Ethyl Acetate → HCID 15063398, compound

HRID 510017Notes

Reaction equation

HRID 510017 reaction equation
[C:1]([O:5][C:6](=[O:24])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[C:9]1/[CH:17]=[CH:18]/[C:19](OCC)=[O:20])([CH3:4])([CH3:3])[CH3:2].CC(=O)OCC.CC([O-])(C)C.[K+]>[Pd].O=[Pt]=O.C1COCC1>[O:20]=[C:19]1[CH:7]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:24])[N:8]2[C:16]3[C:11]([CH:10]=[C:9]2[CH2:17][CH2:18]1)=[CH:12][CH:13]=[CH:14][CH:15]=3

Participants

7

Reactant 3

HCID 8857Ethyl AcetateHCID 15063396HCID 15063396, compoundHCID 23665647Potassium tert-butoxide

Product 1

HCID 15063398HCID 15063398, compound

Reagents, catalysts & solvents 3

HCID 23938PalladiumCatalystHCID 345198Adams' catalystCatalystHCID 8028TetrahydrofuranSolvent

Procedure

Hydrogenation of the obtained (E)-ethyl 3-(1-(2-(tert-butoxy)-2-oxoethyl)-1H-indol-2-yl)acrylate derivatives (4) over a catalyst such as Pd—C 10% or PtO2 in an aprotic solvent such as EA followed by reaction with KOtBu in an aprotic solvent such as THF gives the corresponding tert-butyl 7-oxo-6,7,8,9-tetrahydropyrido[1,2-a]indole-6-carboxylate derivatives (5). Decarboxylation by reaction with silica gel in an aprotic solvent such as toluene and subsequent reductive aminations with, first, benzylamine in the presence of a reducing agent such NaBH(OAc)3 in an aprotic solvent such as DCM, and with, second, an appropriate aldehyde (as precursor of R3) in the presence of a reducing agent such NaBH4 in a protic solvent such as MeOH gives the corresponding N-benzyl-6,7,8,9-tetrahydropyrido[1,2-a]indol-7-amine derivatives (6). Friedel-Craft acylation with oxalyl chloride in an aprotic solvent such as DCM, followed by esterification with MeOH and subsequent reduction with triethylsilane in the presence of TFA gives the corresponding methyl 2-(7-(benzylamino)-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl)acetate derivatives (7). Debenzylation by hydrogenation over a catalyst such as Pd—C 10% in a protic solvent such as EtOH or by reaction with 1-chloroethyl chloroformate and MeOH in an aprotic solvent such as DCM gives the respective N-substituted methyl 2-(7-amino-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl)acetate derivatives (8). Reaction with an appropriate heteroaryl halide like R4—Cl in the presence of a base such as K2CO3 in an aprotic solvent such as DMA followed by saponification with a base such as NaOH furnished the compounds of formula (I) (Method A).

Sources & evidence

ORD record
ord-e94ab383fdf84caf97abf5da62b3f75f
Source dataset
uspto-grants-2015_08
Patent number
US09096595B2

Reaction notes

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