Tetrahydro-4H-pyran-4-one → 5-Cyano-1H-imidazole-2-carboxylic acid [2-(4,4-dimethyl-cyclohex-1-enyl)-4-(4-hydroxy-tetrahydro-pyran-4-yl)-phenyl]-amide

HRID 1992028Notes

Reaction equation

HRID 1992028 reaction equation
Br[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[NH:12][CH:13]=[C:14]([C:16]#[N:17])[N:15]=2)=[O:10])=[C:4]([C:18]2[CH2:23][CH2:22][C:21]([CH3:25])([CH3:24])[CH2:20][CH:19]=2)[CH:3]=1.C([Mg]Cl)(C)C.[Li]C(C)(C)C.[O:36]1[CH2:41][CH2:40][C:39](=[O:42])[CH2:38][CH2:37]1>C1COCC1>[CH3:24][C:21]1([CH3:25])[CH2:22][CH2:23][C:18]([C:4]2[CH:3]=[C:2]([C:39]3([OH:42])[CH2:40][CH2:41][O:36][CH2:37][CH2:38]3)[CH:7]=[CH:6][C:5]=2[NH:8][C:9]([C:11]2[NH:15][C:14]([C:16]#[N:17])=[CH:13][N:12]=2)=[O:10])=[CH:19][CH2:20]1

Participants

6

Reactant 4

HCID 121599Tetrahydro-4H-pyran-4-oneHCID 178418306HCID 178418306, compoundHCID 178418918HCID 178418918, compoundHCID 1784244434-Cyano-1H-imidazole-2-carboxylic acid [4-bromo-2-(4,4-dimethyl-cyclohex-1-enyl)-phenyl]-amide

Product 1

HCID 591285735-Cyano-1H-imidazole-2-carboxylic acid [2-(4,4-dimethyl-cyclohex-1-enyl)-4-(4-hydroxy-tetrahydro-pyran-4-yl)-phenyl]-amideYield 79%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Conditions

Temperature
0 °C

Procedure

To a suspension of 4-cyano-1H-imidazole-2-carboxylic acid [4-bromo-2-(4,4-dimethyl-cyclohex-1-enyl)-phenyl]-amide (0.550 g, 1.38 mmol, as prepared in the previous step) in 20 mL THF at −40° C. was added i-PrMgCl (1.40 mL, 2 M in THF) and the solution was then warmed to 0° C. and stirred for 10 min. The solution was then cooled to −78° C. and t-BuLi (2.15 mL, 1.7 M in pentane) was added dropwise over 5 min and then tetrahydropyran-4-one (0.650 mL, 7.05 mmol) was added immediately thereafter. After 5 min at −78° C. the reaction was quenched with satd NH4Cl (20 mL) and extracted with EtOAc (3×20 mL) and dried over Na2SO4. The title compound was purified by flash chromatography (silica gel) eluting with 50% EtOAc/DCM to give 0.46 g (79%) of a white solid: 1H-NMR (400 MHz, DMSO-d6) δ 14.28 (s, 1H), 9.77 (s, 1H), 8.21 (s, 1H), 7.98 (d, J=8.5 Hz, 1H), 7.38 (dd, J=8.5, 2.2 Hz, 1H), 7.34 (d, J=2.2 Hz, 1H), 5.67 (m, 1H), 5.03 (s, 1H), 3.83-3.66 (m, 4H), 2.31-2.22 (m, 2H), 2.04-1.92 (m, 4H), 1.58-1.46 (m, 4H), 1.01 (s, 6H). Mass spectrum (ESI, m/z) calcd. for C24H28N4O3 421.2 (M+H), found 421.1.

Workup

  1. temperatureThe solution was then cooled to −78° C.
  2. customAfter 5 min at −78° C. the reaction was quenched with satd NH4Cl (20 mL)
  3. extractionextracted with EtOAc (3×20 mL)
  4. dry with materialdried over Na2SO4
  5. customThe title compound was purified by flash chromatography (silica gel)
  6. washeluting with 50% EtOAc/DCM

Sources & evidence

ORD record
ord-dfc4ede905ec4ea283e8b93339fce9de
Source dataset
uspto-grants-2010_01
Patent number
US07645755B2

Reaction notes

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