Synthesis of CRN11300: Detailed Reaction and Isolation Overview

Synthesis Routes Overview

  • Multiple synthetic routes for CRN11300 utilizing different intermediates and conditions.

Route 1: Reductive Amination

  • Step 1: Using NaBH(OAc)_3 (3.0 equiv.), NaOAc in THF at low temperatures (0-5 °C) for 12 hours.
    • Reaction: Converts precursor to amine derivative.
  • Step 2: Cbz protection and subsequent H2, Pd-C in MeOH for deprotection.
  • Step 3: Final steps involve filtration and purification via chromatography.

Route 2: Cbz Protection

  • Step 1: Start with CRN11300-08, allowed to react with QLS-155-005 and Pd2(dba)3 at 25 °C with N2 sparging.
    • Optimized Condition: 6h at 75 °C with solvent DMAc.
  • Step 2: Isolation by column chromatography with yields around 83-91% depending on conditions.

Reaction Conditions for Intermediate Steps

  • Step 11:
    • Reaction: CRN11300-SM5 (1.0 equiv), DEANB (1.2 equiv), Dry THF (10 vol), at 0-5 °C for 16 h.
    • Yield: 89.4% from 100 g, purity quantified by GC method.
  • Step 12: LiOH (2 equiv), THF:H2O solvent system at varying temps (0-25 °C) for reactions.
    • Yield: 85% obtained from specified amounts.

Step 13: Oxidative Reactions Screening

  • Utilization of various oxidizing agents (TEMPO, TCCA, Des-Martin).
    • Results: Different conditions produced various yields and reaction timings noted in the documentation.

Summary of Analytical Data

  • GC Data of final products (CRN11300, QLS-155-006A): Retention Times (RT) indicate separation efficiency.
  • Overall use of NMR, HPLC, and GC for quantifying purity and product yields at each step.

Isolation Process

  • Consistent steps involving filtration, column chromatography, and concentration under reduced pressure to purify products.
  • Special attention required for sensitive intermediates to prevent degradation during isolation.

Key Parameters and Yields

  • Overall effective yields from various steps ranged between 53% and 91% based on effective reaction conditions and proper optimization of parameters (time, temperature, equivalent ratio).
  • Continuous improvements noted through modifications in both reaction and isolation strategies.