Formic Acid → HCID 59255293, compound

HRID 77859Notes

Reaction equation

HRID 77859 reaction equation
Cl[C:2]1[CH:3]=[C:4]([C:9]2[CH:13]=[C:12]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([CH2:21][O:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=4)=[CH:17][CH:16]=3)[O:11][N:10]=2)[C:5]([NH2:8])=[N:6][CH:7]=1.C(O)=O.C(N(CC)C(C)C)(C)C.O>CN1CCCC1=O.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.C(OCC)(=O)C>[N:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[O:22][CH2:21][C:18]1[CH:19]=[CH:20][C:15]([CH2:14][C:12]2[O:11][N:10]=[C:9]([C:4]3[C:5]([NH2:8])=[N:6][CH:7]=[CH:2][CH:3]=3)[CH:13]=2)=[CH:16][CH:17]=1

Participants

8

Reactant 4

HCID 284Formic AcidHCID 962WaterHCID 81531DiisopropylethylamineHCID 592552525-Chloro-3-(5-(4-(pyridin-2-yloxymethyl)-benzyl)-isoxazol-3-yl)-pyridin-2-ylamine

Product 1

HCID 59255293HCID 59255293, compoundYield 2%

Reagents, catalysts & solvents 3

HCID 178418397HCID 178418397, compoundCatalystHCID 8857Ethyl AcetateSolventHCID 13387N-methyl-2-pyrrolidoneSolvent

Conditions

Temperature
100 °C

Procedure

To a solution of 5-chloro-3-(5-(4-(pyridin-2-yloxymethyl)-benzyl)-isoxazol-3-yl)-pyridin-2-ylamine (37 mg, 94 μmol) described in Manufacturing Example 30-1-3 in N-methyl-2-pyrrolidinone (2 mL) were added formic acid (5.3 μL, 0.14 mmol), N,N-diisopropylethylamine (49 μL, 0.28 mmol) and bis(tri-tert-butylphosphine)palladium (0) (9.6 mg, 19 μmol) at room temperature, which was stirred under nitrogen atmosphere for 1 hour and 25 minutes at 100° C. Water and ethyl acetate were added to the reaction solution at room temperature, which was then filtered through a Celite pad. The filtrate was partitioned into water and ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride, and dried over anhydrous magnesium sulfate, and the solvent was evaporated 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 silica gel column chromatography (heptane:ethyl acetate=1:1) to obtain the title compound (0.66 mg, 2.0%).

Workup

  1. filtrationwhich was then filtered through a Celite pad
  2. customThe filtrate was partitioned into water and ethyl acetate
  3. washThe organic layer was washed with water and saturated aqueous sodium chloride
  4. dry with materialdried over anhydrous magnesium sulfate
  5. customthe solvent was evaporated under a reduced pressure
  6. customThe residue was purified by reverse-phase high performance liquid chromatography (
  7. additioncontaining 0.1% trifluoroacetic acid), and
  8. customthen further purified by silica gel column chromatography (heptane:ethyl acetate=1:1)

Sources & evidence

ORD record
ord-a32d4ed5cdec4598970a06ecae19890a
Source dataset
uspto-grants-2014_09
Patent number
US08841327B2

Reaction notes

Loading…