Multistep synthesis of a valsartan precursor in continuous flow

Abstract

Valsartan is a potent, orally active angiotensin II receptor blocker and is widely used in the treatment of hypertension and chronic heart failure. Herein, we present an approach for the continuous synthesis of a late-stage precursor of valsartan in three steps. The applied synthetic route involves N-acylation, Suzuki-Miyaura cross-coupling and methyl ester hydrolysis. After optimization of the individual steps in batch, they were successfully transferred to continuous flow processes employing different reactor designs. The first step of the synthetic route (N-acylation) as well as the third step (methyl ester hydrolysis) are performed in coil reactor setups. The key step of the reaction cascade (Suzuki-Miyaura cross-coupling) is catalyzed by a heterogeneous palladiumsubstituted cerium-tin-oxide with the molecular formula Ce 0.20 Sn 0.79 Pd 0.01 O 2-δ. The catalyst particles are implemented in an in-house developed packed-bed reactor, which features an HPLC column as fixed-bed. The combination of the individual reaction modules facilitates the consecutive performance of the three reaction steps. Using the developed multistep continuous setup, the targeted valsartan precursor was obtained with up to 96% overall yield.

A chemo-enzymatic tandem reaction in a mixture of deep eutectic solvent and water in continuous flow

“…Furthermore, the combination of both reactions as cascade in flow lower the risks associated to the spontaneous polymerization of the intermediate hydroxystyrene. While conventional flow chemistry, [38][39][40][41][42][43] also including C-C coupling reactions, 39,[44][45][46][47] and continuous biocatalysis [48][49][50] are currently in the focus of many researchers, examples for their successful combination are rare, which can also be attributed by the difficulties to find suitable reaction media. 51 In this work we present a fully integrated two-step flow setup consisting of an enzymatic decarboxylation with a phenolic acid decarboxylase from Bacillus subtilis (BsPAD), followed by a Heck reaction catalyzed by a Pd-substituted Ce-Sn-oxide as shown in Scheme 1.…”

Development of a multistep reaction cascade for the synthesis of a sacubitril precursor in continuous flow

“…Their successful utilization for the Suzuki coupling of aryl halides with boronic acid derivatives in batch as well as in continuous flow has already been reported by our group [28][29][30][31]. In previous studies and preliminary experiments, the catalyst Ce 0.20 Sn 0.79 Pd 0.01 O 2-δ proved to be the best choice for the Suzuki cross-coupling of advanced chemical intermediates [28]. Therefore, we tested the applicability of the respective palladium catalyst (standard reaction conditions: 1 mol eq.…”

“…First, we aimed for the identification of a successful cross-coupling reaction facilitated by the class of heterogeneous palladium catalysts with the molecular [11] formula Ce 0.99-x Sn x Pd 0.01 O 2-δ (x = 0, 0.20, 0.495, 0.79, 0.99) [29] developed and available in our lab. Their successful utilization for the Suzuki coupling of aryl halides with boronic acid derivatives in batch as well as in continuous flow has already been reported by our group [28][29][30][31]. In previous studies and preliminary experiments, the catalyst Ce 0.20 Sn 0.79 Pd 0.01 O 2-δ proved to be the best choice for the Suzuki cross-coupling of advanced chemical intermediates [28].…”

“…Accordingly, as part of the ONE-FLOW research project [27], we are aiming for the development of catalyzed cascade reactions for the formation of active pharmaceutical ingredients. Recently, our group has demonstrated the applicability of flow methodology for the multistep synthesis of an advanced valsartan precursor in a continuous fashion [28]. Hence, our next goal was to prove our concept also for the integrated synthesis of a late-stage sacubitril intermediate 16 in continuous flow, which we report in this paper.…”

“…In particular, the Suzuki-Miyaura reaction between aryl halides and boronic acid derivatives plays an important role for the formation of biphenyl motifs [38][39][40]. In the past couple of years, our group has gained experience with Suzuki-Miyaura reactions in continuous flow facilitated by heterogeneous Pd-Ce-Sn-oxides [28][29][30][31]. Reviewing published literature procedures for the synthesis of sacubitril 1, only the route developed by Ksander et al [4] comprises a Suzuki coupling step and served as our point of reference.…”