4-benzylmorpholine-2-carbonitrile

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

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

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

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

Conditions: temp:-10.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 4-Benzyl-morpholine-2-carbonitrile (10 g, 50 mmol) in dry diethyl ether (100 ml) at −10° C. under an atmosphere of nitrogen was added (time of addition 30 minutes) a solution of 3-fluorophenylmagnesium bromide (0.5N solution in tetrahydrofuran, 120 ml, 60 mmol, 1.2 equivalents, available from Aldrich Chemical Company or Rieke Metals) and the reaction mixture was further stirred at −10° C. for 30 minutes. Then the reaction was allowed to warm to room temperature and stirred for one hour. The reaction was then cooled to 0° C. and quenched by addition of hydrochloric acid (2N aqueous solution, 50 ml) and the resulting mixture was stirred for 30 minutes at 0° C. Then the solution was concentrated in vacuo and the residue was taken-up by sodium hydroxide (2N aqueous solution, 60 ml). The aqueous solution was extracted with diethyl ether, the organics fractions were collected and dried (MgSO4) and the solvent removed under reduced pressure to give the title compound as a brown oil (15 g, 100%). FIA [M+H]+=300.1. to warm to room temperature stirred for one hour The reaction was then cooled to 0° C. quenched by addition of hydrochloric acid (2N aqueous solution, 50 ml) the resulting mixture was stirred for 30 minutes at 0° C Then the solution was concentrated in vacuo The aqueous solution was extracted with diethyl ether the organics fractions were collected dried (MgSO4) the solvent removed under reduced pressure

Conditions: temp:17.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A 31 double jacket reactor was charged with 4-Benzyl-morpholine-2-carbonitrile (135.05 g; 1 eq) and dry diethyl ether (1.4 l). Alternatively, toluene may be used in place of diethyl ether. When Tj=0° C. and Tm=1° C. (Tj=temperature of the jacket, Tm=temperature of the mass), phenyl magnesium chloride (2M sol. in tetrahydrofuran, 360 ml, 1.08 equiv., available from Aldrich Chemical Company) was added dropwise over 1 hour. Tm rose to 4° C. and came back to 2° C. at the end of the addition. Tm was progressively raised to 17.5° C. over 45 minutes and the mixture stirred at this temperature for another 45 minutes. The reactor was cooled down to Tm=2° C. and Tj=0° C. (75 minutes) and hydrochloric acid (700 ml of 5N solution) was added in two portions. Tm rose to 33° C. After some minutes, the hydrochloride salt of the ketone crystallised. When Tm=Tj=room temperature, the triphasic suspension was filtered. The organic layer of the mother liquors was eliminated. The filtration cake was then washed with methylene chloride (700 ml). This liquor was charged in the reactor with the acid aqueous layer. Treatment of the hydrochloride salt: After drying under vacuum, 164.4 g of the hydrochloride contaminated with MgCl2 were suspended in a biphasic mixture of water/methylenechloride (500 ml/800 ml). The suspension was basified with aqueous sodium hydroxide (75 ml of a 30% solution) under ice bath cooling. Mg(OH)2 precipitated and the aqueous layer was extracted with methylene chloride. The organic layers were filtered on a bed of Celite 512 after addition of Celite. The filtered organic phase was dried over magnesium sulphate and evaporated to dryness. The ketone crystallized readily on standing (132.4 g; 70%). Treatment of the mother liquors: The combined organic phases were washed with aqueous sodium hydroxide (750 ml of a 2N solution). Celite 512 (160 g) was added to the suspension which was then filtrated through a bed of Celite. The aqueous layer was separated and extracted with methylene chloride. The combined organic phases were dried over magnesium sulphate and evaporated to dryness to provide 35.8 g of the title compound enriched with unreacted nitrile. Chiral compound was obtained after separation using chiral HPLC on a Daicel chiralpak AD 20 μm column with 100% Ethanol/0.3% DMEA as eluent at a flow rate of 150 ml/min and UV-detection at 300 nm. Alternatively, the two enantiomers may be separated by fractional crystallization from acetonitrile using from 0.55 to 1 equivalent of dibenzoyltartaric acid to generate diastereoisomeric salts of the title compound. The crystals may be collected by filtration and neutralized with 30% NaOH to afford the optically enriched title compound. rose to 4° C. came back to 2° C. at the end of the addition was added in two portions rose to 33° C After some minutes the hydrochloride salt of the ketone crystallised When Tm=Tj=room temperature, the triphasic suspension was filtered The filtration cake was then washed with methylene chloride (700 ml) This liquor was charged in the reactor with the acid aqueous layer Treatment of the hydrochloride salt: After drying under vacuum, 164.4 g of the hydrochloride were suspended in a biphasic mixture of water/methylenechloride (500 ml/800 ml) cooling Mg(OH)2 precipitated the aqueous layer was extracted with methylene chloride The organic layers were filtered on a bed of Celite 512 after addition of Celite The filtered organic phase was dried over magnesium sulphate evaporated to dryness The ketone crystallized readily Treatment of the mother liquors: The combined organic phases were washed with aqueous sodium hydroxide (750 ml of a 2N solution) Celite 512 (160 g) was added to the suspension which was then filtrated through a bed of Celite The aqueous layer was separated extracted with methylene chloride The combined organic phases were dried over magnesium sulphate evaporated to dryness

