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1-Butanol → 3-[7-(3,5-Dimethylisoxazol-4-yl)-2-oxo-1,2,4,5-tetrahydroimidazo[1,5,4-de][1,4]benzoxazin-4-yl]pyridine-2-carbonitrile

HRID 589107
Notes
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Reaction equation

HRID 589107 reaction equation
[F-].[Cs+].Br[C:4]1[C:13]2[O:12][CH2:11][CH:10]([C:14]3[C:15]([C:20]#[N:21])=[N:16][CH:17]=[CH:18][CH:19]=3)[N:9]3[C:22](=[O:24])[NH:23][C:7]([C:8]=23)=[CH:6][CH:5]=1.[CH3:25][C:26]1[C:30](B(O)O)=[C:29]([CH3:34])[O:28][N:27]=1.C(O)CCC>C(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)(C)C.Cl[Pd]Cl.O>[CH3:25][C:26]1[C:30]([C:4]2[C:13]3[O:12][CH2:11][CH:10]([C:14]4[C:15]([C:20]#[N:21])=[N:16][CH:17]=[CH:18][CH:19]=4)[N:9]4[C:22](=[O:24])[NH:23][C:7]([C:8]=34)=[CH:6][CH:5]=2)=[C:29]([CH3:34])[O:28][N:27]=1
ParticipantsConditionsProcedureWorkupSources & evidenceReaction notes

Participants

7

Reactant 4

HCID 2631-ButanolHCID 25953Cesium fluorideHCID 27343463,5-Dimethylisoxazole-4-boronic acidHCID 904099623-(7-Bromo-2-oxo-1,2,4,5-tetrahydroimidazo[1,5,4-de][1,4]benzoxazin-4-yl)pyridine-2-carbonitrile

Product 1

HCID 862991793-[7-(3,5-Dimethylisoxazol-4-yl)-2-oxo-1,2,4,5-tetrahydroimidazo[1,5,4-de][1,4]benzoxazin-4-yl]pyridine-2-carbonitrile
Yield 90.7%

Reagents, catalysts & solvents 2

HCID 86647055di-tert-butyl(4-dimethylaminophenylphosphine) dichloropalladium(II)CatalystHCID 962WaterSolvent

Conditions

Temperature
100 °C

Procedure

A sealed tube containing 4-(di-tert-butylphosphino)-N,N-dimethylaniline-dichloropalladium (2:1) (11.5 mg, 0.0162 mmol), cesium fluoride (574 mg, 3.78 mmol), 3-(7-bromo-2-oxo-1,2,4,5-tetrahydroimidazo[1,5,4-de][1,4]benzoxazin-4-yl)pyridine-2-carbonitrile (386 mg, 1.01 mmol) and (3,5-dimethylisoxazol-4-yl)boronic acid (533 mg, 3.78 mmol) was placed under vacuum and back-filled with nitrogen (repeated 3×). The sealed tube was charged with 1-butanol (4.92 mL) and water (1.2 mL) and the mixture was degassed by bubbling nitrogen for 15 min and heated at 100° C. for 2 h. The reaction mixture was diluted with ethyl acetate, washed with water and brine, dried over magnesium sulfate, filtered, and concentrated to give the crude product. Purification by preparative LCMS (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 60 mL/min) gave the desired product (342 mg, 85%) as a racemic mixture. 1H NMR (300 MHz, DMSO-d6) δ 11.00 (br s, 1H), 8.81-8.66 (m, 1H), 7.80-7.62 (m, 2H), 6.90 (d, J=8.0 Hz, 1H), 6.80 (d, J=8.0 Hz, 1H), 5.74-5.51 (m, 1H), 4.58 (d, J=3.4 Hz, 2H), 2.29 (s, 3H), 2.12 (s, 3H); LCMS calculated for C20H16N5O3 (M+H)+: m/z=374.1. found: 374.1.

Workup

  1. additionback-filled with nitrogen (repeated 3×)
  2. customthe mixture was degassed
  3. customby bubbling nitrogen for 15 min
  4. additionThe reaction mixture was diluted with ethyl acetate
  5. washwashed with water and brine
  6. dry with materialdried over magnesium sulfate
  7. filtrationfiltered
  8. concentrationconcentrated
  9. customto give the crude product
  10. customPurification by preparative LCMS (XBridge C18 column
  11. washeluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 60 mL/min)

Sources & evidence

ORD record
ord-d1483cab99ca420e8c6b9cf7116d5b73
Source dataset
uspto-grants-2016_01
DOI
10.6084/m9.figshare.5104873.v1
Patent number
US09227985B2

Reaction notes

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On this pageParticipantsConditionsProcedureWorkupSources & evidenceReaction notes