Isobutylamine → 3-(3-Fluoro-4-pyrrolidin-1-ylmethyl-phenyl)-3-hydroxy-cyclobutanecarboxylic acid isobutyl-amide

HRID 1943272Notes

Reaction equation

HRID 1943272 reaction equation
[F:1][C:2]1[CH:3]=[C:4]([C:14]2([OH:21])[CH2:17][CH:16]([C:18]([OH:20])=O)[CH2:15]2)[CH:5]=[CH:6][C:7]=1[CH2:8][N:9]1[CH2:13][CH2:12][CH2:11][CH2:10]1.[CH2:22]([NH2:26])[CH:23]([CH3:25])[CH3:24].C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.C([O-])(O)=O.[Na+]>CCOC(C)=O.C1COCC1>[CH2:22]([NH:26][C:18]([CH:16]1[CH2:17][C:14]([C:4]2[CH:5]=[CH:6][C:7]([CH2:8][N:9]3[CH2:10][CH2:11][CH2:12][CH2:13]3)=[C:2]([F:1])[CH:3]=2)([OH:21])[CH2:15]1)=[O:20])[CH:23]([CH3:25])[CH3:24]

Participants

7

Reactant 4

HCID 6558IsobutylamineHCID 111923Propylphosphonic anhydrideHCID 516892Sodium BicarbonateHCID 672787123-(3-Fluoro-4-(pyrrolidin-1-ylmethyl)phenyl)-3-hydroxycyclobutanecarboxylic acid

Product 1

HCID 566482293-(3-Fluoro-4-pyrrolidin-1-ylmethyl-phenyl)-3-hydroxy-cyclobutanecarboxylic acid isobutyl-amideYield 63%

Reagents, catalysts & solvents 2

HCID 8028TetrahydrofuranSolventHCID 8857Ethyl AcetateSolvent

Procedure

A THF solution of crude ˜0.12M intermediate 15, 3-(3-fluoro-4-(pyrrolidin-1-ylmethyl)phenyl)-3-hydroxycyclobutanecarboxylic acid (160 mL, 19.3 mmol) was combined with isobutylamine (3.8 mL, 38.2 mmol) and T3P (50% wt in EtOAc, 13.8 mL, 23.2 mmol) and stirred at room temperature for 20 h. The mixture was made basic with saturated aqueous NaHCO3 and EtOAc (50 mL) was added. The phases were separated and the aqueous phase was extracted again with EtOAc. The combined organics were washed with brine, dried over MgSO4 and concentrated to yield an orange oil. Flash chromatography on a 2″×4″ silica gel column flushing first with EtOAc (1 L) and 10% MeOH/EtOAc (500 mL) to remove higher Rf impurities followed by elution with an additional 500 mL of 10% MeOH/EtOAc and 500 mL 20% MeOH/EtOAc afforded 4.22 g (63%) of the title compound as an waxy, orange solid: Rf=0.3 (30% MeOH/EtOAc); 1H NMR (CDCl3) δ 7.34 (t, J=7.9 Hz, 1H), 7.20-7.13 (m, 2H), 5.84 (br s, 1H), 3.66 (d, JH-F=1.3 Hz, 2H), 3.11 (t, J=6.4 Hz, 2H), 2.84-2.76 (m, 3H), 2.55-2.45 (m, 6H), 1.81-1.72 (m, 4H), 0.91-0.87 (d @ 0.90 (J=6.6 Hz, 6H) overlapping m (1H)); LRMS m/z Calcd for C20H29FN2O2, 348.5, found, 349.4 (M+H) APCI.

Workup

  1. additionwas added
  2. customThe phases were separated
  3. extractionthe aqueous phase was extracted again with EtOAc
  4. washThe combined organics were washed with brine
  5. dry with materialdried over MgSO4
  6. concentrationconcentrated
  7. customto yield an orange oil
  8. customFlash chromatography on a 2″×4″ silica gel column flushing first with EtOAc (1 L) and 10% MeOH/EtOAc (500 mL)
  9. customto remove higher Rf impurities
  10. washfollowed by elution with an additional 500 mL of 10% MeOH/EtOAc and 500 mL 20% MeOH/EtOAc

Sources & evidence

ORD record
ord-e98daf15e4ad4cfda788c3220b08bd31
Source dataset
uspto-grants-2013_03
Patent number
US08389743B2

Reaction notes

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