North Carolina State University

Osi Pharmaceuticals, Inc.

Other

Glaxo Wellcome Inc.

Nc State University

Daniel L Comins

Emilie Despagnet Smith

Matthew F Baevsky

Francis Gerard Fang

Shenlin Huang

Shiping Xie

Laura S King

Edward McDonald Huie

Florence Fevrier

Florence Fevrier Wagner

Pauline Wanjiku Ondachi

James M Salvador

The present invention provides active compounds for modulating nicotinic acetylcholine receptors and methods of making the same. The methods of preparing the active compounds utilize different intermediate compounds.

Synthesis and regioselective substitution of 6-halo- and 6-alkoxy nicotine derivatives

Methods of synthesizing nicotine analogs and derivatives are described. In some embodiments the methods utilize an alkyl or aryl silyl-substituted nicotine analog intermediate. Intermediates useful for the synthesis of nicotine and nicotine analogs are also described.

Synthesis of nicotine derivatives from nicotine

Methods of synthesizing nicotine analogs and derivatives are described. The methods are particularly useful for the regioselective production of enantiomerically pure nicotine analogs having substituents at the C4 position. Intermediates useful for the synthesis of such compounds are also described.

Regiospecific synthesis of nicotine derivatives

Synthesis and regioselective substitution of 6-halo-and 6-alkoxy nicotine derivatives

A first aspect of the present invention is a method for of making a compound of Formula Ia or Formula Ib: wherein X is halo, by (a) metalating a precursor compound to form an organometallic intermediate, and then reacting the organometallic intermediate with a halogenating agent to produce the compound of Formula Ia or Formula Ib.

Regioselective halogenation of nicotine and substituted nicotines

Methods of synthesizing nicotine analogs and derivatives are described. The methods are particularly useful for the regioselective production of enantiomerically pure nicotine anlogs having substituents at the C4 position. Intermediates useful for the synthesis of such compounds are also described.

A method of making a compound of Formula VI:wherein Tr is a triphenyl group; R, Rand Rare each independently selected from the group consisting of H, C1&#x2013;C4 alkyl, C1&#x2013;C4 alkoxy, aryl, heteroaryl, and arylalkyl; Ris C2&#x2013;C6 alkyl, and Rand Rare each independently H or C1&#x2013;C4 alkyl, involves the step of reacting a compound of Formula V:with Tr-OH to produce a compound of Formula VI. The compounds of Formula VI are useful as intermediates in the manufacture of antibiotic agents. Methods of making compounds of Formula V, and intermediates made or used in the foregoing methods, are also described.

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Raleigh, NC, United States of America

Daniel L Comins