Diisopropylethylamine → 2-(3-{[2,2-Difluoro-2-(4-fluoronaphthyl)ethyl]amino]-6-chloro-2-fluorophenyl)-N-({6-[(tert-butoxy)carbonylamino]-2-methyl(3-pyridyl)) methyl)acetamide

HRID 1060225Notes

Reaction equation

HRID 1060225 reaction equation
[F:1][C:2]([F:28])([C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20]([F:27])=[CH:19][CH:18]=1)[CH2:3][NH:4][C:5]1[C:6]([F:16])=[C:7]([CH2:12][C:13](O)=[O:14])[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.[NH2:56][CH2:57][C:58]1[CH:59]=[CH:60][C:61]([NH:65][C:66]([O:68][C:69]([CH3:72])([CH3:71])[CH3:70])=[O:67])=[N:62][C:63]=1[CH3:64].CCN(C(C)C)C(C)C>CN(C=O)C>[F:28][C:2]([F:1])([C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20]([F:27])=[CH:19][CH:18]=1)[CH2:3][NH:4][C:5]1[C:6]([F:16])=[C:7]([CH2:12][C:13]([NH:56][CH2:57][C:58]2[C:63]([CH3:64])=[N:62][C:61]([NH:65][C:66]([O:68][C:69]([CH3:71])([CH3:70])[CH3:72])=[O:67])=[CH:60][CH:59]=2)=[O:14])[C:8]([Cl:11])=[CH:9][CH:10]=1

Participants

6

Reactant 4

HCID 81531DiisopropylethylamineHCID 151348Benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphateHCID 10681361tert-Butyl 5-(aminomethyl)-6-methylpyridin-2-ylcarbamateHCID 224753122-(3-{[2,2-Difluoro-2-(4-fluoronaphthyl)ethyl]amino}-6-chloro-2-fluorophenyl)acetic acid

Product 1

HCID 224753192-(3-{[2,2-Difluoro-2-(4-fluoronaphthyl)ethyl]amino]-6-chloro-2-fluorophenyl)-N-({6-[(tert-butoxy)carbonylamino]-2-methyl(3-pyridyl)) methyl)acetamideYield 49%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent2×

Procedure

To a solution of 2-(3-{[2,2-difluoro-2-(4-fluoronaphthyl)ethyl]amino}-6-chloro-2-fluorophenyl)acetic acid (15 mg, 37 μmol), as prepared according to the procedure of step 10 of Example 4, in DMF (0.3 mL) was added BOP (26 mg, 58 μmol), N-[5-(aminomethyl)-6-methyl(2-pyridyl)](tert-butoxy)carboxamide (12 mg, 51 μmol), and a solution of DIEA (19 mg, 146 μmol) in DMF (0.1 mL) (Sanderson, P. E., et al., WO 97/01338 (1997)). The mixture was stirred overnight, the solvents evaporated, and the resulting mixture was partitioned between saturated NaHCO3 and DCM. The organic layer was separated, and the aqueous layer extracted with DCM. The organic layers were combined, washed with 10% KHSO4, H2O, and brine, dried over Na2SO4, concentrated, and flash chromatographed on silica gel eluting with MeOH/DCM (0.3, 0.6, and 1%) to give the title compound (11 mg, 49% yield) as a white solid. 1H-NMR (400 MHz, CD3OD) δ 8.33 (d, J=8.4 Hz, 1H), 8.17-8.14 (m, 1H), 7.72-7.61 (m, 4H), 7.55 (d, J=8.5 Hz, 1H), 7.19 (dd, J=10.0, 8.3 Hz, 1H), 6.81 (dd, J=8.8, 1.7 Hz, 1H), 6.47 (t, J=9.1 Hz, 1H), 4.32 (s, 2H), 4.12-4.03 (m, 2H), 3.67 (d, J=2.0 Hz, 2H), 2.40 (s, 3H), 1.50 (s, 9H). Mass spectrum (LCMS, ESI) calc'd for C32H32ClF4N4O3 (M+H): 631.2. Found: 631.1.

Workup

  1. customthe solvents evaporated
  2. customthe resulting mixture was partitioned between saturated NaHCO3 and DCM
  3. customThe organic layer was separated
  4. extractionthe aqueous layer extracted with DCM
  5. washwashed with 10% KHSO4, H2O, and brine
  6. dry with materialdried over Na2SO4
  7. concentrationconcentrated
  8. customflash chromatographed on silica gel eluting with MeOH/DCM (0.3, 0.6, and 1%)

Sources & evidence

ORD record
ord-04cf9693db624b94b83b1d00e7d9852e
Source dataset
uspto-grants-2003_02
Patent number
US06521663B2

Reaction notes

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