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Org. Process Res.Dev. 2017, 21, 1286. DOI: 10.1021/acs.oprd.7b00172 From Discovery to FIH Enabling Delivery ◆ The use of 2-MeTHF was identified as an appropriate alternative to 1,4-dioxane at a reduced catalyst loading ◆ The precipitation of palladium black earlyin the reaction was a key observation. So the temperature of the reaction mixture was lowered from reflux to 70 °C. ◆ In addition, the use of tetrabutylammonium bromide (TBAB) as a phase transfer catalyst (PTC) served to increase the reaction yield and consistently consume starting material 2 From FIH Enabling Delivery to Commercially Viable Process ◆ Analyzing the production cost of 1, we determined that 52% of the total cost to manufacture 1 was from the purchase cost of 3. ◆ Using this published procedure to make 7, we projected we could manufacture compound 7 for a third the cost of 3 ◆ During optimization studies, we observed varying levels 9 ◆ Subjecting 4 to the reaction conditions resultedin high
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