3-phenylpropanamide

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

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

Procedure: A mixture of N-(2-hydroxy-1-hydroxymethyl-ethyl)-3-phenyl-propionamide (1.7 g, 7.6 mmol), toluene (70 ml), 4-hydroxybenzaldehyde (1.856 g, 15.2 mmol) and a catalytic amount of p-toluenesulfonic acid was refluxed for 3 h. The mixture was evaporated and CH2Cl2 was added to the residue. The precipitate was filtered off and recrystallised from hot AcOEt (50 ml). The light brown crystals formed collected yielding trans-N-12-(4-hydroxy-phenyl)-[1,3]dioxan-5-yl]-3-phenyl-propionamide (1.41 g, MS: m/e=328.2 (M+H+)). The filtrate was concentrated and left at 4° overnight. The newly formed crystals are collected yielding cis-N-[2-(4-hydroxy-phenyl)-[1,3]dioxan-5-yl]-3-phenyl-propionamide (0.401 g, m/e=326.4 (M−H+)). The mixture was evaporated CH2Cl2 was added to the residue The precipitate was filtered off recrystallised from hot AcOEt (50 ml) The light brown crystals formed collected

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

Procedure: 1.73 g of 3-amino-1,3-dihydro-5-(2,6-dimethoxy-4-methylphenyl)-1-methyl-1,4-benzodiazepin-2-one are dissolved in 30 ml of dimethylformamide in the presence of 1.42 g of BOC-D-phenylalanine, followed by cooling to 5° C. and addition of 1.07 ml of triethylamine and then 2.4 g of BOP. The reaction mixture is allowed to return to room temperature and is left stirring overnight. It is then poured into water and extracted with ethyl acetate. The organic phase is washed with water, separated out after settling of the phases, dried over Na2SO4, filtered and concentrated under vacuum. An oily residue of 2-tertbutoxycarbonylamino-N-]2,3-dihydro-5-(2,6-dimethoxy-4-methylphenyl)-1-methyl-2-oxo-1H-1,4-benzodiazepin-3-yl!-3-phenylpropionamide, obtained in quantitative yield, is used as it is for the following step (Compound 16). to return to room temperature is left extracted with ethyl acetate The organic phase is washed with water separated out dried over Na2SO4 filtered concentrated under vacuum

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

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

Procedure: A suspension of 3-(phenyl)propionamide, the product from Example 18A, benzotriazole, and p-toluenesulfonic acid was processed as described in Example 1C to provide the title compound.

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

Procedure: A suspension of 3-phenyl-propionamide, pivaldehyde, benzotriazole, and p-toluenesulfonic acid was processed as described in Example 1C to provide the title compound.

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

Procedure: A slurry of potassium hydride (from 46 grams of 35% potassium hydride in oil washed three times with hexane)in 50 ml of THF is added with stirring under nitrogen to 20 grams of 3-phenylpropionamide in 350ml of THF. After addition of the hydride is complete, the reaction is allowed to warm to room temperature and is stirred for 30 minutes. The thickened reaction mixture is cooled to 0° to 5° C. and is then added dropwise over 30 minutes to a solution of 30 grams of p-pivaloylbenzoyl chloride in 50 ml of dry THF. The resulting solution is stirred for 15 minutes at 0° to 5° C. and is then quenched with 150 ml of saturated ammonium chloride solution. The THF phase is decanted off, and the aqueous phase is extracted with ethyl acetate. The ethyl acetate extract is combined with the THF phase, dried with magnesium sulfate, filtered, and then evaporated almost to dryness. The resulting solids are triturated with ether, and the white crystals obtained are filtered, washed with ether and dried to yield the title product (m.p. 137°-138° C.). The thickened reaction mixture is cooled to 0° to 5° C. The resulting solution is stirred for 15 minutes at 0° to 5° C. is then quenched with 150 ml of saturated ammonium chloride solution The THF phase is decanted off the aqueous phase is extracted with ethyl acetate The ethyl acetate extract dried with magnesium sulfate filtered evaporated almost to dryness The resulting solids are triturated with ether the white crystals obtained are filtered washed with ether dried

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

Procedure: In Scheme A step f, (S)-2-chloro-cyclohex-2-enylamine is reacted with an appropriate phthalimido-L-phenyalanine derivative to give (S)-N-(2-chloro-cyclohex-2-enyl)-2- 2(S)-1,3-dihydro-1,3-dioxo-isoindol-2-yl)-3-phenyl-propionamide.

