 59-67-6 ]
[ 842133-18-0 ]
canagliflozin nicotinic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
0.3 g	In ethanol; at 25 - 75℃;	To a round bottom flask equipped with reflux condenser, <strong>[842133-18-0]Canagliflozin</strong> (2 gms), ethanol (40ml), and nicotinic acid (0.6 gm) was added at 25-30C. Heated the contents of the flask to 70-75C and allowed to cool to 25-30C. The reaction mass was stined for S hrs at 2S-30C and filtered the solid to obtain <strong>[842133-18-0]Canagliflozin</strong> Nicotinic acid co-crystal (0.3 gm).

Reference： [1]Patent: WO2017/46730,2017,A1 .Location in patent: Page/Page column 39

66
[ 98-97-5 ]
[ 842133-18-0 ]
canagliflozin pyrazine-2-carboxylic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
0.4 g	In ethanol; at 25 - 75℃;	To a round bottom flask equipped with reflux condenser, <strong>[842133-18-0]Canagliflozin</strong> (2 gms) was dissolved in ethanol (40 ml), and added pyrazine-2-carboxylic acid (0.6 gm) at 25-30C. Heat the contents to 70-75 C and allowed to cool to 25-30C. The reaction mass was stined for 5 hrsat 25-30C and filtered the solid to obtain <strong>[842133-18-0]Canagliflozin</strong> pyrazine-2-carboxylic acid co-crystal (0.4 gm).

Reference： [1]Patent: WO2017/46730,2017,A1 .Location in patent: Page/Page column 40

67
[ 288-13-1 ]
[ 842133-18-0 ]
canagliflozin pyrazole [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
4 g	In ethanol; n-heptane; at 55 - 75℃;	To a round bottom flask equipped with reflux condenser, ethanol (100 ml), <strong>[842133-18-0]Canagliflozin</strong> (5 gms) and pyrazole (0.8 gms) were added and the reaction mass was heated to 70-75C. Thecontents of the flask were allowed to cool to 55-60C and added heptane (50 nil). Cooled the reaction mass further to 25-30C and the solid was filtered. The resulting wet solid was purified from mixture of ethanol (75 ml) and n-heptane (75 ml) to obtain <strong>[842133-18-0]Canagliflozin</strong> pyrazole co-crystal co-crystal (4 gm).

Reference： [1]Patent: WO2017/46730,2017,A1 .Location in patent: Page/Page column 40

68
[ 842133-18-0 ]
[ 3105-95-1 ]
canagliflozin L-pipecolic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
3.5 g	In ethanol; ethyl acetate; for 0.5h;Reflux;	To a round bottom flask equipped with reflux condenser, <strong>[842133-18-0]Canagliflozin</strong> (5 gm), ethanol (10ml) and ethyl acetate (50 ml) were added and the reaction mass was stined for 10 mm at 25-30C. L-Pipecolic acid (1.74 gm) was added, the reaction mass was allowed to rise to reflux and stined for 30 mm. Then the reaction mass was cooled to 25-30C and the solid was filtered. To the resulting wet solid, ethanol (10 ml) and ethyl acetate (50 ml) was added and raised the temperature of the reaction mass to reflux. The reaction mass was further cooled to25-30C and the solids were filtered to get <strong>[842133-18-0]Canagliflozin</strong> L-pipecolic acid co-crystal (3.5 gms).

Reference： [1]Patent: WO2017/46730,2017,A1 .Location in patent: Page/Page column 39

69
[ 842133-18-0 ]
[ 1723-00-8 ]
canagliflozin D-pipecolic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
3.5 g	In ethanol; ethyl acetate; for 0.5h;Reflux;	To a round bottom flask equipped with reflux condenser, <strong>[842133-18-0]Canagliflozin</strong> (5 gm), ethanol (10ml) and ethyl acetate (50 ml) were added and stined the contents for 10 mm at 25-30C.acid (1.74 gm) was added, heated the contents to reflux temperature and stined for30 mm. Then, the reaction mass was cooled to 25-30C and the solid was filtered. Theresulting wet solid was charged into the mixture of ethanol (10 ml) and ethyl acetate (50 ml), heated to reflux, cooled to 25-30C and the solids were filtered to get <strong>[842133-18-0]Canagliflozin</strong> Dpipecolic acid co-crystal (3.5 gms).

