methyl 3-morpholin-4-ylpropanoate

Conditions: temp:0.00; pressure:0.00; stir:

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

Procedure: Hydrazine (64.1 g, 2 mol) was added dropwise, over 8–10 min, to methyl 3-morpholinopropionate (35 g, 0.202 mol) and the reaction mixture was refluxed for 16 h. The excess hydrazine was removed under reduced pressure and the material was dried in vacuo at room temperature for 16 h to give the crude product as an oil. The 1H NMR showed the presence of hydrazine, so the crude material was dried using a lyophilizer. Then the oil was refluxed in benzene/water (using a Dean-Stark distilling receiver). The benzene was then removed under reduced pressure, and the product was triturated with petroleum ether. After sitting in petroleum ether at room temperature for 16 h, the oil solidified. The petroleum ether was decanted and the solid was dried under house vacuum at room temperature to give the desired product (21.5 g, 61.4%), which was used without further purification. the reaction mixture was refluxed for 16 h The excess hydrazine was removed under reduced pressure the material was dried in vacuo at room temperature for 16 h to give the crude product as an oil so the crude material was dried Then the oil was refluxed in benzene/water ( distilling receiver) The benzene was then removed under reduced pressure the product was triturated with petroleum ether The petroleum ether was decanted the solid was dried under house vacuum at room temperature

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

Procedure: A solution of 4.9 ml (56 mmol) of morpholine in 50 ml of dichloromethane was treated dropwise with 5.0 ml (56 mmol) of methyl acrylate. The resulting solution was allowed to stand at ambient temperature for 3 days, after which it was concentrated in vacuo to an oil. Chromatography on silica gel using 0.5% methanol/2% isopropylamine in chloroform provided 9.54 g (99%) of the desired compound as a colorless liquid. after which it was concentrated in vacuo to an oil

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Potassium hydroxide (485 mg, 8.6mmol) was added to a solution of methyl 3-morpholinopropionate (1 g, 5.7 mmol) in ethanol (20 ml) and the mixture stirred for 2 hours at 80° C. The solution was allowed to cool and adjusted to pH1 with 6M hydrochloric acid. Insoluble material was removed by filtration and the volatiles removed from the filtrate by evaporation. The resulting oil was triturated with ether, the solid product collected by filtration, washed with methylene chloride and dried under vacuum to give 3-morpholinopropionic acid (993 mg, 89%) as a white solid. to cool Insoluble material was removed by filtration the volatiles removed from the filtrate by evaporation The resulting oil was triturated with ether the solid product collected by filtration washed with methylene chloride dried under vacuum

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Potassium hydroxide (485 mg, 8.6mmol) was added to a solution of methyl 3-morpholinopropionate (1 g, 5.7 mmol) in ethanol (20 ml) and the mixture stirred for 2 hours at 80° C. The solution was allowed to cool and adjusted to pH1 with 6M hydrochloric acid. Insoluble material was removed by filtration and the volatiles removed from the filtrate by evaporation. The resulting oil was triturated with ether, the solid product collected by filtration, washed with methylene chloride and dried under vacuum to give 3-morpholinopropionic acid (993 mg, 89%) as a white solid. to cool Insoluble material was removed by filtration the volatiles removed from the filtrate by evaporation The resulting oil was triturated with ether the solid product collected by filtration washed with methylene chloride dried under vacuum

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:160.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To 2-phenylbenzo[d]oxazol-5-amine (75 mg, 0.36 mmol) and methyl 3-morpholinopropanoate (63 μL, 0.39 mmol) in toluene (2.5 mL) was added a 2M solution of trimethylaluminum in toluene (0.22 mL, 0.43 mmol). The resulting solution was heated twice for 5 min at 160° C. in the microwave. After cooling, sodium bicarbonate solution was added and the aqueous layer was extracted with ethyl acetate. The organic layer was then washed with brine and the combined organic layers were dried over anhydrous MgSO4. After evaporation, the impurities were removed by filtering through on a plug of silica eluting with ethyl acetate/hexanes 50:50 v/v and the desired product was obtained by elution with methanol to afford 17.5 mg (14%) of the title compound (LCMS RT=5.54 min, MH+ 352.0) After cooling the aqueous layer was extracted with ethyl acetate The organic layer was then washed with brine the combined organic layers were dried over anhydrous MgSO4 After evaporation the impurities were removed by filtering through on a plug of silica eluting with ethyl acetate/hexanes 50:50 v/v

