methyl (2S)-2-amino-3-(4-hydroxyphenyl)propanoate

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

Procedure: bis-(2-Chloroethyl)amine hydrochloride 26 (200 mg, 1.1 mmol) was dissolved in dichloromethane (15 mL) and triethylamine (0.45 mL, 3.3 mmol) was added. The mixture was stirred for 5 minutes at ambient temperature and methyl chlorothioformate (1.32 mmol) was added. The mixture was stirred until no bis-(2-chloroethyl)amine remained by TLC (ethyl acetate). Tyrosine methyl ester (411 mg, 2.1 mmol) was added and the mixture was heated under reflux for 4 hours. The mixture was allowed to cool purified by dry flash column chromatography (silica gel, dichloromethane 200 mL) and concentrated in vacuo to yield prodrug 30 as an orange/brown oil (278 mg, 60%). νmax 3400, 1740, 1660, 1444, 1380, 1145/cm−1; δ 1H (400 MHz, CDCl3) 2.32 (3H, s, CH3) 2.60 (2H, t, J 3.72 Hz, CH2Ar), 2.64 (3H, s, CH3) 3.12–3.25 (9H, m, ArCH2CH, 2×CH2CH2Cl), 6.67 (2H, d, J 5.7 Hz, 2×ArH), 6.9 (2H, d, J 5.7 Hz, 2×ArH), 7.82 (1H, brs, NH);. 13C (100 MHz, CDCl3) 29.8 (CH2), 43.3 (CH2), 44.1 (CH2), 44.2 (CH2), 45.2 (CH2), 46.6 (CH2), 47.1 (CH3) 115.9 (2×CH), 130 (2×CH), 130.1 (C), 155.6 (C), 160.3 (C) 161.5 (C). m/z (Cl) 242 (72%), 227 (45), 183 (75) 152 (100), 121 (45), 108 (35). the mixture was heated under reflux for 4 hours to cool purified by dry flash column chromatography (silica gel, dichloromethane 200 mL) concentrated in vacuo

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

Procedure: Following General Procedure A and using N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and L-tyrosine methyl ester (Bachem), the title compound was prepared as a solid (mp=85-88° C.). The reaction was monitored by tlc (Rf=0.27 in 50% EtOAc/hexanes) and the product was purified by silica gel column chromatography. the product was purified by silica gel column chromatography

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

Procedure: (1S)-1-(4-Hydroxyphenylmethyl)-2-hydroxyethylamine was made from (L)-tyrosine methyl ester as described in Method B1b. The 2-hydroxyethylamine was converted to (4S)-2-isopropyl-4-(4-hydroxyphenylmethyl)-1,3-oxazolidine according to Method B4c, Step 1. The oxazolidine was reduced to N-((1S)-1-(4-hydroxyphenylmethyl)-2-hydroxyethyl)-N-isobutylamine according to Method B4c, Step 2. The resulting 2-hydroxyethylamine was treated with SOCl2 according to Method B7c to give N-((1S)-1-(4-hydroxyphenylmethyl)-2-chloroethyl)-N-isobutylammonium chloride. 2-Ethyl-4-cyanophenyl isothiocyanate was reacted with N-((1S)-1-(4-hydroxyphenylmethyl)-2-chloroethyl)-N-isobutylammonium chloride according to Method C1b to give (4S)-2-(2-ethyl-4-cyanophenylimino)-4-(4-hydroxyphenylmethyl)-3-isobutyl-1,3-thiazolidine HCl salt.

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

Procedure: (1S)-1-(4-Hydroxyphenylmethyl)-2-hydroxyethylamine was made from (L)-tyrosine methyl ester as described in Method B1b. The 2-hydroxyethylamine was converted to (4S)-2-isopropyl-4-(4-hydroxyphenylmethyl)-1,3-oxazolidine according to Method B4c, Step 1. The oxazolidine was reduced to N-((1S)-1-(4-hydroxyphenylmethyl)-2-hydroxyethyl)-N-isobutylamine according to Method B4c, Step 2. The resulting 2-hydroxyethylamine was treated with SOCl2 according to Method B7c to give N-((1S)-1-(4-hydroxyphenylmethyl)-2-chloroethyl)-N-isobutylammonium chloride. 2-Ethyl-4-cyanophenyl isothiocyanate was reacted with N-((1S)-1-(4-hydroxyphenylmethyl)-2-chloroethyl)-N-isobutylammonium chloride according to Method C1b to give (4S)-2-(2-ethyl-4-cyanophenylimino)-4-(4-hydroxyphenylmethyl)-3-isobutyl-1,3-thiazolidine HCl salt.

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

Procedure: Following General Procedure A and using N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and L-tyrosine methyl ester (Bachem), the title compound was prepared as a solid (mp=85-88° C.). The reaction was monitored by tlc (Rf=0.27 in 50% EtOAc/hexanes) and the product was purified by silica gel column chromatography. the product was purified by silica gel column chromatography

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

Procedure: To a solution of 12-cyclohexyl-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carbonyl chloride (100 mg, 0.26 mmol) in chloroform (2 ml) was added methyl (S)-2-amino-3-(4-hydroxyphenyl)propionate (154 mg, 0.78 mmol). The mixture was stirred at room temperature for 12 hr, 1N hydrochloric acid was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was successively washed with water and saturated brine and dried over anhydrous sodium sulfate. After filtration and concentration, diethyl ether was added to the obtained residue, and the precipitated solid was collected by filtration. The solid was washed with diethyl ether to give methyl (S)-2-[(12-cyclohexyl-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carbonyl)amino]-3-(4-hydroxyphenyl)propionate (102 mg, yield 82%). the mixture was extracted with ethyl acetate The organic layer was successively washed with water and saturated brine dried over anhydrous sodium sulfate After filtration and concentration, diethyl ether was added to the obtained residue the precipitated solid was collected by filtration The solid was washed with diethyl ether