Reference： [1]Patent: WO2017/46730,2017,A1 .Location in patent: Page/Page column 39

70
(2S,3R,4R,5S,6R)-2-{3-[5-[4-fluorophenyl]thiophen-2-ylmethyl]-4-methylphenyl}-6-hydroxymethyl tetrahydropyran-3,4,5-triol pipecolic acid [ No CAS ]
[ 842133-18-0 ]

Yield	Reaction Conditions	Operation in experiment
3.0 g	With sodium hydrogencarbonate; In water; ethyl acetate; at 25 - 30℃; for 0.5h;	To a round bottom flask equipped with reflux condenser, ethyl acetate (30 ml) andCanagliflozin DL-pipecolic acid co-crystal (5 gms) was added at 25-30 C. Sodiumbicarbonate solution (2.5 gm dissolved in 50 ml water) was added to the reaction mass at 25-30C and stirred for 30 mm at the same temperature. The resulting organic layer was washedwith water and solvent from the organic layer was distilled completely under vacuum at below45C. Cyclohexane (30 ml) was added to the resulting residue at 25-30C, stined for 30 mm at 25-30C, filtered the solid and washed with cyclohexane (5 ml). The obtained solids are dried under vacuum at below 45 C for 10.0 hrs to obtain amorphous canagliflozin (3.0 gms). HPLC purity: 99.8%.Alpha isomer content by HPLC: <0.05%, The PXRD is set forth in Figure 06, The TGA is set forth in Figure 07, The IR is set forth in Figure 08.

Reference： [1]Patent: WO2017/46730,2017,A1 .Location in patent: Page/Page column 40

71
(2R,3S,4R,5R)-1-(3-((5-(4-fluorophenyl)thiophen-2-yl)methyl)-4-methylphenyl)-2,3,4,5,6-pentahydroxyhexan-1-one [ No CAS ]
[ 842133-18-0 ]

Yield	Reaction Conditions	Operation in experiment
3.5 g		In a round bottom flask (2R,3S,4R,5R)-1 -(3-((5-(4-fluorophenyl)thiophen-2- yl)methyl)-4-methylphenyl)-2, 3,4,5, 6-pentahydroxyhexan-1 -one (10 gm) and methanol (75 ml) were added and stirred at room temperature. The reaction mass was cooled to 2C. At this temperature methanesulfonic acid (0.914 gm) was added and temperature is raised to 13C and stirred for 2 hours. The reaction mixture was quenched with 1.6% sodiumbicarbonate (1 .120 gm) and dichloromethane (100 ml). The layers were separated and to the dichloromethane layer DM water (50 ml) was added and stirred. Now concentrate the contents to 2-3 volumes under vacuum and stripped with dichloromethane (50 ml). Dichloromethane (100 ml) charged to the reaction mass, stirred for 10 minutes and cooled to -30 to -40C. Now triethyl silane (4.97 gm) added and BF3.Etherate (5.41 gm) were added and stirred for 2 to 3 hours. Now raise the temperature to 0 to -5C and maintain for 55±15 minutes. pH of the reaction mass was adjusted to 7.0 to 8.0 with 9% NaHC03 (12 gm) and temperature raised to 25-35C and maintained for 10 minutes. Methanol (20 ml) was added and maintained for about 30 minutes and layers separated. Organic layer was washed twice with water (50 ml) and methanol (20 ml). The organic layer was separated and layers were combined, SC-40 charcoal was added and stirred. The reaction mass was filtered and through hyflow and washed with dichloromethane (10 ml) and filtered.

