Potassium Hydroxide → N-({4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2-fluorophenyl}methyl)-4-({[(1,1-dimethylethyl)(dimethyl)silyl]oxy}methyl)-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazole-2-carboxamide

HRID 1875214Notes

Reaction equation

HRID 1875214 reaction equation
[CH3:1][C:2]([Si:5]([CH3:27])([CH3:26])[O:6][CH2:7][C:8]1[N:9]=[C:10]([C:21](OCC)=[O:22])[N:11]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[CH:12]=1)([CH3:4])[CH3:3].[OH-].[K+].[NH2:30][CH2:31][C:32]1[C:33]([F:49])=[C:34]([O:39][C:40]2[CH:41]=[C:42]([CH:45]=[C:46]([Cl:48])[CH:47]=2)[C:43]#[N:44])[C:35]([Cl:38])=[CH:36][CH:37]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.C([O-])(O)=O.[Na+]>C(O)C.CN(C=O)C>[Cl:38][C:35]1[CH:36]=[CH:37][C:32]([CH2:31][NH:30][C:21]([C:10]2[N:11]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:18])([CH3:19])[CH3:20])[CH:12]=[C:8]([CH2:7][O:6][Si:5]([C:2]([CH3:3])([CH3:1])[CH3:4])([CH3:27])[CH3:26])[N:9]=2)=[O:22])=[C:33]([F:49])[C:34]=1[O:39][C:40]1[CH:41]=[C:42]([C:43]#[N:44])[CH:45]=[C:46]([Cl:48])[CH:47]=1

Participants

9

Reactant 6

HCID 14797Potassium HydroxideHCID 81531DiisopropylethylamineHCID 516892Sodium BicarbonateHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 594513923-{[3-(Aminomethyl)-6-chloro-2-fluorophenyl]oxy}-5-chlorobenzonitrileHCID 70937136Ethyl 4-({[(1,1-dimethylethyl)(dimethyl)silyl]oxy}methyl)-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazole-2-carboxylate

Product 1

HCID 70937189N-({4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2-fluorophenyl}methyl)-4-({[(1,1-dimethylethyl)(dimethyl)silyl]oxy}methyl)-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazole-2-carboxamideYield 58%

Reagents, catalysts & solvents 2

HCID 702EthanolSolventHCID 6228DimethylformamideSolvent

Procedure

A solution of ethyl 4-({[(1,1-dimethylethyl)(dimethyl)silyl]oxy}methyl)-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazole-2-carboxylate (0.201 g, 0.49 mmol) in 6N KOH (0.10 mL, 0.6 mmol) and ethanol (1.5 mL) was stirred at RT for 30 mins and evaporated to dryness. The residue was stirred with 3-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-5-chlorobenzonitrile (0.10 g, 0.32 mmol), HATU (0.203 g, 0.53 mmol) and DIEA (0.085 mL, 0.49 mmol) in DMF (3 mL) at RT overnight. Sat'd NaHCO3 was added and the aqueous layer was extracted with CH2Cl2. The organic phase was dried (Na2SO4), filtered, and purified by silica gel chromatography (0-50% EtOAc/hex) to afford N-({4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2-fluorophenyl}methyl)-4-({[(1,1-dimethylethyl)(dimethyl)silyl]oxy}methyl)-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazole-2-carboxamide (0.13 mg, 58%) as a brown oil and as a mixture of the expected two isomers. This material was stirred in TBAF (2 mL of a 1N solution in THF, 0.2 mmol) for 1 h. Sat'd NaHCO3 was added and the aqueous layer was extracted with CH2Cl2. The residue was stirred with TFA (0.4 mL) in EtOH (0.02 mL) and CH2Cl2 (0.8 mL) for 8 h and the solution was evaporated and purified by silica gel chromatography (0-100% EtOAc/hexs, then 0-5% MeOH (2M NH3)/CH2Cl2) to provide the title compound (0.0163 g, 20%) as a white solid. 1H NMR (400 MHz, METHANOL-d4) δ ppm 7.55 (t, J=1.51 Hz, 1H), 7.35-7.43 (m, 2 H), 7.28 (t, J=2.06 Hz, 1H), 7.22-7.26 (m, 1H), 7.15 (br. s., 1H), 4.64 (s, 2H), 4.57 (s, 2H). ES-LCMS: m/z 435.1, 437.0 (M+1).

Workup

  1. customevaporated to dryness
  2. extractionthe aqueous layer was extracted with CH2Cl2
  3. dry with materialThe organic phase was dried (Na2SO4)
  4. filtrationfiltered
  5. custompurified by silica gel chromatography (0-50% EtOAc/hex)

Sources & evidence

ORD record
ord-e8ad96ed8e854c69868e77048030a731
Source dataset
uspto-grants-2012_11
Patent number
US08304419B2

Reaction notes

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