Synthesis of Urea Derivatives in Two Sequential Continuous-Flow Reactors

Abstract

A continuous-flow system consisting of two sequential microreactors was developed for the synthesis of nonsymmetrically substituted ureas starting from tert-butoxycarbonyl protected amines. Short reaction times could be achieved under mild conditions. In-line FT-IR analytical technique was used to monitor the reaction, including the formation of the isocyanate intermediate, thus allowing optimization of the reagent ratios. The mechanistic role of the applied base was also clarified. The setup was successfully utilized for the synthesis of several urea derivatives including the active pharmaceutical ingredient cariprazine.

Flow synthesis kinetics for lomustine, an anti-cancer active pharmaceutical ingredient

“…For example, reactions with slow kinetics are better suited to batch operation and the existence of multiple phases can limit the benefits of operating in one mode vs. the other. 13,14 Moreover, if an existing process route has acceptable performance with respect to yield, scale, process time, purity etc., and can be operated safely, then switching operating mode is not worthwhile. Judicious process selection and design is imperative for successful continuous process implementation.…”

“…Expanding from eqn (2), the resulting material balances in reactor 2 are as per eqn ( 12)- (14). Stoichiometric coefficients and reaction orders for reactor 2 are listed in Table 4.…”

Efficient access to 3′-O-phosphoramidite derivatives of tRNA relatedN6-threonylcarbamoyladenosine (t6A) and 2-methylthio-N6-threonylcarbamoyladenosine (ms2t6A)

“…In so far reported procedures for the one-pot syntheses of ureas from carbamates, the use of an excess of amine substrate, usually up to 3 equivalents (or more for less nucleophilic amines) is recommended to obtain the higher efficiency of the process. 48,50,51 However, in the case of t 6 A/ms 2 t 6 A synthesis, the amine nucleoside substrate, especially non-native 2-methylthioadenosine (ms 2 A) is a very costly reagent. Therefore, in the second step of optimizations we examined an excess of N-Boc protected L-threonine derivative 1 to nucleoside 3a in a range 1.5-2.5 (entries 8-10), yet the concentrations of Tf 2 O and 2-Cl-Py against 1 were kept as determined previously (entry 2).…”

“…N-Boc protecting group). [44][45][46][47][48][49][50][51][52][53] Most likely, such variant of the isocyanate method (Scheme 1, path B3) applied in the synthesis of the 3 0 -O-phosphoramidite derivatives of t 6 A/ms 2 t 6 A would be greatly advantageous in comparison to our previous isocyanate route (Scheme 1, path B2) owing to a smaller number of synthesis steps in the preparation of threonine derivative (the removal of N-Boc protection is unnecessary) and escaping the use of toxic phosgene.…”

C-N Bond Formation by Consecutive Continuous-Flow Reductions towards A Medicinally Relevant Piperazine Derivative

“…As a recent addition to this class, cariprazine ( 4 ) was approved by the FDA in 2015 for the treatment of schizophrenia and bipolar I disorder [ 28 , 29 ]. As a continuation of our efforts to develop a continuous-flow protocol for the synthesis of this API [ 30 ], we aimed to explore the key C-N bond formation through the production of its tert -butoxycarbonyl protected intermediate ( 3 ). For this purpose, a sequence of consecutive continuous-flow reductions was designed, starting from a known ester ( 1 ) maintaining the beneficial trans geometry ( Scheme 1 ).…”