Conditions: temp:-5.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A one-litre reactor with mechanical stirring, cooled by an ice bath, was charged with N-benzylethanolamine (172.2 g; 1 equiv. available from Aldrich Chemical Company). 2-Chloroacrylonitrile (100 g; 1 equiv. available from Aldrich Chemical Company) was added dropwise over 2 minutes. The temperature was maintained between 23° C. and 29° C. by means of the ice bath and subsequently a water bath at 15° C. N-Benzylethanolamine was still detected on TLC after 4.5 h stirring. After one night stirring at room temperature (water bath), no N-benzylethanolamine was detectable by 1H NMR. The mixture was dissolved in tetrahydrofuran and transferred to a 2 L reactor cooled to −5° C. by ice/NaCl bath. The total volume of tetrahydrofuran was 1.35 L. Potassium tert-butoxide (148 g; 1.1 equiv.) was added by portions in 1 hour, keeping the reaction temperature at 0±2° C. After 1 hour post-stirring at 0° C., the mixture was quenched with saturated NaHCO3 (500 mL). The aqueous layer was extracted with diethyl ether (500 mL). Organic layers were dried on MgSO4 and evaporated to dryness. The title compound (149.8 g; 65%) was obtained after percolation of the 250 g dry residue on 1 kg of SiO2, eluting with the following gradient: A one-litre reactor with mechanical stirring, cooled by an ice bath transferred to a 2 L reactor at 0±2° C After 1 hour post-stirring at 0° C. the mixture was quenched with saturated NaHCO3 (500 mL) The aqueous layer was extracted with diethyl ether (500 mL) Organic layers were dried on MgSO4 evaporated to dryness

Conditions: temp:-5.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A one-litre reactor with mechanical stirring, cooled by an ice bath, was charged with N-benzylethanolamine (172.2 g; 1 equiv. available from Aldrich Chemical Company). 2-Chloroacrylonitrile (100 g; 1 equiv. available from Aldrich Chemical Company) was added dropwise over 2 minutes. The temperature was maintained between 23° C. and 29° C. by means of the ice bath and subsequently a water bath at 15° C. N-Benzylethanolamine was still detected on TLC after 4.5 h stirring. After one night stirring at room temperature (water bath), no N-benzylethanolamine was detectable by 1H NMR. The mixture was dissolved in tetrahydrofuran and transferred to a 2 L reactor cooled to −5° C. by ice/NaCl bath. The total volume of tetrahydrofuran was 1.35 L. Potassium tert-butoxide (148 g; 1.1 equiv.) was added by portions in 1 hour, keeping the reaction temperature at 0±2° C. After 1 hour post-stirring at 0° C., the mixture was quenched with saturated NaHCO3 (500 mL). The aqueous layer was extracted with diethyl ether (500 mL). Organic layers were dried on MgSO4 and evaporated to dryness. The title compound (149.8 g; 65%) was obtained after percolation of the 250 g dry residue on 1 kg of SiO2, eluting with the following gradient: A one-litre reactor with mechanical stirring, cooled by an ice bath transferred to a 2 L reactor at 0±2° C After 1 hour post-stirring at 0° C. the mixture was quenched with saturated NaHCO3 (500 mL) The aqueous layer was extracted with diethyl ether (500 mL) Organic layers were dried on MgSO4 evaporated to dryness

