Trifluoroacetic acid → Trifluoroacetic acid

HRID 1694423Notes

Reaction equation

HRID 1694423 reaction equation
[C:1]([OH:7])([C:3]([F:6])([F:5])[F:4])=[O:2].[CH3:8][N:9]([CH3:30])[C:10]([CH:12]1[CH2:15][C:14]([C:17]2[CH:22]=[CH:21][C:20]([CH2:23][N:24]3[CH2:28][CH2:27][CH2:26][CH2:25]3)=[C:19]([F:29])[CH:18]=2)(O)[CH2:13]1)=[O:11].CN(C)C(C1CC(C2C=CC(N3CCCC3)=C(F)C=2C)(O)C1)=O>>[C:1]([OH:7])([C:3]([F:6])([F:5])[F:4])=[O:2].[CH3:8][N:9]([CH3:30])[C:10]([CH:12]1[CH2:15][C:14]([C:17]2[CH:22]=[CH:21][C:20]([CH2:23][N:24]3[CH2:28][CH2:27][CH2:26][CH2:25]3)=[C:19]([F:29])[CH:18]=2)=[CH:13]1)=[O:11]

Participants

5

Reactant 3

HCID 6422Trifluoroacetic acidHCID 67278746HCID 67278746, compoundHCID 86619860HCID 86619860, compound

Product 2

HCID 6422Trifluoroacetic acidHCID 86619859HCID 86619859, compound

Conditions

Temperature
75 °C

Procedure

TFA (9.9 ml, 128 mmol) was added to a DCE solution (64 ml) of example 19, 3-(3-fluoro-4-pyrrolidin-1-yl-methyl-phenyl)-3-hydroxy-cyclobutanecarboxylic acid dimethylamide (2.05 g, 6.4 mmol) and the mixture was heated to 75° C. for 18 hrs and concentrated down to obtain TFA salt of intermediate 3-(3-fluoro-4-pyrrolidin-1-ylmethyl-phenyl)-cyclobut-2-enecarboxylic acid dimethylamide. This was redissolved in absolute EtOH (64 ml), Wilkinson's catalyst (296 mg) was then added and this mixture was subjected to hydrogenation at 60° C. using 45 psi H2. After 1 hr 45 min reaction time, it was concentrated down and the residue was redissolved into 1N HCl (50 m) and extracted twice with EtOAc (2×120 ml). The aqueous layer was then basified with 15% aq. NaOH (40 ml) and extracted with EtOAc (3×200 ml). The combined organic phases were dried over MgSO4, and concentrated down to obtain crude material. This was purified by flash chromatography using a 120 g ISCO™ column and 4% MeOH/CH2Cl2 with 0.1% NH4OH. The product containing fractions were combined and concentrated under reduced pressure to give the title compound (1.0 g, 51% yield). Rf=0.40 (10% MeOH/CH2Cl2+0.2% NH4OH); LRMS m/z Calcd for C18H25FN2O, 304.4, found, 305.4 (M+1) APCI; 400 MHz 1H NMR (CDCl3) δ 7.10 (t, J=7.8 Hz, 1H), 6.78 (dd, J=1.2, 6.6 Hz, 1H), 6.72 (dd, J=1.7, 11.2 Hz, 1H), 3.4 (s, 2H), 3.48-3.38 (m, 1H), 3.13-3.04 (m, 1H), 2.79 (s, 3H), 2.70 (s, 3H), 2.58-2.50 (m, 2H), 2.37-2.30 (m 4H), 2.22-2.12 (m, 2H), 1.60-1.52 (m, 4H); 100 MHz 13C NMR (CDCl3) δ 174.3, 161.2 (d, JC-F=245.7 Hz), 147.0, 131.4, 123.4 (d, JC-F=15.0 Hz), 121.9, 113.0 (d, JC-F=22.5 Hz), 54.0, 52.5, 36.7, 35.8, 35.5, 33.3, 31.6, 23.5.

Workup

  1. concentrationconcentrated down

Sources & evidence

ORD record
ord-bc7722bf98f54392b4b8c21472f5bbf4
Source dataset
uspto-grants-2012_04
Patent number
US08158673B2

Reaction notes

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