Reference： [1]Patent: WO2017/93949,2017,A1 .Location in patent: Page/Page column 12-14
[2]Organic Process Research and Development,2018,vol. 22,p. 27 - 39

72
[ 572-09-8 ]
[ 842133-18-0 ]

Reference： [1]Journal of the American Chemical Society,2017,vol. 139,p. 10693 - 10701

73
[ 498-94-2 ]
[ 842133-18-0 ]
(2S,3R,4R,5S,6R)-2-[3-[[5-(4-fluorophenyl)-2-thienyl]methyl]-4-methylphenyl]-6-(hydroxymethyl)tetrahydropyran-3,4,5-triol piperdine-4-carboxylic acid complex [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
80%	In water; acetone; at 40℃; for 6h;	Into a 250 mL RB flask, were added, (2S ,3R,4R,5S ,6R)-2- [3- [[5-(4-fluorophenyl)-2-thienylj methylj -4-methyl-phenylj -6-(hydroxymethyl) tetrahydropyran-3 ,4,5-triol of formula (1) (25g, 0.05 moles), acetone (125 ml), piperdine-4- carboxylic acid (7.2 g, 0.05), and DM water (12.5 ml). The reaction mixture was heated to 40 C and stirred for 6h and then cooled to ambient temperature. The resulting precipitated solid was cooled to 0-5 C, stirred for lh and filtered and dried at 50-55 C under reduced pressure to yield (26.1 g, 80% ) complex of formula (5)as an off white solid.Analytical data:JR (cm-i) KBr: 3477, 3355, 2970, 2915, 2524, 2489, 1699, 1644, 1576, 1509, 1369, 1225,1045, 1013.1HNMR (400 MHz; CD3OD+D20; ppm): 7.55 (dd, 2H); 7.31 (s, 1H), 7.25 (d, 1=8.0 Hz; 3H)),7.18 (d, 1=7.6 Hz, 1H), 7.11 (d, 1=3.6 Hz, 1H), 7.07 (t, 1=8.8 Hz, 2H), 6.71 (d, 1=3.6 Hz, 1H),4.12-4.15 (m, 1H), 3.88 (d, 1=12 Hz, 1H), 3.68-3.72 (m, 1H), 3.33-3.53 (m, 6H), 2.94-3.01 (m,2H), 2.34-2.42 (m, 1H),2.30 (s, 3H), 2.03-2.08 (m, 2H), 1.79-1.89 (m, 2H).13CNMR (400 MHz; CD3OD+D20; ppm): 181.60; 164.56; 144.98, 142.38, 139.33, 137.71;132.29, 131.35, 130.40, 128.i0(d, JC-F=8.OHz); 127.50, 127.18, 123.92, 116.75 (d, ICF=22.OHz), 83.30, 81.97, 79.57, 76.19, 71.77, 62.95, 44.76, 42.74, 34.87, 27.19, 19.35.Mass: 574.8 (M+i)PXRD (20 (±0.2): 3.48, 10.38, 11.36, 11.96, 13.86, 16.27, 16.61, 17.24, 17.60,18.00,19.01,19.93, 20.47, 21.05, 21.77, 21.99, 22.25, 22.8, 23.4, 24.05, 24.61, 24.86, 25.58,26.02, 26.23,26.71,28.34, 29.10, 31.33, 32.21, 33.61.

Reference： [1]Patent: WO2018/20506,2018,A1 .Location in patent: Page/Page column 13; 14; 15

74
(2S,3R,4R,5S,6R)-2-[3-[[5-(4-fluorophenyl)-2-thienyl]methyl]-4-methylphenyl]-6-(hydroxymethyl)tetrahydropyran-3,4,5-triol piperdine-4-carboxylic acid complex [ No CAS ]
[ 842133-18-0 ]

