1,4-Dioxane → Crizotinib acetate

HRID 1471294Notes

Reaction equation

HRID 1471294 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—1 H—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)δ7.84 (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-b87f9c200db54c3a850c7205206de759
Source dataset
uspto-grants-2015_04
Patent number
US09011865B2

Reaction notes

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