Diisopropylethylamine → 2-{3-[(2,2-Difluoro-2-phenylethyl)amino]-6-chloro-2-fluorophenyl}-n-({6-[(tert-butoxy)carbonylamino]-2,4-dimethyl(3-pyridyl)}methyl) acetamide

HRID 2184197Notes

Reaction equation

HRID 2184197 reaction equation
[F:1][C:2]([F:23])([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:3][NH:4][C:5]1[C:6]([F:16])=[C:7]([CH2:12][C:13]([OH:15])=O)[C:8]([Cl:11])=[CH:9][CH:10]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C.[NH2:60][CH2:61][C:62]1[C:63]([CH3:77])=[CH:64][C:65]([NH:69][C:70]([O:72][C:73]([CH3:76])([CH3:75])[CH3:74])=[O:71])=[N:66][C:67]=1[CH3:68]>CN(C=O)C>[F:23][C:2]([F:1])([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:3][NH:4][C:5]1[C:6]([F:16])=[C:7]([CH2:12][C:13]([NH:60][CH2:61][C:62]2[C:67]([CH3:68])=[N:66][C:65]([NH:69][C:70]([O:72][C:73]([CH3:75])([CH3:74])[CH3:76])=[O:71])=[CH:64][C:63]=2[CH3:77])=[O:15])[C:8]([Cl:11])=[CH:9][CH:10]=1

Participants

6

Reactant 4

HCID 81531Diisopropylethylamine2×HCID 151348Benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphateHCID 224753482-{3-[(2,2-Difluoro-2-phenylethyl)amino]-6-chloro-2-fluorophenyl}acetic AcidHCID 22475372N-[5-(aminomethyl)-4,6-dimethyl(2-pyridyl)] (tert-butoxy)carboxamide

Product 1

HCID 224753562-{3-[(2,2-Difluoro-2-phenylethyl)amino]-6-chloro-2-fluorophenyl}-n-({6-[(tert-butoxy)carbonylamino]-2,4-dimethyl(3-pyridyl)}methyl) acetamideYield 44%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent2×

Procedure

To a solution of 2-{3-[(2,2-difluoro-2-phenylethyl)amino]-6-chloro-2-fluorophenyl}acetic acid (25 mg, 73 μmol), as prepared in step 15 of Example 1, in DMF (0.25 mL) was added BOP (52 mg, 116 μmol), a solution of DIEA (38 mg, 295 mol) in DMF (0.1 mL), and N-[5-(aminomethyl)-4,6-dimethyl(2-pyridyl)](tert-butoxy)carboxamide (23 mg, 91 μmol) (Sanderson, P. E., et al. WO 97/01338 (1997)). After stirring at ambient temperature for 2 days, additional amine (7 mg, 28 μmol) BOP (16 mg, 36 μmol), and DIEA (9 mg, 70 μmol) were added, and the mixture was stirred for another 16 hours. The solvents were evaporated, and the resulting residue was partitioned between saturated NaHCO3 and DCM. The organic layer was separated, and the aqueous layer was extracted with DCM. The organic layers were combined, washed with 10% citric acid, H2O, and brine, dried over Na2SO4, concentrated, and flash chromatographed on silica gel eluting with MeOH/DCM (0, 1, 2%) to produce the title compound (18.5 mg, 44% yield) as a pale brown solid. 1H-NMR (400 MHz, CDCl3) δ 7.58 (s, 1H), 7.50-7.41 (m, 5H), 7.24 (s, 1H), 6.98 (dd, J=8.8, 1.1 Hz, 1H), 6.55 (t, J=9.0 Hz, 1H), 5.33 (bs, 1H), 4.40 (d, J=4.7 Hz, 2H), 4.24-4.20 (m, 1H), 3.78-3.70 (m, 4H), 2.39 (s, 3H), 2.28 (s, 3H), 1.50 (s, 9H). Mass spectrum (LCMS, ESI) calcd for C29H33ClF3N4O3 (M+H): 577.0. Found: 577.1.

Workup

  1. stirringthe mixture was stirred for another 16 hours
  2. customThe solvents were evaporated
  3. customthe resulting residue was partitioned between saturated NaHCO3 and DCM
  4. customThe organic layer was separated
  5. extractionthe aqueous layer was extracted with DCM
  6. washwashed with 10% citric acid, H2O, and brine
  7. dry with materialdried over Na2SO4
  8. concentrationconcentrated
  9. customflash chromatographed on silica gel eluting with MeOH/DCM (0, 1, 2%)

Sources & evidence

ORD record
ord-d947fb70c4844e8bacdc0c78bc2de033
Source dataset
uspto-grants-2005_05
Patent number
US06900231B2

Reaction notes

Loading…