Two-Step Synthesis of\na Dolutegravir Intermediate\nDTG‑6 in a Microfluidized Bed Cascade System: Route Design\nand Kinetic Study

In the existing two-step method for the preparation of\nDTG-6 (i.e.,\nan important intermediate of the anti-HIV drug Dolutegravir (DTG)),\na strong base is required to neutralize the homogeneous strong acid\ncatalyst of the first step to make the reaction solution weakly acidic\nfor the DTG-5 cyclization in the second step. The DTG-6 yield in the\ntwo-step synthesis is affected by the reaction of the strong base\nwith the carboxyl group on the generated intermediate DTG-5. In this\narticle, a solid acid catalyst, titanium cation-exchanged montmorillonite\n(Ti<sup>4+</sup>-mont), was used in the microfluidized bed to catalyze\nthe conversion of DTG-4 to DTG-5. DTG-5 can be directly cyclized with\n(<i>R</i>)-3-aminobutanol (RABO) to form DTG-6 without the\nintroduction of a strong base into the reaction solution. After the\nparametric screening on the flow rate, solid acid type, temperature,\nresidence time, and solvent type, the DTG-6 yield increased from 90%\n(in our previous work) to 95% in the microfluidized bed cascade system.\nDue to the easy separation of heterogeneous catalyst, the utilization\nof a microfluidized bed not only simplified operations, but also improved\nsynthetic efficiency. Moreover, the kinetics of the cyclization of\nunstable intermediate DTG-5 with RABO was investigated and verified\nby means of experimental data.