PHARMACEUTICALS
Figure 3 – Seqens ’ two-step batch process to Propofol ( a ) & continuous flow process in decarboxylation step
Ixazomib , or boronic acids and esters for their ability to be oxidised in vivo to their active analogue by tumour environments abundant in reactive oxygen species . In 2004 , a small molecule dipeptidyl peptidase inhibitor called talabostat ( Val-boroPro , VbP , Figure 2a ) was found to possess anti-tumour effects on tumours from fibrosarcoma , lymphoma , melanoma , and mastocytoma cell lines . 11
Intensive efforts have been devoted to the synthesis of α- and ß-aminoboronic acid derivatives . 12 One of the green strategies is to produce boronamide compounds within an efficient visible lightinduced decarboxylative borylation starting from α- or ß-amino redox-active esters .
In this photochemical process , an amino-stabilised boron reagent B ( dan ) ( 1,8-diaminonaphthalene ) is used . This group leads easily to the corresponding active boronic acid species under acidic conditions . Furthermore , by conducting this photochemical reaction under flow conditions , an efficient process can be obtained within a shorter reaction time under mild conditions . 13
By carefully selecting the solvent , the operational conditions , and the terminal boron ligand , a large panel of amino acid derivatives can be performed with visible light-induced reaction on redoxactive esters derivatives under practical and environmentally benign procedure . A renewable starting material is used , there is no need for cryogenic conditions or a sensitive organometallic base like a
BuLi , while the synthetic approach is industrially relevant and easily implemented in flow .
Case study : Propofol synthesis
Propofol ( 2,6-diisopropylphenol , Figure 3a ), is a potent intravenous hypnotic agent , which is widely used for the induction and maintenance of anaesthesia and for sedation in delete intensive care units . 14 It has been recognised as an essential medicine by the WHO since April 2013.15
In order to produce propofol , several synthetic approaches have been
Figure 4 – PMI in batch process v . optimised process developed under batch conditions , such as from phenol and propylene by Friedel-Crafts alkylation . 16 Seqens has developed a batch process ( Figure 3 ), in which the alkylation step was carried out using isopropanol , and the decarboxylation step was performed in an autoclave at 140 ° C for five hours at under 4 bar .
To improve productivity , limit capex investment and reach a more sustainable process , we developed a continuous flow process , with a specific focus on the decarboxylation step . 17 The process was carried out in water , resulting in poor solubility of the product , but propofol could be easily separated from the aqueous phase . Advantageously , propofol is obtained with high purity of 97 %.
Further scale-up studies have allowed us to implement a continuous flow process at kilolab scale , leading to 91 % yield and above 97 % purity . For the isolation step , continuous liquid-liquid separation was conducted . Our work has led to increased productivity within a reduced residence time and with such advantages as :
• No organic solvent ( synthesis and extraction ) or organic base
• No work-up beside phase separation
• Enhanced space time yield ( x 35 )
• < 10 minutes in flow v . 5 hours in batch , with higher conversion
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