A Continuous Process for Buchwald–Hartwig Amination at Micro-, Lab-, and Mesoscale Using a Novel Reactor Concept

Abstract

A continuous Buchwald−Hartwig reaction using the bulky N-heterocyclic carbene (NHC) precatalyst [Pd(IPr*)(cin)Cl] 4 has been developed for the synthesis of a key pharmaceutical intermediate 2. Using microreactor technology, the reaction could be optimized under dilute conditions with low material burden and the kinetic parameters investigated. For larger lab-scale operation (gram scale), process-relevant concentrations could be employed and the conditions developed for continuous workup effectively demonstrated (batch methodology published concurrently). The stability of the NHC catalyst allowed for a continuous acidic extraction of the product and on-stream recycling of the catalyst in the organic phase. At this scale, sonication is employed to prevent clogging in the reactor unit. Finally, a bespoke continuous flow reactor has been developed for carrying out the reaction beyond lab scale. This novel reactor concept for running heterogeneous reactions in flow combines the flexibility of continuously stirred tank reactors (CSTRs) with the smooth operation, low residence time distribution and excellent heat transfer capability of a conventional flow reactor. A LCA (life cycle analysis) study has been carried out on the resulting process in comparison with the existing batch protocol, revealing it to be favorable under the majority of environmental factors considered.

Recyclable NHC Catalyst for the Development of a Generalized Approach to Continuous Buchwald–Hartwig Reaction and Workup

“…This work forms the foundation of a multi-kilo process for the Buchwald-Hartwig reaction run in a continuous flow reactor with continuous work-up, which is reported in tandem. 9 It is envisaged that this combination of a highly active catalyst, a generalized approach to continuous work-up and purification and an efficient methodology for catalyst recycling could form the basis for a universal approach for the implementation of Buchwald-Hartwig reactions in flow beyond the immediate case study. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 diphenylmethanol (250 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 ...…”

Steady and unsteady regimes in a T-shaped micro-mixer: Synergic experimental and numerical investigation

“…Moreover, the scale-up procedures of the synthetic route and process from laboratory on gram, or even milligram, scale to ton and multi-ton scale, that are hardly to be derived in conventional batch or semi-batch processes, are straightforward [7] or completely avoided in micro-rectors, as the required production rate is simply obtained by a numbering-up of the reactors often assembled in modular systems [8].…”

Recent Applications of Continuous Flow in Homogeneous Palladium Catalysis

“…Optimisation of the pilotplant was undertaken with the cooperation of AstraZeneca. 33 In the experimental procedure, the product was separated as an ammonium salt from the organic phase contain-…”