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

HRID 2203857ノート

反応式

HRID 2203857 の反応式
[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

参加物

8

反応物 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

生成物 1

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

試薬・触媒・溶媒 3

HCID 6344Dichloromethane溶媒HCID 8857Ethyl Acetate溶媒HCID 13387N-methyl-2-pyrrolidone溶媒

反応条件

温度
156 °C

実験手順

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)+.

後処理

  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

出典と根拠

ORDレコード
ord-2085fae55f1241a795ee687297ed674f
出典データセット
uspto-grants-2016_06
特許番号
US09365568B2

反応ノート

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