Classroom Enters the Courtroom: Stereochemistry of S_N1 and S_N2 Reactions in Enantiomer Patent Litigations of the Antidepressant Escitalopram

Abstract

The role of elementary stereochemistry is illustrated in the patent litigations of the blockbuster antidepressant drug escitalopram oxalate. An undergraduate student of organic chemistry would recognize the stereochemical courses of the intramolecular SN 2 and SN 1 reactions of the single-enantiomer (S)-diol intermediate in the synthesis of the blockbuster antidepressant drug escitalopram oxalate: retention of configuration of the chiral carbon atom under basic conditions and racemization under acidic conditions, respectively. He/she, in searching for a stereoselective ring-closure reaction of the enantiomeric diol, will think of an SN 2 reaction in a basic medium. From these points of view, the process claim in the enantiomer patents of escitalopram is obvious/lacks an inventive step. An organic chemistry examination problem based on this scenario is offered.

The Quest for Secondary Pharmaceuticals: Drug Repurposing/Chiral-Switches Combination Strategy

“…‘Enantiomer patent’ (see Box ), a type of secondary pharmaceutical patent, is an essential constituent of a chiral switch . The definition of an enantiomer patent is “a patent that claims a single enantiomer of a chiral drug that has been claimed previously in the corresponding basic (broader) patent as a racemate or as a mixture of diastereomers” …”

“…5 The definition of an enantiomer patent is "a patent that claims a single enantiomer of a chiral drug that has been claimed previously in the corresponding basic (broader) patent as a racemate or as a mixture of diastereomers". 52 The FDA and EMA published guidelines for the development of chiral-switch drugs. 53,54 The FDA's 1992 Guidance Document entitled "Development of New Stereoisomeric Drugs" states, in section IV, 'Developing a Single Stereoisomer After the Racemate is Studied', "[...] an abbreviated, appropriate pharmacology/toxicology evaluation could be conducted to allow the existing knowledge of the racemate available to the sponsor to be applied to the pure stereoisomer."…”

Chirality of antidepressive drugs: an overview of stereoselectivity

“…“Chiral switch” is an expression used to describe the substitution of an already-accepted-and-sold racemic drug mixture with a pure enantiomer [ 24 , 25 ]. Citalopram was originally marketed as a racemate, but the difference between the physiological actions of the individual enantiomers resulted in a chiral switch to escitalopram, the pharmacologically active S -(+)-enantiomer of racemic citalopram [ 26 , 27 ]. Presently, citalopram is among the antidepressive agents that are available on the market as both racemates and a single enantiomer.…”