Sodium Chloride → methyl 4-amino-3-chloro-5-fluoro-6-(7-fluoro-1H-indol-6-yl)pyridine-2-carboxylate

HRID 923695Notes

Reaction equation

HRID 923695 reaction equation
[F:1][C:2]1[C:3](B2OC(C)(C)C(C)(C)O2)=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([Si](C(C)C)(C(C)C)C(C)C)[CH:8]=[CH:7]2.[NH2:30][C:31]1[C:36]([F:37])=[C:35](Cl)[N:34]=[C:33]([C:39]([O:41][CH3:42])=[O:40])[C:32]=1[Cl:43].[F-].[Cs+].[Na+].[Cl-]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(OCC)(=O)C.C(#N)C.O>[NH2:30][C:31]1[C:36]([F:37])=[C:35]([C:3]2[C:2]([F:1])=[C:10]3[C:6]([CH:7]=[CH:8][NH:9]3)=[CH:5][CH:4]=2)[N:34]=[C:33]([C:39]([O:41][CH3:42])=[O:40])[C:32]=1[Cl:43]

Participants

8

Reactant 4

HCID 5234Sodium ChlorideHCID 25953Cesium fluorideHCID 22677265Methyl 4-amino-3,6-dichloro-5-fluoropicolinateHCID 904186597-Fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(triisopropylsilyl)-1H-indole

Product 1

HCID 78319091methyl 4-amino-3-chloro-5-fluoro-6-(7-fluoro-1H-indol-6-yl)pyridine-2-carboxylateYield 54.3%

Reagents, catalysts & solvents 3

HCID 178418476HCID 178418476, compoundCatalystHCID 8857Ethyl AcetateSolventHCID 18373917Acetonitrile--water (1/1)Solvent

Conditions

Temperature
115 °C

Procedure

7-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(triisopropylsilyl)-1H-indole (500 mg, 1.2 mmol), methyl 4-amino-3,6-dichloro-5-fluoropicolinate (290 mg, 1.2 mmol), cesium fluoride (360 mg, 2.4 mmol) and bis(triphenylphosphine)palladium(II) chloride (84 mg, 0.12 mmol) were combined in 4 mL of a 1:1 v/v acetonitrile-water and heated at 115° C. for 25 min in a Biotage Initiator microwave reactor. The mixture was partitoned between ethyl acetate and sat. NaCl and the organic phase was dried and evaporated. Purification by flash chromatography (SiO2; eluting with 0-20% ethyl acetate in dichloromethane) provided impure product. The material was purified by flash chromatography again (SiO2; eluting with 0-30% ethyl acetate in hexanes) to provide the title compound as a white solid (220 mg, 52%).

Workup

  1. customthe organic phase was dried
  2. customevaporated
  3. customPurification
  4. washby flash chromatography (SiO2; eluting with 0-20% ethyl acetate in dichloromethane)
  5. customprovided impure product
  6. customThe material was purified by flash chromatography again (SiO2; eluting with 0-30% ethyl acetate in hexanes)

Sources & evidence

ORD record
ord-08eba69f9cac4baaa134835ba417ef85
Source dataset
uspto-grants-2016_03
Patent number
US09278985B2

Reaction notes

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