Lonza Inc.

Lonza Ag

John McGarrity

Thomas Meul

Leander Tenud

Rudolf Fuchs

Dominique Michel

Hanspeter Mettler

Markus Banziger

Laurent Duc

Martin Eyer

Walter Brieden

Aleksander Warm

David Laffan

Martin Clausen

Felix Spindler

Andreas Kiener

Wilhelm Quittmann

Beat Schmidt

Thomas Muel

Colette Mettler, Legal Representative

A process for the preparation of N-monosubstituted &#x3b2;-aminoalcohol sulfonates of formula (1a), (1b): wherein Ris C-aryl or C-heteroaryl, each optionally being substituted with one or more halogen atoms and/or one or more C-alkyl or C-alkoxy groups, Ris C-alkyl or C-aryl, each aryl optionally being substituted with one or more halogen atoms and/or one or more C-alkyl or C-alkoxy groups, and wherein Ris selected from the group consisting of C-alkyl, C-cycloalkyl, C-aryl and C-aralkyl residues; including a) reacting a methyl ketone, a primary amine, formaldehyde and a sulfonic acid, at a pressure above 1.5 bar, optionally in a organic solvent, said organic solvent which can include water to provide N-monosubstituted &#x3b2;-aminoketone sulfonates of formula (II): wherein R, Rand Rare as defined above, and b) asymmetrically hydrogenating.

Process for the preparation of enantiomerically pure 1-substituted-3-aminoalcohols

A process for the preparation of N-monosubstituted &#x3b2;-aminoalcohol sulfonates of formula (Ia), (Ib): wherein Ris C-aryl or C-heteroaryl, each optionally being substituted with one or more halogen atoms and/or one or more C-alkyl or C-alkoxy groups, Ris C-alkyl or C-aryl, each aryl optionally being substituted with one or more halogen atoms and/or one or more C-alkyl or C-alkoxy groups and wherein Ris selected from the group consisting of C-alkyl, C-cycloalkyl, C-aryl and C-aralkyl residues. The process has the steps of (a) reacting a methyl ketone, a primary amine, formaldehyde and a sulfonic acid, at a pressure above 1.5 bar, optionally in a organic solvent, the organic solvent optionally containing water, to afford N-monosubstituted &#x3b2;-aminoketone sulfonates of formula (II): wherein R, Rand Rare as defined above, and (b) asymmetrically hydrogenating. The sulfonates in the presence of a base and a catalyst of a transition metal and a disphosphine ligand, in a polar solvent, optionally in the presence of water.

A salt of a carboxylic acid with an aminoketone of formula II.

A salt of a carboxylic acid with an aminoalcohol of formula I.

A process for the preparation of enantiomerically pure 1-substituted-3-amino-alcohols, particularly of (S)-(&#x2212;)- and (R)-(+)-3-N-methylamino-1-(2-thienyl)-1-propanol, by asymmetrically hydrogenating salts of a carboxylic acids with an aminoketone of the formula: wherein Ris 2-thienyl, 2-furanyl or phenyl, each optionally substituted with one or more halogen atoms and/or one or more C-alkyl or C-alkoxy groups, and wherein Ris C-alkyl or phenyl, each optionally substituted with one or more halogen atoms and/or one or more C-alkyl or C-alkoxy groups. The corresponding aminoalcohols are obtained by subsequent hydrolysis of their salts. Salts of a carboxylic acid with the aminoketones and the aminoalcohols obtained by asymmetrically hydrogenating the aminoketones, respectively.

A process for the preparation of dihydroxypyrimidine derivatives of the general formula:

Method of producing dihydroxypyrimidine derivatives

A process for the asymmetric hydrogenation of the furoimidazole derivatives of the general formula: ##STR1## wherein R.sub.1 is a protective group, which is cleavable in a known way, and R.sub.2 is hydrogen or a protective group, which is cleavable in a known way, with hydrogen in the presence of a homogeneous catalyst to the corresponding diastereomeric tetrahydrofuroimidazole derivatives of the general formula: ##STR2## The tetrahydrofuroimidazole derivatives of the general formula II are intermediate products for the production of vitamin (+) biotin.

