3-(Trifluoromethyl)aniline → Methyl 7-[3-({[3-(trifluoromethyl)phenyl]amino}carbonyl)phenyl]-5,6,7,8-tetrahydro-2,7-naphthyridine-4-carboxylate

HRID 338774Notes

Reaction equation

HRID 338774 reaction equation
[CH3:1][O:2][C:3]([C:5]1[CH:14]=[N:13][CH:12]=[C:11]2[C:6]=1[CH2:7][CH2:8][N:9]([C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=1)[C:18](O)=[O:19])[CH2:10]2)=[O:4].C(N(CC)CC)C.CCCP(=O)=O.[F:37][C:38]([F:47])([F:46])[C:39]1[CH:40]=[C:41]([CH:43]=[CH:44][CH:45]=1)[NH2:42]>CN(C1C=CN=CC=1)C.ClCCCl>[F:37][C:38]([F:46])([F:47])[C:39]1[CH:40]=[C:41]([NH:42][C:18]([C:17]2[CH:16]=[C:15]([N:9]3[CH2:10][C:11]4[CH:12]=[N:13][CH:14]=[C:5]([C:3]([O:2][CH3:1])=[O:4])[C:6]=4[CH2:7][CH2:8]3)[CH:23]=[CH:22][CH:21]=2)=[O:19])[CH:43]=[CH:44][CH:45]=1

Participants

7

Reactant 4

HCID 73753-(Trifluoromethyl)anilineHCID 8471TriethylamineHCID 16167369Propylphosphoric anhydrideHCID 866958813-[5-(methoxycarbonyl)-3,4-dihydro-2,7-naphthyridin-2(1H)-yl]benzoic acid

Product 1

HCID 71736343Methyl 7-[3-({[3-(trifluoromethyl)phenyl]amino}carbonyl)phenyl]-5,6,7,8-tetrahydro-2,7-naphthyridine-4-carboxylateYield 55%

Reagents, catalysts & solvents 2

HCID 142844-(Dimethylamino)pyridineCatalystHCID 111,2-DichloroethaneSolvent

Procedure

To a mixture of 3-[5-(methoxycarbonyl)-3,4-dihydro-2,7-naphthyridin-2(1H)-yl]benzoic acid (63 mg, 0.20 mmol), triethylamine (0.084 mL, 0.60 mmol), and catalytic DMAP in 3.0 mL 1,2-dichloroethane at rt was added propylphosphonic anhydride solution (50 wt % in EtOAc, 0.143 mL, 0.24 mmol). After 5 min at rt, 3-(trifluoromethyl)aniline (0.037 mL, 0.30 mmol) was added and the reaction stirred at rt for 18 hours. The reaction was quenched with aqueous NaHCO3 solution, extracted with EtOAc, the EtOAc layer washed with H2O, dilute aqueous NaHCO3 solution, brine, dried with anhydrous Na2SO4 and rotary evaporated. This material was chromatographed eluting with CHCl3/EtOAc to give the title compound as a yellow solid (50 mg, 55%). 1H NMR (Acetone-d6) δ: 9.75 (br. s., 1H), 8.89 (s, 1H), 8.66 (s, 1H), 8.32 (s, 1H), 8.09 (d, J=7.9 Hz, 1H), 7.69 (s, 1H), 7.60 (t, J=7.9 Hz, 1H), 7.37-7.47 (m, 3H), 7.28-7.34 (m, 1H), 4.61 (s, 2H), 3.92 (s, 3H), 3.67-3.73 (m, 2H), 3.37 (t, J=5.9 Hz, 2H).

Workup

  1. customThe reaction was quenched with aqueous NaHCO3 solution
  2. extractionextracted with EtOAc
  3. washthe EtOAc layer washed with H2O, dilute aqueous NaHCO3 solution, brine
  4. dry with materialdried with anhydrous Na2SO4 and rotary evaporated
  5. customThis material was chromatographed
  6. washeluting with CHCl3/EtOAc

Sources & evidence

ORD record
ord-d6489bbb2dd248b0bc507e44ff8a4189
Source dataset
uspto-grants-2014_11
Patent number
US08889870B2

Reaction notes

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