1,2-Dichloroethane → Trifluoroacetic acid

HRID 1818627Notes

Reaction equation

HRID 1818627 reaction equation
[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=1)[C:6]([C:22]([CH:24]([CH2:36][CH2:37][CH3:38])[CH2:25][C:26]1[CH:35]=[CH:34][C:29]([C:30]([O:32]C)=O)=[CH:28][CH:27]=1)=[O:23])=[CH:5]2.[Li+].[OH-:40].C(Cl)CCl.C1C=CC2N([OH:54])N=NC=2C=1.[NH2:55][C:56]1[NH:60][N:59]=[N:58][N:57]=1.CCN(C(C)C)C(C)C>O1CCOCC1.O.CN(C=O)C>[C:15]([OH:54])([C:18]([F:21])([F:20])[F:19])=[O:40].[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=1)[C:6]([C:22]([CH:24]([CH2:36][CH2:37][CH3:38])[CH2:25][C:26]1[CH:27]=[CH:28][C:29]([C:30]([NH:55][C:56]3[NH:60][N:59]=[N:58][N:57]=3)=[O:32])=[CH:34][CH:35]=1)=[O:23])=[CH:5]2

Participants

11

Reactant 6

HCID 111,2-DichloroethaneHCID 3939Lithium HydroxideHCID 757711-HydroxybenzotriazoleHCID 81531DiisopropylethylamineHCID 67482502Methyl 4-[(2rs)-2-({5-chloro-1-[4-(trifluoromethyl)benzyl]-1h-indol-2-yl}carbonyl)pentyl]benzoateHCID 178509299HCID 178509299, compound

Product 2

HCID 6422Trifluoroacetic acidHCID 178442160HCID 178442160, compound

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 6228DimethylformamideSolventHCID 312751,4-DioxaneSolvent

Procedure

To a solution of the title compound of Example 6 Step A (49.0 mg, 0.091 mmol) in 1,4-dioxane (0.5 mL) was added a solution of LiOH (22.0 mg, 0.91 mmol) in H2O (0.5 mL), and the resultant mixture was stirred at 45° C. for 4 h. The mixture was allowed to cool to room temperature whereupon it was quenched by the addition of 2 N aq. HCl. The aqueous phase was extracted with EtOAc, and the organic phase was dried over Na2SO4 and concentrated in vacuo. To the crude carboxylic acid obtained above were added EDC (52.0 mg, 0.27 mmol), HOBt (37.0 mg, 0.27 mmol), and 5-amino-1H-tetrazole (28.0 mg, 0.27 mmol). The resultant mixture was dissolved in DMF (1 mL), DIEA (0.158 mL, 0.91 mmol) was added, and the reaction mixture was stirred at 50° C. for 2 h. The reaction mixture was quenched by addition of sat. aq. NH4Cl, and the aqueous phase was extracted with EtOAc (2×). The combined organic phases were concentrated in vacuo. Purification by reverse phase HPLC (30 to 100% CH3CN in H2O, each with 0.1% v/v TFA) provided the title compound: LCMS A, tr=4.15 min, m/z 595.1 [M+H]+; 1H NMR (500 MHz, d6DMSO) δ 7.92 (d, J=8.0 Hz, 2H), 7.82 (d, J=2.0 Hz, 1H), 7.70 (m, 1H), 7.64 (d, J=8.0 Hz, 1H), 7.55 (d, J=9.0 Hz, 2H), 7.36-7.34 (m, 3H), 6.98 (d, J=8.0 Hz, 2H), 5.90 (ABq, J=16.5 Hz, Δν=37.0 Hz), 3.93-3.89 (m, 1H), 2.98 (dd, J=14.0, 9.0 Hz, 1H), 2.81 (dd, J=14.0, 6.0 Hz, 1H), 1.56-1.51 (m, 1H), 1.44-1.37 (m, 1H), 1.09-1.01 (m, 2H), 0.71 (t, J=7.0 Hz, 3H).

Workup

  1. customwas quenched by the addition of 2 N aq. HCl
  2. extractionThe aqueous phase was extracted with EtOAc
  3. dry with materialthe organic phase was dried over Na2SO4
  4. concentrationconcentrated in vacuo
  5. customTo the crude carboxylic acid obtained
  6. customThe reaction mixture was quenched by addition of sat. aq. NH4Cl
  7. extractionthe aqueous phase was extracted with EtOAc (2×)
  8. concentrationThe combined organic phases were concentrated in vacuo
  9. customPurification by reverse phase HPLC (30 to 100% CH3CN in H2O

Sources & evidence

ORD record
ord-7e2a6a49e5e746bfbfd12cd8c3863963
Source dataset
uspto-grants-2009_10
Patent number
US07598398B2

Reaction notes

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