Single isomer drugs

T. Andersson, Single-isomer drugs True therapeutic advances, Clin. Pharma-cokinet. 43 (2004), 279-285. 

Enzymes have found frequent use in the synthesis of single isomer drugs from racemic or prochiral compounds at the larger manufacturing scales. The use of enzymes to effect chiral transformations in the medicinal chemistry laboratory has been far less frequent however, the increasing availability of immobilized and stabilized forms of enzymes has made their use easier and the resultant transformations more predictable. 

In addition to the widely reported techniques of amide bond formation, transesterification, and hydrolysis, enzymic enantioselective oxidation is also used in the synthesis of single isomer drugs. Patel described the elficient oxidation of benzopyran (75), an intermediate in thesynthesisof potassium channel openers (123). The transformationwas ef-fected w i t h a cell suspension of MortiereUa raman-niana with glucose over a 48-h period, the isolated product (77) was obtained in a 76%yield with an optical purity of 97%and a chemical purity of 98%, as shown in Pig. 18.32. 

Impurities. For single-isomer drug substances, the other enantiomer should be considered the same as any other impurity. 

Handley, D. (2001) The therapeutic advantages achieved through single-isomer drugs. Pharmaceutical News 8 18-24. 

Andersson T. Single-isomer drugs true therapeutic advances. Clin Pharmacokinet 2004 43 279-285. 

Ibuprofen 128 is another well-known analgesic, anti-inflammatory drug and it is believed that it will be marketed as a single isomer drug. The kinetic enzymatic resolution of racemic ibuprofen has been reported [228]. The reaction for the resolution has been scaled up to make gram quantities of 5-ibuprofen. This was accomplished by two enantioselective reactions each catalyzed by Novozyme 435. In the first reaction, 3(X) g of racemic ibuprofen was esterified with 1-dodecanol to yield the / ester and 5-ibuprofen to produce 89 g of 5-ibuprofen in 85% e.e. In the second reaction, 75 g of the 85% e.e. material was used to prepare 39 g of 5-ibuprofen with a 97.5% e.e. 

Many currently used antidepressants are chiral drugs (for example, tricyclic antidepressants, mianserin, mirtazepine, venlafaxine, reboxetine, fluoxetine, paroxetine, sertraline, citalopram), some of which are administered as racemates (such as the tricyclics, mianserin, mirtazepine, fluoxetine, reboxetine, venlafaxine, citalopram) while others are given as single isomers (paroxetine and sertraline). 

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