Yield	Reaction Conditions	Operation in experiment
80%	In tert-butyl methyl ether; water; for 1h;	Into a 3L 4 necked RB flask, were added (2S,3R,4R,5S,6R)-2-[3-[[5-(4-fluorophenyl)-2- thienylj methylj -4-methyl-phenylj -6-(hydroxymethyl) tetrahydropyran-3, 4, 5-triol complex compound of formula (6) (100 g ), DM Water (500 ml) and methyl tert-butyl ether (2000m1). The resulting mixture was stirred for 60 mm, separated the organic layer, clarified over activated carbon and filtered. The filtrate was distilled off partially under reduced pressure and to the remaining solution added drop wise into cyclohexane (2400 ml). The precipitated solid was filtered and dried under vacuum to afford highly pure compound of formula (1) (64.3g, 80%) as a white solid.Analytical data:JR (cm?) KBr: 3404, 3072, 2918, 1509, 1231, 1048, 1159.?HNMR (400 MHz; DMSO-d6; ppm):7.59 (dd 1=8.8 Hz, 1=2.4Hz, 2H), 7.27 (d, 1=3.6Hz, 1H) 7.15-7.21(m, 3H) 7.14 (d, 1=8.0Hz, 1H), 7.11(d, 1=8.0Hz, 1H), 6.79 (d, 1=3.6Hz, 1H), 4.93-4.94(m, 2 -0-H); 4.74 (d, 1=5.6Hz, -0-H), 4.46 (t, 1=5.6Hz, -0-H), 4.14(d, 1=16.0Hz, 1H), 4.09 (d, 1=16.0Hz, 1H), 3.96 (d, 1=9.6Hz, 1H), 3.67-3.69 (m, 1H), 3.40-3.46 (m, 1H),3.13-3.28 (m, 4H), 2.25 (s, 3H).?3CNMR (400 MHz; DMSO-d6; ppm): 161.40(d, JC-F=243.OHz), 143.66, 140.26, 138.24, 137.40, 134.98, 130.54, 129.70, 129.09, 126.98 (d, JC-F=8.OHz), 126.38, 126.27, 123.40,115.90 (d, JC-F=22.OHz), 81.35, 81.21, 78.51, 74.71, 70.47, 61.47, 33.47, 18.83.Mass: 462.19 [M+NH4j+.HPLC: >99.5% (by area normalization)

Reference： [1]Patent: WO2018/20506,2018,A1 .Location in patent: Page/Page column 15

75
[ 842133-18-0 ]
[ 141-78-6 ]
((2R,3S,4R,5R,6S)-6-(3-((5-(4-fluorophenyl)thiophen-2-yl)methyl)-4-methylphenyl)-3,4,5-trihydroxytetrahydro-2H-pyran-2-yl)methyl acetate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	In n-heptane; water; at 40℃; for 3h;	800 g of the above compound was dissolved in ethyl acetate, purified water was added, and the temperature was raised to 40 degrees Celsius.N-heptane was added dropwise, and Caglexdine seed crystals were added, and the crystals were filtered for 3 hours.135 g of a mother liquor concentrate containing the compound represented by Formula 1 was obtained, and the liquid phase content of Compound 1 was determined to be about 5.1%.

Reference： [1]Patent: CN107286143,2017,A .Location in patent: Paragraph 0063; 0064; 0065; 0066; 0067; 0068-0078

76
[ 842133-18-0 ]
[2-methyl-5-(β-D-glucopyranosyl)phenyl][5-(4-fluorophenyl)-2-thienyl]methanone [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With 2,3-dicyano-5,6-dichloro-p-benzoquinone; In ethanol; at 20℃; for 24h;	Example 2: Preparation of a compound of formula IIAdd cagliflozin (30g, 67.5mmol) in 300ml absolute ethanol and slowly add 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) with stirring at room temperature.(30.6 g, 134.8 mmol) in anhydrous ethanol (240 ml) was reacted at room temperature for about 24 hours, and the reaction was completely confirmed by TLC, and the reaction was stopped.The reaction solution was slowly poured into a mixture of dichloromethane and water under ice cooling.Medium, liquid separation, and the aqueous phase was extracted twice with dichloromethane.The combined dichloromethane layers were dried with anhydrous magnesium sulfate, filtered and evaporated.The crude product was mixed with methanol and dichloromethane as an eluent.Purification by column chromatography to give [2-methyl-5-(beta-D-glucopyranosyl)phenyl][5-(4-fluorophenyl)-2-thienyl]methanone (compound of formula II) , HPLC: 99.3%.

