2,2,2-Trifluoroethyl trifluoromethanesulfonate → HCID 86680098, compound

HRID 1915892Notes

Reaction equation

HRID 1915892 reaction equation
[NH2:1][C@@H:2]1[CH2:8][CH2:7][CH2:6][N:5]([C:9]2[N:13]([CH3:14])[N:12]=[CH:11][C:10]=2[NH:15][C:16]([C:18]2[N:19]=[C:20]([C:31]3[C:36]([F:37])=[CH:35][CH:34]=[CH:33][C:32]=3[F:38])[S:21][C:22]=2[NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:17])[CH2:4][CH2:3]1.FC(F)(F)S(O[CH2:45][C:46]([F:49])([F:48])[F:47])(=O)=O.C(N(CC)C(C)C)(C)C>C(Cl)Cl.CN(C=O)C>[F:38][C:32]1[CH:33]=[CH:34][CH:35]=[C:36]([F:37])[C:31]=1[C:20]1[S:21][C:22]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[C:18]([C:16](=[O:17])[NH:15][C:10]2[CH:11]=[N:12][N:13]([CH3:14])[C:9]=2[N:5]2[CH2:6][CH2:7][CH2:8][C@@H:2]([NH:1][CH2:45][C:46]([F:49])([F:48])[F:47])[CH2:3][CH2:4]2)[N:19]=1

Participants

5

Reactant 3

HCID 803662,2,2-Trifluoroethyl trifluoromethanesulfonateHCID 81531DiisopropylethylamineHCID 67437389HCID 67437389, compound

Product 1

HCID 86680098HCID 86680098, compoundYield 75%

Reagents, catalysts & solvents 1

HCID 22350042dichloromethane N,N-dimethylformamideSolvent

Procedure

(R)-tert-butyl 4-(5-(4-aminoazepan-1-yl)-1-methyl-1H-pyrazol-4-ylcarbamoyl)-2-(2,6-difluorophenyl)thiazol-5-ylcarbamate (112 mg, 0.204 mmol) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (95 mg, 0.409 mmol) were dissolved in methylene chloride/DMF (1.5 mL/1.5 mL). N,N-diisopropylethylamine (132 mg, 1.02 mmol) was added and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated to remove DMF, redissolved in ethyl acetate and washed with brine. The aqueous layer was extracted with ethyl acetate 3×. Combined organic layers were concentrated and purified by flash chromatography eluted with 0 to 100% ethyl acetate in heptane to give (R)-tert-butyl 2-(2,6-difluorophenyl)-4-(1-methyl-5-(4-(2,2,2-trifluoroethylamino)azepan-1-yl)-1H-pyrazol-4-ylcarbamoyl)thiazol-5-ylcarbamate (96 mg, 75%), which was deprotected by 4N HCl in dioxane and purified on reversed phase HPLC to give 197. 1H NMR (400 MHz, DMSO) δ 8.65 (s, 1H), 7.59-7.43 (m, 4H), 7.25 (t, J=8.7 Hz, 2H), 3.64 (s, 3H), 3.24-3.01 (m, 6H), 2.81 (s, 1H), 2.14 (d, J=6.1 Hz, 1H), 1.96-1.74 (m, 3H), 1.65-1.48 (m, 3H). MS (ESI) m/z: 530.2 [M+H+].

Workup

  1. concentrationThe reaction mixture was concentrated
  2. customto remove DMF
  3. dissolutionredissolved in ethyl acetate
  4. washwashed with brine
  5. extractionThe aqueous layer was extracted with ethyl acetate 3×
  6. concentrationCombined organic layers were concentrated
  7. custompurified by flash chromatography
  8. washeluted with 0 to 100% ethyl acetate in heptane

Sources & evidence

ORD record
ord-1cf3d6540adb428bac30864cb99c7eef
Source dataset
uspto-grants-2013_12
Patent number
US08614206B2

Reaction notes

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