Efficient and practical asymmetric synthesis of 1-tert-butyl 3-methyl (3R,4R)-4-(2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)piperidine-1,3-dicarboxylate, a useful intermediate for the synthesis of nociceptin antagonists

An efficient and practical asymmetric synthesis of 1-tert-butyl 3-methyl (3R,4R)-4-(2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)piperidine-1,3-dicarboxylate 1, a useful intermediate for the synthesis of nociceptin antagonists, has been developed. This method includes the following key steps: (1) diastereoselective reduction of a chiral enaminoester 3 having (R)-1-phenylethylamine as a chiral pool constituent with the use of a combined TFA–NaBH4 reduction system and (2) efficient isomerization from 3,4-cis-substituted piperidine 8 to 3,4-trans-substituted piperidine 1 under basic conditions. The above methods proved to be applicable for large-scale operation and hundred grams of enantiomerically pure compound 1 (>98% ee) was obtained.

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1-tert-Butyl 3-methyl 4-{[(1R)-1-phenylethyl]amino}-5,6-dihydropyridine-1,3(2H)-dicarboxylateC20H28N2O4[α]D24=-277 (c 1.0, CHCl3)Source of chirality: [(1R)-1-phenylethyl]amineAbsolute configuration: (1R)

1-tert-Butyl 3-methyl (3S,4R)-4-{[(1R)-1-phenylethyl]amino}piperidine-1,3-dicarboxylateC20H30N2O4[α]D25=+30 (c 1.0, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (3R,4R)-4-{[(1R)

1-tert-Butyl 3-methyl (3R,4S)-4-{[(1R)-1-phenylethyl]amino}piperidine-1,3-dicarboxylateC20H30N2O4[α]D25=+47 (c 1.0, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (3R, 4S)-4-{[(1R)

1-tert-Butyl 3-methyl (3R,4R)-4-{[(1R)-1-phenylethyl]amino}piperidine-1,3-dicarboxylateC20H30N2O4[α]D25=+14 (c 1.0, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (3R,4R)-4-{[(1R)

1-tert-Butyl 3-methyl (3S,4S)-4-{[(1R)-1-phenylethyl]amino}piperidine-1,3-dicarboxylateC20H30N2O4[α]D24=+32 (c 1.0, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (3R,4S)-4-{[(1R)

1-tert-Butyl 3-methyl (3S,4R)-4-[(2-nitrophenyl)amino]piperidine-1,3-dicarboxylateC18H25N3O6[α]D25=-60 (c 1.0, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (3S,4R)

1-tert-Butyl 3-methyl (3R,4R)-4-[(2-nitrophenyl)amino]piperidine-1,3-dicarboxylateC18H25N3O6[α]D25=-140 (c 1.0, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (3R,4R)

1-tert-Butyl 3-methyl (3S,4R)-4-(2-oxo-2,3-dihydro-1H-benzimidazol-1-yl) piperidine-1,3-dicarboxylateC19H25N3O5[α]D25=+31 (c 1.0, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (3S,4R)

1-tert-Butyl 3-methyl (3R,4R)-4-(2-oxo-2,3-dihydro-1H-benzimidazol-1-yl) piperidine-1,3-dicarboxylateC19H25N3O5[α]D25=+50 (c 1.0, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (3R,4R)

1-tert-Butyl 3-methyl (3R,4R)-4-(3-ethyl-2-oxo-2,3-dihydro-1H-benzimidazol -1-yl) piperidine-1,3-dicarboxylateC21H29N3O5[α]D24=+50 (c 1.0, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (3R,4R)

Methyl (3R,4R)-1-(cyclooctylmethyl)-4-(3-ethyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)piperidine-3-carboxylateC25H37N3O3[α]D24=+24 (c 1.0, MeOH)Source of chirality: asymmetric synthesisAbsolute configuration: (3R,4R)

1-[(3R,4R)-1-(Cyclooctylmethyl)-3-(hydroxymethyl)piperidin-4-yl]-3-ethyl-1,3- dihydro-2H-benzimidazol-2-oneC24H37N3O2[α]D24=+7.8 (c 1.0, 2-propanol)Source of chirality: asymmetric synthesisAbsolute configuration: (3R,4R)