Trifluoroacetic acid → [(+)-2-(4-{2-[6-(methylamino)pyridin-2-yl]ethoxy}phenyl)cyclopropyl]Acetic Acid Trifluoroacetate

HRID 897150Notes

Reaction equation

HRID 897150 reaction equation
[CH3:1][NH:2][C:3]1[N:8]=[C:7]([CH2:9][CH2:10][OH:11])[CH:6]=[CH:5][CH:4]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O[C:32]1[CH:37]=[CH:36][C:35]([CH:38]2[CH2:40][CH:39]2[CH2:41][C:42]([O:44]CC)=[O:43])=[CH:34][CH:33]=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.[C:61]([OH:67])([C:63]([F:66])([F:65])[F:64])=[O:62]>C1COCC1>[F:64][C:63]([F:66])([F:65])[C:61]([OH:67])=[O:62].[CH3:1][NH:2][C:3]1[N:8]=[C:7]([CH2:9][CH2:10][O:11][C:32]2[CH:37]=[CH:36][C:35]([CH:38]3[CH2:40][CH:39]3[CH2:41][C:42]([OH:44])=[O:43])=[CH:34][CH:33]=2)[CH:6]=[CH:5][CH:4]=1

Participants

7

Reactant 5

HCID 6422Trifluoroacetic acidHCID 11776TriphenylphosphineHCID 75555Diisopropyl diazene-1,2-dicarboxylateHCID 105348582-[6-(Methylamino)-2-pyridyl]ethan-1-olHCID 11298964Ethyl [(+)-2-(4-hydroxyphenyl)cyclopropyl]acetate

Product 1

HCID 69743442[(+)-2-(4-{2-[6-(methylamino)pyridin-2-yl]ethoxy}phenyl)cyclopropyl]Acetic Acid TrifluoroacetateYield 15%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Procedure

To a solution of 2-[6-(methylamino)pyridin-2-yl]ethanol (1 g, 6.6 mmol) and PPh3 polymer bound (1.4 g, 9.9 mmole) in dry THF (50 mL) was added ethyl [(+)-2-(4-hydroxyphenyl)cyclopropyl]acetate (1.4 g, 6.6 mmol) from example 1 step 1, followed by diisopropyl azodicarboxylate (1.5 ml, 7.7 mmol). The reaction mixture was stirred at room temperature. After 18 hours, PPh3 polymer was filtered through celite and washed with excess THF. Filtrate was concentrated. The concentrated residue was dissolved in 1:1/acetonitrile:water (40 ml) and treated with LiOH (1 g). Reaction was heated two hours at 55° C. then cooled to room temperature. Reaction was acidified by adding TFA and purified on reverse phase HPLC twice to give 0.45 g (15%) of title compound. 1H NMR (400 MHz, CD3OD) δ 7.8 (m, 1 H), 7.0 (d, 2 H, J=8.6 Hz), 6.9-6.6 (m, 4 H), 4.26 (t, 2 H, J=6 Hz), 3.21 (t, 2 H, J=6 Hz), 3.0 (s, 3 H), 2.35-2.33 (m, 2 H), 1.71-1.67 (m, 1 H), 1.21-1.18 (m, 1 H), 0.89-0.76 (m, 2 H). HRMS calcd for C19H22N2O3 (M+H): 327.1703. found 327.1677.

Workup

  1. filtrationPPh3 polymer was filtered through celite
  2. washwashed with excess THF
  3. concentrationFiltrate was concentrated
  4. dissolutionThe concentrated residue was dissolved in 1:1/acetonitrile
  5. additionwater (40 ml) and treated with LiOH (1 g)
  6. customReaction
  7. temperaturewas heated two hours at 55° C.
  8. temperaturethen cooled to room temperature
  9. customReaction
  10. custompurified on reverse phase HPLC twice

Sources & evidence

ORD record
ord-a268ae0c04ba47c6bea61bc9f15673d1
Source dataset
uspto-grants-2005_07
Patent number
US06921767B2

Reaction notes

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