(5-Bromo-2-chlorophenyl)(4-ethoxyphenyl)methanone

2) Under nitrogen atmosphere, 2.1 g of tert-butyldimethylchlorosilane and 5-bromo-2-chlorobenzoyl chloride obtained in step 1) are first mixed in anhydrous dichloromethane at 0 to 10 ° C. for 30 min, Then, maintaining the temperature, 14.7 g (1.2 mol) of phenetole and 17.8 g (1.1 mol) of ferric chloride were sequentially added to the reaction system, the reaction was stirred for 5 hours, and the reaction was completed.Poured into ice water to quench the reaction, extracted with dichloromethane, washed with water, concentrated to give dapagliflozin Intermediate 5-bromo-2-chloro-4'-ethoxy benzophenone 31g, yield: 91.4percent Purity: 99.49percent.Step two: Using 500 ml of methylene chloride as a solvent, add 10 g of a solid acid catalyst (preparation method for solid acid attached below) to a reaction kettle, add phenylethyl ether (59.6 g, 0.49 mol) at room temperature, and stir for 2 hours after the addition.Then, the 5-bromo-2-chlorobenzoyl chloride concentrate obtained in Step 1 was added dropwise and reacted at a temperature of 30° C. for 4 hours.After completion of the reaction, the mixture was concentrated by filtration to obtain 123.7 g (yield 90percent) of 5-bromo-2-chloro-4-ethoxybenzophenone.Compound 3 10.0g (42mmol) is dissolved in 100mL dry dichloromethane, were added a catalytic amount of DMF, 20mL diluted with dichloromethane dried oxalyl chloride 14.4mL (168mmol), stirred at RT for 5 h, and concentrated to give a yellow oil. 4, 4 the resulting oil was dissolved in 100mL of dry dichloromethane was cooled to 0 °C, aluminum trichloride was added portionwise 6.2 g (46.2mmol), stirred for 0.5 h, diluted with 20mL methylene chloride was slowly added dropwise 5.3mL phenetole (42mmol), 0°C addition was complete the reaction. After completion of the reaction, the reaction solution was poured into ice water, (100ml × 3) was extracted with dichloromethane and the combined organic phases, the organic phase was washed with 1N HCl × 2, 1N NaOH × 2, water × 2, washed with saturated brine × 2, no water Na2SO4 dry. Concentrated to give a light yellow solid, recrystallized from ethanol as white crystals 511.6 g, yield: 80.2percent.Step 2: Synthesis of (2R, 3R, 4R, 5S, 6S)-2-(acetoxymethyl)-6-(4-chloro-3-(4-((l- ethylcyclopentyl )methoxy )benzyl )phenyl )tetrahydro-2H-pyran-3, 4, 5-triyl triacetate:To a solution of (2R, 3R, 4R, 5S, 6S)-2-(acetoxymethyl)-6-(4-chloro-3-(4-((l- ethylcyclo-pentyl)methoxy)benzyl)phenyl)-tetrahydro-2H-pyran-3, 4, 5-triyl triacetate (step 1, 1.3 g) in dichloromethane (50 ml) at 0°C was added pyridine (2.1 ml), acetic anhydride (2.5 ml) and catalytic amount of DMAP. The reaction mixture was stirred at room temperature for about an hour. After completion of reaction as indicated by TLC, reaction mixture was diluted with dichloromethane, washed with water, 1percent HC1 solution followed by saturated brine solution. The organic layer was dried over anhydrous NaUnder nitrogen atmosphere, 6.9 g of 2-chloro-5-bromobenzoyl chloride was dissolved in 30 mL of methylene chloride and added into a 100 mL reaction flask. 3.4 g of anhydrous aluminum trichloride was added and the complexation reaction was carried out at 15-25 ° C. for 1 hour, cooled to -5-0 ° C, 2.7 g of phenetoleSoluble10mL methylene chloride slowly dropping, the control temperature <5 , After the dropwise addition, the temperature was raised to 15-20 ° C. and reacted for 6 hrs. The reaction solution was poured into 50 mL of 1 mol / L dilute hydrochloric acid slowly to control the temperature <10 ° C. and the layers were separated. The aqueous phase was extracted twice with 60 mL of methylene chloride, The organic phases were combined, washed successively with water, saturated sodium bicarbonate solution and saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the crude product as a