Reference： [1]Patent: CN108530434,2018,A .Location in patent: Paragraph 0030; 0031

77
[ 842133-18-0 ]
[2-methyl-5-(β-D-glucopyranosyl)phenyl][5-(4-fluorophenyl)-2-thienyl]methanol [ No CAS ]

Reference： [1]Patent: CN108530434,2018,A

78
[ 842133-18-0 ]
(2S,3R,4R,5S,6R)-2-(3-((5-(4-fluorophenyl)thiophen-2-yl)(hydroperoxy)methyl)-4-methylphenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
35%		Add 1.0g of Cagliflozin (2.25mmol) to 20mL of acetonitrile and 2mL of water, add 1.2mL of 30% aqueous hydrogen peroxide solution (10.7mmol), heat to 60 for 12 hours; then cool to 25 , add 1.1mL Fluorophosphoric acid (11.8 mmol), 20 mL of acetonitrile and 3 mL of 30% aqueous hydrogen peroxide solution (29.7 mmol), stirring was continued at 25 C for 48 hours. After the reaction was completed, 80 mL of water was added, and after stirring for 30 minutes, it was cooled to -5 C and filtered. The obtained solid was washed twice with purified water, and the remaining solution was lyophilized with a lyophilizer. The obtained solid was subjected to column chromatography [HP-Silica normal phase silica gel, eluent was dichloromethane: methanol = (12 : 1, V / V)] The target product was separated, and the solvent was finally blown off with nitrogen to finally obtain caglitazone peroxide 0.38 g, HPLC purity 98.9%, and yield 35%.

Reference： [1]Patent: CN110790755,2020,A .Location in patent: Paragraph 0051-0074
[2]Patent: CN108530434,2018,A

79
[ 604-68-2 ]
[ 842133-18-0 ]

Reference： [1]Patent: CN109180662,2019,A

80
C₄₄H₄₉Cl₈FO₉S [ No CAS ]
[ 842133-18-0 ]

Yield	Reaction Conditions	Operation in experiment
92.1%	With water; lithium hydroxide; In methanol; at 0 - 5℃; for 16h;	Compound XII-10 (16.2 mmol) was suspended in methanol (50 mL) and stirred to warm to 0 C.20 mL of an aqueous solution of lithium hydroxide (0.21 g, 8.4 mmol) was added dropwise (when the dropwise addition, the temperature of the control system did not exceed 5 C),After the completion of the dropwise addition, the reaction was carried out at 0-5 C, and HPLC detection (when the detection result showed that the compound XII-10 was less than 1%, the reaction was judged to be completed). After completion of the reaction (reaction time is about 16 hours), the organic solvent is removed under reduced pressure (ie, methanol is removed).The aqueous layer was extracted with ethyl acetate (50 mL×3).Dry over anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure (concentrated to 20% of the original volume under a pressure of 5 kPa), add 20 ml of absolute ethanol, stir, and cool to 0 C.The crystal was incubated for 1 hour, and the solid was precipitated, and filtered under reduced pressure (pressure of 5 kPa). The filter cake was dried under reduced pressure (pressure of 5 kPa) at 35 C to obtain white or off-white solid XII, yield 92.1%, HPLC purity 99.33%.

Reference： [1]Patent: CN109111490,2019,A .Location in patent: Paragraph 0134; 0135; 0148; 0149; 0150

