3-iodopropan-1-ol

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:; See reaction.notes.procedure_details.

Procedure: In a manner similar to that of Example (25a), by reaction of 500 μL (5.2 mmol, 7.4 eq) of 3-iodo-1-propanol and 300 mg (0.7 mmol, 1 eq) of methyl 3-[3′-(3-heptyl-1-methylureido)-2-hydroxybiphenyl-4-yl]propanoate (prepared in Example 15f) in 10 ml of methyl ethyl ketone in the presence of 500 mg (3.61 mmol, 5.1 eq) of potassium carbonate at 80° C. for 15 hours, 270 mg of methyl 3-[3′-(3-heptyl-1-methylureido)-2-(3-hydroxypropoxy)biphenyl-4-yl]propanoate are obtained in oil form. Yield=79%

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

Procedure: In a manner similar to that of Example (25a), by reaction of 500 μL (5.2 mmol, 7.4 eq) of 3-iodo-1-propanol and 300 mg (0.7 mmol, 1 eq) of methyl 3-[3′-(3-heptyl-1-methylureido)-2-hydroxybiphenyl-4-yl]propanoate (prepared in Example 15f) in 10 ml of methyl ethyl ketone in the presence of 500 mg (3.61 mmol, 5.1 eq) of potassium carbonate at 80° C. for 15 hours, 270 mg of methyl 3-[3′-(3-heptyl-1-methylureido)-2-(3-hydroxypropoxy)biphenyl-4-yl]propanoate are obtained in oil form. Yield=79%

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

Procedure: To a stirred mixture of 3-iodo-1-propanol (4.3 g, 23 mmol) and imidazole (3.74 g, 55 mmol) in dimethylformamide (20 ml) was added tert-butylchlorodiphenylsilane (6.8 g, 24.7 mmol) at ambient temperature and the reaction mixture was stirred for 20 hours. The reaction mixture was then poured into cold water. The combined extracts were washed with dilute hydrochloric acid, 5 percent sodium bicarbonate dried over magnesium sulfate, and concentrated in vacuo. The residue was purified by flash chromatography over silica gel eluted with CH2Cl2 :hexane (1:5, v:v) and further by distillation to afford the desired product as a colorless oil: b.p. 134°-5° C./0.01 mmHg. The combined extracts were washed with dilute hydrochloric acid, 5 percent sodium bicarbonate dried over magnesium sulfate concentrated in vacuo The residue was purified by flash chromatography over silica gel eluted with CH2Cl2 :hexane (1:5, v:v) and further by distillation

Conditions: temp:25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a stirring solution of 4-nitrophenol (10.0 g, 71.94 mmol) in tetrahydrofuran (100 mL) at 0° C. was added triphenylphosphine (22.6 g, 86.33 mmol), 3-iodopropanol (16.73 g, 89.93 mmol), and diethylazodicarboxylate (14.3 mL, 86.33 mmol). The resulting mixture was stirred at 25° C. overnight. The mixture was partitioned between brine and ethyl acetate. The organic phase was dried and concentrated. The residue was triturated with 8:1 ether/ethyl acetate to induce the precipitation of 22 g of triphenylphosphine oxide which was separated by filtration. The filtrate was preabsorbed onto silica gel and flash-chromatographed (5:1 hexane/ethyl acetate) to afford 17.5 g (79%) of white solid product. The mixture was partitioned between brine and ethyl acetate The organic phase was dried concentrated The residue was triturated with 8:1 ether/ethyl acetate the precipitation of 22 g of triphenylphosphine oxide which was separated by filtration The filtrate was preabsorbed onto silica gel flash-chromatographed (5:1 hexane/ethyl acetate)

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

Procedure: Following General Procedure B and using N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylalanine (prepared by coupling IV-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and L-phenylalanine (Aldrich) using General Procedure B) and 3-iodo-1-propanol (Aldrich), the title compound was prepared as a solid. The reaction was monitored by tlc (Rf=0.45 in 5% MeOH/methylene chloride) and the product was purified by preparative tlc using 5% MeOH/methylene chloride. the product was purified by preparative tlc

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

Procedure: Following General Procedure B and using N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylalanine (prepared by coupling IV-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and L-phenylalanine (Aldrich) using General Procedure B) and 3-iodo-1-propanol (Aldrich), the title compound was prepared as a solid. The reaction was monitored by tlc (Rf=0.45 in 5% MeOH/methylene chloride) and the product was purified by preparative tlc using 5% MeOH/methylene chloride. the product was purified by preparative tlc

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

Procedure: Following General Procedure B and using N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylalanine (prepared by coupling N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and L-phenylalanine (Aldrich) using General Procedure B) and 3-iodo-1-propanol (Aldrich), the title compound was prepared as a solid. The reaction was monitored by tlc (Rf=0.45 in 5% MeOH/methylene chloride) and the product was purified by preparative tlc using 5% MeOH/methylene chloride. the product was purified by preparative tlc

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

Procedure: To (3R,9S)-6-[4-hydroxyphenyl]-3-[8-oxo-4-oxa-1,7-diazatricyclo[9.6.1.012,17 ]octadeca-11(18),12,14,16-tetraen-9-ylcarbamoyl)-hexanoic acid t-butyl ester (1.0 g, 1.72 mmol) in DMF (20 mL) at 0° C. was added 3-iodopropanol(363mg, 1.95 mmol) and cesium carbonate (636 mg, 1.95 mmol). The mixture was then stirred at room temperature for 2.5 hours. DMF was removed under reduced pressure. The remaining residue was taken up in EtOAc (70 mL) and brine (40 mL). The EtOAc layer was washed with brine and dried (MgSO,). Removal of solvents to give pure (3R,9S)-6-[4-(3-hydroxy-propoxy)-phenyl]-3-[8-oxo-4-oxa-1,7-diazatricyclo[9.6.1.012,17 ]octadeca-11(18),12,14,16-tetraen-9-ylcarbamoyl)-hexanoic acid t-butyl ester (1.1 g, 100%), MS: 622.4 (M+H+). DMF was removed under reduced pressure The EtOAc layer was washed with brine dried (MgSO,) Removal of solvents

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

Procedure: 3-Iodopropanol (11.23 g) was added to a mixture of 4-bromo-2-(trifluoromethyl)-phenol (15 g) and potassium carbonate (172 g) in acetonitrile (150 ml). The above mixture was refluxed for 4 hours then diluted with ethyl acetate (500 ml) and water (300 ml). Organic layer was seperated, dried over magnesium sulphate, solvent removed under reduced pressure to give expected product clean enough for use at the next step (18.6 g). 1H NMR (CDCl3) δ: 7.67 (d, 1H), 7.58 (dd, 1H), 6.90 (dd, 1H), 4.18 (t, 2H), 3.87 (q, 2H), 2.07 (tt, 2H). The above mixture was refluxed for 4 hours Organic layer was seperated dried over magnesium sulphate, solvent removed under reduced pressure