84% |
With lithium aluminium tetrahydride In tetrahydrofuran for 12h; Reflux; |
|
55% |
With lithium aluminium tetrahydride In tetrahydrofuran at 0 - 20℃; |
2 Step 2:
To a suspension of LiAIH4 (30.91 g, 0.81 mol) in THF (300 mL) was added a solution of rea- gent 2 (108.90 g, 0.37 mol) in THF (100 mL) drop wise at 0°C. The mixture was stirred at room temperature for 14 h. The mixture was quenched by the sequential addition of H20 (94 mL), 15%NaOH (94 mL) and H20 (188 mL). The mixture was diluted with EtOAc (500 mL) and then filtered. The filtrate was evaporated to dryness to give reagent 3 as a colorless oil (42.6 g, 55%) sufficiently pure for the next step. 1H NMR (CDCI3) δ 7.21 -7.33 (m, 5 H), 4.80 (s, 2 H), 3.49-3.71 (m, 8 H), 1 .77-1 .81 (m, 1 H), 1 .56-1 .62 (m, 2 H). |
54% |
With lithium aluminium tetrahydride In diethyl ether at 0 - 20℃; |
|
47% |
With lithium aluminium tetrahydride In tetrahydrofuran at 20℃; for 12h; Inert atmosphere; Cooling with ice; |
16.B
Step B: To a suspension of LiAlH4 (1.71 g, 45.0 mmol) in anhydrous THF (80 mL) was added diethyl 2-(2-(benzyloxy)ethyl)malonate (6.6 g, 22.5 mmol) dropwise in an ice bath. The reaction was warmed to room temperature and stirred for 12 hours. The reaction was quenched with water, diluted with EtOAc (50 mL), washed with water (50 mL x 2), dried over anhydrous Na2S04 and concentrated under vacuum. The crude residue was purified by silica gel chromatography eluting with a gradient of 10% - 30% EtOAc/hexanes to afford 2-(2-(benzyloxy)ethyl)propane-l,3-diol (2.2 g, 10.6 mmol, 47% yield) as a colorless oil. |
47% |
With lithium aluminium tetrahydride In tetrahydrofuran at 20℃; for 12h; Cooling with ice; |
16.B Step B:
To a suspension of LiAlH4 (1.71 g, 45.0 mmol) in anhydrous THF (80 mL) was added diethyl 2-(2-(benzyloxy)ethyl)malonate (6.6 g, 22.5 mmol) dropwise in an ice bath. The reaction was warmed to room temperature and stirred for 12 hours. The reaction was quenched with water, diluted with EtOAc (50 mL), washed with water (50 mL x 2), dried over anhydrous Na2S04 and concentrated under vacuum. The crude residue was purified by silica gel chromatography eluting with a gradient of 10% - 30% EtOAc/hexanes to afford 2-(2-(benzyloxy)ethyl)propane-l,3-diol (2.2 g, 10.6 mmol, 47% yield) as a colorless oil. |
|
With lithium aluminium tetrahydride In tetrahydrofuran for 5h; Heating; |
|
67 g |
With lithium aluminium tetrahydride |
4.3 Step 3
According to the method described in patent CN105001879A, compound 19 was obtained from 2-bromoethoxymethylbenzene and diethyl malonate under the action of sodium methoxide, and compound 20 was obtained as a light yellow oil after reduction by lithium tetrahydro lithium aluminum, a total of 67 g , HPLC: 94.2%. |
67 g |
With lithium aluminium tetrahydride |
4.3
According to the method described in patent CN105001879A, compound 19 is obtained from 2-bromoethoxymethylbenzene and diethyl malonate under the action of sodium methoxide,Reduction by lithium tetrahydroaluminum yielded compound 20 as a pale yellow oil, 67 g in total, HPLC: 94.2%. |
|
With lithium aluminium tetrahydride In toluene for 3h; Reflux; |
1.2 1.2 Synthesis of 2-(2-benzyloxyethyl)propane-1,3-diol (2)
A solution of 5 g (20 mmol) of the malonate 1 in 60 ml toluene is added to a suspension of 930 mg (24 mmol) Lithium aluminum hydride in 8 ml Toluene. After 3h reflux the cooled reaction mixture is quenched with ethyl acetate. The mixture is acidified with 2mol/l hydrochloric acid (pH 3- 4). The aqueous layer is extracted with MTB ether. The combined organic layers are washed with water and dried over sodium sulfate. The solvent is evaporated. The residue is purified by silica chromatography (ethyl acetate to give 2. |