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

Procedure: To a solution of 12-cyclohexyl-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carbonyl chloride (100 mg, 0.26 mmol) in chloroform (2 ml) was added methyl (S)-2-amino-3-(4-hydroxyphenyl)propionate (154 mg, 0.78 mmol). The mixture was stirred at room temperature for 12 hr, 1N hydrochloric acid was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was successively washed with water and saturated brine and dried over anhydrous sodium sulfate. After filtration and concentration, diethyl ether was added to the obtained residue, and the precipitated solid was collected by filtration. The solid was washed with diethyl ether to give methyl (S)-2-[(12-cyclohexyl-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carbonyl)amino]-3-(4-hydroxyphenyl)propionate (102 mg, yield 82%). the mixture was extracted with ethyl acetate The organic layer was successively washed with water and saturated brine dried over anhydrous sodium sulfate After filtration and concentration, diethyl ether was added to the obtained residue the precipitated solid was collected by filtration The solid was washed with diethyl ether

Conditions: temp:20.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of N-(tert-butoxycarbonyl)-L-leucine (7 g) in acetonitrile (100 ml), under a nitrogen atmosphere, was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (5.9 g) and 1-hydroxybenzotriazole (4.2 g). After stirring for 30 mins at 20° C. L-tyrosine methyl ester (5.5 g) was added and stirring was continued for 18 h. The mixture was concentrated in vacuo to ca. 10 ml and the residue was partitioned between 1M hydrochloric acid (200 ml) and ethyl acetate (100 ml). The layers were separated and the aqueous phase was further extracted with ethyl acetate (100 ml). The combined organic extracts were washed with saturated aqueous sodium hydrogen carbonate (100 ml), water (2×100 ml) and brine (50 ml), dried over sodium sulphate and evaporated in vacuo. The residue was co-evaporated with chloroform to give the title compound as a white foam (11.3 g, 98%). LCMS: Rt 3.11 min; m/z 409 (MH+). stirring was continued for 18 h The mixture was concentrated in vacuo to ca. 10 ml the residue was partitioned between 1M hydrochloric acid (200 ml) and ethyl acetate (100 ml) The layers were separated the aqueous phase was further extracted with ethyl acetate (100 ml) The combined organic extracts were washed with saturated aqueous sodium hydrogen carbonate (100 ml), water (2×100 ml) and brine (50 ml) dried over sodium sulphate evaporated in vacuo

Conditions: temp:20.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of N-(tert-butoxycarbonyl)-L-leucine (7 g) in acetonitrile (100 ml), under a nitrogen atmosphere, was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (5.9 g) and 1-hydroxybenzotriazole (4.2 g). After stirring for 30 mins at 20° C. L-tyrosine methyl ester (5.5 g) was added and stirring was continued for 18 h. The mixture was concentrated in vacuo to ca. 10 ml and the residue was partitioned between 1M hydrochloric acid (200 ml) and ethyl acetate (100 ml). The layers were separated and the aqueous phase was further extracted with ethyl acetate (100 ml). The combined organic extracts were washed with saturated aqueous sodium hydrogen carbonate (100 ml), water (2×100 ml) and brine (50 ml), dried over sodium sulphate and evaporated in vacuo. The residue was co-evaporated with chloroform to give the title compound as a white foam (11.3 g, 98%). LCMS: Rt 3.11 min; m/z 409 (MH+). stirring was continued for 18 h The mixture was concentrated in vacuo to ca. 10 ml the residue was partitioned between 1M hydrochloric acid (200 ml) and ethyl acetate (100 ml) The layers were separated the aqueous phase was further extracted with ethyl acetate (100 ml) The combined organic extracts were washed with saturated aqueous sodium hydrogen carbonate (100 ml), water (2×100 ml) and brine (50 ml) dried over sodium sulphate evaporated in vacuo

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

Procedure: Following General Procedure A and using N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and L-tyrosine methyl ester (Bachem), the title compound was prepared as a solid (mp=85-88° C.). The reaction was monitored by tlc (Rf=0.27 in 50% EtOAc/hexanes) and the product was purified by silica gel column chromatography. the product was purified by silica gel column chromatography

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

Procedure: Following General Procedure A and using N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and L-tyrosine methyl ester (Bachem), the title compound was prepared as a solid (mp=85-88° C.). The reaction was monitored by tlc (Rf=0.27 in 50% EtOAc/hexanes) and the product was purified by silica gel column chromatography. the product was purified by silica gel column chromatography

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

Procedure: 21.2 g (0.1 mol) of 2-bromo-1-(4-methylphenyl)ethanol and 8.66 g (0.107 mol) of dry sodium thiocyanate in ethanol (200 ml) were stirred for 3 h at 50° C. The solution of 19.51 g (0.1 mol) of (S)-tyrosine methyl ester in ethanol (100 ml) was then added in one portion and the reaction mixture was stirred for 12 h. After removing ethanol by distillation, water and ethyl acetate were added. Aqueous phase was extracted twice with ethyl acetate, combined organic phases were dried over sodium sulfate and the solvent was evaporated. The product was purified by chromatography (SiO2, ethyl acetate/hexane). The yield was 17.67 g (48%). MS (ES) 368 (M+, 100%) After removing ethanol by distillation, water and ethyl acetate were added Aqueous phase was extracted twice with ethyl acetate were dried over sodium sulfate the solvent was evaporated The product was purified by chromatography (SiO2, ethyl acetate/hexane)