Syntex (u.s.a.) Inc.

Roche Palo Alto LLC

Roche Colorado Corporation

F. Hoffmann-la Roche Ag

Christopher R Roberts

Humberto Bartolome Arzeno

Eric Roy Humphreys

Yeun-Kwei Han

Paul Ross Fatheree

Colin C Beard

Lawrence Emerson Fisher

Charles Alois Dvorak

Douglas L Wren

Sam Linh Nguyen

Jan P Lund

Steven D Axt

Jim-wah Wong

Lin Chen

Jim-Wah Wong

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 present invention provides a process for producing a N-acyl-5'-deoxy-5-fluorocytidine compound of the formula: where Ris alkyl, cycloalkyl, aralkyl, aryl, or alkoxy.

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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

Intermediates of Formula (III) ##STR1## wherein P.sup.1 is hydrogen or an amino-protecting group, R is lower alkyl, allyl or aralkyl, and Z is hydrogen, lower alkyl, aryl or aralkyl; and Formula (VI) ##STR2## wherein P.sup.1 is hydrogen or an amino-protecting group, P.sup.2 is an amino protecting group, and Z is hydrogen, lower alkyl, aryl or aralkyl, are useful in a novel process for preparing the mono-L-valine ester of 2-(2-amino-1,6-dihydro-6-oxo-purin-9-yl)methoxy-1,3-propanediol (ganciclovir). The mono-L-valine ester of ganciclovir and its pharmaceutically acceptable salts are of value as antiviral agents with improved absorption.

Process for preparing a

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)

Process and novel intermediates for preparing the mono-L-valine ester of 2-(2-amino-1,6-dihydro-6-oxo-purin-9-yl)methoxy-1,3-propanediol ganciclovir) and its pharmaceutically acceptable salts. The present process and monoester intermediates provide for mono-esterification by an L-valine derivative, resulting in a monocarboxylate-monovalinate which is then selectively hydrolyzed under basic or enzymatic conditions to give the monovaline ester of ganciclovir in high yield and purity. These products are of value as antiviral agents with improved absorption.

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Berthoud, CO, United States of America

Christopher R Roberts