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

HRID 522787Notes

Reaction equation

HRID 522787 reaction equation
[Cl:1][C:2]1[C:10]([F:11])=[C:9]2[C:5]([C:6]([S:26][C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([O:35][CH2:36][CH3:37])=[O:34])[C:28]=3[F:38])=[C:7]([CH:23]3[CH2:25][CH2:24]3)[N:8]2[C:12]2[CH:13]=[N:14][N:15]([CH2:17][CH2:18][CH2:19][C:20](O)=[O:21])[CH:16]=2)=[CH:4][CH:3]=1.CC[N:41]=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.[NH4+].[Cl-]>CN(C=O)C.O>[NH2:41][C:20](=[O:21])[CH2:19][CH2:18][CH2:17][N:15]1[CH:16]=[C:12]([N:8]2[C:9]3[C:5](=[CH:4][CH:3]=[C:2]([Cl:1])[C:10]=3[F:11])[C:6]([S:26][C:27]3[C:28]([F:38])=[C:29]([CH:30]=[CH:31][CH:32]=3)[C:33]([O:35][CH2:36][CH3:37])=[O:34])=[C:7]2[CH:23]2[CH2:24][CH2:25]2)[CH:13]=[N:14]1

Participants

8

Reactant 5

HCID 79724-MethylmorpholineHCID 25517Ammonium ChlorideHCID 757711-HydroxybenzotriazoleHCID 27239391,3-Propanediamine, N'-(ethylcarbonimidoyl)-N,N-dimethyl-, monohydrochlorideHCID 1181041884-(4-(6-chloro-2-cyclopropyl-3-((3-(ethoxycarbonyl)-2-fluorophenyl) thio)-7-fluoro-1H-indol-1-yl)-1H-pyrazol-1-yl)butanoic acid

Product 1

HCID 118874638ethyl 3-((1-(1-(4-amino-4-oxobutyl)-1H-pyrazol-4-yl)-6-chloro-2-cyclopropyl-7-fluoro-1H-indol-3-yl)thio)-2-fluorobenzoateYield 10.3%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 6228DimethylformamideSolvent

Procedure

To a stirred solution of indole 1 (Example 16, Step 2; 150 mg, 0.26 mmol) in DMF (3 mL) under inert atmosphere were added EDCI.HCl (36 mg, 0.40 mmol), HOBt (61.5 mg, 0.40 mmol), NMM (0.07 mL, 0.67 mmol) at RT and stirred for 10 min. To this, NH4Cl (17.1 mg, 0.32 mmol) was added at RT and stirred for 16 h. The mixture was diluted with water (30 mL) and extracted with EtOAc (2×30 mL). The combined organic extracts were washed with brine (20 mL), dried (Na2SO4), filtered and dried under reduced pressure to obtain the crude. This was purified (silica gel; 2% MeOH/CH2Cl2) to afford compound 2 (15 mg, 10%) as an off-white solid. 1H NMR (400 MHz, DMSO-d6): δ 8.23 (s, 1H), 7.81 (s, 1H), 7.60 (dt, J=8.0, 1.6 Hz, 1H), 7.29 (br s, 1H), 7.22-7.11 (m, 3H), 6.84 (dt, J=8.0, 1.6 Hz, 1H), 6.78 (br s, 1H), 4.33 (q, 2H), 4.20 (t, J=6.4 Hz, 2H), 2.08-2.02 (m, 4H), 1.82-1.77 (m, 1H), 1.32 (t, J=7.2 Hz, 3H), 0.92-0.88 (m, 2H), 0.86-0.80 (m, 2H); MS: m/z 559.6 (M+H+).

Workup

  1. stirringstirred for 16 h
  2. extractionextracted with EtOAc (2×30 mL)
  3. washThe combined organic extracts were washed with brine (20 mL)
  4. dry with materialdried (Na2SO4)
  5. filtrationfiltered
  6. customdried under reduced pressure
  7. customto obtain the crude
  8. customThis was purified (silica gel; 2% MeOH/CH2Cl2)

Sources & evidence

ORD record
ord-99230791da804e48a6f8e69949ce9364
Source dataset
uspto-grants-2016_05
Patent number
US09334261B2

Reaction notes

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