methyl N-(3-methoxy-3-oxopropyl)-N-methyl-beta-alaninate

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

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

Procedure: To 75 milliliters of methylene chloride maintained at 0°-5° C. via an ice bath were added 1.4 grams of 4-methyl-6-methoxy-2-amino-1,3,5-triazine and 1.55 grams of chlorosulfonyl isocyanate. After stirring for 3 hours at ice bath temperature a methylene chloride solution containing 1.0 gram of triethylamine and 1.37 grams of 2-(1-hydroxyethyl)aniline was added dropwise. The reaction mixture was removed from the ice bath, allowed to stir an additional one-half hour and then poured into 100 milliliters of 2 percent aqueous hydrochloric acid solution. After phase separation, the organic layer was washed in water and concentrated on a rotary evaporator affording a dark oil. Addition of diethyl ether to the dark oil resulted in the formation of a precipitate which was filtered-off. The filtrate was evaporated and the residue was taken-up in chloroform and again evaporated affording a powdery solid. Vacuum drying afforded 1.7 grams of light tan solid confirmed by NMR analysis as the desired product. was added dropwise The reaction mixture was removed from the ice bath poured into 100 milliliters of 2 percent aqueous hydrochloric acid solution After phase separation the organic layer was washed in water concentrated on a rotary evaporator affording a dark oil resulted in the formation of a precipitate which The filtrate was evaporated again evaporated affording a powdery solid Vacuum drying afforded 1.7 grams of light tan solid

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

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

Procedure: Acetic acid (1 ml) was added dropwise to a solution of N-tert-butoxycarbonyl-4-piperidone (9.4 g), 1-(2-amino-phenyl)-ethanol (4.3 g) and sodium cyanoborohydride (10 g) in dichloromethane and the mixture stirred at room temperature overnight. The mixture was partitioned between ethyl acetate and water, the organics separated and washed with aqueous sodium hydrogencarbonate solution, water, dried, and evaporated under reduced pressure. The crude product was dissolved in tetrahydrofuran (100 ml) and N,N-diisopropylethylamine (23 ml), cooled to 0° C., then triphosgene (4.3 g) added. The mixture was warmed to room temperature and stirred overnight. The mixture was partitioned between ethyl acetate and water, the organics washed with water, dried and evaporated under reduced pressure. Purification was by chromatography eluting with 20% ethyl acetate/isohexane. Yield 1.4 g. The mixture was partitioned between ethyl acetate and water the organics separated washed with aqueous sodium hydrogencarbonate solution, water dried evaporated under reduced pressure The crude product was dissolved in tetrahydrofuran (100 ml) N,N-diisopropylethylamine (23 ml), cooled to 0° C. triphosgene (4.3 g) added The mixture was warmed to room temperature stirred overnight The mixture was partitioned between ethyl acetate and water the organics washed with water dried evaporated under reduced pressure Purification eluting with 20% ethyl acetate/isohexane

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

Procedure: Acetic acid (1 ml) was added dropwise to a solution of N-tert-butoxycarbonyl-4-piperidone (9.4 g), 1-(2-amino-phenyl)-ethanol (4.3 g) and sodium cyanoborohydride (10 g) in dichloromethane and the mixture stirred at room temperature overnight. The mixture was partitioned between ethyl acetate and water, the organics separated and washed with aqueous sodium hydrogencarbonate solution, water, dried, and evaporated under reduced pressure. The crude product was dissolved in tetrahydrofuran (100 ml) and N,N-diisopropylethylamine (23 ml), cooled to 0° C., then triphosgene (4.3 g) added. The mixture was warmed to room temperature and stirred overnight. The mixture was partitioned between ethyl acetate and water, the organics washed with water, dried and evaporated under reduced pressure. Purification was by chromatography eluting with 20% ethyl acetate/isohexane. Yield 1.4 g. The mixture was partitioned between ethyl acetate and water the organics separated washed with aqueous sodium hydrogencarbonate solution, water dried evaporated under reduced pressure The crude product was dissolved in tetrahydrofuran (100 ml) N,N-diisopropylethylamine (23 ml), cooled to 0° C. triphosgene (4.3 g) added The mixture was warmed to room temperature stirred overnight The mixture was partitioned between ethyl acetate and water the organics washed with water dried evaporated under reduced pressure Purification eluting with 20% ethyl acetate/isohexane

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

Procedure: 2-(1-hydroxyethyl)aniline (30 g, 0.32 mol) and ethyl 2-butyryl-3-ethoxyacrylate (47.3 g, 0.22 mol) were heated together on a rotary evaporator (bath temperature 100° C.) for 1 hour to give ethyl 2-butyryl-3-(2-(1-hydroxyethyl)-phenylamino)acrylate as an oil (65 g, 96%).

