Tetrahydrofuran → HCID 89612506, compound

HRID 630997

Reaction equation

HRID 630997 reaction equation
[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C@@H:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C@H:17]([O:24][C:25]3[CH:26]=[CH:27][C:28]4[N:29]([C:31]([N:34]5[CH2:39][CH2:38][CH2:37][CH2:36][C@@H:35]5[CH3:40])=[N:32][N:33]=4)[CH:30]=3)[CH2:16][CH2:15]2)=[O:12])[N:7]([C:41]2[CH:42]=[C:43]([CH:50]=[CH:51][CH:52]=2)[CH2:44][O:45]S(C)(=O)=O)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:53]1[CH2:57][CH2:56][CH2:55][CH2:54]1.C1C[O:61]CC1>>[CH:44]([OH:45])=[O:61].[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C@@H:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C@H:17]([O:24][C:25]3[CH:26]=[CH:27][C:28]4[N:29]([C:31]([N:34]5[CH2:39][CH2:38][CH2:37][CH2:36][C@@H:35]5[CH3:40])=[N:32][N:33]=4)[CH:30]=3)[CH2:16][CH2:15]2)=[O:12])[N:7]([C:41]2[CH:52]=[CH:51][CH:50]=[C:43]([CH2:44][N:53]3[CH2:57][CH2:56][CH2:55][CH2:54]3)[CH:42]=2)[N:6]=1)([CH3:2])([CH3:3])[CH3:4]

Participants

4

Reactant 3

HCID 8028TetrahydrofuranHCID 31268PyrrolidineHCID 89612464Methanesulfonic acid 3-[3-tert-butyl-5-(3-{(1S,4R)-4-[3-((S)-2-methyl-piperidin-1-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl}-ureido)-pyrazol-1-yl]benzyl ester

Product 1

HCID 89612506HCID 89612506, compoundYield 22%

Conditions

Temperature
50 °C

Procedure

To a solution of Intermediate 167b (0.16 mmol) in THF (2 mL) was added pyrrolidine (273 μl, 3.27 mmol) and the reaction stirred at 50° C. for 24 h. The crude reaction mixture was cooled and partitioned between EtOAc and water. The aqueous phase was extracted with EtOAc (×3) and the combined organic layers were washed with brine, dried (MgSO4) and concentrated in vacuo. The resultant residue was purified by FCC on silica, using a gradient of 0-10% (2M NH3 in MeOH) in DCM, followed by MDAP (Method 7) purification, to give the title compound (26 mg, 22%). LCMS (Method 5): Rt 3.64 min, m/z 702 [MH+]. 1H NMR (400 MHz, d6-DMSO): 0.86 (3H, d, J=6.2 Hz), 1.23 (9H, s), 1.42-1.50 (2H, m), 1.58-1.66 (6H, m), 1.70-1.84 (3H, m), 1.84-1.92 (1H, m), 1.95-2.12 (2H, m), 2.36-2.42 (4H, m), 2.86 (1H, ddd, J=12.7, 9.0, 3.9 Hz), 3.12 (1H, dt, J=11.9, 4.1 Hz), 3.58 (2H, s), 4.77 (1H, td, J=8.4, 5.7 Hz), 5.46 (1H, t, J 4.2 Hz), 6.28 (1H, s), 7.01 (1H, d, J=8.6 Hz), 7.15 (1H, dd, J=9.8, 2.1 Hz), 7.20-7.25 (2H, m), 7.26-7.34 (4H, m), 7.35 (1H, s), 7.39 (1H, t, J=7.8 Hz), 7.59 (1H, d, J=10.0 Hz), 7.64 (1H, d, J=1.8 Hz), 8.07 (1H, s), 8.19 (0.7H, s).

Workup

  1. customThe crude reaction mixture
  2. temperaturewas cooled
  3. custompartitioned between EtOAc and water
  4. extractionThe aqueous phase was extracted with EtOAc (×3)
  5. washthe combined organic layers were washed with brine
  6. dry with materialdried (MgSO4)
  7. concentrationconcentrated in vacuo
  8. customThe resultant residue was purified by FCC on silica
  9. customfollowed by MDAP (Method 7) purification

Sources & evidence

ORD record
ord-de82d3b506684552856cc06800b8c8b5
Source dataset
uspto-grants-2016_04
Patent number
US09315503B2

Linked notes

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