yellow-brown solid which was recrystallized three times from absolute ethanol to give 2g white solid in a yield of 28 percent.Step (3) 5-bromo-2-chlorobenzoyl chloride (10.7g) was dissolved in methylene dichloride (4OmL) and the reaction mixture was cooled to about -8°C to about -12°C under inert atmosphere. Aluminum chloride (5.65g) was added to the reaction mixture followed by addition of a solution of ethoxybenzene in methylene dichloride. The reaction mixture was stirred for about lh at about -8°C to -12°C and then quenched in dilute hydrochloric acid followedby extraction with methylene dichloride. The organic layer was washed with sodium bicarbonate solution and concentrated. The residue obtained was crystallized from methanol to give 5-bromo-2-chloro-4’-ethoxybenzophenone (8.5g). HPLC purity: 99.34percentTo a stirred suspension of 5-bromo-2-chlorobenzoic acid 3a (10.0 g, 42.0 mmol) in CH2Cl2 (100 mL) was added oxalyl chloride (14.4 mL, 168.0 mmol) and DMF (0.5 mL). After stirring at room temperature overnight, the reaction was concentrated under reduced pressure. Following dissolution of the obtained 5-bromo-2-chlorobenzoyl chloride in CH2Cl2 (100 mL), the resulting yellow solution was transferredto a 250 mL 3-neck flask equipped with a mechanical stirrer, and an internal thermometer. This mixture was cooled to −5 °C prior to adding phenetole (5.3 mL, 42 mmol). Subsequently, AlCl3 (6.2 g, 46.2 mmol) was added in small portions over 30 min at a rate to ensure that the temperature did not exceed 0 °C. After 2 h, the reaction was quenched by pouring over ice. The resulting suspension was diluted with H2O and extracted with CH2Cl2. The combined organic extracts were washed with HCl (1N), H2O, NaOH (1N), and brine prior to drying over Na2SO4. Filtration, concentration under reduced pressure and recrystallization twice from absolute EtOH yielded 5-bromo-2-chloro-4′-ethoxybenzophenone 4a (11.6 g, 80percent) as a white solid. mp 60-62 °C.1H NMR (300 MHz, CDCl3) δ: 7.79–7.75 (m, 2H), 7.55–7.48 (m, 1H), 7.33–7.26 (m, 2H), 6.95 (d, J=8.73 Hz, 2H), 4.15 (q, J=7.0 Hz, 2H), 1.45 (t, J=7.0 Hz, 2H).Take another 500mL three-neck round bottom flask.Add phenylethyl ether (13.5 g, 110.4 mmol, 1.3 eq), Dichloromethane (100 mL), aluminum trichloride (17.0 g, 127.4 mmol, 1.5 eq). The resulting mixture is stirred well to 0 to 10 ° C.The dichloromethane solution of 5-bromo-2-chlorobenzoyl chloride obtained in the above step was slowly added dropwise to the cooled reaction mixture.After the completion of the dropwise addition, the reaction was kept at 0 to 10 ° C and stirred overnight.After TLC detects the reaction, 10percent dilute hydrochloric acid solution (100 mL) was slowly added dropwise to the reaction solution at 0 to 10 °C.Quench the reaction. The quenched reaction solution was allowed to stand to separate layers, and a dichloromethane layer was layered.The methylene chloride layer was saturated with sodium bicarbonate (100 mL×2).The saturated sodium chloride solution (100 mL x 2) was washed twice.The organic layer was transferred to a 500 mL single-neck round bottom flask and 50 mL of water was added.The dichloromethane was concentrated under normal pressure at 40 to 50 °C. In the obtained suspension, Add 150 mL of methanol, heat to 40-50 ° C and stir for 2 hours.Then cool to room temperature and stir for 1 hour, then cool down to 0 ~ 10 ° C for stirring.2 hours. The suspension was filtered and the resulting cake was washed twice with water (50 mL×2).The filter cake was dried to give a white solid (24.7 g, yield: 85.9percent).Add 5-bromo-2-chlorobenzoic acid (20.0 g, 0.085mol) to a solution of 2.0 M oxalyl chloride in dichloromethane (50 ml, 0.1 mol), stir to a suspension, then add 8 drops of DMF solution with bubbles After the reaction was carried out for 3 hours, the reaction was substantially complete, and thesolvent