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

Procedure: Sodium borohydride (40 g, 1.0 mol) was added portionwise to a stirred solution of o-aminoacetophenone (80 g) in methanol (800 ml) at 0°, allowing the effervescence to subside between each addition. Cooling was removed and the mixture allowed to warm to reflux temperature to complete the reaction. When cool, the solvent was evaporated and the residue partioned between dichloromethane-water. The organic solution was washed successively with water and brine, dried (anhyd. MgSO4), filtered and evaporated to a light yellow oil which crystallised from petroleum spirit (40°-60°) to give white crystals (52 g, 64%), m.p. 50°-52°. to subside between each addition Cooling was removed to warm to reflux temperature the reaction When cool the solvent was evaporated The organic solution was washed successively with water and brine dried (anhyd. MgSO4) filtered evaporated to a light yellow oil which crystallised from petroleum spirit (40°-60°)

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

Procedure: That is, 1-acetyl-aminobenzene (300 mg, 2.2 mmol) was dissolved in methanol, sodium borohydride (418 mg, 11 mmol) was added, the temperature was raised from under ice-cooling to room temperature, and the mixture was stirred for 1 hr. Then, water was added to the reaction mixture, and unreacted sodium borohydride was decomposed. Then, the solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel chromatography (eluent; chloroform:methanol (30:1)) to give 1-(aminophenyl)ethanol (yield; 242 mg, 80%). According to the final step in Example 2 (step for condensing Y222 and Y491), compound Y491 (the aforementioned) (196 mg, 4.3 mmol) and 1-(aminophenyl)ethanol (147 mg, 10.8 mmol) were condensed to give the title compound (yield; 157 mg, 66%). the temperature was raised from under ice- Then, the solvent was evaporated under reduced pressure the obtained residue was purified by silica gel chromatography (eluent; chloroform:methanol (30:1))

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

Procedure: 2-(1-hydroxyethyl)aniline (30 g, 0.32 mol) and ethyl 2-butyryl-3-ethoxyacrylate (47.3 g, 0.22 mol) were heated together on a rotary evaporator (bath temperature 100° C.) for 1 hour to give ethyl 2-butyryl-3-(2-(1-hydroxyethyl)-phenylamino)acrylate as an oil (65 g, 96%).

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

Procedure: Sodium borohydride (40 g, 1.0 mol) was added portion wise to a stirred solution of o-aminoacetophenone (80 g) in methanol (800 ml) at 0°, allowing the effervescence to subside between each addition. Cooling was removed and the mixture allowed to warm to reflux temperature to complete the reaction. When cool, the solvent was evaporated and the residue partioned between dichloromethane-water. The organic solution was washed successively with water and brine, dried (anhyd. MgSO4), filtered and evaporated to a light yellow oil which crystallized from petroleum spirit (40°-60°) to give white crystals (52 g, 64%), m.p. 50°-52°. to subside between each addition Cooling was removed to warm to reflux temperature the reaction When cool the solvent was evaporated The organic solution was washed successively with water and brine dried (anhyd. MgSO4) filtered evaporated to a light yellow oil which crystallized from petroleum spirit (40°-60°)

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

Procedure: Methyl-2-aminophenyl carbinol from Step 1 above (0.86 g, 6.3 mmol), N-Boc-4-piperidone (2.5 g, 12.6 mmol), and acetic acid (1.08 mL, 1.13 g, 18.9 mmol) were combined in methanol (10 mL). Sodium cyanoborohydride (0.79 g, 12.5 mmol) was added in portions, and the mixture was stirred at ambient temperature for 18 hours. The mixture was concentrated in vacuo. Ethyl acetate (100 mL) was added to the residue and the resulting mixture was washed with saturated aqueous sodium bicarbonate, dried over sodium sulfate, filtered, and evaporated in vacuo. The residue was chromatographed on silica gel eluted with 1:9 then 15:85 EtOAc:hexane. The combined product fractions were evaporated to dryness in vacuo to give methyl-(2-(1-Boc-4-piperidinylamino)phenyl) carbinol. The mixture was concentrated in vacuo Ethyl acetate (100 mL) was added to the residue the resulting mixture was washed with saturated aqueous sodium bicarbonate dried over sodium sulfate filtered evaporated in vacuo The residue was chromatographed on silica gel eluted with 1:9 The combined product fractions were evaporated to dryness in vacuo

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

Procedure: Sodium borohydride (1.12 g, 29.6 mmol) was stirred under nitrogen in THF (40 mL) in an ice bath. Acetic acid (3.38 mL, 3.55 g, 59.2 mmol) was added dropwise. The mixture was stirred until hydrogen evolution had ceased, then neat 2-aminoacetophenone (2.0 g, 14.8 mmol) was added dropwise. The mixture was stirred at ambient temperature for 5 days, then treated with water (40 mL) and neutralized with saturated aqueous sodium bicarbonate. The mixture was extracted with ether, and the combined ether layers were dried over sodium sulfate, filtered, and evaporated to dryness in vacuo to give methyl-2-aminophenyl carbinol. The mixture was extracted with ether the combined ether layers were dried over sodium sulfate filtered evaporated to dryness in vacuo