Diisopropylethylamine → 1-[4-(6-Fluoronaphthalen-2-yl)piperazin-1-yl]-2-[(4-[[4-nitro-3-(trifluoromethyl)phenyl]amino]cyclohexyl)oxy]ethan-1-one

HRID 1772197Notes

Reaction equation

HRID 1772197 reaction equation
[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH:11]2[CH2:16][CH2:15][CH:14]([O:17][CH2:18][C:19]([OH:21])=O)[CH2:13][CH2:12]2)=[CH:6][C:5]=1[C:22]([F:25])([F:24])[F:23])([O-:3])=[O:2].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[F:59][C:60]1[CH:61]=[C:62]2[C:67](=[CH:68][CH:69]=1)[CH:66]=[C:65]([N:70]1[CH2:75][CH2:74][NH:73][CH2:72][CH2:71]1)[CH:64]=[CH:63]2>ClCCl>[F:59][C:60]1[CH:61]=[C:62]2[C:67](=[CH:68][CH:69]=1)[CH:66]=[C:65]([N:70]1[CH2:71][CH2:72][N:73]([C:19](=[O:21])[CH2:18][O:17][CH:14]3[CH2:15][CH2:16][CH:11]([NH:10][C:7]4[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[C:5]([C:22]([F:24])([F:23])[F:25])[CH:6]=4)[CH2:12][CH2:13]3)[CH2:74][CH2:75]1)[CH:64]=[CH:63]2

Participants

6

Reactant 4

HCID 81531DiisopropylethylamineHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 672837722-(4-(4-Nitro-3-(trifluoromethyl)phenylamino)cyclohexyloxy)acetic acidHCID 867194671-(6-Fluoronaphthalen-2-yl)piperazine

Product 1

HCID 747667031-[4-(6-Fluoronaphthalen-2-yl)piperazin-1-yl]-2-[(4-[[4-nitro-3-(trifluoromethyl)phenyl]amino]cyclohexyl)oxy]ethan-1-oneYield 11.3%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

To a solution of 2-[(4-[4-nitro-3-(trifluoromethyl)phenyl]aminocyclohexyl)-oxy]acetic acid (173 mg, 0.48 mmol, 1 eq) in dichloromethane (50 ml) was added DIEA (61.8 mg, 0.48 mmol, 1 eq), HATU (182 mg, 0.48 mmol, 1 eq) and 1-(6-fluoronaphthalen-2-yl)piperazine (110 mg, 0.48 mmol, 1 eq) at room temperature under an inert atmosphere of nitrogen. The resulting solution was stirred overnight. The reaction was then quenched by the addition of water (100 ml) and extracted with dichloromethane (3×50 ml) and the organic layers were combined and then dried over anhydrous sodium sulfate. The solids were filtered off. The resulting mixture was concentrated under vacuum to give a residue, which was applied onto a silica gel column and eluted with 2% methanol in dichloromethane. The product-containing fractions were combined and concentrated under vacuum to afford 1-[4-(6-fluoronaphthalen-2-yl)piperazin-1-yl]-2-[(4-[[4-nitro-3-(trifluoromethyl)phenyl]amino]cyclohexyl)oxy]ethan-1-one as a yellow solid (31.1 mg, 11%); (ES, m/z): [M−H]− 573.2; 1H NMR (300 MHz, DMSO/D2O): δ 8.05 (d, J=6.9 Hz, 1H), 7.77-7.82 (m, 2H), 7.53-7.56 (dd, J=1.8, 7.5 Hz, 1H), 7.43-7.46 (dd, J=1.5, 6.9 Hz, 1H), 7.28-7.33 (m, 1H), 7.25 (d, J=1.2 Hz, 1H), 7.06 (s, 1H), 6.83-6.86 (dd, J=1.8, 6.9 Hz, 1H), 4.21 (s, 2H), 3.63 (broad s, 4H), 3.37-3.52 (m, 2H), 3.21-3.26 (m, 4H), 1.94-2.05 (m, 4H), 1.34-1.39 (m, 2H), 1.23-1.29 (m, 2H).

Workup

  1. customThe reaction was then quenched by the addition of water (100 ml)
  2. extractionextracted with dichloromethane (3×50 ml)
  3. dry with materialdried over anhydrous sodium sulfate
  4. filtrationThe solids were filtered off
  5. concentrationThe resulting mixture was concentrated under vacuum
  6. customto give a residue, which
  7. washeluted with 2% methanol in dichloromethane
  8. concentrationconcentrated under vacuum

Sources & evidence

ORD record
ord-0742ac9c6f9043e3bdd6a50e04188d9e
Source dataset
uspto-grants-2016_02
Patent number
US09249102B2

Reaction notes

Loading…