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

Procedure: To a stirred solution of 4-benzylmorpholine-2-carbonitrile (intermediate 25, 5.0 g, 24.7 mmol) in the mixture of ethanol and water (2/1, 75 ml) was added hydroxylamine hydrochloride (5.2 g, 74.2 mmol) and sodium bicarbonate (13.1 g, 123.5 mmol), and the reaction mixture was stirred under reflux for 12 hours. The reaction was diluted with chloroform, and the reaction mixture was washed with water and brine. The organic layer was dried over magnesium sulfate, and concentrated in vacuo. The resulting 4-benzyl-N′-hydroxymorpholine-2-carboxamidine (intermediate 26) was used for next reaction without further purification. under reflux for 12 hours the reaction mixture was washed with water and brine The organic layer was dried over magnesium sulfate concentrated in vacuo The resulting 4-benzyl-N′-hydroxymorpholine-2-carboxamidine (intermediate 26) was used for next reaction without further purification

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

Procedure: A mixture of N-benzylethanolamine (intermediate 23, 44.8 ml, 314 mmol) and 2-chloroacrylonitrile (intermediate 24, 25 ml, 314 mmol) was stirred at room temperature for 24 hours. After the mixture was cooled to 0° C., tetrahydrofuran (300 ml) and then potassium tert-butoxide was added to the mixture, and the mixture was stirred at 0° C. for one hour. The mixture was diluted by ethyl ether, and then washed with water and brine and dried over magnesium sulfate. Solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (eluent; 5% ethyl acetate in hexane) to afford 4-benzylmorpholine-2-carbonitrile (intermediate 25) as colorless oil. After the mixture was cooled to 0° C. the mixture was stirred at 0° C. for one hour washed with water and brine dried over magnesium sulfate Solvent was removed under reduced pressure the residue was purified by silica gel column chromatography (eluent; 5% ethyl acetate in hexane)

Conditions: temp:-5.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A one-litre reactor with mechanical stirring, cooled by an ice bath, was charged with N-benzylethanolamine (172.2 g; 1 equiv. available from Aldrich Chemical Company). 2-Chloroacrylonitrile (100 g; 1 equiv. available from Aldrich Chemical Company) was added dropwise over 2 minutes. The temperature was maintained between 23° C. and 29° C. by means of the ice bath and subsequently a water bath at 15° C. N-Benzylethanolamine was still detected on TLC after 4.5 h stirring. After one night stirring at room temperature (water bath), no N-benzylethanolamine was detectable by 1H NMR. The mixture was dissolved in tetrahydrofuran and transferred to a 2 L reactor cooled to −5° C. by ice/NaCl bath. The total volume of tetrahydrofuran was 1.35 L. Potassium tert-butoxide (148 g; 1.1 equiv.) was added by portions in 1 hour, keeping the reaction temperature at 0±2° C. After 1 hour post-stirring at 0° C., the mixture was quenched with saturated NaHCO3 (500 mL). The aqueous layer was extracted with diethyl ether (500 mL). Organic layers were dried on MgSO4 and evaporated to dryness. The title compound (149.8 g; 65%) was obtained after percolation of the 250 g dry residue on 1 kg of SiO2, eluting with the following gradient: A one-litre reactor with mechanical stirring, cooled by an ice bath transferred to a 2 L reactor at 0±2° C After 1 hour post-stirring at 0° C. the mixture was quenched with saturated NaHCO3 (500 mL) The aqueous layer was extracted with diethyl ether (500 mL) Organic layers were dried on MgSO4 evaporated to dryness

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Grignard's reagent was prepared by reaction of magnesium (932 mg, 5.93 mmol) with bromobenzene (144 mg, 5.93 mmol) in diethyl ether (20 ml) at room temperature for 10 min. After cooling to 0° C., a solution of 2-cyano-4-benzyl-morpholine (1.00 g, 4.94 mmol) in diethyl ether (2.0 ml) was added and then tetrahydrofuran (6.0 ml) was added. The mixture was stirred at room temperature for 30 min. After decomposition with saturated aqueous sodium hydrogen carbonate, the mixture was filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel (n-hexane-ethyl acetate 3:1 to 2:1) to give the 2-benzoyl-4-benzylmorpholine (608 mg, 44%). After decomposition with saturated aqueous sodium hydrogen carbonate, the mixture was filtered concentrated under reduced pressure The crude product was purified by flash chromatography on silica gel (n-hexane-ethyl acetate 3:1 to 2:1)