Nitro-Aldol Approach for Commercial Manufacturing of Fenspiride Hydrochloride

Abstract

An efficient, short manufacturing process for fenspiride hydrochloride is reported. Nitro-aldol condensation is the key reaction in the developed process. Improved routes to key building blocks are demonstrated by expedient multikilogram production. Hazardous reactions are avoided. API produced following this new route meets the quality requirement NLT 99.70% purity by HPLC with any individual impurity NMT 0.10% with very good yield.

Enantioselective Synthesis of Functionalized Diazaspirocycles from 4‐Benzylideneisoxazol‐5(4H)‐one Derivatives and Isocyanoacetate Esters

“…[3] Furthermore, the spirocyclic motif is becoming a prevalent template in drug discovery, [4] since this structural feature conveys both increased three-dimensionality for potential improved activity, and novelty for patenting purposes. An example of spirocyclic drugs is the marketed fenspiride, [5] used for the treatment of some respiratory diseases (Figure 1).…”

An Efficient Synthesis of 4-Aminomethyl-1-(2-Phenylethyl)-Piperidin-4-ol: A Key Intermediate in Fenspiride HCl Synthesis

“…Pramanik et.al [11] reported the synthesis (Scheme 4) starting from N-(2-phenylethyl)-4piperidone (2) which was undergoes for nitro aldol condensation with nitro methane in presence of potassium carbonate, followed by zinc reduction to get intermediate 4. Finally, BOC anhydride is used for cyclization to arrive at Fenspiride HCl (1).…”

“…Piperidone 2 on Corey−Chaykovsky [14] epoxide formation using trimethyl sulfoxonium iodide in DMSO in the presence of sodium hydroxide as base resulted in epoxide 10 in good yield. In situ epoxide opening using sodium azide in DMSO at 45−50 °C afforded azido intermediate (11). Reduction of azide (11) was best affected under hydrogenation conditions using hydrazine hydrate under heating to arrive at amine (4).…”

“…In situ epoxide opening using sodium azide in DMSO at 45−50 °C afforded azido intermediate (11). Reduction of azide (11) was best affected under hydrogenation conditions using hydrazine hydrate under heating to arrive at amine (4). The final oxazolidone formation was accomplished using carbonyl diimidazole (CDI) under basic medium to arrive at fenspiride free base (12) followed by salt formation using HCl-EtOAc NH O N O .HCl which provided the target molecule fenspiride HCl with high HPLC purity (>99.7%) complying with ICH guidelines.…”

A One-Pot Iodo-Cyclization/Transition Metal-Catalyzed Cross-Coupling Sequence: Synthesis of Substituted Oxazolidin-2-ones from N-Boc-allylamines

“…In 1978, E.I. Du Pont de Nemours and Company reported for the first time their antibiotic activity, and since then, these heterocycles are highly represented among several bioactive compounds, such as linezolid and derivatives as antibacterial agents, the antidepressant toloxatone, and fenspiride, a bronchodilator . In addition, functionalized oxazolidin-2-ones are also present in alkaloid natural products such as in the stemoxazolidinone family (Figure ).…”