Lithium Hydroxide → N-(5-{4-[6-amino-5-(4-fluorobenzoyl)-2-oxopyridin-1(2H)-yl]-3,5-difluorophenoxy}pentyl)-L-leucine

HRID 1667385Notes

Reaction equation

HRID 1667385 reaction equation
[NH2:1][C:2]1[N:7]([C:8]2[C:33]([F:34])=[CH:32][C:11]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][NH:18][C@H:19]([C:24]([O:26]C3CCCC3)=[O:25])[CH2:20][CH:21]([CH3:23])[CH3:22])=[CH:10][C:9]=2[F:35])[C:6](=[O:36])[CH:5]=[CH:4][C:3]=1[C:37](=[O:45])[C:38]1[CH:43]=[CH:42][C:41]([F:44])=[CH:40][CH:39]=1.[Li+].[OH-]>C1COCC1.O>[NH2:1][C:2]1[N:7]([C:8]2[C:9]([F:35])=[CH:10][C:11]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][NH:18][C@H:19]([C:24]([OH:26])=[O:25])[CH2:20][CH:21]([CH3:23])[CH3:22])=[CH:32][C:33]=2[F:34])[C:6](=[O:36])[CH:5]=[CH:4][C:3]=1[C:37](=[O:45])[C:38]1[CH:39]=[CH:40][C:41]([F:44])=[CH:42][CH:43]=1

Participants

5

Reactant 2

HCID 3939Lithium HydroxideHCID 24798351Cyclopentyl N-(5-{4-[6-amino-5-(4-fluorobenzoyl)-2-oxopyridin-1(2H)-yl]-3,5-difluorophenoxy}pentyl)-L-leucinate

Product 1

HCID 57658443N-(5-{4-[6-amino-5-(4-fluorobenzoyl)-2-oxopyridin-1(2H)-yl]-3,5-difluorophenoxy}pentyl)-L-leucine

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 8028TetrahydrofuranSolvent

Procedure

From Example 55. To a solution of cyclopentyl N-(5-{4-[6-amino-5-(4-fluorobenzoyl)-2-oxopyridin-1(2H)-yl]-3,5-difluorophenoxy}pentyl)-L-leucinate (33 mg, 0.05 mmol) in THF (1 ml) and water (1 ml) was added LiOH (25 mg, 1.05 mmol, 20 eq). The mixture was stirred at room temperature for 16 hours, before being heated at 80° C. for 10 hours. The mixture was concentrated under reduced pressure and water (5 ml) added. The pH was adjusted to 7 using 1M HCl and the aqueous layer extracted with 1-butanol (3×5 ml). The combined organic extracts were concentrated under reduced pressure. The solid residue was triturated with Et2O, collected by filtration and purified by preparative HPLC to provide the title compound as a white solid as the mono-TFA salt (7 mg, 24% yield). LC/MS: m/z 560 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ: 7.62-7.51 (3H, m), 7.34 (2H, m), 7.05 (2H, m), 5.72 (1H, d, J=9.8 Hz), 4.09 (2H, t, J=5.7 Hz), 3.23 (1H, m), 2.80 (2H, m), 1.79-1.43 (9H, m), 0.89 (6H, t, J=6.7 Hz).

Workup

  1. temperaturebefore being heated at 80° C. for 10 hours
  2. concentrationThe mixture was concentrated under reduced pressure and water (5 ml)
  3. additionadded
  4. extractionthe aqueous layer extracted with 1-butanol (3×5 ml)
  5. concentrationThe combined organic extracts were concentrated under reduced pressure
  6. customThe solid residue was triturated with Et2O
  7. filtrationcollected by filtration
  8. custompurified by preparative HPLC

Sources & evidence

ORD record
ord-1ae9bb94225b4fbe92711b34d8959b13
Source dataset
uspto-grants-2011_10
Patent number
US08044211B2

Reaction notes

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