2-[2-(2,2,2-Trifluoroethoxy)phenoxy]ethyl methanesulfonate

In a 5000 mL four-necked flask equipped with mechanical stirring, 200 g (0.85 mol, 1.0 eq) of 2-[2-(2, 2, 2-trifluoroethoxy)phenoxy]ethyl alcohol which was involved in the reaction was sequentially added. , The temperature of the reaction system was lowered to about 0 ° C under 155 g (1.53 mol, 1.8 eq) of triethylamine and 2400 ml of ice cream in dichloromethane.388 g (3.4 mol, 4.0 eq) of methanesulfonyl chloride dissolved in 1000 ml of dichloromethane was slowly added dropwise.The temperature of the reaction system was controlled to be not higher than 20 °C. After the addition is completed, remove the ice salt bath.The temperature was raised to reflux for 4 hours, cooled to room temperature, and triethylamine hydrochloride was removed by filtration.The filtrate was washed with 1000 ml of *3 saturated sodium carbonate.Dry over anhydrous sodium sulfate, filter, dry EtOAc m.400 g of isopropanol was added and stirred at 0 ° C for 6 hours, and filtered.Vacuum drying to 247 g of a white solid.Melting point 39-42 ° C, The yield is 92.5percent.The purity is 98.3percent.20 mL of acetonitrile, 1.09 g of potassium carbonate (7.89 mmol) and 0.65 g of potassium iodide (3.92 mmol) were added to a 100 mL three-necked flask, and 2.02 g of 5-[(2S)-2-aminopropyl]-1-[3-(benzoyloxy)propyl]-2, 3-dihydro-7-cyano-1H-indole tartrate (3.93 mmol) and 1.61g General procedure: To a solution of SI-II (531 g, 1.46 mol) as the free base in tert-butanol (2.5 L) was added IM-A (528 g, 1.68 mol) and sodium carbonate (92.9 g, 0.876 mol), all in a round bottom flask (5 L). The reaction mixture was heated under reflux until TLC (dichloromethane/methanol, 20/1) showed the reaction to be complete. After cooling, the mixture was extracted with ethyl acetate twice (2 L 2). The combined organic layer was washed with brine, dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure and iso-propanol (4 L) was added. To the solution was added an aqueous solution of L-tartaric acid (329 g, 2.19 mol) with stirring for 2 h at room temperature.The precipitate was collected and washed with iso-propanol/water (100 ml/100 ml) twice and recrystallized from iso-propanol/water (2.6 L/1.3 L) to give SI-IV tartrate(717 g, 67.2%, HPLC 98.5%) as a white solid. SI-III (free base): 1H NMR(400 MHz, CDCl3): d 1.01 (d, 3H), 2.07 (t, 2H), 2.40 (m, 1H), 2.56 (m, 2H), 2.63 (m, 2H), 2.97 (m, 2H), 3.49 (t, 2H), 3.67 (t, 2H), 4.03 (m, 2H), 4.30 (m, 2H), 4.39 (t, 2H), 6.81-6.96 (m, 6H), 7.36 (m, 2H), 7.47 (m, 1H), 7.91 (m, 2H), 8.01 (d, 2H). The motherliquor was purified by column chromatograph to give the IM-C as a yellow oil.15 IMC:1H NMR (400 MHz, CDCl3): d 1.03 (d, 3H), 2.13-2.38 (m, 5H), 2.82 (t, 2H), 3.03(m, 4H), 3.51 (t, 2H), 3.72 (t, 2H), 4.00 (m, 4H), 4.35 (q, 4H), 4.48 (t, 2H), 6.88-7.04(m, 12H), 7.45 (m, 2H), 7.55 (m, 1H), 8.08 (d, 2H). These NMR data agreed with theliterature values.General procedure: To a solution of SI-II (531 g, 1.46 mol) as the free base in tert-butanol (2.5 L) was added IM-A (528 g, 1.68 mol) and sodium carbonate (92.9 g, 0.876 mol), all in a round bottom flask (5 L). The reaction mixture was heated under reflux until TLC (dichloromethane/methanol, 20/1) showed the reaction to be complete. After cooling, the mixture was extracted with ethyl acetate twice (2 L 2). The combined organic layer was washed with brine, dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure and iso-propanol (4 L) was added. To the solution was added an