Straightforward continuous synthesis of α-aminophosphonates under microreactor conditions

Abstract

The synthesis of α-aminophosphonates on a large scale is not always straightforward. One of the described methodologies has now been adjusted for use in a microreactor system. The CPC College System was used to investigate the continuous production of α-aminophosphonates. This technology couples miniaturisation to optimal reaction conditions for the production of chemical and pharmaceutical intermediates. The reaction of an imine with a dialkyl phosphite in different solvents was optimised, since the use of a solvent is necessary when using a microreactor. When methanol was used, a considerable reduction of the reaction time was noticed in comparison with other commonly used solvents. Subsequently, several reaction parameters were optimised in batch and compared with the continuous process in the microreactor. Similar yields and purities were obtained compared to the batch reaction. Using the microreactor system, the scale-up problems were avoided and large amounts of α-aminophosphonates could be generated in a short time.

Experimental and computational study of the ring opening of tricyclic oxanorbornenes to polyhydro isoindole phosphonates

“…The reaction sequence starts with the synthesis of aminoalkyl phosphonate 2 following our previously reported protocol. 20 Then, aminophosphonate 2 was acylated, as this facilitates the IMDAFreaction by its electronic and steric properties (Scheme 1). 21 Stirring acylaminophosphonate 3 under reflux in acetonitrile completed the IMDAF-reaction.…”

“…The spectrum was derived from the spectral data of the mixture of the cyclohexene derivatives. Dimethyl (1R,3aR,5S,6S)-and (1S,3aS,5R,6R)-[6-chloro-5-hydroxy-2-(2,2,2-trichloroacetyl)-2,3,3a,4,5,6-hexahydro-1Hisoindol-1-yl] phosphonate (20). (Found: C, 33.7; H, 3.7; N, 3.3.…”

Recent advances in synthetic micro reaction technology

“…More recently, Stevens and co-workers 56 described the use of a CPC college system for the continuous flow synthesis of an array of pharmaceutically important a-aminophosphonates (Scheme 13) via the Kabachnik-Fields reaction. The authors found that by maintaining the micro reactor at 50 uC and operating at a flow rate of 600.0 ml min 21 (residence time = 78 min), quantitative conversion of an aldimine 46 to the respective a-aminophosphonate 47 could be obtained.…”

Continuous flow synthesis of α-aryl-α-aminophosphonates

“…Stevens and co-workers investigated the aza-Pudovik reaction of α-aliphatic and α-aromatic imines with dimethyl phosphite in a microreactor (Scheme 2) [14]. In the first stage, the reaction conditions were optimized in a batch reactor, and then the best set of conditions was transferred to the flow system.…”