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Tetrahydrofuran → 3-(3-(4-(5-Fluoro-pyridin-2-ylmethoxy)-benzyl)-isoxazol-5-yl)-pyridin-2,6-diamine

HRID 1891814
Notes
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Reaction equation

HRID 1891814 reaction equation
O1CCCC1.[NH2:6][C:7]1[C:12]([C:13]2[O:17][N:16]=[C:15]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=3)[CH:14]=2)=[CH:11][CH:10]=[C:9]([NH2:26])[N:8]=1.[OH-].[Na+].Cl[CH2:30][C:31]1[CH:36]=[CH:35][C:34]([F:37])=[CH:33][N:32]=1>CN(C)C=O>[F:37][C:34]1[CH:35]=[CH:36][C:31]([CH2:30][O:25][C:22]2[CH:23]=[CH:24][C:19]([CH2:18][C:15]3[CH:14]=[C:13]([C:12]4[C:7]([NH2:6])=[N:8][C:9]([NH2:26])=[CH:10][CH:11]=4)[O:17][N:16]=3)=[CH:20][CH:21]=2)=[N:32][CH:33]=1
ParticipantsConditionsProcedureWorkupSources & evidenceReaction notes

Participants

6

Reactant 4

HCID 8028TetrahydrofuranHCID 14798Sodium HydroxideHCID 216980592-(Chloromethyl)-5-fluoropyridineHCID 592553274-(5-(2,6-Diamino-pyridine-3-yl)-isoxazol-3-ylmethyl)phenol

Product 1

HCID 592555053-(3-(4-(5-Fluoro-pyridin-2-ylmethoxy)-benzyl)-isoxazol-5-yl)-pyridin-2,6-diamineYield 67%

Reagents, catalysts & solvents

1
HCID 6228DimethylformamideSolvent2×

Conditions

Temperature
60 °C

Procedure

To a tetrahydrofuran (3 mL) solution of 4(5-(2,6-diamino-pyridin-3-yl)-isoxazol-3-ylmethyl)-phenol (25.5 mg, 0.09 mmol) described in Manufacturing Example 18-1-1 was added a 5 N sodium hydroxide aqueous solution (18.1 μL, 0.09 mmol), which was dissolved by irradiating ultrasonic wave for 1 minute. The reaction solution was concentrated under a reduced pressure, which gave a white solid. An N,N-dimethylformamide (1 mL) solution of 2-chloromethyl-5-fluoropyridine (13.2 mg, 0.09 mmol) described in manufacturing Example 41-1-2 was added to a suspension of this solid in N,N-dimethylformamide (1 mL), which was stirred for 1 hour at 60° C. The reaction mixture was cooled to room temperature and then partitioned into water and ethyl acetate. The organic layer was separated, washed with water and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure. The residue was purified by reverse-phase high performance liquid chromatography (using an acetonitrile-water mobile phase containing 0.1% trifluoroacetc acid) to obtain the title compound (23.6 mg, 67%) as a ditrifluoroacetic acid salt.

Workup

  1. dissolutionwas dissolved
  2. customby irradiating ultrasonic wave for 1 minute
  3. concentrationThe reaction solution was concentrated under a reduced pressure, which
  4. customgave a white solid
  5. temperatureThe reaction mixture was cooled to room temperature
  6. custompartitioned into water and ethyl acetate
  7. customThe organic layer was separated
  8. washwashed with water and saturated aqueous sodium chloride solution
  9. dry with materialdried over anhydrous magnesium sulfate
  10. filtrationfiltered
  11. concentrationThe filtrate was concentrated under a reduced pressure
  12. customThe residue was purified by reverse-phase high performance liquid chromatography (
  13. additioncontaining 0.1% trifluoroacetc acid)

Sources & evidence

ORD record
ord-aa869c21c23e4732b4ed59d8e2bac10d
Source dataset
uspto-grants-2013_08
DOI
10.6084/m9.figshare.5104873.v1
Patent number
US08507530B2

Reaction notes

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On this pageParticipantsConditionsProcedureWorkupSources & evidenceReaction notes