Conditions: temp:160.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To 2-phenylbenzo[d]oxazol-5-amine (75 mg, 0.36 mmol) and methyl 3-morpholinopropanoate (63 μL, 0.39 mmol) in toluene (2.5 mL) was added a 2M solution of trimethylaluminum in toluene (0.22 mL, 0.43 mmol). The resulting solution was heated twice for 5 min at 160° C. in the microwave. After cooling, sodium bicarbonate solution was added and the aqueous layer was extracted with ethyl acetate. The organic layer was then washed with brine and the combined organic layers were dried over anhydrous MgSO4. After evaporation, the impurities were removed by filtering through on a plug of silica eluting with ethyl acetate/hexanes 50:50 v/v and the desired product was obtained by elution with methanol to afford 17.5 mg (14%) of the title compound (LCMS RT=5.54 min, MH+ 352.0) After cooling the aqueous layer was extracted with ethyl acetate The organic layer was then washed with brine the combined organic layers were dried over anhydrous MgSO4 After evaporation the impurities were removed by filtering through on a plug of silica eluting with ethyl acetate/hexanes 50:50 v/v

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

Procedure: To a solution of methyl 4-morpholinepropionate (5.0 g, 28.9 mmol) in MeOH (25 mL) was added 2N NaOH (17.3 mL, 34.6 mmol). The mixture was stirred for 1 h then concentrated in vacuo. The residue was suspended in dichloromethane (125 mL) and DMF (30 μL) was added followed by oxalylchloride (10 mL, 115.6 mmol). The mixture was allowed to stir for 2 h. then concentrated in vacuo. The resulting solid was added portion-wise to a solution of 2-(aminomethyl)pyridine (2.88 mL, 28.2 mmol) and triethylamine (9.0 mL, 64.86 mmol) in dichloromethane (200 mL). The mixture was stirred at ambient temperature for 1 h. then washed with water (300 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated to yield 3-morpholin-4-yl-N-pyridin-2-ylmethyl-propionamide (5.56 g, 77%). then concentrated in vacuo DMF (30 μL) was added to stir for 2 h. then concentrated in vacuo The mixture was stirred at ambient temperature for 1 h. then washed with water (300 mL) The organic layer was dried over anhydrous sodium sulfate concentrated

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

Procedure: Hydrazine (64.1 g, 2 mol) was added dropwise, over 8-10 min, to methyl 3-morpholinopropionate (35 g, 0.202 mol) and the reaction mixture was refluxed for 16 h. The excess hydrazine was removed under reduced pressure and the material was dried in vacuo at room temperature for 16 h to give the crude product as an oil. The 1H NMR showed the presence of hydrazine, so the crude material was dried using a lyophilizer. Then the oil was refluxed in benzene/water (using a Dean-Stark distilling receiver). The benzene was then removed under reduced pressure, and the product was triturated with petroleum ether. After sitting in petroleum ether at room temperature for 16 h, the oil solidified. The petroleum ether was decanted and the solid was dried under house vacuum at room temperature to give the desired product (21.5 g, 61.4%), which was used without further purification. the reaction mixture was refluxed for 16 h The excess hydrazine was removed under reduced pressure the material was dried in vacuo at room temperature for 16 h to give the crude product as an oil so the crude material was dried Then the oil was refluxed in benzene/water ( distilling receiver) The benzene was then removed under reduced pressure the product was triturated with petroleum ether The petroleum ether was decanted the solid was dried under house vacuum at room temperature

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

Procedure: A solution of 4.9 ml (56 mmol) of morpholine in 50 ml of dichloromethane was treated dropwise with 5.0 ml (56 mmol) of methyl acrylate. The resulting solution was allowed to stand at ambient temperature for 3 days, after which it was concentrated in vacuo to an oil. Chromatography on silica gel using 0.5% methanol/2% isopropylamine in chloroform provided 9.54 g (99%) of the desired compound as a colorless liquid. after which it was concentrated in vacuo to an oil

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

Procedure: Hydrazine (64.1 g, 2 mol) was added dropwise, over 8–10 min, to methyl 3-morpholinopropionate (35 g, 0.202 mol) and the reaction mixture was refluxed for 16 h. The excess hydrazine was removed under reduced pressure and the material was dried in vacuo at room temperature for 16 h to give the crude product as an oil. The 1H NMR showed the presence of hydrazine, so the crude material was dried using a lyophilizer. Then the oil was refluxed in benzene/water (using a Dean-Stark distilling receiver). The benzene was then removed under reduced pressure, and the product was triturated with petroleum ether. After sitting in petroleum ether at room temperature for 16 h, the oil solidified. The petroleum ether was decanted and the solid was dried under house vacuum at room temperature to give the desired product (21.5 g, 61.4%), which was used without further purification. the reaction mixture was refluxed for 16 h The excess hydrazine was removed under reduced pressure the material was dried in vacuo at room temperature for 16 h to give the crude product as an oil so the crude material was dried Then the oil was refluxed in benzene/water ( distilling receiver) The benzene was then removed under reduced pressure the product was triturated with petroleum ether The petroleum ether was decanted the solid was dried under house vacuum at room temperature