2-Aminopyridine → 5-Methyl-8-(pyridinylamino)-6-trifluoromethyl-1,3,4,4a,5,9b-hexahydro-pyrido[4,3-b]indole-2-carboxylic acid tert-butyl ester

HRID 2215907Notes

Reaction equation

HRID 2215907 reaction equation
[C:1]([O:5][C:6]([N:8]1[CH2:26][CH2:25][CH:11]2[N:12]([CH3:24])[C:13]3[C:14]([C:20]([F:23])([F:22])[F:21])=[CH:15][C:16](Br)=[CH:17][C:18]=3[CH:10]2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=1.CC([O-])(C)C.[Na+].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1.CCOC(C)=O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:26][CH2:25][CH:11]2[N:12]([CH3:24])[C:13]3[C:14]([C:20]([F:23])([F:22])[F:21])=[CH:15][C:16]([NH:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=4)=[CH:17][C:18]=3[CH:10]2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]

Participants

8

Reactant 4

HCID 104392-AminopyridineHCID 634876Binap, (A+-)-HCID 23676156Sodium t-butoxideHCID 67182325HCID 67182325, compound

Product 1

HCID 671835315-Methyl-8-(pyridinylamino)-6-trifluoromethyl-1,3,4,4a,5,9b-hexahydro-pyrido[4,3-b]indole-2-carboxylic acid tert-butyl ester

Reagents, catalysts & solvents 3

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 1140TolueneSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
80 °C

Procedure

8-bromo-5-methyl-6-trifluoromethyl-1,3,4,4a,5,9b-hexahydro-pyrido[4,3-b]indole-2-carboxylic acid tert-butyl ester (Example 44 or 45, 1.0 eq.), aminopyridine (3.0 eq.), and NaOt-Bu (3.0 eq.) were dissolved in anhydrous toluene (0.17 M). The mixture was degassed with argon for 30 min. Pd2(dba)3 (0.06 eq.) and 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (0.18 eq.) were added; the reaction was heated at 80° C. for 16 h. The reaction was cooled to room temperature, diluted with EtOAc, filtered through a bilayer pad of diatomaceous earth and silica gel, and concentrated. Purification of the residue by flash column chromatography (silica gel, 2–30% EtOAc/hexanes) provided 5-methyl-8-(pyridinylamino)-6-trifluoromethyl-1,3,4,4a,5,9b-hexahydro-pyrido[4,3-b]indole-2-carboxylic acid tert-butyl ester derivatives. The intermediate was dissolved in CH2Cl2/TFA (5/1) at rt stirred for 1 h. Upon concentration in vacuo, the residue was partitioned between CH2Cl2/1 M NaOH. The aqueous phase was extracted with CH2Cl2. The combined organic phases were dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography to give the title compound.

Workup

  1. customThe mixture was degassed with argon for 30 min
  2. temperatureThe reaction was cooled to room temperature
  3. filtrationfiltered through a bilayer pad of diatomaceous earth and silica gel
  4. concentrationconcentrated
  5. customPurification of the residue by flash column chromatography (silica gel, 2–30% EtOAc/hexanes)

Sources & evidence

ORD record
ord-e802fbe54aa4448aa9c1f049fb8250fd
Source dataset
uspto-grants-2006_09
Patent number
US07109339B2

Reaction notes

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