2,2,2-Trifluoroethanol → Trifluoroacetic acid

HRID 511529Notes

Reaction equation

HRID 511529 reaction equation
Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:27]=[CH:26][C:16]([CH2:17][P:18](=[O:25])([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21])=[CH:15][C:14]=2[O:28][CH3:29])[N:3]=1.[NH2:30][C:31]1[CH:32]=[CH:33][C:34]([N:42]2[CH2:47][CH2:46][NH:45][CH:44]([C:48]([O:50]C)=[O:49])[CH2:43]2)=[C:35]2[C:39]=1[C:38](=[O:40])[N:37]([CH3:41])[CH2:36]2.[F:52][C:53]([F:58])([F:57])[C:54]([OH:56])=[O:55].C(O)C(F)(F)F.O.[OH-].[Li+]>O.CO.C1COCC1>[CH2:20]([O:19][P:18]([CH2:17][C:16]1[CH:26]=[CH:27][C:13]([NH:12][C:4]2[N:3]=[C:2]([NH:30][C:31]3[CH:32]=[CH:33][C:34]([N:42]4[CH2:47][CH2:46][NH:45][CH:44]([C:48]([OH:50])=[O:49])[CH2:43]4)=[C:35]4[C:39]=3[C:38](=[O:40])[N:37]([CH3:41])[CH2:36]4)[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=2)=[C:14]([O:28][CH3:29])[CH:15]=1)([O:22][CH2:23][CH3:24])=[O:25])[CH3:21].[F:52][C:53]([F:58])([F:57])[C:54]([OH:56])=[O:55]

Participants

10

Reactant 5

HCID 64092,2,2-TrifluoroethanolHCID 6422Trifluoroacetic acidHCID 168937Lithium hydroxide, monohydrateHCID 67253563HCID 67253563, compound2×HCID 86654002Diethyl (4-{[4-chloro-5-(trifluoromethyl) pyrimidin-2-yl]amino}-3-methoxybenzyl)phosphonate

Product 2

HCID 6422Trifluoroacetic acidYield 48.2%HCID 58293019HCID 58293019, compound

Reagents, catalysts & solvents 3

HCID 887MethanolSolventHCID 962WaterSolventHCID 8028TetrahydrofuranSolvent

Conditions

Temperature
105 °C

Procedure

Diethyl (4-{[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino}-3-methoxybenzyl)phosphonate (18 mg, 0.039 mmol), methyl 4-(7-amino-2-methyl-1-oxo-2,3-dihydro-1H-isoindol-4-yl)piperazine-2-carboxylate (Compound 287A, 6.0 mg, 0.020 mmol), trifluoroacetic acid (4.6 μL, 0.060 mmol) and 0.5 mL trifluoroethanol were mixed. The mixture was heated in microwave 105° C. for 30 minutes. Solvent was evaporated. To the crude solid was added, 0.1 mL THF, 0.1 mL methanol, 0.1 mL water and lithium hydroxide monohydrate (8.3 mg, 0.20 mmol). The mixture was stirred at room temperature overnight. The crude material was purified by MDP to obtain the title compound as a trifluoroacetic acid salt (1.1 mg, 7.9% yield). 1H NMR (400 MHz, methanol-d4) δ=1.28 (t, J=7.3 Hz, 6 H), 3.18 (s, 3 H), 3.21-3.24 (m, 1 H), 3.33 (d, J=21.7 Hz, 2 H), 3.37-3.43 (m, 2 H), 3.45-3.51 (m, 1 H), 3.55-3.61 (m, 2 H), 3.90 (s, 3 H), 4.06-4.11 (m, 4 H), 4.32-4.39 (m, 1 H), 4.44-4.59 (m, 2 H), 6.99 (d, J=7.8 Hz, 1 H), 7.09 (s, 1 H), 7.25 (d, J=8.8 Hz, 1 H), 7.75 (d, J=8.3 Hz, 1 H), 8.35 (s, 1 H), 8.49 (br. s., 1 H). MS (ES+): m/z 708.26 (100) [MH+]; HPLC: tR=0.77 min (UPLC, purity).

Workup

  1. customSolvent was evaporated
  2. additionTo the crude solid was added
  3. customThe crude material was purified by MDP

Sources & evidence

ORD record
ord-db269b2ae9d14d34a2a1c08b68e282b5
Source dataset
uspto-grants-2015_08
Patent number
US09096624B2

Reaction notes

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