2,2,2-Trifluoroethanol → Trifluoroacetic acid

HRID 1948070Notes

Reaction equation

HRID 1948070 reaction equation
[CH2:1]([O:3][P:4]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]2[N:22]=[C:21](Cl)[C:20]([C:24]([F:27])([F:26])[F:25])=[CH:19][N:18]=2)=[C:12]([O:28][CH3:29])[CH:11]=1)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].[NH2:30][C:31]1[CH:32]=[CH:33][C:34]([N:42]2[CH2:47][CH2:46][CH:45]([C:48]([O:50]C)=[O:49])[CH2:44][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>[CH2:6]([O:5][P:4]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]2[N:22]=[C:21]([NH:30][C:31]3[CH:32]=[CH:33][C:34]([N:42]4[CH2:43][CH2:44][CH:45]([C:48]([OH:50])=[O:49])[CH2:46][CH2:47]4)=[C:35]4[C:39]=3[C:38](=[O:40])[N:37]([CH3:41])[CH2:36]4)[C:20]([C:24]([F:26])([F:27])[F:25])=[CH:19][N:18]=2)=[C:12]([O:28][CH3:29])[CH:11]=1)([O:3][CH2:1][CH3:2])=[O:8])[CH3:7].[F:52][C:53]([F:58])([F:57])[C:54]([OH:56])=[O:55]

Participants

9

Reactant 5

HCID 64092,2,2-TrifluoroethanolHCID 6422Trifluoroacetic acidHCID 168937Lithium hydroxide, monohydrateHCID 67254395methyl 1-(7-amino-2-methyl-1-oxo-2,3-dihydro-1H-isoindol-4-yl)piperidine-4-carboxylate2×HCID 86654002Diethyl (4-{[4-chloro-5-(trifluoromethyl) pyrimidin-2-yl]amino}-3-methoxybenzyl)phosphonate

Product 2

HCID 6422Trifluoroacetic acidYield 95.8%HCID 58292904HCID 58292904, compound

Reagents, catalysts & solvents 2

HCID 887MethanolSolventHCID 962WaterSolvent

Procedure

A mixture of diethyl(4-{[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino}-3-methoxybenzyl)phosphonate (30.0 mg, 0.0661 mmol), methyl 1-(7-amino-2-methyl-1-oxo-2,3-dihydro-1H-isoindol-4-yl)piperidine-4-carboxylate (Compound 256A, 20.0 mg, 0.0659 mmol), trifluoroacetic acid (15.2 uL, 0.198 mmol) and trifluoroethanol (1.0 mL, 14 mmol) was irradiated in microwave reactor at 105° C. for 30 minutes. The crude mixture was concentrated to dryness, taken up in THF (0.1 mL), methanol (0.1 mL) and treated with a solution of lithium hydroxide monohydrate (27.7 mg, 0.659 mmol) in water (0.1 mL). The mixture was stirred at room temperature overnight. The crude was purified by MDP to obtain the title compound as a trifluoroacetic acid salt (7.2 mg, 15.5% yield). 1H NMR (400 MHz, DMSO-d6) δ=1.29 (t, J=7.1 Hz, 6H), 1.83-1.97 (m, 2H), 2.03-2.14 (m, 2H), 2.46-2.57 (m, 1H), 2.93 (t, J=10.5 Hz, 2H), 3.18 (s, 3H), 3.34 (d, J+ 18.7 Hz, 2H), 3.40 (d, J=12.1 Hz, 2H), 3.90 (s, 3H), 4.10 (quin, J=7.3 Hz, 4H), 4.52 (s, 2H), 6.94-7.01 (m, 1H), 7.09-7.17 (m, 2H), 7.67 (d, J=8.1 Hz, 1H), 8.27-8.47 (m, 2H). MS (ES+): m/z 707.19 (100) [MH+]; HPLC: tR=1.01 min (UPLC, purity).

Workup

  1. customwas irradiated in microwave reactor at 105° C. for 30 minutes
  2. concentrationThe crude mixture was concentrated to dryness
  3. customThe crude was purified by MDP

Sources & evidence

ORD record
ord-32ccd843004c4580b644e8dd46dafcb8
Source dataset
uspto-grants-2013_03
Patent number
US08399433B2

Reaction notes

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