Method for Preparation of (2R,3S)-2-(benzo[d]imidazolylpropyl)piperidin-3-ol Derivatives

A method for preparing a compound represented by the following Chemical Formula 1, the method comprising the steps of:

• 1) reacting a compound represented by the following Chemical Formula 1-1 with a compound represented by the following Chemical Formula 1-2 in the presence of a base to prepare a compound represented by the following Chemical Formula 1-3;
• 2) reacting a compound represented by the following Chemical Formula 1-3 in the presence of a sulfur-containing reducing agent to prepare a compound represented by the following Chemical Formula 1-4;
• 3) reacting a compound represented by the following Chemical Formula 1-4 with an orthoformate-based compound to prepare a compound represented by the following Chemical Formula 1-5;
• and
• 4) reacting a compound represented by the following Chemical Formula 1-5 with hydrochloric acid in the presence of water and acetone to prepare a compound represented by the following Chemical Formula 1:
• wherein, in Chemical Formulas 1-1 to 1-5,
• P1 and P2 each independently represent a protecting group.

A method for preparing a compound represented by the following Chemical Formula 1-1, the method comprising the steps of:

• 1) reacting a compound represented by the following Chemical Formula 1A with pyrrolidine to prepare a compound represented by the following Chemical Formula 1B;
• 2) reacting a compound represented by the following Chemical Formula 1B with 3-bromo-1-propene to prepare a compound represented by the following Chemical Formula 1C;
• 3) reducing a compound represented by the following Chemical Formula 1C in the presence of a ketoreductase enzyme to prepare a compound represented by the following Chemical Formula 1D;
• 4) reacting a compound represented by the following Chemical Formula 1 D with a compound represented by the following Chemical Formula 1d to prepare a compound represented by the following Chemical Formula 1E;
• 5) {circle around (1)} reacting a compound represented by the following Chemical Formula 1E with a borane-based compound and then {circle around (2)} reacting the reactant with an oxidizing agent to prepare a compound represented by the following Chemical Formula 1F;
• 6) reacting a compound represented by the following Chemical Formula 1F with methanesulfonyl chloride in the presence of a base to prepare a compound represented by the following Chemical Formula 1G;
• 7) reacting a compound represented by the following Chemical Formula 1G with an azidation reagent to prepare a compound represented by the following Chemical Formula 1H;
• and
• 8) reacting a compound represented by the following Chemical Formula 1H in the presence of a base to prepare a compound represented by the following Chemical Formula 1-1:
• wherein, in Chemical Formulas 1-1, 1A to 1H and 1d,
• X is halogen,
• Ms is methanesulfonyl, and
• P1 and P2 each independently represent a protecting group.

A method for preparing a compound represented by the following Chemical Formula 2, which is an intermediate for the preparation of a compound represented by the following Chemical Formula 1-1, the method comprising the steps of:

• 1) reacting a compound represented by the following Chemical Formula 2-1 with propane-1,3-diol to prepare a compound represented by the following Chemical Formula 2-2;
• 2) oxidizing a compound represented by the following Chemical Formula 2-2 to prepare a compound represented by the following Chemical Formula 2-3;
• 3) {circle around (1)} reacting a compound represented by the following Chemical Formula 2-3 with dibenzyl azodicarboxylate or di(C1-4 alkyl)azodicarboxylate, and then {circle around (2)} reacting the reactant with allyl halide to prepare a compound represented by the following Chemical Formula 2-4;
• 4) subjecting a compound represented by the following Chemical Formula 2-4 to a cyclization reaction to prepare a compound represented by the following Chemical Formula 2-5;
• 5) removing benzyl carbamate or C1-4 alkyl carbamate from a compound represented by the following Chemical Formula 2-5 to prepare a compound represented by the following Chemical Formula 2-6;
• 6) subjecting a compound represented by the following Chemical Formula 2-6 to a boronation-oxidation reaction to prepare a compound represented by the following Chemical Formula 2-7;
• 7) subjecting a compound represented by the following Chemical Formula 2-7 to a cyclization reaction to prepare a compound represented by the following Chemical Formula 2-8;
• 8) reacting a compound represented by the following Chemical Formula 2-8 in the presence of a base to prepare a compound represented by the following Chemical Formula 2-9;
• 9) introducing a protecting group into a compound represented by the following Chemical Formula 2-9 to prepare a compound represented by the following Chemical Formula 2-10;
• 10) reacting a compound represented by the following Chemical Formula 2-10 in the presence of an acid to prepare a compound represented by the following Chemical Formula 2-11;
• 11) introducing a protecting group into a compound represented by the following Chemical Formula 2-11 to prepare a compound represented by the following Chemical Formula 2-12;
• and
• 12) reacting a compound represented by the following Chemical Formula 2-12 in the presence of an acid to prepare a compound represented by the following Chemical Formula 2:
• wherein, in Chemical Formulas 1-1, 2 and 2-1 to 2-12,
• R1 is benzyl or C1-4 alkyl, and
• P1 and P2 each independently represent a protecting group.