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Methanol → HCID 66558842, compound

HRID 1530577
Notes
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Reaction equation

HRID 1530577 reaction equation
C(O[C:9]([N:11]1[CH2:16][CH2:15][CH:14]([CH:17]([O:22][C:23]2[CH:45]=[CH:44][C:26]3[C:27]4[N:31]([CH2:32][CH2:33][O:34][C:25]=3[CH:24]=2)[CH:30]=[C:29]([C:35]2[N:36]([CH:41]([CH3:43])[CH3:42])[N:37]=[C:38]([CH3:40])[N:39]=2)[N:28]=4)[C:18]([F:21])([F:20])[F:19])[CH2:13][CH2:12]1)=[O:10])C1C=CC=CC=1.CO.[CH3:48]CN(C(C)C)C(C)C.C(Cl)(=O)C>[Pd].CC(C)=O>[F:21][C:18]([F:19])([F:20])[CH:17]([CH:14]1[CH2:15][CH2:16][N:11]([C:9](=[O:10])[CH3:48])[CH2:12][CH2:13]1)[O:22][C:23]1[CH:45]=[CH:44][C:26]2[C:27]3[N:31]([CH:30]=[C:29]([C:35]4[N:36]([CH:41]([CH3:43])[CH3:42])[N:37]=[C:38]([CH3:40])[N:39]=4)[N:28]=3)[CH2:32][CH2:33][O:34][C:25]=2[CH:24]=1
ParticipantsProcedureWorkupSources & evidenceReaction notes

Participants

7

Reactant 4

HCID 887MethanolHCID 6367Acetyl chlorideHCID 81531DiisopropylethylamineHCID 68313044HCID 68313044, compound

Product 1

HCID 66558842HCID 66558842, compoundYield 8.3%

Reagents, catalysts & solvents 2

HCID 23938
Palladium
Catalyst
HCID 180AcetoneSolvent

Procedure

To a solution of 4-{2,2,2-trifluoro-1-[2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulen-8-yloxy]ethyl}piperidine-1-carboxylic acid benzyl ester from Example 5 (210 mg, 0.34 mmol) in a 1:10 mixture MeOH:acetone (11 mL), was added 10% Pd/C (200 mg). The reaction mixture was stirred at RT under a hydrogen atmosphere for 18 h. The suspension was then filtered through a pad of Celite® and to the filtrate fresh 10% Pd/C (200 mg) was added. The reaction mixture was stirred at RT under a hydrogen atmosphere for 48 h. The suspension was then filtered through a pad of Celite® and the filtrate was concentrated in vacuo. The resulting residue was treated with DIPEA (0.79 mL, 4.42 mmol) and acetyl chloride (0.23 mL, 4.08 mmol) and stirred at RT for 18 h. The crude material was purified by reverse phase HPLC (Phenomenex Gemini 5 μm C18 on a 25 min gradient 10-90% 0.1% HCO2H in acetonitrile/water) affording 179 (15 mg, 8%). LCMS: RT 4.23 min [M+H]+ 533.2. 1H NMR (CDCl3, 400 MHz): δ 8.47 (1H, d, J=8.99 Hz), 7.61 (1H, s), 6.80 (1H, dd, J=9.00, 2.62 Hz), 6.64 (1H, d, J=2.49 Hz), 5.92-5.85 (1H, m), 4.78-4.69 (1H, m), 4.50-4.47 (2H, m), 4.46-4.35 (3H, m), 3.93-3.85 (1H, m), 3.16-3.02 (1H, m), 2.64-2.51 (1H, m), 2.42 (3H, s), 2.27-2.15 (1H, m), 2.10 (3H, d, J=2.36 Hz), 2.05-1.93 (1H, m), 1.89-1.75 (1H, m), 1.64-1.44 (8H, m)

Workup

  1. filtrationThe suspension was then filtered through a pad of Celite® and to the filtrate fresh 10% Pd/C (200 mg)
  2. additionwas added
  3. stirringThe reaction mixture was stirred at RT under a hydrogen atmosphere for 48 h
  4. filtrationThe suspension was then filtered through a pad of Celite®
  5. concentrationthe filtrate was concentrated in vacuo
  6. stirringstirred at RT for 18 h
  7. customThe crude material was purified by reverse phase HPLC (Phenomenex Gemini 5 μm C18 on a 25 min gradient 10-90% 0.1% HCO2H in acetonitrile/water)

Sources & evidence

ORD record
ord-ac657198bf714cd3acbeab0c176f1b99
Source dataset
uspto-grants-2015_07
DOI
10.6084/m9.figshare.5104873.v1
Patent number
US09090628B2

Reaction notes

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On this pageParticipantsProcedureWorkupSources & evidenceReaction notes