Trifluoroacetic acid → (R)-N-(4-(3-aminopiperidin-1-yl)-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-methoxyacetamide hydrochloride

HRID 875776Notes

Reaction equation

HRID 875776 reaction equation
[Cl:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]2[NH:12][CH:13]=[C:14]([NH:15][C:16](=[O:20])[CH2:17][O:18][CH3:19])[C:3]=12.[NH:21]1[CH2:26][CH2:25][CH2:24][C@@H:23]([NH:27]C(=O)OC(C)(C)C)[CH2:22]1.CCN(C(C)C)C(C)C.C(O)(C(F)(F)F)=O>CN1C(=O)CCC1.C(OCC)(=O)C.C(Cl)Cl>[ClH:1].[NH2:27][C@@H:23]1[CH2:24][CH2:25][CH2:26][N:21]([C:2]2[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]3[NH:12][CH:13]=[C:14]([NH:15][C:16](=[O:20])[CH2:17][O:18][CH3:19])[C:3]=23)[CH2:22]1

Participants

8

Reactant 4

HCID 6422Trifluoroacetic acidHCID 81531DiisopropylethylamineHCID 1514172(3R)-3-Aminopiperidine, 3-BOC protectedHCID 60205465N-(4-chloro-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-methoxyacetamide

Product 1

HCID 67045104(R)-N-(4-(3-aminopiperidin-1-yl)-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-methoxyacetamide hydrochlorideYield 29.9%

Reagents, catalysts & solvents 3

HCID 6344DichloromethaneSolventHCID 8857Ethyl AcetateSolventHCID 13387N-methyl-2-pyrrolidoneSolvent

Conditions

Temperature
156 °C

Procedure

A mixture of N-(4-chloro-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-methoxyacetamide (154 mg, 0.501 mmol), (R)-tert-butyl piperidin-3-ylcarbamate (301 mg, 1.50 mmol) and DIEA (0.17 mL, 1.00 mmol) in NMP (2 mL) was stirred at 156° C. for 10 hours. The solvent was removed in vacuo. The residue obtained was dissolved in ethyl acetate (20 mL), washed with water (10 mL) and followed by brine (10 mL). The organic layer was separated, dried (Na2SO4), and concentrated in vacuo. The residue obtained was purified by C-18 reverse phase flash chromatography (Biotage SP4 unit, C-18, 25M+ column, 30-70% CH3CN/water gradient; 30 CV). The solid isolated was dissolved in DCM (3 mL), and TFA (0.5 mL) was added. The mixture was stirred at room temperature for 1 hour, and the solvent was removed in vacuo. The resulting residue was dissolved in DCM (1 mL) and treated with 2N HCl in ether (3 mL). The solid formed was collected by filtration and dried to give (R)—N-(4-(3-aminopiperidin-1-yl)-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-methoxyacetamide hydrochloride (61 mg, 27% yield) as a solid. 1H NMR (400 MHz, D2O) δ 8.42 (s, 1H), 7.52 (s, 1H), 4.12 (s, 2H), 3.40 (s, 3H), 3.38 (m, 2H), 2.96 (m, 3H), 2.00 (m, 1H), 1.73 (m, 1H), 1.68 (m, 1H), 1.54 (m, 1H); LCMS (APCI+) m/z 372 (M+H)+.

Workup

  1. customThe solvent was removed in vacuo
  2. customThe residue obtained
  3. washwashed with water (10 mL)
  4. customThe organic layer was separated
  5. dry with materialdried (Na2SO4)
  6. concentrationconcentrated in vacuo
  7. customThe residue obtained
  8. customwas purified by C-18 reverse phase flash chromatography (Biotage SP4 unit, C-18, 25M+ column, 30-70% CH3CN/water gradient; 30 CV)
  9. customThe solid isolated
  10. stirringThe mixture was stirred at room temperature for 1 hour
  11. customthe solvent was removed in vacuo
  12. dissolutionThe resulting residue was dissolved in DCM (1 mL)
  13. additiontreated with 2N HCl in ether (3 mL)
  14. customThe solid formed
  15. filtrationwas collected by filtration
  16. customdried

Sources & evidence

ORD record
ord-ad8920d1bcc64f1db02732950048e998
Source dataset
uspto-grants-2015_03
Patent number
US08981085B2

Reaction notes

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