Formic Acid → HCID 59255521, compound

HRID 78197Notes

Reaction equation

HRID 78197 reaction equation
CN1CCCC1=O.Cl[C:9]1[CH:10]=[C:11]([C:16]2[CH:20]=[C:19]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([O:28][CH2:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=4)=[CH:24][CH:23]=3)[O:18][N:17]=2)[C:12]([NH2:15])=[N:13][CH:14]=1.C(O)=O.C(N(CC)C(C)C)(C)C>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[N:31]1[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=1[CH2:29][O:28][C:25]1[CH:26]=[CH:27][C:22]([CH2:21][C:19]2[O:18][N:17]=[C:16]([C:11]3[C:12]([NH2:15])=[N:13][CH:14]=[CH:9][CH:10]=3)[CH:20]=2)=[CH:23][CH:24]=1

Participants

7

Reactant 4

HCID 284Formic AcidHCID 13387N-methyl-2-pyrrolidoneHCID 81531DiisopropylethylamineHCID 59255373HCID 59255373, compound

Product 1

HCID 59255521HCID 59255521, compoundYield 6.5%

Reagents, catalysts & solvents 2

HCID 178418397HCID 178418397, compoundCatalystHCID 962WaterSolvent

Conditions

Temperature
100 °C

Procedure

To a N-methylpyrrolidinone (4 mL) solution of 5-chloro-3-(5-(4-(pyridin-2-ylmethoxy)-benzyl)-isoxazol-3-yl)-pyridin-2-ylamine (141 mg, 0.359 mmol) described in Manufacturing Example 189-1-2 were added tetrakis(triphenylphosphine)palladium (0) (42 mg, 36 μmol), formic acid (20 μL, 0.58 mmol), and N,N-diisopropylethylamine (193 μL, 1.08 mmol), which was stirred under nitrogen atmosphere for 5 hours and 35 minutes at 100° C. Water was added to the reaction mixture at room temperature, which was extracted with ethyl acetate. The organic layer was separated, washed with water and saturated aqueous sodium chloride, 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% trifluoroacetic acid), and then further purified by NH silica gel column chromatography (ethyl acetate: methanol=10:1) to obtain the title compound (8.3 mg, 6.5%).

Workup

  1. extractionwhich was extracted with ethyl acetate
  2. customThe organic layer was separated
  3. washwashed with water and saturated aqueous sodium chloride
  4. dry with materialdried over anhydrous magnesium sulfate
  5. filtrationfiltered
  6. concentrationThe filtrate was concentrated under a reduced pressure
  7. customThe residue was purified by reverse-phase high performance liquid chromatography (
  8. additioncontaining 0.1% trifluoroacetic acid), and
  9. customthen further purified by NH silica gel column chromatography (ethyl acetate: methanol=10:1)

Sources & evidence

ORD record
ord-2869d978e0d148b68611db8b7fef8211
Source dataset
uspto-grants-2014_09
Patent number
US08841327B2

Reaction notes

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