81
C₄₄H₄₅Cl₁₂FO₉S [ No CAS ]
[ 842133-18-0 ]

Yield	Reaction Conditions	Operation in experiment
93.3%	With water; lithium hydroxide; In methanol; at 0 - 5℃; for 16h;	Compound XII-14 (16.2 mmol) was suspended in methanol (50 mL) and stirred to warm to 0 C.20 mL of an aqueous solution of lithium hydroxide (0.21 g, 8.4 mmol) was added dropwise (when the dropwise addition, the temperature of the control system did not exceed 5 C), and the reaction was kept at 0-5 C after the dropwise addition.HPLC detection (when the detection result showed that the compound XII-14 was less than 1%, the reaction was judged to be completed).After completion of the reaction (reaction time: about 16 hours), the organic solvent was removed under reduced pressure (i.e., methanol was removed), and the aqueous layer was extracted with ethyl acetate (50 mL × 3), and the organic phase was combined.It was washed with a saturated aqueous solution of ammonium chloride and a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate.Filtration and concentration of the filtrate under reduced pressure (concentrated to 20% of the original volume under a pressure of 5 kPa).Add 20 ml of absolute ethanol, stir, cool to 0 C, crystallization for 1 hour, precipitate solids, and filter under reduced pressure (pressure of 5 kPa).The filter cake was dried under reduced pressure (pressure of 5 kPa) at 35 C to give white or off-white solid XII, yield 93.3%, HPLC purity 99.42%.

Reference： [1]Patent: CN109111490,2019,A .Location in patent: Paragraph 0170; 0171; 0186; 0187; 0188

82
C₃₁H₄₇Cl₅O₁₁ [ No CAS ]
[ 842133-18-0 ]

Reference： [1]Patent: CN109111490,2019,A

83
C₄₄H₅₃Cl₄FO₉S [ No CAS ]
[ 842133-18-0 ]

Yield	Reaction Conditions	Operation in experiment
92.1%	With water; potassium hydroxide; In tetrahydrofuran; methanol; at 0 - 5℃; for 16h;	Compound XII-6 (16.2 mmol) was suspended in methanol (50 mL) and tetrahydrofuran (50 mL).Stirring to a temperature of 0 C, and adding 20 mL of an aqueous solution of potassium hydroxide (8.4 mmol) (when the dropwise addition, the temperature of the control system does not exceed 5 C),After the completion of the dropwise addition, the reaction was carried out at 0-5 C, and HPLC detection (when the detection result showed that the compound XII-6 was less than 1%, the reaction was judged to be completed). After completion of the reaction (reaction time: 16 hours), the organic solvent was removed under reduced pressure (i.e., methanol and tetrahydrofuran were removed), and the aqueous layer was extracted with ethyl acetate (50 mL × 3).Washed with saturated aqueous ammonium chloride solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and filtered.The filtrate was concentrated under reduced pressure (concentrated to 20% of the original volume under a pressure of 5 kPa), stirred with 20 ml of absolute ethanol, cooled to 0 C, and incubated for 1 hour.The solid was precipitated, filtered under reduced pressure (pressure of 5 kPa), and the filter cake was dried under reduced pressure (pressure of 5 kPa) at 35 C to obtain white or off-white solid XII, yield 93.2%, HPLC purity 99.43%.

Reference： [1]Patent: CN109111490,2019,A .Location in patent: Paragraph 0090; 0092; 0109-0111; 0208; 0223; 0225; 0234-0236

84
[ 4701-17-1 ]
[ 842133-18-0 ]

Reference： [1]Patent: CN109336874,2019,A

85
[ 249504-38-9 ]
[ 842133-18-0 ]

Reference： [1]Patent: CN109336874,2019,A

86
[ 1225916-69-7 ]
[ 842133-18-0 ]

Reference： [1]Patent: CN109336874,2019,A

87
2-chloromethyl-5-(4-fluorophenyl)thiophene [ No CAS ]
[ 842133-18-0 ]

Reference： [1]Patent: CN109336874,2019,A

88
[ 842133-18-0 ]
[ 609-36-9 ]
canagliflozin [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
30 g	With 2,6-di-tert-butyl-4-methyl-phenol; In water; at 45 - 80℃; for 4h;	Suspend BHT (0.55g) in IPA (350 ml) at 20-30 C. Heat the suspension to 45-50 C and continue stirring at this temperature for 30 min. Took 200 ml of the IPA solution, under N2 atmosphere and Cangaliflozin (25gm) was added at 45-50 C. The obtained solution was treated with DL-proline (9.66 gm) which is dissolved in mixture of IPA solution (lOOml) and DM water (10 ml) at 70-80 C and stirred for 4 hours. Lowering the temperate of solution to 60-65 C and stir for 1 hour to precipitate out DL-proline co-crystal of <strong>[842133-18-0]Canagliflozin</strong> as slurry. Cool the obtained slurry slowly to 15-20 C and continue the stirring for 2 hours. Filter the obtained product at 15-20 C and washed with (50 ml, 20-30 C) IPA. Dried the product at 50-60C. (0069) Purity: 99.99 % (0070) Yield: 30 gm:

