Carbamate → Trifluoroacetic acid

HRID 1891233Notes

Reaction equation

HRID 1891233 reaction equation
C([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:15]2[N:20]=[C:19]([C:21]3[CH:47]=[CH:46][CH:45]=[C:44]([C:48]([F:51])([F:50])[F:49])[C:22]=3[O:23][CH2:24][C:25]3[CH:30]=[CH:29][C:28]([CH:31]4[CH2:36][CH2:35][N:34]([C:37]([O:39][C:40](C)(C)C)=[O:38])[CH2:33][CH2:32]4)=[CH:27][CH:26]=3)[CH:18]=[CH:17][N:16]=2)[C:10]=1[C:11]([F:14])([F:13])[F:12])=[O:5])C.[C:52]([OH:58])([C:54]([F:57])([F:56])[F:55])=[O:53].CCN(C(C)C)C(C)C.ClC(OC)=O.C(=O)([O-])N.[OH-].[Li+].Cl>C(Cl)Cl.O1CCOCC1.C(#N)C>[C:52]([OH:58])([C:54]([F:57])([F:56])[F:55])=[O:53].[CH3:40][O:39][C:37]([N:34]1[CH2:33][CH2:32][CH:31]([C:28]2[CH:27]=[CH:26][C:25]([CH2:24][O:23][C:22]3[C:44]([C:48]([F:49])([F:50])[F:51])=[CH:45][CH:46]=[CH:47][C:21]=3[C:19]3[CH:18]=[CH:17][N:16]=[C:15]([N:9]4[C:10]([C:11]([F:12])([F:13])[F:14])=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=[N:8]4)[N:20]=3)=[CH:30][CH:29]=2)[CH2:36][CH2:35]1)=[O:38]

Participants

12

Reactant 7

HCID 276CarbamateHCID 313Hydrochloric AcidHCID 3939Lithium HydroxideHCID 6422Trifluoroacetic acid2×HCID 6586Methyl chloroformateHCID 81531DiisopropylethylamineHCID 91092987HCID 91092987, compound

Product 2

HCID 6422Trifluoroacetic acidHCID 59452103HCID 59452103, compound

Reagents, catalysts & solvents 3

HCID 6342AcetonitrileSolventHCID 6344DichloromethaneSolvent2×HCID 312751,4-DioxaneSolvent

Procedure

To a solution of the title compound from Example 167 Step C (198 mg, 0.30 mmol) in DCM (3 mL) was added TFA (0.5 mL). After 3 min, the reaction mixture was concentrated in vacuo, and the crude TFA salt was used without further purification: LCMS m/z 619.9 [M+1-1]+. To a portion of the crude TFA salt (−0.15 mmol) in DCM (1.5 mL) were added DIEA (262 μL, 1.50 mmol) and methyl chloroformate (34 μL, 0.45 mmol), and the resulting mixture was allowed to stir at room temperature. After 90 min, the reaction mixture was quenched by addition of sat aq NaHCO3 and the aqueous phase was extracted with DCM. The organic phase was separated and concentrated in vacuo to provide the crude carbamate, which was used without further purification: LCMS m/z 677.9 [M+H]+. To a solution of the carbamate in dioxane (2 mL) was added lithium hydroxide (1 mL, 2N aqueous, 2 mmol), and the mixture was stirred at 50° C. After 1 h, the reaction mixture was rendered acidic by addition of HCl (2N aqueous), then was diluted with acetonitrile and purified by reverse phase HPLC (30 to 100% acetonitrile/water, both 0.1% v/v TFA) to provide the title compound: LCMS m/z 649.9 [M+H]+; 1H NMR (500 MHz, d6-DMSO) δ 9.07 (d, J=5.5 Hz, 1H), 8.35 (s, 1H), 8.16 (d, J=5.5 Hz, 1H), 8.07 (dd, J=8.0, 1.5 Hz, 1H), 7.96 (dd, J=8.0, 1.5 Hz, 1H), 7.58 (t, J=8.0 Hz, 1H), 7.17 (d, J=8.5 Hz, 2H), 7.09 (d, J=8.5 Hz, 2H), 4.63 (s, 2H), 4.10-4.04 (m, 2H), 3.58 (s, 3H), 2.88-2.62 (m, 3H), 1.72-1.68 (m, 2H), 1.50-1.42 (m, 2H).

Workup

  1. concentrationthe reaction mixture was concentrated in vacuo
  2. customthe crude TFA salt was used without further purification
  3. waitAfter 90 min
  4. customthe reaction mixture was quenched by addition of sat aq NaHCO3
  5. extractionthe aqueous phase was extracted with DCM
  6. customThe organic phase was separated
  7. concentrationconcentrated in vacuo
  8. customto provide the crude carbamate, which
  9. customwas used without further purification
  10. stirringthe mixture was stirred at 50° C
  11. waitAfter 1 h
  12. custompurified by reverse phase HPLC (30 to 100% acetonitrile/water

Sources & evidence

ORD record
ord-47652c1bb78b4aeb8985b8f864cbdbdc
Source dataset
uspto-grants-2013_08
Patent number
US08507512B2

Reaction notes

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