Structure of 218595-25-6
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| CAS No. : | 218595-25-6 |
| Formula : | C6H13NO2 |
| M.W : | 131.17 |
| SMILES Code : | COC[C@@H]1NCCOC1 |
| English Name : | (S)-3-(Methoxymethyl)morpholine |
| MDL No. : | MFCD14586376 |
| InChI Key : | ROHMLTGBCWLCIW-RGMNGODLSA-N |
| Pubchem ID : | 53338714 |
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.

| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| Stage #1: carbon disulfide; (3S)-3-(methoxymethyl)morpholine With potassium hydroxide In water at 50℃; Stage #2: With sodium nitrite In methanol; water at 0℃; for 0.5h; |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| Multi-step reaction with 3 steps 1: thionyl chloride / dichloromethane / 2 h / 20 °C 2: sodium iodide / methanol / Reflux 3: 10% Pd/C; hydrogen / methanol / 20 °C / 760.05 Torr |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| Multi-step reaction with 2 steps 1: sodium iodide / methanol / Reflux 2: 10% Pd/C; hydrogen / methanol / 20 °C / 760.05 Torr |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| With 10% Pd/C; hydrogen In methanol at 20℃; |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| With sodium bicarbonate; N-ethyl-N,N-diisopropylamine; paraformaldehyde In 1,4-dioxane; methanol; chloroform; ethyl acetate | 69 EXAMPLE 69 EXAMPLE 69 Paraformaldehyde (0.034 g) and copper(I) iodide (12 mg) were added to a mixture of (2R)-1-[3,5-bis(trifluoromethyl)-benzoyl]-2-(3,4-dimethylbenzyl) -4-(2-propynyl)piperazine (0.21 g), (3S)-3-methoxymethylmorpholine (0.09 g) and N,N-diisopropylethylamine (0.1 ml) in 1,4-dioxane (5 ml) and the whole was stirred at room temperature for 30 minutes and then heated at 70° C. for 2.5 hours. After cooling, ethyl acetate and sodium hydrogen carbonate solution were added to the mixture. The organic layer was separated, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by column chromatography on silica gel with 3% of methanol in chloroform as an eluent to give (2R)-1-[3,5-bis-(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-4-[4-((3S)-3-methoxymethylmorpholino)-2-butynyl]piperazine. |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 36.8 % | With palladium diacetate; caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl In 1,4-dioxane at 100℃; Inert atmosphere; | 30.1 Step 1 Synthesis of (S)-4-(3-chloro-5-nitrophenyl)-3-(methoxymethyl)morpholine To a mixture of (3S)-3-(methoxymethyl)morpholine (1 g, 7.60 mmol), 1-bromo-3-chloro- 5-nitrobenzene (2.16 g, 9.10 mmol), BINAP (0.95 g, 1.50 mmol) and Cs2CO3 (4.95 g, 15.20 mmol) in dioxane (10 mL) was added Pd(OAc)2 (0.34 g, 1.50 mmol), the mixture was stirred at 100 °C under N2 atmosphere for 16 hours. LC-MS was checked, and the reaction was completed. After the reaction, the solvent was removed under reduced pressure and the residue was purified by column chromatography on silica gel (ethyl acetate/petroleum ether = 4% ~ 5%) to afford (S)-4-(3-chloro-5-nitrophenyl)-3-(methoxymethyl)morpholine (0.83 g, 36.8% yield) as a yellow solid. LCMS (ESI) calcd C12H16ClN2O4+[M + H]+m/z 287.08, found 286.9. |
| 36.8 % | With palladium diacetate; caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl In 1,4-dioxane at 100℃; Inert atmosphere; | 30.1 Step 1 Synthesis of (S)-4-(3-chloro-5-nitrophenyl)-3-(methoxymethyl)morpholine To a mixture of (3S)-3-(methoxymethyl)morpholine (1 g, 7.60 mmol), 1-bromo-3-chloro- 5-nitrobenzene (2.16 g, 9.10 mmol), BINAP (0.95 g, 1.50 mmol) and Cs2CO3 (4.95 g, 15.20 mmol) in dioxane (10 mL) was added Pd(OAc)2 (0.34 g, 1.50 mmol), the mixture was stirred at 100 °C under N2 atmosphere for 16 hours. LC-MS was checked, and the reaction was completed. After the reaction, the solvent was removed under reduced pressure and the residue was purified by column chromatography on silica gel (ethyl acetate/petroleum ether = 4% ~ 5%) to afford (S)-4-(3-chloro-5-nitrophenyl)-3-(methoxymethyl)morpholine (0.83 g, 36.8% yield) as a yellow solid. LCMS (ESI) calcd C12H16ClN2O4+[M + H]+m/z 287.08, found 