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Stage #1: With sodium hydroxide In water at 20℃; for 5 h; Stage #2: With hydrogenchloride In water
Ester hydrolysisThe resulting above ester (20.00g:0.11 mol) was stirred in water (100ml) adjusted to approx pH13 by the addition of sodium hydroxide pellets. After stirring for a total of 5 hours at room temperature the pH was adjusted to pH 1 by the addition of 2N hydrochloric acid and the precipitate filtered. The resulting solid was stirred with acetone filtered and dried to give an off white solid (9.2Og: 59percent; mass spectrum (M H) -ve 141 ).
Ester hydrolysisThe resulting above ester (20.00g:0.11 mol) was stirred in water (100ml) adjusted to approx pH13 by the addition of sodium hydroxide pellets. After stirring for a total of 5 hours at room temperature the pH was adjusted to pH 1 by the addition of 2N hydrochloric acid and the precipitate filtered. The resulting solid was stirred with acetone filtered and dried to give an off white solid (9.2Og: 59%; mass spectrum (M H) -ve 141 ).
The resulting diazonium was then added dropwise over 5 min to a stirred a solution of <strong>[58364-97-9]3-carboxy-5-hydroxy-1-methylpyrazole</strong> (1.7Og; 0.012mol) at 0 to 100C and pH 6-8. After stirring overnight, the product was salted out with lithium chloride, filtered and then washed with lithium chloride solution. The damp paste was dissolved in water at pH9, dialysed using Viskingtubing (<3.0?Scr??1) and then screened through a cascade of filters (GF/F, 0.45?m nylon). The resulting solution was dried in an oven to give a reddish black solid of the title compound (6.52g:70%; ? max 66,679; ?max(H2O) 579nm; mass spectrum (M-H) -ve 900).
(2R,4R)-5-(3'-chlorobiphenyl-4-yl)-2-hydroxy-4-[(5-hydroxy-1-methyl-1H-pyrazole-3-carbonyl)amino]pentanoic acid ethyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
Example 2A (2R,4R)-5-(3'-Chlorobiphenyl-4-yl)-2-hydroxy-4-[(5-hydroxy-1-methyl-1H-pyrazole-3-carbonyl)amino]pentanoic Acid 5-Hydroxy-1-methyl-1H-pyrazole-3-carboxylic acid (19.6 mg, 138 μmol) was combined with HCTU (56.9 mg, 138 μmol) in DMF. The mixture was stirred for 10 minutes at room temperature before adding DIPEA (72 μL, 413 μmol) and (2R,4R)-4-amino-5-(3'-chlorobiphenyl-4-yl)-2-hydroxypentanoic acid ethyl ester (50 mg, 0.1 mmol). The resulting mixture was stirred overnight at room temperature. EtOH (402 μL, 6.9 mmol) and 1 M LiOH in water (1.1 mL, 1.1 mmol) was added and the mixture was stirred at room temperature for 1 hour. The mixture was evaporated under reduced pressure and purified by preparative HPLC to yield the title compound (6.4 mg). MS m/z [M+H]+ calc'd for C22H22ClN3O5, 444.12; found 444.4.
(2R,4R)-5-(3'-chlorobiphenyl-4-yl)-2-hydroxy-4-[(5-hydroxy-1-methyl-1H-pyrazole-3-carbonyl)amino]pentanoic acid benzyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
81.4 mg
Example 2G (2R,4R)-5-(3′-Chlorobiphenyl-4-yl)-2-hydroxy-4-[(5-hydroxy-1-methyl-1H-pyrazole-3-carbonyl)amino]pentanoic Acid Benzyl Ester [0350] (2R,4R)-4-amino-5-(3′-chlorobiphenyl-4-yl)-2-hydroxypentanoic acid ethyl ester (150.0 mg, 431 μmol), benzyl alcohol (446.2 μL, 4.3 mmol), and 4.0 M HCl in 1,4-dioxane (431 μL, 1.7 mmol) was stirred at room temperature overnight, then at 50 C. for 1 hour. The mixture was then concentrated under reduced pressure. 5-Hydroxy-1-methyl-1H-pyrazole-3-carboxylic acid (30.6 mg, 216 μmol) and HATU (98.4 mg, 259 mol) were stirred in DMF (0.5 mL, 5 mmol) for 10 minutes, then added to the concentrated mixture, along with DIPEA (113 μL, 647 μmol). The resulting mixture was stirred at room temperature for 2 hours and concentrated under reduced pressure. The residue was dissolved in 50% AcOH-water (5 mL), filtered, and purified by reverse phase preparative HPLC to yield the title compound (81.4 mg).
(2R,4R)-5-(3'-chlorobiphenyl-4-yl)-2-hydroxy-4-[(5-hydroxy-1-methyl-1H-pyrazole-3-carbonyl)amino]pentanoic acid 5-methyl-2-oxo-[1,3]dioxol-4-ylmethyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
7 mg
Example 2B (2R,4R)-5-(3'-Chlorobiphenyl-4-yl)-2-hydroxy-4-[(5-hydroxy-1-methyl-1H-pyrazole-3-carbonyl)amino]pentanoic Acid 5-Methyl-2-oxo-[1,3]dioxol-4-ylmethyl 5-Hydroxy-1-methyl-1H-pyrazole-3-carboxylic acid (5.6 mg, 39 μmol) and HCTU (16.2 mg, 39 μmol) were combined in DMF (166 μL, 2.1 mmol) and stirred at room temperature for 15 minutes. DIPEA (19 μL, 0.1 mmol) and (2R,4R)-4-amino-5-(3'-chlorobiphenyl-4-yl)-2-hydroxypentanoic acid 5-methyl-2-oxo[1,3]dioxol-4-ylmethyl ester (15.4 mg, 36 μmol) were added, and the resulting mixture was stirred at room temperature for 30 minutes. The solvent was removed in vacuo and the crude product was purified by preparative HPLC to yield the title compound (7 mg). MS m/z [M+H]+ calc'd for C27H26ClN3O8, 556.14; found 556.1.
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