Sodium Carbonate → 3-Amino-6-(4-fluoro-phenyl)-5-trifluoromethyl-pyridine-2-carboxylic acid (2-hydroxy-2-methyl-propyl)-amide

HRID 444905

반응식

HRID 444905 반응식
[OH:1][C:2]([CH3:20])([CH3:19])[CH2:3][NH:4][C:5]([C:7]1[C:12]([NH2:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[C:9](Br)[N:8]=1)=[O:6].[F:21][C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1.C([O-])([O-])=O.[Na+].[Na+].CSC1NC(=S)NC(=S)N=1>CCOC(C)=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl.CCO.C1(C)C=CC=CC=1>[OH:1][C:2]([CH3:20])([CH3:19])[CH2:3][NH:4][C:5]([C:7]1[C:12]([NH2:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[C:9]([C:25]2[CH:26]=[CH:27][C:22]([F:21])=[CH:23][CH:24]=2)[N:8]=1)=[O:6]

참가 물질

10

반응물 4

HCID 10340Sodium CarbonateHCID 2856454-Fluorophenylboronic acidHCID 12210973Si-TMTHCID 584423673-Amino-6-bromo-5-trifluoromethyl-pyridine-2-carboxylic acid (2-hydroxy-2-methyl-propyl)-amide

생성물 1

HCID 584423153-Amino-6-(4-fluoro-phenyl)-5-trifluoromethyl-pyridine-2-carboxylic acid (2-hydroxy-2-methyl-propyl)-amide

시약·촉매·용매 5

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)촉매HCID 702Ethanol용매HCID 1140Toluene용매HCID 6344Dichloromethane용매2회HCID 8857Ethyl Acetate용매

실험 절차

To a stirred suspension of 3-amino-6-bromo-5-trifluoromethyl-pyridine-2-carboxylic acid (2-hydroxy-2-methyl-propyl)-amide (Ex. 1.10) (180 mg, 0.505 mmol) and 4-fluorophenylboronic acid (106 mg, 0.758 mmol) in a 2:1 mixture of toluene:EtOH (12 ml) under nitrogen was added 2M Na2CO3(aq) (1.011 ml, 2.022 mmol) followed by Pd(dppf)Cl2.CH2Cl2 adduct (41 mg, 0.051 mmol). The reaction mixture was heated using microwave radiation at 140° C. for 1 hour and then allowed to cool to RT. The mixture was diluted with EtOAc (100 ml) and washed with water (100 ml). The organic phase was separated, filtered through Celite® (filter material) dried (MgSO4) and concentrated in vacuo to yield a brown oil/solid. Purification by chromatography on silica eluting with MeOH/DCM yielded a yellow oil/solid. This was passed through a 500 mg Isolute® Si-TMT cartridge (2,4,6-trimercaptotriazine silica, pre-wetted with DCM) eluting with 30% MeOH/DCM (50 ml) to afford a yellow oil/solid. The crude product was dried in vacuo and slurried in ˜0.5 ml DCM. The resulting suspension was removed by filtration and the filtrate was evaporated to yield the title compound as a light yellow/brown foam-like solid; LC-MS Rt=5.30 mins [M+H]+ 372 (Method 10 minLC_v002).

후처리

  1. temperatureThe reaction mixture was heated
  2. customat 140° C.
  3. customfor 1 hour
  4. washwashed with water (100 ml)
  5. customThe organic phase was separated
  6. filtrationfiltered through Celite® (filter material)
  7. dry with materialdried (MgSO4)
  8. concentrationconcentrated in vacuo
  9. customto yield a brown oil/solid
  10. customPurification by chromatography on silica eluting with MeOH/DCM
  11. customyielded a yellow oil/solid
  12. washeluting with 30% MeOH/DCM (50 ml)
  13. customto afford a yellow oil/solid
  14. dry with materialThe crude product was dried in vacuo
  15. customThe resulting suspension was removed by filtration
  16. customthe filtrate was evaporated

출처 및 근거

ORD 기록
ord-560688d4c67f47ba8099443bfd4a5fce
출처 데이터셋
uspto-grants-2013_07
특허 번호
US08476269B2

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