Lithium Hydroxide → 6-{(S)-2-[4-(2-chloro-6-fluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-3-cyclohexyl-propionylamino}-nicotinic acid

HRID 19008Notes

Reaction equation

HRID 19008 reaction equation
C[O:2][C:3](=[O:36])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:35])[C@@H:12]([N:20]2[CH2:24][C:23]([O:25][C:26]3[C:31]([F:32])=[CH:30][CH:29]=[CH:28][C:27]=3[Cl:33])=[CH:22][C:21]2=[O:34])[CH2:13][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=[N:6][CH:5]=1.[OH-].[Li+]>O1CCCC1.C(OCC)(=O)C>[Cl:33][C:27]1[CH:28]=[CH:29][CH:30]=[C:31]([F:32])[C:26]=1[O:25][C:23]1[CH2:24][N:20]([C@@H:12]([CH2:13][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[C:11]([NH:10][C:7]2[CH:8]=[CH:9][C:4]([C:3]([OH:36])=[O:2])=[CH:5][N:6]=2)=[O:35])[C:21](=[O:34])[CH:22]=1

Participants

5

Reactant 2

HCID 3939Lithium HydroxideHCID 442517366-{(S)-2-[4-(2-chloro-6-fluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-3-cyclohexyl-propionylamino}-nicotinic acid methyl ester

Product 1

HCID 442517376-{(S)-2-[4-(2-chloro-6-fluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-3-cyclohexyl-propionylamino}-nicotinic acidYield 13%

Reagents, catalysts & solvents 2

HCID 8028TetrahydrofuranSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
25 °C

Procedure

To a magnetically stirred mixture of 6-{(S)-2-[4-(2-chloro-6-fluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-3-cyclohexyl-propionylamino}-nicotinic acid methyl ester (prepared as in Example 69, 80 mg, 0.16 mmol) in tetrahydrofuran (3.0 mL) was added 0.5N lithium hydroxide solution (1.0 mL, 0.5 mmol). After addition was complete the mixture was stirred at 25° C. for 4 h. The reaction mixture was diluted with ethyl acetate, washed with 1N aqueous hydrochloric acid, water, a saturated sodium chloride solution and dried over sodium sulfate. The crude product was recrystallized from ethyl acetate to afford 6-{(S)-2-[4-(2-chloro-6-fluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-3-cyclohexyl-propionylamino}-nicotinic acid (10 mg, 13%) as a white solid: 1H NMR (300 MHz, DMSO-d6) δ ppm 0.73-1.42 (m, 6H) 1.41-1.90 (m, 7H) 4.28 (d, J=18.7 Hz, 1H) 4.64 (d, J=18.7 Hz, 1H) 4.99 (s, 1H) 5.01-5.10 (m, 1H) 7.31-7.57 (m, 3H) 8.14 (d, J=8.5 Hz, 1H) 8.25 (dd, J=8.5, 2.1 Hz, 1H) 8.84 (d, J=2.1 Hz, 1H) 11.26 (s, 1H) 13.18 (br. s., 1H). HR-ES-MS m/z calculated for C25H25ClFN3O5 [M+H]+ 502.1540, observed 502.1537.

Workup

  1. additionAfter addition
  2. washwashed with 1N aqueous hydrochloric acid, water
  3. dry with materiala saturated sodium chloride solution and dried over sodium sulfate
  4. customThe crude product was recrystallized from ethyl acetate

Sources & evidence

ORD record
ord-7d9a9181fa8440108234d939b3eb3700
Source dataset
uspto-grants-2010_06
Patent number
US07741327B2

Reaction notes

Loading…