Dicyclohexylcarbodiimide → HCID 178495112, compound

HRID 2065806Notes

Reaction equation

HRID 2065806 reaction equation
[NH2:1][C:2]1[C:3]([OH:24])=[N:4][C:5]([C:8]2[N:9]=[C:10]([CH:21]3[CH2:23][CH2:22]3)[NH:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=2[F:20])=[CH:6][CH:7]=1.[N:25]([C@@H:28]([CH3:33])[CH2:29][CH2:30][O:31][CH3:32])=[C:26]=S.C1(N=C=NC2CCCCC2)CCCCC1>C(O)C>[CH:21]1([C:10]2[NH:11][C:12]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=3[F:20])=[C:8]([C:5]3[N:4]=[C:3]4[O:24][C:26]([NH:25][C@@H:28]([CH3:33])[CH2:29][CH2:30][O:31][CH3:32])=[N:1][C:2]4=[CH:7][CH:6]=3)[N:9]=2)[CH2:22][CH2:23]1

Participants

5

Reactant 3

HCID 10868Dicyclohexylcarbodiimide3×HCID 86666178HCID 86666178, compoundHCID 178507437HCID 178507437, compound

Product 1

HCID 178495112HCID 178495112, compoundYield 16%

Reagents, catalysts & solvents 1

HCID 702EthanolSolvent

Conditions

Temperature
85 °C

Procedure

A KIMAX® tube is charged with 3-amino-6-[2-cyclopropyl-5-(2,4-difluorophenyl)-1H-imidazol-4-yl]pyridin-2-ol (0.7 g, 2.13 mmol) and ethanol (7 mL). (3S)-3-isothiocyanato-1-methoxy-butane (0.46 g, 3.2 mmol) is added, the flask sealed, and the mixture is heated to 85° C. After 16 h, N,N′-dicyclohexylcarbodiimide (0.88 g, 4.26 mmol) is added and the mixture is stirred for 4 h at 85° C. in the sealed tube. After this time, additional N,N′-dicyclohexylcarbodiimide (0.44 g, 2.13 mmol) is added to the mixture. Heating is continued at 85° C. overnight. After this time, additional N,N′-dicyclohexyl-carbodiimide (0.88 g, 4.26 mmol) is added to the mixture, and heating is continued at 85° C. for 4 h. The crude reaction is concentrated under reduced pressure, and the residue is purified by normal phase chromatography (120 g silica-gel cartridge, dichloromethane-ethanol gradient). The fractions containing the desired compound are further purified by semi-preparative reverse phase high performance (LC/MS) using an XBRIDGE™ column (5 μm, 19×100 mm) and an isocratic program of 36% of acetonitrile in NH4HCO3 20 mM (pH 9), in 5 min at flow 25 mL/min to afford the title compound (0.15 g, 16%). LCES/MS m/z 440 (M+1); [α]D22+58.60°, (c=0.50, methanol).

Workup

  1. customthe flask sealed
  2. temperatureHeating
  3. waitis continued at 85° C. overnight
  4. temperatureheating
  5. waitis continued at 85° C. for 4 h
  6. customThe crude reaction
  7. concentrationis concentrated under reduced pressure
  8. customthe residue is purified by normal phase chromatography (120 g silica-gel cartridge, dichloromethane-ethanol gradient)
  9. additionThe fractions containing the desired compound
  10. customare further purified by semi-preparative reverse phase high performance (LC/MS)

Sources & evidence

ORD record
ord-87bf7f8fb78a4a74a2f37bc56113be65
Source dataset
uspto-grants-2012_10
Patent number
US08288548B2

Reaction notes

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