Reference： [1]Patent: WO2019/116169,2019,A1 .Location in patent: Page/Page column 10

Type	HazMat fee for 500 gram (Estimated)
Excepted Quantity	USD 0.00
Limited Quantity	USD 15-60
Inaccessible (Haz class 6.1), Domestic	USD 80+
Inaccessible (Haz class 6.1), International	USD 150+
Accessible (Haz class 3, 4, 5 or 8), Domestic	USD 100+
Accessible (Haz class 3, 4, 5 or 8), International	USD 200+

Purity	Size	Price	VIP Price	USA Stock *0-1 Day	Global Stock *5-7 Days	Quantity
{[ item.p_purity ]}	{[ item.pr_size ]}	{[ getRatePrice(item.pr_usd, 1,1) ]} {[ getRatePrice(item.pr_usd,item.pr_rate,item.mem_rate) ]}	{[ getRatePrice(item.pr_usd, 1,1) ]}	Inquiry {[ getRatePrice(item.pr_usd,item.pr_rate,item.mem_rate) ]} {[ getRatePrice(item.pr_usd,1,item.mem_rate) ]}	{[ item.pr_usastock ]}	Inquiry -	{[ item.pr_chinastock ]}	Inquiry -

CAS No. :	842133-18-0	MDL No. :	MFCD18251436
Formula :	C₂₄H₂₅FO₅S	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	XTNGUQKDFGDXSJ-ZXGKGEBGSA-N
M.W :	444.52	Pubchem ID :	24812758
Synonyms :	JNJ 28431754;TA-7284;JNJ-24831754

Signal Word:	Danger	Class:	N/A
Precautionary Statements:	P201-P202-P280-P281-P305+P351+P338-P308+P313-P310-P405-P501	UN#:	N/A
Hazard Statements:	H318-H361	Packing Group:	N/A
GHS Pictogram:

