Org. Process Res. Dev.2019, 23, 2482. DOI: 10.1021/acs.oprd.9b00359
◆A screen of Lewis acids was conducted, and lithium chloride afforded the best conversion and selectivity for activating the mixed anhydride intermediate toward nucleophilic attack by auxiliary 31.
◆In the initial scale-up, it was discovered that the Evans auxiliary 31 was difficult to purge since it has low solubility in the crystallization system.
◆Fortunately, we could take advantage of the slower side reaction between the Evans auxiliary and pivaloyl chloride.
◆Stress experiments and IR studies indicated, the in situ generated sodium enolate of 32 decomposes over time.
◆There was no background reaction between methyl iodide and 32 under the reaction conditions, which enabled in situ generation of the enolate in the presence of methyl iodide. Charging NaHMDS last mitigates the challenge of enolate instability, and the new reaction conditions also provide a cleaner reaction profile.
◆During early process development, it was challenging to consistently achieve high conversion. It was noted that stalled reactions often times remained as a heterogeneous solution, whereas completed reactions were consistently homogeneous.
◆The solids of 32 introduced to the reaction were a neat form that could fully dissolve in THF at room temperature given sufficient time. Once the THF solution was cooled, a fine precipitate developed. These fine solids were found to be a THF solvate form. The physical properties of the two forms are different - the THF solvate is of smaller and more uniform particle size than the neat form. We hypothesized that the stalled reactions were never homogeneous at roomtemperature; hence, there was a mixture of neat form and THF solvate form at the reaction temperature. The neat form was not able to fully dissolve in the reaction mixture during the NaHMDS addition and reaction age, which led to reaction stalling.
◆Two changes were implemented based on this hypothesis. First, the THF was increased to >10 L/kg and initially heated to 45 °C for 2 h to ensure complete dissolution of the neat form of 32. Second, the reactiontemperature was increased from −40 to −20°C to enhance the solubility of 32, which notably had a very minimal impact on the diastereoselectivity of the methylation.
Note
◆Commercial Process to BMS-986205 MSA Salt
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