Ethyl Acetate → HCID 86732276, compound

HRID 930439Notes

Reaction equation

HRID 930439 reaction equation
[NH2:1][C:2]1[CH:3]=[C:4]([F:21])[C:5]([Cl:20])=[C:6]([C@:8]2([CH3:19])[CH2:13][C@@H:12]([C:14]([F:17])([F:16])[F:15])[O:11][C:10]([NH2:18])=[N:9]2)[CH:7]=1.[Cl:22][C:23]1[CH:24]=[CH:25][C:26]([C:29](O)=[O:30])=[N:27][CH:28]=1.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O.C(OCC)(=O)C>CN(C=O)C>[NH2:18][C:10]1[O:11][C@H:12]([C:14]([F:17])([F:16])[F:15])[CH2:13][C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:29](=[O:30])[C:26]3[CH:25]=[CH:24][C:23]([Cl:22])=[CH:28][N:27]=3)[CH:3]=[C:4]([F:21])[C:5]=2[Cl:20])([CH3:19])[N:9]=1

Participants

6

Reactant 4

HCID 8857Ethyl AcetateHCID 111923Propylphosphonic anhydrideHCID 27628725-Chloro-2-picolinic acidHCID 86732275HCID 86732275, compound

Product 1

HCID 86732276HCID 86732276, compoundYield 23.4%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

To a mixture of (4S,6S)-4-(5-amino-2-chloro-3-fluorophenyl)-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-amine (0.060 g, 0.184 mmol) and 5-chloropicolinic acid (0.035 g, 0.221 mmol) in DMF (1.5 mL) at 0° C. was added 1-propanephosphonic acid cyclic anhydride, 50% solution in ethyl acetate (0.130 mL, 0.221 mmol). The reaction was gradually warmed to rt and stirred for 2 h. The reaction mixture was partitioned between EtOAc and saturated solution of NaHCO3. The organic layer was separated, washed twice with water, then washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. The crude was purified by flash chromatography on silica gel (12 g, 0-100% EtOAc/DCM in 15 min). The fractions were combined and concentrated in vacuo. The resulting white solid was dissolved in MeOH and purified by reverse phase prep HPLC: 10-80% MeCH in Water (with 0.1% TFA). The fractions were collected and neutralized with solid Na2CO3, extracted with DCM three times. The organic solution was dried over sodium sulfate and concentrated in vacuo to give N-(3-((4S,6S)-2-amino-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-4-yl)-4-chloro-5-fluorophenyl)-5-chloropicolinamide (20 mg, 23.3% yield). MS m/z=465 [M+H]+. Calculated for C18H14Cl2F4N4O2: 465.2.

Workup

  1. customThe reaction mixture was partitioned between EtOAc and saturated solution of NaHCO3
  2. customThe organic layer was separated
  3. washwashed twice with water
  4. washwashed with brine
  5. dry with materialdried over MgSO4
  6. filtrationfiltered
  7. concentrationconcentrated in vacuo
  8. customThe crude was purified by flash chromatography on silica gel (12 g, 0-100% EtOAc/DCM in 15 min)
  9. concentrationconcentrated in vacuo
  10. dissolutionThe resulting white solid was dissolved in MeOH
  11. custompurified by reverse phase prep HPLC
  12. customThe fractions were collected
  13. extractionextracted with DCM three times
  14. dry with materialThe organic solution was dried over sodium sulfate
  15. concentrationconcentrated in vacuo

Sources & evidence

ORD record
ord-34ad79c5d99f4d75a8fa5f4e3c91a4bf
Source dataset
uspto-grants-2016_03
Patent number
US09296734B2

Reaction notes

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