1,4-Dioxane → Crizotinib acetate

HRID 467403Notes

Reaction equation

HRID 467403 reaction equation
C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH:18]=[C:17]([C:19]3[CH:20]=[N:21][C:22]([NH2:37])=[C:23]([O:25][C@@H:26]([C:28]4[C:33]([Cl:34])=[CH:32][CH:31]=[C:30]([F:35])[C:29]=4[Cl:36])[CH3:27])[CH:24]=3)[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=O)(C)(C)C.[O:38]1CCOCC1>CO>[C:26]([OH:38])(=[O:25])[CH3:28].[Cl:36][C:29]1[C:30]([F:35])=[CH:31][CH:32]=[C:33]([Cl:34])[C:28]=1[C@H:26]([O:25][C:23]1[C:22]([NH2:37])=[N:21][CH:20]=[C:19]([C:17]2[CH:16]=[N:15][N:14]([CH:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)[CH:18]=2)[CH:24]=1)[CH3:27]

Participants

4

Reactant 2

HCID 312751,4-DioxaneHCID 49765979tert-Butyl 4-(4-(6-aMino-5-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate, (R)-

Product 1

HCID 67175389Crizotinib acetateYield 78%

Reagents, catalysts & solvents 1

HCID 887MethanolSolvent

Procedure

To a solution of 4-(4-{6-amino-5-[(R)-1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-pyrazol-1-yl)-piperidine-1-carboxylic acid tert-butyl ester (566.7 mg, 1.03 mmol) in methanol (5 mL) or dichlorometha[pi]e (30 mL) was added 4N HCI/dioxane (15 mL). The solution was stirred for about 1 hour or until the de-protection was complete. The solvents were evaporated and the residue was dissolved in methanol and purified on a reversed phase C-18 preparative HPLC eluting with acetonitrile/water with 0.1% acetic acid from 5% to 30% with a linear gradient. After lyophilization, 3-[(R)-1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-5-(1-piperidin-4-yl-1H-pyrazol-4-yl)-pyridin-2-ylamine acetate was obtained as a white solid (410 mg, 78% yield, 100% HPLC purity, 96.4% ee). 1H NMR (DMSO-d6, 400 MHz) δ 7.84 (s, 1H), 7.68 (d, 1H), 7.50 (dd, 1H), 7.46 (s, 1H), 7.37 (t, 1H), 6.83 (d, 1H), 6.02 (q, 1H), 5.57 (bs, 2H), 4.09 (m, 1H), 2.98 (m, 2H), 2.53 (m, 2H), 1.88 (m, 2H), 1.82 (s, 3H), 1.73 (d, 3H), 1.70 (m, 2H). MS m/e 450 (M+1)+.

Workup

  1. customThe solvents were evaporated
  2. dissolutionthe residue was dissolved in methanol
  3. custompurified on a reversed phase C-18 preparative HPLC
  4. washeluting with acetonitrile/water with 0.1% acetic acid from 5% to 30% with a linear gradient

Sources & evidence

ORD record
ord-69e2a6e3331b47b5af92bd1b2fb74b67
Source dataset
uspto-grants-2014_01
Patent number
US08623359B2

Reaction notes

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