2-(2-phenylmethoxyethoxy)ethanol

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a 1 L three-neck round bottom flask equipped with mechanical stirrer were charged diethylene glycol monobenzyl ether (98.0 g, 0.5 mol), anhydrous triethylamine (120 mL, 0.85 mol), and anhydrous THF (300 mL). The solution was cooled in an ice/salt bath under dry air blanket for 15 minutes. Acryloyl chloride (55 mL, 0.68 mol) was added into the vigorously stirred cold solution through an addition funnel over 90 minutes and the addition rate was adjusted to keep the temperature of the reaction mixture below 10° C. After the addition, the reaction mixture was stirred in the ice/salt bath for additional two hours followed by quenching with the addition of 2M HCl (400 mL). The mixture was extracted with ethyl acetate (300 mL×3) and the combined organic layer was washed with DI water (200 mL×3), aqueous sodium bicarbonate (200 mL×2), and dried over MgSO4. Filtration and removal of solvents under reduced pressure gave the crude product as light brown oil which was purified on silica gel using Hexanes/Ethyl acetate (4/1, v/v) as eluent to give the final product as a colorless oil (105.0 g, 0.42 mol, yield: 84%). To a 1 L three-neck round bottom flask equipped with mechanical stirrer The solution was cooled in an ice/salt bath under dry air blanket for 15 minutes the temperature of the reaction mixture below 10° C After the addition by quenching with the addition of 2M HCl (400 mL) The mixture was extracted with ethyl acetate (300 mL×3) the combined organic layer was washed with DI water (200 mL×3), aqueous sodium bicarbonate (200 mL×2) dried over MgSO4 Filtration and removal of solvents under reduced pressure gave the crude product as light brown oil which was purified on silica gel

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: [2-(benzyloxy)ethoxy]acetaldehyde was prepared by Swern oxidation of commercially available 2-[2-(benzyloxy)ethoxy]ethanol. A 0.15M solution of the foregoing aldehyde and methyl (7R)-7-amino-14-cyclohexyl-7,8-dihydro-6H-indolo[1,2-e][1,5]benzoxazocine-11-carboxylate (prepared as described in Example 1, Step 4) in CH(OMe)3 was stirred overnight at RT; the residue obtained after removing volatiles in vacuo was dissolved in MeOH (0.15M solution), NaCNBH3 (2.3 eq) was added and the mixture was left stirring for 4 h. All volatiles were evaporated and the residual material was dissolved in EtOAc and washed with sat. aq. NaHCO3 and brine. After drying over Na2SO4 all volatiles were evaporated in vacuo; FC (Biotage, PE/EtOAc 1:1 to 1:3 with 0.5% NEt3) afforded 35% of methyl (7R)-7-({2-[2-(benzyloxy)ethoxy]ethyl}amino)-14-cyclohexyl-7,8-dihydro-6H-indolo[1,2-e][1,5]benzoxazocine-11-carboxylate. the residue obtained after removing volatiles in vacuo was dissolved in MeOH (0.15M solution) the mixture was left All volatiles were evaporated the residual material was dissolved in EtOAc washed with sat. aq. NaHCO3 and brine After drying over Na2SO4 all volatiles were evaporated in vacuo

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: MsCl (15.8 mL. 204 mmol) was added to a solution of 2-(2-(benzyloxy)ethoxy)ethanol (46) (25 g, 127 mmol) and Et3N (36 mL, 255 mmol) in DCM (180 mL) at 0° C., the reaction mixture was allowed to warm up to RT and stirred for 16 h. The reaction mixture was diluted with DCM (50 mL) and washed with water (2×50 mL), 1M HCl (aq.) (2×50 mL), the organic layer was dried (MgSO4), filtered and concentrated in vacuo to afford 2-(2-(benzyloxy)ethoxy)ethyl methanesulfonate (47) (35 g, 100%) as an orange oil: m/z 275 (M+H)+ (ES+). 1H NMR (400 MHz, CDCl3) δ: 7.37-7.27 (m, 5H), 4.55 (s, 2H), 4.40-4.37 (m, 2H), 3.78-3.76 (m, 2H), 3.71-3.68 (m, 2H), 3.64-3.62 (m, 2H), 3.02 (s, 3H). washed with water (2×50 mL), 1M HCl (aq.) (2×50 mL) the organic layer was dried (MgSO4) filtered concentrated in vacuo