was evaporated on a rotary evaporator, then 15 ml of dichloromethane was added and the solvent was evaporated.After spin-drying, add 30 ml of dichloromethane, stir, cool to 0-5 ° C, add phenylethyl ether (10.9 g, 0.089 mol), add anhydrous aluminum trichloride (12.5g, 0.093mol) inbatches, control temperature is not After more than 5 ° C, after the addition is completed, stirring is continued at 4 ° C for 1 h. The reaction is almost complete by TLC. Thereaction mixture is quenched on ice-water mixture. The organic phase is separated, and the aqueous phase is extracted with dichloromethane. The organic phase was washed twice with 1 mol/L hydrochloric acid, and washed once with water. Wash twice with /L NaOH solution and wash twice with saturated sodium chloride. Dry over anhydrous sodium sulfate. Filter by suction and spin dry to give a white solid.Recrystallization from absolute ethanol gave 20.2 g (70.0percent) of white solid.Thionyl chloride (194.78 ml) was slowly added to a mixture of 5-bromo-2-chlorobenzoic acid compound of formula-2 (200 gms), dichloromethane (1000 ml) and dimethylformamide (1 ml) at 25-30° C. Step 1: (15.0 g, 20 mmol) (5-bromo-2-chlorophenyl)(4-fluorophenyl)methanone, 150 ml were sequentially added to the reaction flask.DMF, 10mL ethanol and (6.5g, 95.7mmol) NaOH, warmed to 50 ~ 60 ° C; reaction 12 ~ 15h, TLC monitoring showed a small amountThe raw material remains, the reaction liquid is poured into 400-500 ml of water to precipitate a solid, filtered, and the filter cake is washed and dried, and the product is combined by the column.I (5-bromo-2-chlorophenyl)(4-ethoxyphenyl)methanone 11.8 g, yield 72.6percent.(5-bromo-2-chlorophenyl) (4-fluorophenyl) methanone (18.03 g, 50 mmo 1) was added DMF (90 mL), Ice bath slowly add sodium ethoxide (3.748, 1.1 called), After adding the reaction at room temperature for 1 h, (Filter), washed with water (200mL), beat with ethanol (50mL), filtered and dried to give compound Ila (50ml). After the reaction was finished, add water (180mL) slowly under ice bath. Of pale yellow solid 14.47 g, yield: 85.2percent, purity: 99.38percentTake another 500 mL three-neck round bottom flask, add fluorobenzene (10.6 g, 110.4 mmol, 1.3 eq), dichloromethane(100 mL), aluminum trichloride (17.0 g, 127.4 mmol, 1.5 eq). The resulting mixture is stirred well and then lowered to 0-10 ° C, which will beThe dichloromethane solution of 5-bromo-2-chlorobenzoyl chloride obtained in the above step was slowly added dropwise to the cooled reaction mixture. dropAfter the addition was completed, the reaction was kept at 0 to 10 ° C for 24 hours. After the TLC detection reaction is completed, 0 to 10 ° C is slowly added to the reaction solution.A 10percent dilute hydrochloric acid solution (100 mL) was added dropwise to quench the reaction. The quenched reaction solution was allowed to stand to separate layers, and a dichloromethane layer was layered. DichloroThe methane layer was washed twice with a saturated sodium hydrogen carbonate solution (100 mL×2) and a saturated sodium chloride solution (100 mL×2). Organic layer transferIt was placed in a 500 mL one-neck round bottom flask, and 50 mL of water was added thereto, and dichloromethane was concentrated under normal pressure at 40 to 50 °C. In the obtained suspension, plusInto 150mL of methanol, heated to 40 ~ 50 ° C for 2 hours, then cooled to room temperature for 1 hour, then cooled to 0 ~ 10 ° CStir for 2 hours. The suspension was filtered and the resulting cake was washed twice with water (50 mL×2). The filter cake is dried to give a white solid24.5 g, yield 92.1percent.

Molecular Weight:339.61
XLogP3:4.9
Hydrogen Bond Acceptor Count:2
Rotatable Bond Count:4
Exact Mass:337.97092
Monoisotopic Mass:337.97092
Topological Polar Surface Area:26.3
Heavy Atom Count:19
Complexity:303
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes