Glycolic Acid → HCID 57542359, compound

HRID 2080302Notes

Reaction equation

HRID 2080302 reaction equation
[F:1][C:2]1[C:3]([C:33]2[CH:34]=[N:35][N:36]([CH3:38])[CH:37]=2)=[N:4][C:5]([NH:23][CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=2)=[C:6]([CH:22]=1)[C:7]([NH:9][CH2:10][C@H:11]1[CH2:14][CH2:13][N:12]1[C:15](OC(C)(C)C)=[O:16])=[O:8].FC(F)(F)[C:41](O)=[O:42].C(O)(=O)CO.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>C(Cl)Cl.CCOC(C)=O>[F:1][C:2]1[C:3]([C:33]2[CH:34]=[N:35][N:36]([CH3:38])[CH:37]=2)=[N:4][C:5]([NH:23][CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=2)=[C:6]([CH:22]=1)[C:7]([NH:9][CH2:10][C@H:11]1[CH2:14][CH2:13][N:12]1[C:15](=[O:16])[CH2:41][OH:42])=[O:8]

Participants

9

Reactant 6

HCID 757Glycolic AcidHCID 6422Trifluoroacetic acidHCID 757711-HydroxybenzotriazoleHCID 81531DiisopropylethylamineHCID 2733084Methanaminium, N-((1H-benzotriazol-1-yloxy)(dimethylamino)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 57542846HCID 57542846, compound

Product 1

HCID 57542359HCID 57542359, compound

Reagents, catalysts & solvents 2

HCID 6344DichloromethaneSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
0 °C

Procedure

To a mixture of (R)-tert-butyl 2-((5-fluoro-2-(3-fluorophenethylamino)-6-(1-methyl-1H-pyrazol-4-yl)nicotinamido)methyl)azetidine-1-carboxylate (16.5 g, 31.4 mmol) in 100 mL DCM at 0° C. was added trifluoroacetic acid (24 mL, 314 mmol) slowly. The mixture was stirred at r.t for 2 hours until the Boc protection group was completely removed. The mixture was then concentrated. The residue was dissolved in 100 mL DMF and cooled down to 0° C. To the mixture was added a mixture of glycolic acid (2.86 g, 38 mmol), HBTU (14.3 g, 38 mmol), HOBT (5.1 g, 38 mmol) and DIEA (16.4 ml, 94 mmol). The mixture was warmed up to r.t and stirred at r.t. for 2 hours. The mixture was extracted with EtOAc. The organic layer was further washed with 1N NaOH (300 ml) and brine, dried and concentrated. The residue was subjected to a Biotage silica gel chromatography using gradient 0-40% B as eluant (A=dichloromethane, B=10% MeOH in dichloromethane) to give the crude product. The yellow solid was further tritirated with 100 mL EtOAc. (R)-5-fluoro-2-(3-fluorophenethylamino)-N-((1-(2-hydroxyacetyl)azetidin-2-yl)methyl)-6-(1-methyl-1H-pyrazol-4-yl)nicotinamide was obtained as a pale yellow solid (12.7 g, 83% yield). LRMS (M+H+) m/z 485.1.

Workup

  1. customwas completely removed
  2. concentrationThe mixture was then concentrated
  3. dissolutionThe residue was dissolved in 100 mL DMF
  4. additionTo the mixture was added
  5. temperatureThe mixture was warmed up
  6. extractionThe mixture was extracted with EtOAc
  7. washThe organic layer was further washed with 1N NaOH (300 ml) and brine
  8. customdried
  9. concentrationconcentrated
  10. customto give the crude product

Sources & evidence

ORD record
ord-5fdf1314fd6d465fa23b67a3c59bf05e
Source dataset
uspto-grants-2011_04
Patent number
US07932270B2

Reaction notes

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