Ziprasidone synthesis

The first synthesis of ziprasidone was disclosed by Lowe and Nagel in a patent issued to Pfizer in 1989. Initially, the left-hand fragment of ziprasidone, 3-benzisothiazolylpiperazine (40), was prepared according to the method of Yevich and coworkers (Scheme 12). The amide 38 was treated with phosphorous oxychloride to give 3-chloro-l,2-benzisothiazole (39). Compound 39 was then reacted with molten piperazine at 125 °C to provide piperazine 40 in 68% yield. 

The synthesis of the right-hand fragment of ziprasidone started with a Wolff-Kishner reduction of isatin 43 to give the oxmdole 44 (Scheme 14). Friedel-Crafts acylation with chloroacetyl chloride afforded aryl ketone 45, which was reduced with triethylsilane in trifluoroacetic acid to the phenethyl chloride 46. The two fragments were joined by alkylation of 40 with 46 in the presence of Nal and Na2CO3 to give ziprasidone (4) in low yield. The yield of the coupling step was improved dramatically when the reaction was conducted in water (Scheme 15). 

Scheme 15. Improved coupling conditions for the synthesis of ziprasidone (4).

Pfizer has also prepared both and " C-labelled ziprasidone (Schemes 18 and 19) to detennine its metabolism and tissue distnbution. It was envisioned that tritium could be introduced in the last step of e synthesis utilizing the selective replacement of a bromine atom on the benzisothiazole nng. Therefore, the synthesis began with the bromination of 39 using bromine in acetic acid with FeCls catalysis. The dibrominated regioisomer 60 was isolated by liquid chromatography in 18% yield and reacted with... 

Introduction 8.2 Synthesis of risperidone 8.3 Synthesis of olanzapine 8.4 Synthesis of quetiapine fumarate 8.5 Synthesis of ziprasidone 8.6 Synthesis of aripiprazole 8.7 References... 

The first synthesis of ziprasidone was disclosed by Lowe and Nagel in a patent issued to Pfizer in 1989. Initially, the left-hand fragment of ziprasidone, 3-... 

In the synthesis of an intermediate to the antipsychotic drug ziprasidone, Krapcho conditions produced an unexpected side reaction.31 In trying to decarboxylate compound 53 to produce 54, by-products 55 and 56 were formed instead. Their formation was likely a result of the electron withdrawing substituents on the benzene ring. Although these products were unwanted and not part of the overall synthetic pathway, their formation is an interesting potential application of the Krapcho reaction when applied to compounds with electron withdrawing substituents, and could prove useful. 

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