Syntex (u.s.a.) Inc.

Roche Colorado Corporation

Roche Palo Alto LLC

F. Hoffmann-la Roche Ag

Yeun-Kwei Han

David A Johnston

Christopher R Roberts

Robert J Topping

Sam Linh Nguyen

Paul Ross Fatheree

Michelangelo Scalone

Colin C Beard

Lawrence Emerson Fisher

Kurt Puentener

Charles Alois Dvorak

Humberto Bartolome Arzeno

Douglas L Wren

Michael P Fleming

Eric Roy Humphreys

Lewis M Hodges

Mark A Schwindt

Roger P Micheli

Chris R Roberts

Steven D Axt

Jan P Lund

George C Schloemer

Hiralal N Khatri

Peter John Harrington

Eric Lodewijk

L Mark Hodges

Lin Chen

The present invention relates to the preparation of insulinotropic peptides that are synthesized using a solid and solution phase ('hybrid') approach. Generally, the approach includes synthesizing three different peptide intermediate fragments using solid phase chemistry. Solution phase chemistry is then used to add additional amino acid material to the third fragment which is then coupled to the second fragment and then the first fragment in solution. Alternatively, a different second fragment is coupled to the first fragment in the solid phase. Then, solution phase chemistry is then used to add additional amino acid material to a different third fragment. Subsequently, this different third fragment is coupled to the coupled first and different second fragment in the solution phase. The use of a pseudoproline in one of the fragments eases solid phase synthesis of that fragment and also eases subsequent solution phase coupling of this fragment to the other fragments. The present invention is very useful for forming insulinotropic peptides such as GLP-1(7-36) and its natural and non-natural counterparts.

Insulinotropic peptide synthesis using solid and solution phase combination techniques

The invention provides methods of obtaining a peptide that include steps of synthesizing a peptide intermediate having one or more side chain protecting groups; providing a solvent to the peptide intermediate to form a peptide intermediate composition; and providing a precipitating agent in an amount sufficient to precipitate the peptide intermediate from the peptide intermediate composition, wherein the precipitating agent is an alcohol having three or more carbon atoms. Also provided are methods for precipitating peptides, methods for concentration peptides, and methods for filtering peptides.

Process and systems for recovery of peptides

Methods for the solid phase synthesis of T-1249 peptides and peptide intermediates, in particular methods involving synthesizing T-1249 peptide intermediates at low loading factors to produce products having excellent purity and yield.

Synthesis using peptide intermediate fragments

The present invention relates to a novel process for producing a &#x3b4;-lactone of the formula:using an acyl halide of the formula:wherein R, RRand X are described herein, as well as novel intermediates. In particular, the present invention relates to a process for enantioselectively producing the (R)-&#x3b4;-lactone.

Synthesis of 3,6-dialkyl-5,6-dihydro-4-hydroxy-pyran-2-one

Process for preparing a 2-(2-amino-1, 6-dihydro-6-oxo-purin-9-yl)methoxy-1,3-propanediol derivative

Process for preparing intermediates of formula (III)

Process for preparing a 2-(2-amino-1,6-dihydro-6-oxo-purin-9-yl)methoxy-1,3-propanediol derivative

Process and novel intermediates for preparing the L-mono-valine ester of 2-(2-amino-1,6-dihydro-6-oxo-purin-9-yl)methoxy-1,3-propanediol and its pharmaceutically acceptable salts. The present process and intermediates provide for reduced impurities in the mono-valine ester end-product and lower overall production costs. The process involves the condensation of a silylated guanine compound with a substituted glycerol derivative and esterification of this product with an L-valine derivative. These mono-valine products are of value as antiviral agents with improved absorption.

Process for preparing a 2-(2-amino-1,6-dihydro-6-oxo-purin-9-yl)

A process for the preparation of acyclovir includes contacting an at least partially silylated guanine or mixture of at least partially silylated guanines with 1,3-dioxolane in the presence of a selective alkylation catalyst selected from the group consisting of trifluoromethanesulfonic acid, trimethylsilyl trifluoromethanesulfonate, and bistrimethylsilyl sulfonate, and hydrolyzing the product thus formed.

Preparation of acyclovir using 1,3 dioxolane

The invention relates to efficient and selective processes for the synthesis of the antiviral N-9 substituted guanine compounds acyclovir and ganciclovir.

Preparation of N-9 substituted guanine compounds

Growing community of inventors

Louisville, CO, United States of America

Yeun-Kwei Han