Trifluoroacetic acid → {4-[4-[(5-Cyano-1H-imidazole-2-carbonyl)-amino]-3-(4,4-dimethyl-cyclohex-1-enyl)-phenyl]-tetrahydro-pyran-4-yloxy}-acetic acid

HRID 1054241Notes

Reaction equation

HRID 1054241 reaction equation
[CH3:1][C:2]1([CH3:31])[CH2:7][CH2:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]3([OH:20])[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[CH:11]=[CH:10][C:9]=2[NH:21][C:22]([C:24]2[NH:25][C:26]([C:29]#[N:30])=[CH:27][N:28]=2)=[O:23])=[CH:4][CH2:3]1.[C:32]([O:36]C)(=[O:35])[CH2:33]O.C(O)(C(F)(F)F)=O.[OH-].[K+]>C(Cl)Cl>[C:29]([C:26]1[NH:25][C:24]([C:22]([NH:21][C:9]2[CH:10]=[CH:11][C:12]([C:14]3([O:20][CH2:33][C:32]([OH:36])=[O:35])[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)=[CH:13][C:8]=2[C:5]2[CH2:6][CH2:7][C:2]([CH3:31])([CH3:1])[CH2:3][CH:4]=2)=[O:23])=[N:28][CH:27]=1)#[N:30]

Participants

6

Reactant 4

HCID 6422Trifluoroacetic acidHCID 14797Potassium HydroxideHCID 66774Methyl GlycolateHCID 591285735-Cyano-1H-imidazole-2-carboxylic acid [2-(4,4-dimethyl-cyclohex-1-enyl)-4-(4-hydroxy-tetrahydro-pyran-4-yl)-phenyl]-amide

Product 1

HCID 24875270{4-[4-[(5-Cyano-1H-imidazole-2-carbonyl)-amino]-3-(4,4-dimethyl-cyclohex-1-enyl)-phenyl]-tetrahydro-pyran-4-yloxy}-acetic acidYield 30%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

To a suspension of 5-cyano-1H-imidazole-2-carboxylic acid [2-(4,4-dimethyl-cyclohex-1-enyl)-4-(4-hydroxy-tetrahydro-pyran-4-yl)-phenyl]-amide (48.0 mg, 0.114 mmol)(prepared in Example 1, step (h)) in 1 mL of DCM was added methyl glycolate (0.215 mL, 2.78 mmol), TFA (0.036 mL, 0.464 mmol), and the mixture was stirred for 8 h at RT. The mixture was concentrated and the methyl ester of the title compound was eluted from a 10-g SPE column with 50% EtOAc/hexanes. The resulting ester was dissolved in 1 mL of MeOH, 2N KOH (0.30 mL, 0.60 mmol) was added and the mixture stirred for 8 h at RT. The title compound was purified by RP-HPLC on a C18 column eluting with a linear gradient of 30-60% CH3CN in 0.1% TFA/H2O over 12 min to give 13 mg (30%) of a white solid. 1H-NMR (400 MHz, CD3OD): δ 8.34 (d, J=8.6 Hz, 1H), 7.85 (s, 1H), 7.60 (s, 1H), 7.37 (dd, J=8.6, 2.2 Hz, 1H), 7.28 (d, J=2.2 Hz, 1H), 5.79 (m, 1H), 4.03-3.94 (m, 2H), 3.88-3.80 (m, 2H), 3.72 (s, 2H), 2.35-2.27 (m, 2H), 2.13-2.06 (m, 4H), 1.60 (t, J=6.3 Hz, 2H), 1.11 (s, 6H). Mass spectrum (ESI, m/z): Calcd. for C26H30N4O5, 477.2 (M−H). found 477.2.

Workup

  1. concentrationThe mixture was concentrated
  2. washthe methyl ester of the title compound was eluted from a 10-g SPE column with 50% EtOAc/hexanes
  3. dissolutionThe resulting ester was dissolved in 1 mL of MeOH
  4. stirringthe mixture stirred for 8 h at RT
  5. customThe title compound was purified by RP-HPLC on a C18 column
  6. washeluting with a linear gradient of 30-60% CH3CN in 0.1% TFA/H2O over 12 min

Sources & evidence

ORD record
ord-ca6951f8eeaa49c9a34b069286f5d0dd
Source dataset
uspto-grants-2016_07
Patent number
US09394289B2

Reaction notes

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