Ammonia → ethyl 3-((6-chloro-2-cyclopropyl-7-fluoro-1-(1-(2-ureidoethyl)-1H-pyrazol-4-yl)-1H-indol-3-yl)thio)-2-fluorobenzoate

HRID 522784Notes

Reaction equation

HRID 522784 reaction equation
[NH2:1][CH2:2][CH2:3][N:4]1[CH:8]=[C:7]([N:9]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([Cl:19])[C:16]=3[F:18])[C:11]([S:20][C:21]3[C:22]([F:32])=[C:23]([CH:29]=[CH:30][CH:31]=3)[C:24]([O:26][CH2:27][CH3:28])=[O:25])=[C:10]2[CH:33]2[CH2:35][CH2:34]2)[CH:6]=[N:5]1.CCN(CC)CC.ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl.[N-:55]=[C:56]=[O:57].N>C1COCC1.O>[Cl:19][C:15]1[C:16]([F:18])=[C:17]2[C:12]([C:11]([S:20][C:21]3[C:22]([F:32])=[C:23]([CH:29]=[CH:30][CH:31]=3)[C:24]([O:26][CH2:27][CH3:28])=[O:25])=[C:10]([CH:33]3[CH2:35][CH2:34]3)[N:9]2[C:7]2[CH:6]=[N:5][N:4]([CH2:3][CH2:2][NH:1][C:56]([NH2:55])=[O:57])[CH:8]=2)=[CH:13][CH:14]=1

Participants

8

Reactant 5

HCID 222AmmoniaHCID 8471TriethylamineHCID 94429TriphosgeneHCID 105034IsocyanateHCID 118104181ethyl 3-((1-(1-(2-aminoethyl)-1H-pyrazol-4-yl)-6-chloro-2-cyclopropyl-7-fluoro-1H-indol-3-yl)thio)-2-fluorobenzoate

Product 1

HCID 118104183ethyl 3-((6-chloro-2-cyclopropyl-7-fluoro-1-(1-(2-ureidoethyl)-1H-pyrazol-4-yl)-1H-indol-3-yl)thio)-2-fluorobenzoateYield 34%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 8028TetrahydrofuranSolvent

Procedure

To a stirred solution of indole 1 (Example 14, Step 2; 80 mg, 0.15 mmol) in THF (5 mL) under inert atmosphere were added Et3N (0.04 mL, 0.31 mmol) and triphosgene (18.3 mg, 0.06 mmol) at 0° C., stirred for 1 h, warmed to RT and stirred for 2 h. To this solution of crude isocyanate was passed ammonia gas at −78° C. for 10 min; warmed to 0° C. and stirred for 1 hr. The mixture was diluted with water and extracted with EtOAc (2×20 mL). The combined organic extracts were dried (Na2SO4), filtered and concentrated under reduced pressure to obtain the crude. This was purified by triturating with Et2O (2×5 mL) and dried under reduced pressure to afford 2 (30 mg, 34%) as an off-white solid. 1H NMR (400 MHz, DMSO-d6): δ 8.19 (s, 1H), 7.82 (s, 1H), 7.60 (t, J=7.2 Hz, 1H), 7.22-7.11 (m, 3H), 6.84 (t, J=7.2 Hz, 1H), 6.04-6.03 (m, 1H), 5.53 (br s, 2H), 4.33 (q, 2H), 4.21 (t, J=6.0 Hz, 2H), 3.43 (t, J=6.0 Hz, 2H), 1.84-1.78 (m, 1H), 1.32 (t, J=7.2 Hz, 3H), 0.92-0.91 (m, 2H), 0.87-0.85 (m, 2H); MS: m/z 560.6 (M+H+).

Workup

  1. stirringstirred for 2 h
  2. customat −78° C.
  3. customfor 10 min
  4. temperaturewarmed to 0° C.
  5. stirringstirred for 1 hr
  6. extractionextracted with EtOAc (2×20 mL)
  7. dry with materialThe combined organic extracts were dried (Na2SO4)
  8. filtrationfiltered
  9. concentrationconcentrated under reduced pressure
  10. customto obtain the crude
  11. customThis was purified
  12. customby triturating with Et2O (2×5 mL)
  13. customdried under reduced pressure

Sources & evidence

ORD record
ord-f9b37967c53d49d6bdb339ceb0395ae9
Source dataset
uspto-grants-2016_05
Patent number
US09334261B2

Reaction notes

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