Asymmetric hydrogenation of dihyrofuroimidazole derivatives

Asymmetric hydrogenation of dihydrofuroimidazole derivatives

.gamma.-Mercaptocarboxylic acids and their derivatives, in particular esters and amides, are prepared from .gamma.-butyrolactones via the corresponding thiolactones. The thiolactones are obtained by reaction of a .gamma.-lactone with thiocarboxylates in polar solvents and are converted by ring opening using nucleophilic reagents, such as, alkali metal alkoxides, into the .gamma.-mercaptocarboxylic acid derivatives. These are intermediates, for example, for the synthesis of leucotriene antagonists.

Process for preparing .gamma.-mercaptocarboxylic acid derivatives

A process for the asymmetric hydrogenation of furoimidazole derivatives of the general formula: ##STR1## wherein R.sub.1 is a protective group and R.sub.2 is hydrogen or a protective group, with hydrogen in the presence of a homogeneous catalyst to give the corresponding diastereomeric dihydrofuroimidazole derivatives of the general formula: ##STR2## The dihydrofuroimidazole derivatives of the general formula II are intermediates for the preparation of the vitamin (+)-biotin.

Asymmetric hydrogenation of furoimidazole derivatives

Process for the production of 4-hydroxy-2-oxoyrrolidin-1-yl-acetamide, a cerebrally active pharmaceutical agent. A 4-halo-3-alkoxy-butenoic acid ester is reacted with glycine to new intermediate products of the formula: ##STR1## There is further by acid hydrolysis of the alkoxy group, subsequent hydrogenation, esterification of the carboxyl function and finally conversion to the end product by reaction with ammonia.

Process for the production of 4-hydroxy-2-oxopyrrolidin-1-yl-acetamide

Starting from 5-alkylidene or 5-benzylidenetetramic acid optically-active 4-amino-3-hydroxy-carboxylic acids are produced in the (rel-3R,4R) configuration, especially statine. The synthesis process includes the O-acylation of the tetramic acid to the corresponding 4-acyloxy-3-pyrrolin-2-one, a stereoselective hydrogenation to (rel-4R,5R)-4-acyloxy-5-alkyl or 5-benzylpyrrolidin-2-one and an enantioselective enzymatic hydrolysis of the (4R,5R)-enantiomer to the corresponding 4-hydroxypyrrolidin-2-one. The nonhydrolyzed enantiomer is separated and converted into the target compound with (3S,4S) configuration by hydrolytic cleavage of the lactam ring and the ester function and optionally introduction of an amino protective group. Analogously the (3R,4R)-enantiomer can be obtained from the 4-hydroxypyrrolidin-2-one from the enzymatic hydrolysis. The 4-amino-3-hydroxycarboxylic acids producible according to the invention are the structural elements of enzyme inhibitors.

Process for the production of optically-active

Starting from 5-alkylidene or 5-benzylidenetetramic acid, optically-active 4-amino-3-hydroxy-carboxylic acids are produced in the (rel-3R,4R) configuration, especially statine. The synthesis process includes the O-acylation of the tetramic acid to the corresponding 4-acyloxy-3-pyrrolin-2-one, a stereoselective hydrogenation to (rel-4R,5R)-4-acyloxy-5-alkyl or 5-benzylpyrrolidin-2-one and an enantioselective enzymatic hydrolysis of the (4R,5R)-enantiomer to the corresponding 4-hydroxypyrrolidin-2-one. The nonhydrolyzed enantiomer is separated and converted into the target compound with (3S,4S) configuration by hydrolytic cleavage of the lactam ring and the ester function and optionally introduction of an amino protective group. Analogously the (3R,4R)-enantiomer can be obtained from the 4-hydroxypyrrolidin-2-one from the enzymatic hydrolysis. The 4-amino-3-hydroxycarboxylic acids producible according to the invention are the structural elements of enzyme inhibitors.

(2R,3E)-4-halo-3-buten-2-ols are produced by kinetic resolution of racemates from the corresponding racemates. The racemate is esterified by reaction with a carboxylic acid derivative, preferably with chloroacetyl chloride. Then the (R)-ester is enantioselectively hydrolyzed with a lipase from Pseudomonas fluorescens. The corresponding (2R,3E)-4-halo-3-buten-2-ol also can be obtained from the remaining (S)-ester after separation. The compounds are chiral synthesis structural elements for the production of optically active natural substances.

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John McGarrity