Lithium Hydroxide → 7-(3-(1-(3-Cyclopentylureido)-1-(3-fluoro-5-(trifluoromethyl)phenyl)-2-phenylethyl)phenyl)heptanoic acid

HRID 1712709Notes

Reaction equation

HRID 1712709 reaction equation
[NH2:1][C:2]([C:21]1[CH:22]=[C:23]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][C:33]([O:35]CC)=[O:34])[CH:24]=[CH:25][CH:26]=1)([C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([F:20])[CH:11]=1)[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH:38]1([N:43]=[C:44]=[O:45])[CH2:42][CH2:41][CH2:40][CH2:39]1.C1COCC1.[OH-].[Li+]>C(Cl)Cl>[CH:38]1([NH:43][C:44](=[O:45])[NH:1][C:2]([C:21]2[CH:22]=[C:23]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][C:33]([OH:35])=[O:34])[CH:24]=[CH:25][CH:26]=2)([C:10]2[CH:15]=[C:14]([C:16]([F:18])([F:17])[F:19])[CH:13]=[C:12]([F:20])[CH:11]=2)[CH2:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH2:42][CH2:41][CH2:40][CH2:39]1

Participants

6

Reactant 4

HCID 3939Lithium HydroxideHCID 8028TetrahydrofuranHCID 643500Cyclopentyl IsocyanateHCID 59458680Ethyl 7-(3-(1-amino-1-(3-fluoro-5-(trifluoromethyl)phenyl)-2-phenylethyl)phenyl)heptanoate

Product 1

HCID 235824017-(3-(1-(3-Cyclopentylureido)-1-(3-fluoro-5-(trifluoromethyl)phenyl)-2-phenylethyl)phenyl)heptanoic acidYield 53%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

To a solution of ethyl 7-(3-(1-amino-1-(3-fluoro-5-(trifluoromethyl)phenyl)-2-phenylethyl)phenyl)heptanoate (169 mg, 0.33 mmol) in anhydrous DCM (1 mL) was added cyclopentyl isocyanate (22 mg, 0.2 mmol). The reaction mixture was stirred at rt for 18 h. To the reaction mixture was added anhydrous THF (1 mL) and the mixture was stirred at room temperature for additional 1 h. The solvents were evaporated on a rotary evaporator and the residue was dissolved in methanol and purified by preparative HPLC (RT=11.3 min, Waters Sunfire C18 OBD, 19×100 mm eluting with 26-90% MeCN/H2O containing 0.1% TFA over 9 min and hold at 90% for 7 more minutes; 40 mL/min, monitoring at 220 nm). The resulting solid was dissolved in methanol (1 mL) followed by the addition of aqueous lithium hydroxide (1 N, 0.25 mL, 0.25 mmol). The reaction mixture was heated at 36° C. for 18 h. The crude product was purified by preparative HPLC (RT=10.7 min, Waters Sunfire C18 OBD, 19×100 mm eluting with 18-90% MeCN/H2O over 10 min and hold at 90% for 6 additional minutes containing 0.1% TFA; 40 mL/min, monitoring at 220 nm) to yield 7-(3-(1-(3-cyclopentylureido)-1-(3-fluoro-5-(trifluoromethyl)phenyl)-2-phenylethyl)phenyl)heptanoic acid (Example 234, 32 mg, 53% yield for 2 steps). LCMS: RT=4.33 min, Purity >95%, [M+H] 599.4 (Sunfire-S5-C18 column, 4.6×50 mm eluting with 10-90% MeOH/H2O over 4 minutes containing 0.1% TFA; 4 mL/min, monitoring at 220 nm); NMR: 400 MHz 1H (CDCl3) 7.36 ppm, 1H, s; 7.16-7.24 ppm, 4H, m; 7.10-7.13 ppm, 3H, m; 6.97 ppm, 1H, d, J=7.7 Hz; 6.94 ppm, 1H, s; 6.67 ppm, 2H, d, J=7.1 Hz; 5.58 ppm, 1H, brd, s; 3.87 ppm, 1H, d, J=12.6 Hz; 3.83 ppm, 1H, m; 3.65 ppm, 1H, d, J=12.7 Hz; 2.54, 2H, t, J=7.5 Hz; 2.29 ppm, 2H, t, J=7.4 Hz; 1.73-1.84 ppm, 2H, m; 1.50-1.60 ppm, 8H, m; 1.15-1.36 ppm, 6H, m.

Workup

  1. stirringthe mixture was stirred at room temperature for additional 1 h
  2. customThe solvents were evaporated on a rotary evaporator
  3. dissolutionthe residue was dissolved in methanol
  4. custompurified by preparative HPLC (RT=11.3 min, Waters Sunfire C18 OBD, 19×100 mm eluting with 26-90% MeCN/H2O containing 0.1% TFA over 9 min and hold at 90% for 7 more minutes; 40 mL/min, monitoring at 220 nm)
  5. dissolutionThe resulting solid was dissolved in methanol (1 mL)
  6. temperatureThe reaction mixture was heated at 36° C. for 18 h
  7. customThe crude product was purified by preparative HPLC (RT=10.7 min, Waters Sunfire C18 OBD, 19×100 mm eluting with 18-90% MeCN/H2O over 10 min and hold at 90% for 6 additional minutes containing 0.1% TFA; 40 mL/min, monitoring at 220 nm)

Sources & evidence

ORD record
ord-18f5ec4a998d4ce6aa76ef5990aa38d6
Source dataset
uspto-grants-2010_09
Patent number
US07790770B2

Reaction notes

Loading…