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

Procedure: reacting (S)-2-chloro-cyclohex-2-enylamine with phthalimido-L-phenyalanine derivative to give (S)-N-(2-chloro-cyclohex-2-enyl)-2- 2(S)-1,3-dihydro-1,3-dioxo-isoindol-2-yl)-3-phenyl-propionamide;

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

Procedure: To a solution of 3-phenylpropionamide (1.653 g, 6.827 mmol) in toluene (20 mL) was added Lawesson's reagent (0.716 g, 1.77 mmol). The reaction was refluxed overnight, cooled to room temperature and concentrated yielding an orange oil. Flash chromatography of this oil (1:1 hexane:methylene chloride with 1% acetic acid) yielded 3-phenylthiopropionamide (0.070 g) as a white solid: mp 82°-83° C.; 1HNMR (DMSO d6) 300 mHz 9.35 (br s, 1 H), 9.15 (br s, 1 H), 7.34-7.10 (m, 2 H), 2.95 (t, J=8.48 Hz, 2 H), 2.72 (t, J=8.48 Hz, 2 H). The reaction was refluxed overnight concentrated yielding an orange oil

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

Procedure: A mixture of N-(2-hydroxy-1-hydroxymethyl-ethyl)-3-phenyl-propionamide (1.7 g, 7.6 mmol), toluene (70 ml), 4-hydroxybenzaldehyde (1.856 g, 15.2 mmol) and a catalytic amount of p-toluenesulfonic acid was refluxed for 3 h. The mixture was evaporated and CH2Cl2 was added to the residue. The precipitate was filtered off and recrystallised from hot AcOEt (50 ml). The light brown crystals formed collected yielding trans-N-12-(4-hydroxy-phenyl)-[1,3]dioxan-5-yl]-3-phenyl-propionamide (1.41 g, MS: m/e=328.2 (M+H+)). The filtrate was concentrated and left at 4° overnight. The newly formed crystals are collected yielding cis-N-[2-(4-hydroxy-phenyl)-[1,3]dioxan-5-yl]-3-phenyl-propionamide (0.401 g, m/e=326.4 (M−H+)). The mixture was evaporated CH2Cl2 was added to the residue The precipitate was filtered off recrystallised from hot AcOEt (50 ml) The light brown crystals formed collected

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

Procedure: 1.73 g of 3-amino-1,3-dihydro-5-(2,6-dimethoxy-4-methylphenyl)-1-methyl-1,4-benzodiazepin-2-one are dissolved in 30 ml of dimethylformamide in the presence of 1.42 g of BOC-D-phenylalanine, followed by cooling to 5° C. and addition of 1.07 ml of triethylamine and then 2.4 g of BOP. The reaction mixture is allowed to return to room temperature and is left stirring overnight. It is then poured into water and extracted with ethyl acetate. The organic phase is washed with water, separated out after settling of the phases, dried over Na2SO4, filtered and concentrated under vacuum. An oily residue of 2-tertbutoxycarbonylamino-N-]2,3-dihydro-5-(2,6-dimethoxy-4-methylphenyl)-1-methyl-2-oxo-1H-1,4-benzodiazepin-3-yl!-3-phenylpropionamide, obtained in quantitative yield, is used as it is for the following step (Compound 16). to return to room temperature is left extracted with ethyl acetate The organic phase is washed with water separated out dried over Na2SO4 filtered concentrated under vacuum