Avitriptan Synthesis Essay

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  • The eletriptan dimer impurity 2 is observed at 0.3–0.5% during the basic hydrolysis of enesulfone derivative 12 and the impurity level is reduced to less than 0.20% during the isolation and purification process [12]. It is necessary to remove the impurity at this stage or control the formation during basic hydrolysis. Otherwise, the reduction rate of this impurity in later stages is low. Impurity 2 was prepared by the dimerization of desacetyl-ensulfone derivative 13 using a strong base, such as sodium hydride, under Michael addition reaction conditions in an anhydrous medium (Scheme 2). This impurity can be controlled by using hydrous conditions during the deacetylation reaction.

    Eletriptan N-oxide isomers 3 and 4 are possible contaminants that can be formed by oxidation in air. These compounds were prepared by oxidation of eletriptan (14) with aqueous hydrogen peroxide (~50%, w/w) in the presence of catalytic amounts of ammonium molybdate. The isomers 3 and 4 were separated by preparative HPLC and confirmed by 1H NMR spectroscopy [13,14] (Scheme 3). The combined contamination by 3 and 4 was 0.05–0.25% in eletriptan hydrobromide. Formation of this impurity can be controlled by using peroxide-free solvents during the final stage of synthesis.

    Impurity 5 is formed at 1.0–1.5% during hydrogenation due to hydrolytic cleavage. This impurity is reduced down to 0.25–0.50% during isolation and in further stages. Impurity 5 was prepared by alkylation of N-acetyl bromoindolyl pyrrolidine 10 with triethylborane [15-17] in the presence of a catalytic amount of palladium acetate in tetrahydrofuran, as in the following reaction scheme (Scheme 4).

    The content of indole pyrrolidine 6 in bromoindolyl pyrrolidine 9 is controlled by its specification to not more than 0.5%. However, during basic hydrolysis of enesulfone derivative 12, unreacted N-acetyl bromoindolyl pyrrolidine 10 is converted to bromoindolyl pyrrolidine 9. Further, 9 will convert into 6 due to debromination during the hydrogenation reaction of 13 and it can carry forward up to eletriptan hydrobromide (1). Indolyl pyrrolidine 6 was prepared by catalytic hydrogenation of bromoindolyl pyrrolidine (9) with palladium on carbon (Scheme 5). The contamination of this impurity in eletriptan hydrobromide (1) was 0.10–0.20%. This impurity can be controlled by tightening up the in-process control of the N-acetyl bromoindole pyrrolidine during the Heck reaction.

    During the initial process development of eletriptan, the deacetylation of enesulfone derivative 12 was performed in anhydrous methanol at ambient temperature with potassium carbonate. The reaction was completed within 30 min, but the formation of eletriptan methoxy impurity 7 was high (0.20–0.70%). Moreover, after isolation and the subsequent stage, it was still about 0.25%. To control the formation of 7, the deacetylation reaction should be carried out in aqueous methanol instead of anhydrous methanol. Thus, a content of 7 below 0.05% is observed. Compound 7 was prepared by treating desacetyl-ensulfone 13 with potassium carbonate in anhydrous methanol (Scheme 6). This impurity can be controlled by using the hydrous conditions during the deacetylation reaction.

    Surprisingly, we found that one unknown impurity (40–60%, by HPLC area normalization) was formed during the force degradation study of eletriptan hydrobromide (1) at higher temperatures (80–85 °C) in the presence of peroxide in aqueous acetonitrile. It was also observed that only 4.5% of this impurity was formed when 10% (w/w) hydrogen peroxide was used. However, this impurity was formed at 40–60%, when 30% (w/w) hydrogen peroxide used. This impurity was identified by LC–MS and characterized by 1H NMR, 13C NMR, LC–MS and FTIR. Based on the spectral data, the impurity was named as, 4-methyl-8-[2-(phenylsulfonyl)ethyl]-1,2,3,5,10,10a-hexahydropyrrolizino[3,2-b]indole-4-ium (tetracyclic eletriptan impurity, 8). A similar tetracyclic impurity (UK-373,236) is also reported in literature [18]. This impurity is forming only in aprotic solvents, e.g., acetonitrile in the presence of peroxides at higher temperature. It was prepared by treating eletriptan hydrobromide (1) with aqueous hydrogen peroxide (30% w/w) in aqueous acetonitrile at 80–85 °C (Scheme 7). Formation of this impurity can be controlled by using peroxide-free aprotic solvents at lower temperature.

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