286.9. |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| Multi-step reaction with 4 steps 1: palladium diacetate; caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl / 1,4-dioxane / 16 h / 100 °C / Inert atmosphere 2: iron; ammonium chloride / water; ethanol / 16 h / 80 °C / Inert atmosphere 3: N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 0.5 h / 25 °C / Inert atmosphere 4: boron tribromide / dichloromethane / 3 h / 0 - 25 °C / Inert atmosphere |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| Multi-step reaction with 3 steps 1: palladium diacetate; caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl / 1,4-dioxane / 16 h / 100 °C / Inert atmosphere 2: iron; ammonium chloride / water; ethanol / 16 h / 80 °C / Inert atmosphere 3: N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 0.5 h / 25 °C / Inert atmosphere |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| Multi-step reaction with 2 steps 1: palladium diacetate; caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl / 1,4-dioxane / 16 h / 100 °C / Inert atmosphere 2: iron; ammonium chloride / water; ethanol / 16 h / 80 °C / Inert atmosphere |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 48 mg | With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; N-ethyl-N,N-diisopropylamine In dichloromethane; ethyl acetate at 0 - 20℃; | 103 0453 Synthesis of 4-(2-chloro-4-fluorophenyl)-7-(((R)-1-((S)-3- (methoxymethyl)morpholino)-1-oxopropan-2-yl)oxy)isoquinolin-1(2H)-one, Example 103: To a stirred solution of (R)-2-((4-(2-chloro-4-fluorophenyl)-1-oxo-1,2- dihydroisoquinolin-7-yl)oxy)propanoic acid (Example 90, 60 mg, 0.2 mmol) in CH2Cl2 (9 mL) was added DIPEA (0.1 mL, 0.8 mmol) followed by (S)-3- (methoxymethyl)morpholine (35 mg, 0.2 mmol). The reaction mixture was cooled to 0°C, and T3P (0.14 mL, 0.2 mmol, 50 % in EtOAc) was added. The reaction mixture was allowed to warm to ambient temperature and stirred for 16 h. The reaction mixture was quenched with water and extracted with CH2Cl2. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The product was purified by reverse phase prep-HPLC and lyophilized to afford 4-(2-chloro-4-fluorophenyl)-7-(((R)-1-((S)-3-(methoxymethyl)morpholino)-1- oxopropan-2-yl)oxy)isoquinolin-1(2H)-one (Example 103, 48 mg). LCMS (ESI) Calcd. for C24H24ClFN2O5: 474, found [M+H]+ = 475.1H NMR (400 MHz, DMSO-d6) δ 11.39 (br s, 1H), 7.66-7.59 (m, 2H), 7.50-7.45 (m, 1H), 7.36-7.24 (m, 2H), 7.00-6.90 (m, 2H), 5.50-5.33 (m, 1H), 4.37 (br s, 1H), 4.04 (br s, 2H), 3.85 (br s, 1H), 3.52 (br s, 1H), 3.41 (br s, 1H), 3.35-2.85 (m, 6H), 1.50-1.41 (m, 3H). |
| 48 mg | With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; N-ethyl-N,N-diisopropylamine In dichloromethane; ethyl acetate at 0 - 20℃; | 103 0453 Synthesis of 4-(2-chloro-4-fluorophenyl)-7-(((R)-1-((S)-3- (methoxymethyl)morpholino)-1-oxopropan-2-yl)oxy)isoquinolin-1(2H)-one, Example 103: To a stirred solution of (R)-2-((4-(2-chloro-4-fluorophenyl)-1-oxo-1,2- dihydroisoquinolin-7-yl)oxy)propanoic acid (Example 90, 60 mg, 0.2 mmol) in CH2Cl2 (9 mL) was added DIPEA (0.1 mL, 0.8 mmol) followed by (S)-3- (methoxymethyl)morpholine (35 mg, 0.2 mmol). The reaction mixture was cooled to 0°C, and T3P (0.14 mL, 0.2 mmol, 50 % in EtOAc) was added. The reaction mixture was allowed to warm to ambient temperature and stirred for 16 h. The reaction mixture was quenched with water and extracted with CH2Cl2. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The product was purified by reverse phase prep-HPLC and lyophilized to afford 4-(2-chloro-4-fluorophenyl)-7-(((R)-1-((S)-3-(methoxymethyl)morpholino)-1- oxopropan-2-yl)oxy)isoquinolin-1(2H)-one (Example 103, 48 mg). LCMS (ESI) Calcd. for C24H24ClFN2O5: 474, found [M+H]+ = 475.1H NMR (400 MHz, DMSO-d6) δ 11.39 (br s, 1H), 7.66-7.59 (m, 2H), 7.50-7.45 (m, 1H), 7.36-7.24 (m, 2H), 7.00-6.90 (m, 2H), 5.50-5.33 (m, 1H), 4.37 (br s, 1H), 4.04 (br s, 2H), 3.85 (br s, 1H), 3.52 (br s, 1H), 3.41 (br s, 1H), 3.35-2.85 (m, 6H), 1.50-1.41 (m, 3H). |

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