Process for preparing (S)-1-[2(S)-(1,3-dihyrdro-1,3-dioxo-isoindo-2-yl)-1-oxo-3-phenylpropyl]- 1,2,3,4,-tetrahydro-2-pyridine-carboxylic acid methyl ester

A process for preparing (S)-1-[2(S)-(1,3-dihydro-1,3-dioxo-isoindo-2-yl)-1-oxo-3-phenylpropyl]-1,2 ,3,4-tetrahydro-2-pyridine-carboxylic acid methyl ester comprising the steps

• (a) reacting cyclohexenone sequentially with an appropriate chlorinating agent and an appropriate base to give 2-chlorocyclohex-2-en-1-one;
• (b) reacting 2-chlorocyclohex-2-en-1-one with an appropriate chiral auxiliary and an appropriate reducing agent to give (R)-2-chloro-cyclohex-2-enylalcohol;
• (c) reacting (R)-2-chloro-cyclohex-2-enylalcohol with trichloroacetonitrile to give (R)-2,2,2-trichloro-1-(2-chloro-cyclohex-2-enyloxy)-ethylideneamine;
• (d) reacting (R)-2,2,2-trichloro-1-(2-chloro-cyclohex-2-enyloxy)-ethylideneamine with heat to give (S)-2,2,2-trichloro-N-(2-chloro-cyclohex-2-enyl)-acetamide;
• (e) reacting (S)-2,2,2-trichloro-N-(2-chloro-cyclohex-2-enyl)-acetamide with an appropriate solvolysis agent to give (S)-2-chloro-cyclohex-2-enylamine;
• (f) reacting (S)-2-chloro-cyclohex-2-enylamine with phthalimido-L-phenyalanine derivative to give (S)-N-(2-chloro-cyclohex-2-enyl)-2-[2(S)-1,3-dihydro-1,3-dioxo-isoindol-2- yl)-3-phenyl-propionamide;
• (g) reacting (S)-N-(2-chloro-cyclohex-2-enyl)-2-[2(S)-1,3-dihydro-1,3-dioxo-isoindol-2- yl)-3-phenylpropionamide with ozone in the presence of methanol to give after a reductive work-up N-[2(S)-[(6-oxo)-hexanoic acid methyl ester]]-2-[2(S)-1,3-dihydro-1,3-dioxo-isoindol-2-yl)-3-phenyl-propionamide methyl ester;
• (h) reacting N-[2(S)-[(6-oxo)-hexanoic acid methyl ester]]-2-[2(S)-1,3-dihydro-1,3-dioxo-isoindol-2-yl)-3-phenyl-propionamide with an appropriate cyclizing acid.