Multistep Continuous Flow Synthesis of Stavudine

Abstract

Herein, we demonstrate an elegant multistep continuous flow synthesis for stavudine (d4T), a potent nucleoside chemotherapeutic agent for human immunodeficiency virus, acquired immunodeficiency syndrome (AIDS) and AIDS-related conditions. This was accomplished via six chemical transformations in five sequential continuous flow reactors from an affordable starting material, 5-methyluridine. In the first instance, single step continuous flow synthesis was demonstrated with an average of 97% yield, 21.4 g/h throughput per step, and a total of 15.5 min residence time. Finally, multistep continuous flow synthesis of d4T in 87% total yield with a total residence time of 19.9 min and 117 mg/h throughput without intermediate purification was demonstrated.

Rapid plugged flow synthesis of nucleoside analogues via Suzuki-Miyaura coupling and heck Alkenylation of 5-Iodo-2’-deoxyuridine (or cytidine)

“…Rapid synthesis of modified nucleoside analogues is synthetically useful and certainly opens an opportunity to extensively apply flow chemistry-based catalytic methodologies [82] not only for the synthesis of coupled products (as mentioned in this report) but also performing rapid multistep synthetic strategies for a variety of nucleosidebased commercially relevant drugs [83]. nContributions from Jamiso [84] and Watts [85,86] laboratories need special mention for the development of several flow chemistrybased scale-up protocols for bio-active nucleosides. Inspired by this effort, we further envisaged performing gram scale synthesis of 3 k via semi-continuous flow methodology by injecting the reaction solutions multiple times and isolating the cross-coupled product at the end.…”

Towards 4th industrial revolution efficient and sustainable continuous flow manufacturing of active pharmaceutical ingredients

“…Sagandira and co-workers 35 recently reported an end-to-end multistep synthesis of stavudine (d4T) 11 under continuous flow conditions, a nucleoside reverse transcriptase inhibitor (NRTI) drug active against human immunodeficiency virus (HIV) (Fig. 4).…”

“…4). 35,36 The authors started from a commercially available starting material, 5-methyluridine 12 and accomplished the synthesis via six chemical transformations in five sequential continuous flow reactors. 35…”

Sustainable Protocol for the Synthesis of 2′,3′-Dideoxynucleoside and 2′,3′-Didehydro-2′,3′-dideoxynucleoside Derivatives

“…Various methodologies are reported in the literature for the synthesis of the title compounds. These protocols require formation of the glycosidic bonds [5][6][7][8][9][10][11], the Eastwood procedure [12,13], the Corey-Winter synthesis [14][15][16][17][18], the Barton-McCombie deoxygenation [16,[19][20][21][22], the Garegg-Samuelsson reaction [23], photoinduced deoxygenations [24,25], reductive elimination [13,[26][27][28][29][30][31][32][33][34][35], or metathesis reaction [36,37]. However, careful review of the literature indicated that the majority of these protocols are not amenable for large-scale production to meet the global demand of antiviral nucleosides.…”