Hoffmann-la Roche Inc.

Dsm IP Assets B.v.

Roche Vitamins Inc.

Rudolf Schmid

Joseph Foricher

David L Coffen

Mark J Sebastian

Emil A Broger

Bruno Lohri

Max Schmid

Bernd Heiser

Hans-Jurgen Hansen

Ulrich Zutter

Michel Lalonde

Werner Bonrath

Patrizio Mattei

Eric Vieira

Michelangelo Scalone

Thomas Netscher

Frank Kienzle

Albert E Fischli

Yvo Crameri

Jean-Michel Adam

Shaoning Wang

Alec Fettes

Marco Cereghetti

Theodor Siegfried

Stefan Abrecht

Rolf G&uuml;ller

Gerard Moine

Thomas Heinrich Pabst

Claus Dittel

Kazimierz Michal Pietrusiewicz

Piotr Osinski

Wolfgang Burkart

This invention relates to a process of the preparation of the novel intermediate (S)-4-fluoromethyl-dihydro-furan-2-one of the formula and with its use for the manufacture of pyrido[2,1-a]isoquinoline derivatives of the formula which are useful for the treatment and/or prophylaxis of diseases which are associated with DPP IV.

Process for the preparation of (S)-4-fluoromethyl-dihydro-furan-2-one useful in the preparation of the DPP-IV inhibitor (S)-1 ((2S,3S,11bS)-2-amino-9,10-dimethoxy-1,3,4,6,7, 11b-hexahydro-2H-pyrido[2,1-a] isoquinolin-3-yl)-4-fluoromethyl-pyrrolidin-2-one

Compounds of formula I and a process for the preparation of such compounds are disclosed.

Synthesis of &#x3b1;-amino-&#x3b2;-alkoxy-carboxylic acid esters

A process for the manufacture of 3-phytyl-2,5,6-trimethylhydroquinone-1-acetate, and optionally therefrom tocopheryl acetate, comprises either C-alkylating 2,3,6-trimethylhydroquinone-1-acetate with isophytol or phytol in the presence of a sulphur(VI) containing catalyst of the formula RSOOH, wherein Rsignifies hydroxy, halogen, lower alkyl, halogenated lower alkyl or aryl, in an aprotic organic solvent, or O-alkylating 2,3,6-trimethylhydroquinone-1-acetate with a phytyl halide in a polar aprotic organic solvent in the presence of a base, and subjecting the so-obtained 4-O-phytyl-2,3,6-trimethylhydroquinone-1-acetate to a rearrangement reaction, and in each case optionally submitting the so-obtained 3-phytyl-2,5,6-trimethylhydroquinone-1-acetate to a ring closure reaction to produce tocopheryl acetate. The invention also includes the novel compound 3-phytyl-2,5,6-trimethylhydroquinone-1-acetate and certain stereoisomers thereof, and also the further novel compound 4-hydroxy-2,3,6-trimethyl-5-[3-(4,8,12-trimethyltridecyl)-but-3enyl]phenyl acetate which itself is one of several isomers of 3-phytyl-2,5,6-trimethylhydroquinone-1-acetate formed by isomerization under the influence of heating, e.g. during its distillation as part of the isolation and purification procedure following its manufacture as indicated above. (All-rac)-&#x3b1;-tocopherol, which may be derived from its acetate, is known to be the most active industrially important member of the vitamin E group.

Manufacture of tocopheryl acetate

The invention is concerned with new phosphine ligands of formula Iwherein

Phosphine ligands

Chiral amido-phosphine-phosphinite compounds

A process for the racemization of atropisomeric bis(phosphine oxide) compounds of formula I:

Racemization of atropisomeric bis(phosphine oxide) compounds

The present invention concerns intermediates useful in and a process for the preparation of a compound of formula 1 or a salt thereof

Process and intermediates for preparation of substituted piperidines

Process and intermediates for preparation of substituted piperidine-epoxides

A process for the manufacture of bisphosphine oxide compounds and bisphosphonates as intermediates for the production of bisphosphine ligands, in which in a single step process

Process for the manufacture of bisphosphine oxide and bisphosphonate

.alpha., .beta.-Unsaturated acids of the formula ##STR1## wherein R.sup.1 signifies C.sub.1 -C.sub.5 -alkyl and Ar signifies an aryl group which is optionally substituted by one or more substituents selected from the group consisting of halogen, phenyl, C.sub.1 -C.sub.5 -alkyl, C.sub.1 -C.sub.5 -alkoxy, perfluorinated C.sub.1 -C.sub.5 -alkyl or perfluorinated C.sub.1 -C.sub.5 -alkoxy can be obtained from new or known compounds of the formula ##STR2## Compounds I can be converted by asymmetric hydrogenation into corresponding optically active saturated acids.

Process for making .alpha.,.beta.-unsaturated carboxylic acids

The compounds of the formula ##STR1## wherein R is OH, NH.sub.2, lower-alkyl-NH or phenyl-lower alkyl-NH are presented. These compounds can be catalytically hydrogenated to the corresponding .alpha.-aminocarboxylic acid derivatives which are intermediates in the synthesis of therapeutic pseudopeptides.

Optically active iminocarboxylic acid derivatives

The present invention is concerned with a process for the manufacture of optically active compounds of the formula ##STR1## wherein R signifies lower alkyl, lower alkoxy, phenyl, benzyl or --NR.sub.2.sup.1, R.sup.1 signifies lower alkyl, phenyl, benzyl or hydrogen and * signifies an optically active center, by asymmetrically hydrogenating an enol derivative of ketoisophorone of the formula ##STR2## wherein R has the significance given above, in the presence of a rhodium complex of an optically active diphosphine ligand.

Process for the enantioselective hydrogenation of ketosiophorone

The invention is concerned with novel water-soluble racemic or optically active compounds of formulae ##STR1## wherein R.sup.1, R.sup.2, R.sup.3 and R.sup.4 independently signify lower alkyl or lower alkoxy;

Tetrasulfonated diphosphine compounds and metal complexes thereof for

Novel chiral phosphorus compounds of the formula ##STR1## wherein R signifies lower alkyl, R.sup.1 signifies phenyl and R.sup.2 and R.sup.3 signify hydrogen or lower alkoxy, which are suitable in the form of complexes with a metal of Group VIII as catalysts for asymmetric hydrogenations and for enantioselective hydrogen displacements in prochiral allylic systems.

Chiral phosphorus compounds

Phosphorus compounds

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Basel, Switzerland

Rudolf Schmid