Boron tribromide → 2-(6-((6S)-6-((S)-1-hydroxyethyl)-2,2-dimethylpiperidin-4-yloxy)pyridazin-3-yl)-5-(1H-pyrazol-1-yl)phenol

HRID 1027214Notes

Reaction equation

HRID 1027214 reaction equation
[Si]([O:8][C@H:9]([C@H:11]1[NH:16][C:15]([CH3:18])([CH3:17])[CH2:14][CH:13]([O:19][C:20]2[N:21]=[N:22][C:23]([C:26]3[CH:31]=[CH:30][C:29]([N:32]4[CH:36]=[CH:35][CH:34]=[N:33]4)=[CH:28][C:27]=3[O:37]C)=[CH:24][CH:25]=2)[CH2:12]1)[CH3:10])(C(C)(C)C)(C)C.B(Br)(Br)Br>C(Cl)Cl>[OH:8][C@H:9]([C@H:11]1[NH:16][C:15]([CH3:18])([CH3:17])[CH2:14][CH:13]([O:19][C:20]2[N:21]=[N:22][C:23]([C:26]3[CH:31]=[CH:30][C:29]([N:32]4[CH:36]=[CH:35][CH:34]=[N:33]4)=[CH:28][C:27]=3[OH:37])=[CH:24][CH:25]=2)[CH2:12]1)[CH3:10]

Participants

4

Reactant 2

HCID 25134Boron tribromideHCID 867106113-((6S)-6-((S)-1-(tert-butyldimethylsilyloxy)ethyl)-2,2-dimethylpiperidin-4-yloxy)-6-(2-methoxy-4-(1H-pyrazol-1-yl)phenyl)pyridazine

Product 1

HCID 1363771492-(6-((6S)-6-((S)-1-hydroxyethyl)-2,2-dimethylpiperidin-4-yloxy)pyridazin-3-yl)-5-(1H-pyrazol-1-yl)phenolYield 29.3%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

To a solution of 3-((6S)-6-((S)-1-(tert-butyldimethylsilyloxy)ethyl)-2,2-dimethylpiperidin-4-yloxy)-6-(2-methoxy-4-(1H-pyrazol-1-yl)phenyl)pyridazine (56 mg, 0.1 mmol) in CH2Cl2 (2 mL) was added BBr3 (1 M in heptane, 0.13 mL, 0.13 mmol) dropwise at 0° C. The mixture was stirred overnight. The reaction mixture was quenched with water and then basicifed with saturated NaHCO3 solution. The organic layer was extracted with 10% MeOH in dichloromethane (10 mL×3). The combined extracts were dried over Na2SO4 and concentrated in vacuo. Purification by HPLC gave 12 mg (28%) of 2-(6-((6S)-6-((S)-1-hydroxyethyl)-2,2-dimethylpiperidin-4-yloxy)pyridazin-3-yl)-5-(1H-pyrazol-1-yl)phenol: LCMS Rt=0.52 min (LCMS method Q); MS=410.3 (M+1); 1H NMR (400 MHz, METHANOL-d4) δ 8.23 (d, J=9.6 Hz, 1H), 8.19 (d, J=2.0 Hz, 1H), 7.86 (d, J=8.6 Hz, 1H), 7.65 (d, J=2.0 Hz, 1H), 7.32-7.25 (m, 2H), 7.22 (d, J=9.6 Hz, 1H), 6.47-6.43 (m, 1H), 5.59-5.66 (m, 1H), 3.68-3.77 (m, 1H), 3.02-3.11 (m, 1H), 2.03-2.15 (m, 2H), 1.49-1.59 (m, 2H), 1.24 (s, 3H), 1.11 (d, J=6.4 Hz, 3H), 1.10 (s, 3H).

Workup

  1. customThe reaction mixture was quenched with water
  2. extractionThe organic layer was extracted with 10% MeOH in dichloromethane (10 mL×3)
  3. dry with materialThe combined extracts were dried over Na2SO4
  4. concentrationconcentrated in vacuo
  5. customPurification by HPLC

Sources & evidence

ORD record
ord-f98643de94394c84b36d363c7df096ce
Source dataset
uspto-grants-2014_05
Patent number
US08729263B2

Reaction notes

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