aqueous solution of L-tartaric acid (329 g, 2.19 mol) with stirring for 2 h at room temperature.The precipitate was collected and washed with iso-propanol/water (100 ml/100 ml) twice and recrystallized from iso-propanol/water (2.6 L/1.3 L) to give SI-IV tartrate(717 g, 67.2%, HPLC 98.5%) as a white solid. SI-III (free base): 1H NMR(400 MHz, CDCl3): d 1.01 (d, 3H), 2.07 (t, 2H), 2.40 (m, 1H), 2.56 (m, 2H), 2.63 (m, 2H), 2.97 (m, 2H), 3.49 (t, 2H), 3.67 (t, 2H), 4.03 (m, 2H), 4.30 (m, 2H), 4.39 (t, 2H), 6.81-6.96 (m, 6H), 7.36 (m, 2H), 7.47 (m, 1H), 7.91 (m, 2H), 8.01 (d, 2H). The motherliquor was purified by column chromatograph to give the IM-C as a yellow oil.15 IMC:1H NMR (400 MHz, CDCl3): d 1.03 (d, 3H), 2.13-2.38 (m, 5H), 2.82 (t, 2H), 3.03(m, 4H), 3.51 (t, 2H), 3.72 (t, 2H), 4.00 (m, 4H), 4.35 (q, 4H), 4.48 (t, 2H), 6.88-7.04(m, 12H), 7.45 (m, 2H), 7.55 (m, 1H), 8.08 (d, 2H). These NMR data agreed with theliterature values.General procedure: To a solution of SI-II (531 g, 1.46 mol) as the free base in tert-butanol (2.5 L) was added IM-A (528 g, 1.68 mol) and sodium carbonate (92.9 g, 0.876 mol), all in a round bottom flask (5 L). The reaction mixture was heated under reflux until TLC (dichloromethane/methanol, 20/1) showed the reaction to be complete. After cooling, the mixture was extracted with ethyl acetate twice (2 L 2). The combined organic layer was washed with brine, dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure and iso-propanol (4 L) was added. To the solution was added an aqueous solution of L-tartaric acid (329 g, 2.19 mol) with stirring for 2 h at room temperature.The precipitate was collected and washed with iso-propanol/water (100 ml/100 ml) twice and recrystallized from iso-propanol/water (2.6 L/1.3 L) to give SI-IV tartrate(717 g, 67.2%, HPLC 98.5%) as a white solid. SI-III (free base): 1H NMR(400 MHz, CDCl3): d 1.01 (d, 3H), 2.07 (t, 2H), 2.40 (m, 1H), 2.56 (m, 2H), 2.63 (m, 2H), 2.97 (m, 2H), 3.49 (t, 2H), 3.67 (t, 2H), 4.03 (m, 2H), 4.30 (m, 2H), 4.39 (t, 2H), 6.81-6.96 (m, 6H), 7.36 (m, 2H), 7.47 (m, 1H), 7.91 (m, 2H), 8.01 (d, 2H). The motherliquor was purified by column chromatograph to give the IM-C as a yellow oil.15 IMC:1H NMR (400 MHz, CDCl3): d 1.03 (d, 3H), 2.13-2.38 (m, 5H), 2.82 (t, 2H), 3.03(m, 4H), 3.51 (t, 2H), 3.72 (t, 2H), 4.00 (m, 4H), 4.35 (q, 4H), 4.48 (t, 2H), 6.88-7.04(m, 12H), 7.45 (m, 2H), 7.55 (m, 1H), 8.08 (d, 2H). These NMR data agreed with theliterature values.The foam form N-[(2R) -1- [1- (3-benzoyloxypropyl) -7-cyanoindoline-5-yl] propan-2-yl] -2-form prepared as in Example Nitrobenzene sulfonamide(Compound of formula 5)(32 g, 58.3 mmol)The dimethylformamide (150 mL)After dissolution in potassium carbonate (9.7 g, 1.2 equivalents) was added.To the reaction mixture was added 2- [2- (2, 2, 2-trifluoroethoxy) phenoxy] ethyl methanesulfonate (22 g, 1.2 equivalents) and then warmed to about 110 C., Stirred at the same temperature for 10 hours.After cooling to room temperature, add purified water (300 mL) to the reaction mixture, Extracted with dichloromethane (100 mL × 2).Combine the organic layers, wash with water and brine, After drying over anhydrous MgSO 4 for 30 minutes, it was filtered.The filtrate is concentrated under reduced pressure, Vacuum drying gave 43.53 g of the title compound in foam form.