Trifluoroacetic acid → 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (3-amino-cyclohexyl)-amide

HRID 246349Notes

Reaction equation

HRID 246349 reaction equation
C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][CH2:11][CH:10]([NH:14][C:15]([C:17]2[C:25]3[C:20](=[N:21][CH:22]=[C:23]([C:26]4[C:34]5[C:29](=[CH:30][C:31]([Cl:35])=[CH:32][CH:33]=5)[N:28]([CH3:36])[N:27]=4)[N:24]=3)[NH:19][CH:18]=2)=[O:16])[CH2:9]1)(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl.CO>[NH2:7][CH:8]1[CH2:13][CH2:12][CH2:11][CH:10]([NH:14][C:15]([C:17]2[C:25]3[C:20](=[N:21][CH:22]=[C:23]([C:26]4[C:34]5[C:29](=[CH:30][C:31]([Cl:35])=[CH:32][CH:33]=5)[N:28]([CH3:36])[N:27]=4)[N:24]=3)[NH:19][CH:18]=2)=[O:16])[CH2:9]1

Participants

5

Reactant 2

HCID 6422Trifluoroacetic acidHCID 71279706tert-butyl 3-(2-(6-chloro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamido)cyclohexylcarbamate

Product 1

HCID 712805442-(6-chloro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (3-amino-cyclohexyl)-amide

Reagents, catalysts & solvents 2

HCID 887MethanolSolventHCID 6344DichloromethaneSolvent

Procedure

The more polar, diastereomer A of (3-{[2-(6-chloro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carbonyl]-amino}-cyclohexyl)-carbamic acid tert-butyl ester (53 mg, 101 μmol) was dissolved in dichloromethane (5 mL) and treated with TFA (1.19 g, 803 μL, 10.4 mmol), the light yellow solution became a bright red-orange solution, stirring continued for 18 h at room temperature. Solvents were evaporated and the residue dissolved in dichloromethane/MeOH, adsorbed on silica gel and purified by chromatography (25 g column, 50 μm from Thomson, 0-10% MeOH containing 10% ammonium hydroxide in dichloromethane, 10 min gradient) to give an off white solid that was sonicated in MeOH and allowed to stand to promote complete solid formation. The solid was separated by decanting the mother liquor and dried under high vacuum to give 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (3-amino-cyclohexyl)-amide (diastereomer A) (27 mg, 63%) as an off-white solid. MS (M+H)+=424; 1H NMR (DMSO-d6) δ: 9.05 (s, 1H), 8.38-8.49 (m, 2H), 8.06 (d, J=7.9 Hz, 1H), 7.99 (s, 1H), 7.33 (d, J=10.2 Hz, 1H), 4.16 (s, 3H), 3.91 (d, J=4.2 Hz, 1H), 3.32 (br. s., 1H), 3.15 (s, 1H), 2.22 (d, J=11.0 Hz, 1H), 2.04 (d, J=11.7 Hz, 1H), 1.79 (br. s., 1H), 0.98-1.24 (m, 3H).

Workup

  1. customSolvents were evaporated
  2. dissolutionthe residue dissolved in dichloromethane/MeOH
  3. custompurified by chromatography (25 g column, 50 μm from Thomson, 0-10% MeOH containing 10% ammonium hydroxide in dichloromethane, 10 min gradient)
  4. customto give an off white solid
  5. customThe solid was separated
  6. customby decanting the mother liquor
  7. customdried under high vacuum

Sources & evidence

ORD record
ord-7ddd4fad11fd43da807379c0a9143d4e
Source dataset
uspto-grants-2014_02
Patent number
US08658646B2

Reaction notes

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