| 49% |
Stage #1: 2-Benzyloxyethanol With potassium <i>tert</i>-butylate In <i>tert</i>-butyl alcohol at 20℃; for 0.5h;
Stage #2: bromoacetic acid <i>tert</i>-butyl ester In <i>tert</i>-butyl alcohol at 10 - 20℃; for 16h; |
22.1 Step 1: Synthesis of tert-butyl 2-(2-(benzyloxy)ethoxy)acetate
Potassium tert-butoxide (2.24 g, 20 mmol) was added to a solution of compound 49 (3.00 g, 20 mmol) in anhydrous tert-butanol (24 mL), and stirred at room temperature for 30 minutes.At 10°C, tert-butyl bromoacetate (3.90 g, 20 mmol) was added by injection and stirred at room temperature for 16 hours.Extract with ethyl acetate and H2O.The organic layer was separated, washed with brine, and dried over Na2SO4.After spin-drying the solvent under reduced pressure, the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=6:1) to obtain colorless oil 51 (2.60 g, 9.76 mmol, 49%): |
| 40% |
With potassium <i>tert</i>-butylate In <i>tert</i>-butyl alcohol at 20℃; for 16.5h; |
7.4 Step 4: preparation of tert-butyl 2-(2-(benzyloxy)ethoxy)acetate (7)
To a solution of compound 5 (10.0 g) in fBuOH (100 mL) was added fBuOK (8.1 g) at rt. The mixture was stirred at rt for 0.5 h, and then compound 6 (12.8 g) was added. The mixture was stirred at rt for 16 h. Compound 7 (7.0 g, yield 40%) was obtained after standard work up procedure. |
| 38% |
Stage #1: 2-Benzyloxyethanol With potassium <i>tert</i>-butylate In <i>tert</i>-butyl alcohol at 20℃; for 0.5h; Inert atmosphere;
Stage #2: bromoacetic acid <i>tert</i>-butyl ester In <i>tert</i>-butyl alcohol at 20℃; for 16h; Inert atmosphere; |
|
| 9% |
Stage #1: 2-Benzyloxyethanol With potassium <i>tert</i>-butylate In <i>tert</i>-butyl alcohol at 20℃; for 2h;
Stage #2: bromoacetic acid <i>tert</i>-butyl ester In <i>tert</i>-butyl alcohol at 20℃; |
KOtBu (3.24 g, 29 mmol) was added to a stirred solution of 2 -(benzyloxy) ethanol (commercially available from for example Aldrich) (4 g, 26 mmol) in tBuOH (30 mL) and the mixture was stirred at room temperature for 2 hours. Tert-butyl 2-bromoacetate (commercially available from for example Aldrich) (7 mL, 47 mmol) was then added, and the mixture was stirred at room temperature overnight. The mixture was diluted with DCM (50 mL) and washed with water (2 x 50 mL) and then brine (2 x 50 mL). The organic extract was dried using a hydrophobic frit and concentrated under reduced pressure. The crude product was purified by chromatography on silica (330g cartridge) using a gradient elution from 0 % to 100 % methyl tert-butyl ether in cyclohexane to afford the title compound (724 mg, 2.3 mmol, 9% yield). LCMS RT= 1.10 min, ES+ve m/z 267 A [M+H]+ |
| 9% |
With tetrabutyl-ammonium chloride; sodium hydroxide In dichloromethane at 20℃; |
76.1 1. Step- Synthesis of Tert-butyl 2-(2-(benzyloxy)ethoxy)acetate
To a solution of 2-(benzyloxy)ethanol (10.0 g, 0.07 mol) in DCM ( 150 mL) were added tert-butyl 2-bromoacetate (51.0 g, 0.26 mol), TBACl (18.4 g, 0.07 mol) and 37% NaOH (15 mL) subsequently. The resulting solution was stirred at r.t. overnight. After the reaction was quenched with water (200 mL), the mixture was extracted with DCM (2 x 200 mL). The combined organic layers were washed with brine (100 mL), dried over Na2SO4 and filtered. The solvent was removed under reduced pressure. The residue was purified by column chromatography (DCM : MeOH=20 : 1) to afford the desired product tert-butyl 2-(2-(benzyloxy)ethoxy)acetate (1.5 g, 5.60 mmol, 9%) as colorless oil. (2035) [00700] Chemical Formula: C15H22O4; Molecular Weight: 266.33 |
|
Stage #1: 2-Benzyloxyethanol With potassium <i>tert</i>-butylate In <i>tert</i>-butyl alcohol at 20℃; for 2.5h;
Stage #2: bromoacetic acid <i>tert</i>-butyl ester In <i>tert</i>-butyl alcohol |
1; 2
