Pyrrolidine → 1-Cyclopropyl-3-(3-fluoro-4-(2-(5-(pyrrolidine-1-carbonyl)pyridin-2-yl)thieno[3,2-b]pyridin-7-yloxy)phenyl)urea

HRID 1400873Notizen

Reaktionsgleichung

Reaktionsgleichung von HRID 1400873
[CH:1]1([NH:4][C:5](=[O:33])[NH:6][C:7]2[CH:31]=[CH:30][C:10]([O:11][C:12]3[CH:17]=[CH:16][N:15]=[C:14]4[CH:18]=[C:19]([C:21]5[CH:29]=[CH:28][C:24]([C:25]([OH:27])=O)=[CH:23][N:22]=5)[S:20][C:13]=34)=[C:9]([F:32])[CH:8]=2)[CH2:3][CH2:2]1.CC[N:36]([CH:40]([CH3:42])C)[CH:37]([CH3:39])C.N1CCCC1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH:1]1([NH:4][C:5]([NH:6][C:7]2[CH:31]=[CH:30][C:10]([O:11][C:12]3[CH:17]=[CH:16][N:15]=[C:14]4[CH:18]=[C:19]([C:21]5[CH:29]=[CH:28][C:24]([C:25]([N:36]6[CH2:37][CH2:39][CH2:42][CH2:40]6)=[O:27])=[CH:23][N:22]=5)[S:20][C:13]=34)=[C:9]([F:32])[CH:8]=2)=[O:33])[CH2:3][CH2:2]1

Komponenten

6

Edukt 4

HCID 31268PyrrolidineHCID 81531DiisopropylethylamineHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 674418286-(7-(4-(3-Cyclopropylureido)-2-fluorophenoxy)thieno[3,2-b]pyridin-2-yl)nicotinic acid

Produkt 1

HCID 674418011-Cyclopropyl-3-(3-fluoro-4-(2-(5-(pyrrolidine-1-carbonyl)pyridin-2-yl)thieno[3,2-b]pyridin-7-yloxy)phenyl)ureaAusbeute 19,2 %

Reagenzien, Katalysatoren, Lösungsmittel 1

HCID 6228DimethylformamideLösungsmittel

Versuchsvorschrift

To a solution of acid 225 (70 mg, 0.151 mmol), DIPEA (0.105 mL, 0.603 mmol) and pyrrolidine (0.025 mL, 0.301 mmol) in DMF (4 mL) was added HATU reagent (143 mg, 0.377 mmol). The mixture was stirred for 16 h at RT then partitioned between ethyl acetate and water. The organic phase was collected, washed with water, 1M NaOH, and brine, dried over anhydrous MgSO4, filtered and concentrated. The residue was purified by Biotage (MeOH/DCM, 0-15%, SNAP 10 g cartridge), then using chromatotron (eluent MeOH/DCM, 5-10%) followed by trituration with a mixture Et2O/MeOH/Acetone to give title compound 226 (15 mg, 0.029 mmol, 19% yield) 1H NMR (400 MHz, DMSO-d6) δ (ppm): OH from carboxylic acid is missing, 9.66 (bs, 1H), 8.98 (dd, J=1.9, 0.9 Hz, 114), 8.51 (d, J=5.5 Hz, 1H), 8.31 (s, 1H), 8.22 (dd, J=8.1, 1.9 Hz, 1H), 8.17 (dd, J=8.1, 0.9 Hz, 1H), 7.77 (dd, J=13.7, 2.5 Hz, 1H), 7.45 (bs, 1H), 7.37 (t, J=9.1 Hz, 1H), 7.26 (dd, J=8.9, 1.5 Hz, 1H), 6.62 (d, J=5.3, 0.8 Hz, 1H), 2.60-2.52 (m, 1H), 0.69-0.56 (m, 2H), 0.50-0.37 (m, 2H). MS (m/z): 465.3 (M+H)

Aufarbeitung

  1. customthen partitioned between ethyl acetate and water
  2. customThe organic phase was collected
  3. washwashed with water, 1M NaOH, and brine
  4. dry with materialdried over anhydrous MgSO4
  5. filtrationfiltered
  6. concentrationconcentrated
  7. customThe residue was purified by Biotage (MeOH/DCM, 0-15%, SNAP 10 g cartridge)

Quellen und Nachweise

ORD-Eintrag
ord-1cc1c2a1ee3b499190ee93cc690f67fc
Quelldatensatz
uspto-grants-2014_12
Patentnummer
US08906852B2

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