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of n-butyl lithium in THF (1.6 N, 1.59 mL, 2.55 mmol) was added to 10 mL of a solution of diethylene glycol monobenzyl ether (500 mg, 2.55 mmol) in THF at −78° C., and the mixture was stirred for 15 minutes. Then, DL-epichlorohydrin (0.1 mL, 1.28 mmol) was added thereto. The mixture was stirred at room temperature for one hour and under reflux for one hour. Next, the THF solvent was evaporated under reduced pressure, and the residue was stirred at 100° C. without a solvent to complete the reaction. Aqueous saturated ammonium chloride was added to the residue, followed by extraction with ethyl acetate. The extract was washed with saturated saline and then dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by preparative liquid chromatography (water:acetonitrile=1:1, 0.05% TFA) to obtain 2-[2-(2-benzyloxyethoxy)ethoxy]-1-[2-(2-benzyloxyethoxy)ethoxymethyl]ethanol (129 mg, yield: 23%) as a colorless oil. The mixture was stirred at room temperature for one hour under reflux for one hour Next, the THF solvent was evaporated under reduced pressure the residue was stirred at 100° C. without a solvent the reaction followed by extraction with ethyl acetate The extract was washed with saturated saline dried over anhydrous magnesium sulfate the solvent was evaporated under reduced pressure The resulting residue was purified by preparative liquid chromatography (water:acetonitrile=1:1, 0.05% TFA)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 2-Hydroxybenzonitrile (300 mg, 2.52 mmol), di(ethylene glycol) benzyl ether (593 mg, 3.02 mmol), and 1,1′-azobis(N,N-dimethylformamide) (867 mg, 5.04 mmol) were dissolved in toluene (15 ml). Thereafter, tri-n-butylphosphine (1.26 ml, 5.04 mmol) was added at 20° C. to the obtained solution, and the obtained mixture was stirred at the same above temperature for 2 hours. The generated precipitate was filtrated, and the filtrate was then diluted with ethyl acetate (20 ml). The ethyl acetate solution was washed with water twice, and then with a saturated saline solution once. The resultant was dried over anhydrous sodium sulfate, and was then concentrated under reduced pressure. The obtained pale brown oil product was purified by silica gel column chromatography (dichloromethane), so as to obtain 2-[2-(2-benzyloxyethoxy)ethoxy]benzonitrile (529 mg, 71%) in the form of a colorless oil product. The generated precipitate was filtrated the filtrate was then diluted with ethyl acetate (20 ml) The ethyl acetate solution was washed with water twice The resultant was dried over anhydrous sodium sulfate was then concentrated under reduced pressure The obtained pale brown oil product was purified by silica gel column chromatography (dichloromethane)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a 1 L three-neck round bottom flask equipped with mechanical stirrer were charged diethylene glycol monobenzyl ether (98.0 g, 0.5 mol), anhydrous triethylamine (120 mL, 0.85 mol), and anhydrous THF (300 mL). The solution was cooled in an ice/salt bath under dry air blanket for 15 minutes. Acryloyl chloride (55 mL, 0.68 mol) was added into the vigorously stirred cold solution through an addition funnel over 90 minutes and the addition rate was adjusted to keep the temperature of the reaction mixture below 10° C. After the addition, the reaction mixture was stirred in the ice/salt bath for additional two hours followed by quenching with the addition of 2M HCl (400 mL). The mixture was extracted with ethyl acetate (300 mL×3) and the combined organic layer was washed with DI water (200 mL×3), aqueous sodium bicarbonate (200 mL×2), and dried over MgSO4. Filtration and removal of solvents under reduced pressure gave the crude product as light brown oil which was purified on silica gel using Hexanes/Ethyl acetate (4/1, v/v) as eluent to give the final product as a colorless oil (105.0 g, 0.42 mol, yield: 84%). To a 1 L three-neck round bottom flask equipped with mechanical stirrer The solution was cooled in an ice/salt bath under dry air blanket for 15 minutes the temperature of the reaction mixture below 10° C After the addition by quenching with the addition of 2M HCl (400 mL) The mixture was extracted with ethyl acetate (300 mL×3) the combined organic layer was washed with DI water (200 mL×3), aqueous sodium bicarbonate (200 mL×2) dried over MgSO4 Filtration and removal of solvents under reduced pressure gave the crude product as light brown oil which was purified on silica gel