Hydrochloric Acid → HCID 71811142, compound

HRID 1520927Notes

Reaction equation

HRID 1520927 reaction equation
Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:13][C:14]2[CH:15]=[N:16][C:17]([N:20]3[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[N:22]=[CH:21]3)=[CH:18][CH:19]=2)[C:9]([F:12])([F:11])[F:10])=[CH:4][CH:3]=1.Cl.[NH2:30][CH2:31][CH2:32][C:33]([O:35]CC)=[O:34].N12CCCN=C1CCCC[CH2:39]2.F[B-](F)(F)F.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.[OH-:67].[Li+].Cl>C(#N)C.O.[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[Mo].C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:10][C:9]([F:12])([F:11])[CH:8]([C:5]1[CH:6]=[CH:7][C:2]([C:39]([NH:30][CH2:31][CH2:32][C:33]([OH:35])=[O:34])=[O:67])=[CH:3][CH:4]=1)[NH:13][C:14]1[CH:15]=[N:16][C:17]([N:20]2[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[N:22]=[CH:21]2)=[CH:18][CH:19]=1

Participants

11

Reactant 6

HCID 313Hydrochloric AcidHCID 3939Lithium HydroxideHCID 811841,8-Diazabicyclo(5.4.0)undec-7-eneHCID 458475beta-Alanine, ethyl ester, hydrochlorideHCID 44558591Tri-t-butylphosphine fluoroborateHCID 86669089HCID 86669089, compound

Product 1

HCID 71811142HCID 71811142, compoundYield 31%

Reagents, catalysts & solvents 4

HCID 98885Molybdenum carbonyl (Mo(CO)6)CatalystHCID 167845palladium(II) acetateCatalystHCID 962WaterSolventHCID 6342AcetonitrileSolvent

Conditions

Temperature
170 °C

Procedure

A mixture of (+/−)-N-(1-(4-bromophenyl)-2,2,2-trifluoroethyl)-6-(4-(trifluoromethyl)-1H-imidazol-1-yl)pyridin-3-amine (100 mg, 0.2 mmol), ethyl 3-aminopropanoate hydrochloride (90 mg, 0.6 mmol), molybdenum hexacarbonyl (57 mg, 0.21 mmol), 1,8-diazabicyclo[5.4.0]undec-7-ene (165 mg, 1.07 mmol), palladium(II) acetate (2.4 mg, 0.01 mmol), and tri-tert-butylphosphine tetrafluoroborate (9.4 mg, 0.03 mmol) in acetonitrile (2 mL) was heated to 170° C. for 5 minutes in a microwave. The reaction was diluted with water (20 mL) and extracted with ethyl acetate (2×20 mL). The combined organics were dried over sodium sulfate, filtered, and concentrated. The residue (40 mg) was taken up in tetrahydrofuran (2 mL) and cooled to 0° C. 2 N Aqueous lithium hydroxide (0.4 mL, 0.8 mmol) was added and the mixture was allowed to warm to room temperature and stir for 1 hour. The pH was adjusted to 4 with 1 N aqueous hydrochloric acid. The mixture was extracted with dichloromethane (2×20 mL). The combined organics were washed with water (30 mL) and brine (30 mL), dried over sodium sulfate, filtered, and concentrated. Purification by reversed-phase HPLC gave (+/−)-3-(4-(2,2,2-trifluoro-1-(6-(4-(trifluoromethyl)-1H-imidazol-1-yl)pyridin-3-ylamino)ethyl)benzamido)propanoic acid (12 mg, 31%) as a white solid. 1H NMR (400 MHz, CD3OD, δ): 8.29 (s, 1H), 8.08 (s, 1H), 7.94 (d, J=2.8 Hz, 1H), 7.75 (d, J=8.4 Hz, 2H), 7.58 (d, J=8.0 Hz, 2H), 7.38 (d, J=9.2 Hz, 1H), 7.23 (dd, J=2.8, 8.8 Hz, 1H), 5.40 (m, 1H), 3.51 (t, J=6.8 Hz, 2H), 2.53 (t, J=6.8 Hz, 2H). MS (M+1) 502.0.

Workup

  1. extractionextracted with ethyl acetate (2×20 mL)
  2. dry with materialThe combined organics were dried over sodium sulfate
  3. filtrationfiltered
  4. concentrationconcentrated
  5. temperaturecooled to 0° C
  6. temperatureto warm to room temperature
  7. extractionThe mixture was extracted with dichloromethane (2×20 mL)
  8. washThe combined organics were washed with water (30 mL) and brine (30 mL)
  9. dry with materialdried over sodium sulfate
  10. filtrationfiltered
  11. concentrationconcentrated
  12. customPurification by reversed-phase HPLC

Sources & evidence

ORD record
ord-864e199ee86349a9a4234212f3ea4305
Source dataset
uspto-grants-2015_07
Patent number
US09073871B2

Reaction notes

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