Hydrochloric Acid → 3-Amino-6-(2,6-difluorophenyl)-5-fluoropicolinic acid

HRID 69927

반응식

HRID 69927 반응식
C([O-])(O)=O.[Na+].[NH2:6][C:7]1[C:8]([C:22]([O:24]C)=[O:23])=[N:9][C:10]([C:14]2[C:19]([F:20])=[CH:18][CH:17]=[CH:16][C:15]=2[F:21])=[C:11]([F:13])[CH:12]=1.[Li+].[OH-].Cl>C1COCC1.CO>[NH2:6][C:7]1[C:8]([C:22]([OH:24])=[O:23])=[N:9][C:10]([C:14]2[C:19]([F:20])=[CH:18][CH:17]=[CH:16][C:15]=2[F:21])=[C:11]([F:13])[CH:12]=1

참가 물질

7

반응물 4

HCID 313Hydrochloric AcidHCID 3939Lithium HydroxideHCID 516892Sodium BicarbonateHCID 59226608Methyl 3-amino-6-(2,6-difluorophenyl)-5-fluoropicolinate

생성물 1

HCID 592265133-Amino-6-(2,6-difluorophenyl)-5-fluoropicolinic acid

시약·촉매·용매 2

HCID 887Methanol용매HCID 8028Tetrahydrofuran용매

실험 절차

To a solution of methyl 3-amino-5-fluoropicolinate (1.0 equiv.) in DME/2M Na2CO3 (3:1, 0.05 M) equipped with microwave vial was added 2,6-difluorophenylboronic acid (3.0 equiv.) and Pd(dppf)Cl2-DCM (0.1 equiv.). The reaction mixture was heated to 140° C. for 10 min in microwave reactor. After 2,6-difluorophenylboronic acid (3.0 equiv.) was added more, the reaction mixture was heated once more to 140° C. for 10 min in microwave reactor. After the reaction mixture was cooled to room temperature, H2O and EtOAc were added and the organic phase was washed with brine, then dried with Na2SO4, and concentrated. The crude material was purified via preparative HPLC. The pure methyl 3-amino-6-(2,6-difluorophenyl)-5-fluoropicolinate was obtained after the pure fractions were neutralized with NaHCO3, extracted with EtOAc, and concentrated (34%). The methyl 3-amino-6-(2,6-difluorophenyl)-5-fluoropicolinate (1.0 equiv.) was dissolved in THF and MeOH (2:1, 0.2 M) followed by addition of LiOH (1.8 equiv., 1 M aqueous solution). After the reaction mixture was stirred for 1.5 h at room temperature, the reaction mixture was quenched with 1 N HCl solution (1.8 equiv.) and extracted with EtOAc. The organic phase was washed with brine, then dried with Na2SO4, and concentrated. The crude 3-amino-6-(2,6-difluorophenyl)-5-fluoropicolinic acid was used for the next step without further purification (88%). LCMS (m/z): 269.0 (MH+); LC Rt=3.26 min.

후처리

  1. extractionextracted with EtOAc
  2. concentrationconcentrated (34%)
  3. extractionextracted with EtOAc
  4. washThe organic phase was washed with brine
  5. dry with materialdried with Na2SO4
  6. concentrationconcentrated
  7. customThe crude 3-amino-6-(2,6-difluorophenyl)-5-fluoropicolinic acid was used for the next step without further purification (88%)

출처 및 근거

ORD 기록
ord-726446ce58484ccc86a55324e7df2440
출처 데이터셋
uspto-grants-2014_09
특허 번호
US08822497B2

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