(Yield: 97.3%, HPLC purity: 96.71%)General procedure: Fifty grams of 5-[(2R)-2-aminopropyl]-1-[3-(bezoyloxy)propyl]-2, 3-dihydro-1H-indol-7-carbonitrile (2R, 3R)-2, 3-dihydroxybutanedioate (tartrate salt of the compound of formula (III), 26.9 g of K2CO3, 39.8 g of 2-[2-(2, 2, 2-trifluoroethoxy)phenoxy]ethyl methanosulfonate and 250 mL of acetonitrile are introduced in a 500 mL reactor with mechanical stirring. It is heated to reflux for 24 h. After this time has elapsed, it is cooled at 20 C. and AcOEt (400 mL) and water (250 mL) are added. It is stirred for 30 min, and the phases are separated. The organic phase is dried with anhydrous sodium sulfate, filtered and concentrated to dryness, obtaining 70.9 g of 3-{7-cyano-5-[(2R)-2-({2-[2-(2, 2, 2-trifluoroethoxy)phenoxy]ethyl}amino)propyl]-2, 3-dihydro-1H-indol-1-yl}propyl benzoate (free base). Eighteen grams of 3-{7-cyano-5-[(2R)-2-({2-[2-(2, 2, 2-trifluoroethoxy)phenoxy]ethyl}amino)propyl]-2, 3-dihydro-1H-indol-1-yl}propyl benzoate are weighed and dissolved in 90 mL of 96% EtOH. Fifteen milliliters are distributed in different balloons. A different acid (for example, 0.60 g of maleic acid) dissolved in 15 mL of 96% EtOH is added to each balloon. It is left under stirring at room temperature for two hours, and then cooled at 0-5 C., maintaining stirring. In the case of maleic acid, the maleate precipitates after 30 minutes. If a salt is formed, it is filtered, washed with 96 C. EtOH and vacuum dried. Table 2 shows the result obtained with different acids.In a 5000 mL four-necked flask equipped with mechanical stirring, 200 g (0.85 mol, 1.0 eq) of 2-[2-(2, 2, 2-trifluoroethoxy)phenoxy]ethyl alcohol which was involved in the reaction was sequentially added. , The temperature of the reaction system was lowered to about 0 C under 155 g (1.53 mol, 1.8 eq) of triethylamine and 2400 ml of ice cream in dichloromethane.388 g (3.4 mol, 4.0 eq) of methanesulfonyl chloride dissolved in 1000 ml of dichloromethane was slowly added dropwise.The temperature of the reaction system was controlled to be not higher than 20 C. After the addition is completed, remove the ice salt bath.The temperature was raised to reflux for 4 hours, cooled to room temperature, and triethylamine hydrochloride was removed by filtration.The filtrate was washed with 1000 ml of *3 saturated sodium carbonate.Dry over anhydrous sodium sulfate, filter, dry EtOAc m.400 g of isopropanol was added and stirred at 0 C for 6 hours, and filtered.Vacuum drying to 247 g of a white solid.Melting point 39-42 C, The yield is 92.5%.The purity is 98.3%.NMR (CDCl3) delta: 2.24(1H, br s), 3.90-4.00(2H, m), 4.10-4.15(2H, m), 4.39(2H, q, J=8.3Hz), 6.90-7.10(4H, m) To a solution of 2-[2-(2, 2, 2-trifluoroethoxy)phenoxy]ethanol (210 mg) in methylene chloride (1 ml) were added triethylamine (186 mul) and methanesulfonyl chloride (83 mul) with stirring under ice cooling, and the mixture was reacted at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure. To the concentrate was added water, and the mixture was extracted with diethyl ether. The extract was washed with water, dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by medium pressure liquid column chromatography on silica gel using a mixture of hexane and ethyl acetate (2/1) as eluent to give 273 mg of 2-[2-(2, 2, 2-trifluoroethoxy)phenoxy]ethyl methansulfonate melting at 40.5-42.0 C. IR (KBr): upsilonSO2 1350, 1120 cm-1 Preparation of

Molecular Weight:314.28
XLogP3:2
Hydrogen Bond Acceptor Count:8
Rotatable Bond Count:7
Exact Mass:314.04357917
Monoisotopic Mass:314.04357917
Topological Polar Surface Area:70.2
Heavy Atom Count:20
Complexity:377
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes