Hydrochloric Acid → HCID 59451577, compound

HRID 1875000Notes

Reaction equation

HRID 1875000 reaction equation
C(C1[N:4]=[CH:5][NH:6]C=1C(OCC)=O)#N.[OH-:13].[Li+].[ClH:15].CN(C(ON1N=[N:31][C:26]2[CH:27]=[CH:28][CH:29]=[N:30][C:25]1=2)=[N+](C)C)C.[F:33][P-](F)(F)(F)(F)F.CCN([CH:46]([CH3:48])[CH3:47])C(C)C.[Cl:49][C:50]1[CH:51]=[CH:52][CH:53]=[C:54]([CH:57]=1)[C:55]#[N:56].[CH2:58]1[CH2:62]OCC1.[CH3:63][OH:64].O>>[Cl:15][C:47]1[CH:46]=[CH:48][C:58]([CH2:25][NH:30][C:29]([C:28]2[NH:4][CH:5]=[N:6][C:27]=2[C:26]#[N:31])=[O:13])=[C:62]([F:33])[C:63]=1[O:64][C:52]1[CH:53]=[C:54]([C:55]#[N:56])[CH:57]=[C:50]([Cl:49])[CH:51]=1

Participants

8

Reactant 7

HCID 313Hydrochloric AcidHCID 3939Lithium HydroxideHCID 13015Benzonitrile, m-chloro-HCID 81531DiisopropylethylamineHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 135884911H-Imidazole-5-carboxylic acid, 4-cyano-, ethyl esterHCID 21892291Methanol tetrahydrofuran water

Product 1

HCID 59451577HCID 59451577, compoundYield 28%

Procedure

To a solution of ethyl 4-cyano-1H-imidazole-5-carboxylate (0.025 g, 0.152 mmol) in THF/MeOH/H2O (1:1:1, 1.5 mL) was added lithium hydroxide (0.036 g, 1.52 mmol) and the solution stirred overnight at RT. An aqueous solution of 2.5 N HCl (0.6 mL, 0.240 mmol) was added, the solvents evaporated, and the mixture was azeotroped with toluene (1 mL) and ether (2 mL) successively, and placed under high vacuum. To the crude intermediate dissolved in DMF (1 mL) was added HATU (0.063 g, 0.166 mmol), DIPEA (0.040 mL, 0.226 mmol), 3-{[3-aminomethyl)-6-chloro-2-fluorophenyl]oxy}-5-chlorobenzonitrile (0.052 g, 0.167 mmol). The reaction mixture was stirred 3 h. Purification was accomplished by RPHPLC (water:acetonitrile with 0.1% TFA). The desired fractions were lyophilized and triturated with ethyl acetate to afford N-({4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2-fluorophenyl}methyl)-4-cyano-1H-imidazole-5-carboxamide (0.018 g, 28%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ ppm 8.92-8.99 (m, 1H) 8.07 (s, 1H) 7.79 (s, 1H) 7.40-7.51 (m, 3H) 7.36 (t, 1H) 4.49 (d, 2H). MS: m/z 430.1 (M+1).

Workup

  1. customthe solvents evaporated
  2. customthe mixture was azeotroped with toluene (1 mL) and ether (2 mL) successively
  3. dissolutionTo the crude intermediate dissolved in DMF (1 mL)
  4. stirringThe reaction mixture was stirred 3 h
  5. customPurification
  6. customtriturated with ethyl acetate

Sources & evidence

ORD record
ord-d4fa37586d9f43d99c3e91407dbb5aed
Source dataset
uspto-grants-2012_11
Patent number
US08304419B2

Reaction notes

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