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P221	Take any precaution to avoid mixing with combustibles
P222	Do not allow contact with air.
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P285	In case of inadequate ventilation wear respiratory protection.
P231 + P232	Handle under inert gas. Protect from moisture.
P235 + P410	Keep cool. Protect from sunlight.
Response
Code	Phrase
P301	IF SWALLOWED:
P304	IF INHALED:
P305	IF IN EYES:
P306	IF ON CLOTHING:
P307	IF exposed:
P308	IF exposed or concerned:
P309	IF exposed or if you feel unwell:
P310	Immediately call a POISON CENTER or doctor/physician.
P311	Call a POISON CENTER or doctor/physician.
P312	Call a POISON CENTER or doctor/physician if you feel unwell.
P313	Get medical advice/attention.
P314	Get medical advice/attention if you feel unwell.
P315	Get immediate medical advice/attention.
P320
P302 + P352	IF ON SKIN: wash with plenty of soap and water.
P321
P322
P330	Rinse mouth.
P331	Do NOT induce vomiting.
P332	IF SKIN irritation occurs:
P333	If skin irritation or rash occurs:
P334	Immerse in cool water/wrap n wet bandages.
P335	Brush off loose particles from skin.
P336	Thaw frosted parts with lukewarm water. Do not rub affected area.
P337	If eye irritation persists:
P338	Remove contact lenses, if present and easy to do. Continue rinsing.
P340	Remove victim to fresh air and keep at rest in a position comfortable for breathing.
P341	If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing.
P342	If experiencing respiratory symptoms:
P350	Gently wash with plenty of soap and water.
P351	Rinse cautiously with water for several minutes.
P352	Wash with plenty of soap and water.
P353	Rinse skin with water/shower.
P360	Rinse immediately contaminated clothing and skin with plenty of water before removing clothes.
P361	Remove/Take off immediately all contaminated clothing.
P362	Take off contaminated clothing and wash before reuse.
P363	Wash contaminated clothing before reuse.
P370	In case of fire:
P371	In case of major fire and large quantities:
P372	Explosion risk in case of fire.
P373	DO NOT fight fire when fire reaches explosives.
P374	Fight fire with normal precautions from a reasonable distance.
P376	Stop leak if safe to do so. Oxidising gases (section 2.4) 1
P377	Leaking gas fire: Do not extinguish, unless leak can be stopped safely.
P378
P380	Evacuate area.
P381	Eliminate all ignition sources if safe to do so.
P390	Absorb spillage to prevent material damage.
P391	Collect spillage. Hazardous to the aquatic environment
P301 + P310	IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician.
P301 + P312	IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell.
P301 + P330 + P331	IF SWALLOWED: Rinse mouth. Do NOT induce vomiting.
P302 + P334	IF ON SKIN: Immerse in cool water/wrap in wet bandages.
P302 + P350	IF ON SKIN: Gently wash with plenty of soap and water.
P303 + P361 + P353	IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower.
P304 + P312	IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell.
P304 + P340	IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing.
P304 + P341	IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing.
P305 + P351 + P338	IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing.
P306 + P360	IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes.
P307 + P311	IF exposed: call a POISON CENTER or doctor/physician.
P308 + P313	IF exposed or concerned: Get medical advice/attention.
P309 + P311	IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician.
P332 + P313	IF SKIN irritation occurs: Get medical advice/attention.
P333 + P313	IF SKIN irritation or rash occurs: Get medical advice/attention.
P335 + P334	Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages.
P337 + P313	IF eye irritation persists: Get medical advice/attention.
P342 + P311	IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician.
P370 + P376	In case of fire: Stop leak if safe to Do so.
P370 + P378	In case of fire:
P370 + P380	In case of fire: Evacuate area.
P370 + P380 + P375	In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion.
P371 + P380 + P375	In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion.
Storage
Code	Phrase
P401
P402	Store in a dry place.
P403	Store in a well-ventilated place.
P404	Store in a closed container.
P405	Store locked up.
P406	Store in corrosive resistant/ container with a resistant inner liner.
P407	Maintain air gap between stacks/pallets.
P410	Protect from sunlight.
P411
P412	Do not expose to temperatures exceeding 50 oC/ 122 oF.
P413
P420	Store away from other materials.
P422
P402 + P404	Store in a dry place. Store in a closed container.
P403 + P233	Store in a well-ventilated place. Keep container tightly closed.
P403 + P235	Store in a well-ventilated place. Keep cool.
P410 + P403	Protect from sunlight. Store in a well-ventilated place.
P410 + P412	Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF.
P411 + P235	Keep cool.
Disposal
Code	Phrase
P501	Dispose of contents/container to ...
P502	Refer to manufacturer/supplier for information on recovery/recycling

[ CAS No. 842133-18-0 ] {[proInfo.proName]}

Quality Control of [ 842133-18-0 ]

Related Doc. of [ 842133-18-0 ]

Product Details of [ 842133-18-0 ]

Safety of [ 842133-18-0 ]

Application In Synthesis of [ 842133-18-0 ]

[ 842133-18-0 ] Synthesis Path-Downstream 1~88

Similar Product of
[ 842133-18-0 ]

Precautionary Statements-General

Prevention

Response

Storage

Disposal

Physical hazards

Health hazards

Environmental hazards

Inquiry

[ CAS No. 842133-18-0 ] {[proInfo.proName]}

Quality Control of [ 842133-18-0 ]

Related Doc. of [ 842133-18-0 ]

Product Details of [ 842133-18-0 ]

Safety of [ 842133-18-0 ]

Application In Synthesis of [ 842133-18-0 ]

[ 842133-18-0 ] Synthesis Path-Downstream 1~88

Similar Product of [ 842133-18-0 ]

Precautionary Statements-General

Prevention

Response

Storage

Disposal

Physical hazards

Health hazards

Environmental hazards

Inquiry

Similar Product of
[ 842133-18-0 ]