Morpholine → {(S)-1-[1-Cyclopropyl-6-fluoro-7-(morpholine-4-carbonyl)-1H-benzoimidazol-2-yl]ethyl}carbamic acid tert-butyl ester

HRID 243142Notes

Reaction equation

HRID 243142 reaction equation
CO[C:3]([C:5]1[C:13]2[N:12]([CH:14]3[CH2:16][CH2:15]3)[C:11]([C@@H:17]([NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH3:18])=[N:10][C:9]=2[CH:8]=[CH:7][C:6]=1[F:27])=[O:4].O[Li].O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH:55]1[CH2:60][CH2:59][O:58][CH2:57][CH2:56]1.CCN(C(C)C)C(C)C>CO.O.C(Cl)Cl>[C:23]([O:22][C:20](=[O:21])[NH:19][C@H:17]([C:11]1[N:12]([CH:14]2[CH2:15][CH2:16]2)[C:13]2[C:5]([C:3]([N:55]3[CH2:60][CH2:59][O:58][CH2:57][CH2:56]3)=[O:4])=[C:6]([F:27])[CH:7]=[CH:8][C:9]=2[N:10]=1)[CH3:18])([CH3:25])([CH3:26])[CH3:24]

Participants

9

Reactant 5

HCID 8083MorpholineHCID 81531DiisopropylethylamineHCID 168937Lithium hydroxide, monohydrate2×HCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 681572452-((S)-1-tert-Butoxycarbonylaminoethyl)-3-cyclopropyl-5-fluoro-3H-benzoimidazole-4-carboxylic acid methyl ester

Product 1

HCID 68157617{(S)-1-[1-Cyclopropyl-6-fluoro-7-(morpholine-4-carbonyl)-1H-benzoimidazol-2-yl]ethyl}carbamic acid tert-butyl esterYield 75.1%

Reagents, catalysts & solvents 3

HCID 887MethanolSolventHCID 962WaterSolventHCID 6344DichloromethaneSolvent

Conditions

Temperature
90 °C

Procedure

A solution of 2-((S)-1-tert-butoxycarbonylaminoethyl)-3-cyclopropyl-5-fluoro-3H-benzoimidazole-4-carboxylic acid methyl ester (441 mg, 1.17 mmol) and LiOH.H2O (196 mg, 4.67 mmol) in MeOH (20 mL) and water (2 mL) was heated at 90° C. for 4 h. Additional LiOH.H2O (196 mg) was added and the mixture heated at 90° C. for 48 h. After cooling to RT, the organic solvent was removed in vacuo and the pH of the mixture adjusted to 3 by addition of 1M HCl(aq). The aqueous phase was extracted with EtOAc (×3) and the combined organic fractions were washed with brine, dried (Na2SO4) and concentrated in vacuo. A mixture of this residue (349 mg), HATU (401 mg, 1.06 mmol), morpholine (125 μL, 1.44 mmol) and DIPEA (335 μL, 1.92 mmol) in DCM (10 mL) was stirred at RT for 1 h. The reaction mixture was partitioned between DCM and a saturated solution of NaHCO3. The organic layer was dried and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, gradient 0-100% EtOAc in cyclohexane) to afford the title compound (380 mg, 75% over 2 steps) as a pale yellow oil. LCMS (Method C): RT 2.64 min [M+H]+ 433.25

Workup

  1. temperatureAfter cooling to RT
  2. customthe organic solvent was removed in vacuo
  3. additionthe pH of the mixture adjusted to 3 by addition of 1M HCl(aq)
  4. extractionThe aqueous phase was extracted with EtOAc (×3)
  5. washthe combined organic fractions were washed with brine
  6. dry with materialdried (Na2SO4)
  7. concentrationconcentrated in vacuo
  8. customThe reaction mixture was partitioned between DCM
  9. customThe organic layer was dried
  10. concentrationconcentrated in vacuo
  11. customThe resulting residue was purified by column chromatography (Si—PCC, gradient 0-100% EtOAc in cyclohexane)

Sources & evidence

ORD record
ord-e2b454eab28e46908ae5e84c9530c72f
Source dataset
uspto-grants-2014_02
Patent number
US08653089B2

Reaction notes

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