tert-butyl [2-(benzyloxy)ethoxy]acetate 9. To a stirred solution of 2- (benzyloxy)ethanol 8 (1.7 g, 11.17 mmol) in t-BuOH (25 ml) was added at room temperature t-BuOK (1.38 g, 12.29 mmol). Mixture was stirred at room temperature for 2.5 hrs. t-butyl bromoacetate (2.7 ml, 20.11 mmol) was then added while mixture was cooled with a water bath. Mixture was stirred overnight at room temperature and concentrated. Water was added and aqueous layer was extracted with dichloromethane. Combined organic layers were dried over MgSO4 filtered and concentrated. Flash chromatography on silica gel (EtOAc/pentane 1/4) afforded ester 9 as an oil (1.749 g, 59%). |
|
With potassium carbonate In acetonitrile at 20 - 80℃; for 16h; |
182.1 Step 1 : Synthesis of tert-butyl 2-[2-(benzyloxy)ethoxy] acetate
Step 1 : Synthesis of tert-butyl 2-[2-(benzyloxy)ethoxy] acetate:[0801] To a stirred solution of 2-(benzyloxy)ethanol (5.0 g, 32.8 mmol) and tert-butyl 2- bromoacetate (7.02 g, 36.0 mmol) in acetonitrile (10.0 mL) was added potassium carbonate (6.78 g, 49.1 mmol) at rt. The reaction mixture then stirred at 80 °C for 16 h. The reaction was monitored by TLC analysis, which indicated completion of reaction. The reaction mixture was diluted with water (10.0 mL) and extracted with EtOAc (20.0 mL). The organic layer was washed with water (5.0 mL), brine (5.0 mL), dried over Na2S04, filtered, and concentrated under reduced pressure to give titled product (yield: 100% based on crude) as a yellow oil. This crude material was used in next step reaction without any further purification. |
| 15 g |
With tetrabutyl-ammonium chloride; sodium hydroxide In dichloromethane at 20℃; for 4h; |
6 Step 6: Preparation of tert-butyl 2-[2-(benzyloxy)ethoxy]acetate
Into a 1000-mL round-bottom flask, was placed 2-(benzyloxy)ethan- l-ol (10.0 g, 65.71 mmol, 1.00 equiv), tert-butyl 2-bromoacetate (19.2 g, 98.43 mmol, 1.50 equiv), dichloromethane (150 mL), 37% sodium hydroxide (150 mL), and tetrabutylammonium chloride (18.3 g, 65.83 mmol, 1.00 equiv). The resulting solution was stirred for 4 h at room temperature in a water/ice bath. The resulting solution was extracted with dichloromethane (100 mL x 3) and the organic layers were combined and concentrated under vacuum. The residue was applied onto a silica gel column eluted with ethyl acetate/petroleum ether (1/15). This resulted in 15.0 g (86%) of tert-butyl 2- [2-(benzyloxy)ethoxy] acetate as yellow oil. |
|
With water; tetra(n-butyl)ammonium hydrogensulfate; sodium hydroxide In toluene at 20℃; for 2h; Inert atmosphere; |
94 tert-butyl 2-(2-benzyloxyethoxy)acetate
A mixture of 2-benzyloxyethanol (10.0 g, 65.7 mmol), tert-butyl 2-bromoacetate (19.2 g, 98.6 mmol), tetrabutylammonium hydrogen sulfate (1.1 g, 3.3 mmol), and water (5 mL) in toluene (200 mL) was added NaOH (39.4 g, 985.6 mmol) in water (60 mL). The mixture was stirred at 20 °C for 2 h. The reaction mixture was quenched by ice-water (90 mL) and then extracted with MTBE (3 x 90 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. |
|
With tetrabutyl-ammonium chloride; sodium hydroxide In dichloromethane; water at 20℃; |
|
| 8.998 g |
With tetrabutylammomium bromide; sodium hydroxide In dichloromethane at 20℃; for 18.5h; Cooling with ice; |
13.2 Step 2:Synthesis of tert-butyl 2-(2-(benzyloxy)ethoxy)acetate (Compound 12a-2)
Add 5.931g of compound 12a-1, 15.131g of tert-butyl bromoacetate, 18ml of dichloromethane, 0.303g of tetrabutylammonium bromide to the flask, add 18ml of 35% sodium hydroxide aqueous solution under ice bath,After stirring for 30 minutes, the mixture was transferred to room temperature and stirred for 18 hours. After the reaction was completed, 30ml of dichloromethane was added to separate the layers, and the organic layer was washed twice with water.20ml each time; then dried with anhydrous sodium sulfate, filtered, the filtrate was evaporated under reduced pressure to remove the solvent, and the residue was purified by silica gel column chromatography (eluted with petroleum ether: ethyl acetate (V/V) = 5:1) Obtain 8.998 g of compound 12a-2. |
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