Ciba Specialty Chemicals Corporation

Solvias Ag

Speedel Pharma Ag

Bayer Aktiengesellschaft

Biomarin Pharmaceutical Inc.

Novartis Finance Corporation

Adriano Indolese

Anita Schnyder

Peter Herold

Stefan Stutz

Victor Paul Eliu

Werner Kanert

Ian J Fletcher

Benoit Pugin

Martin Studer

Steven Jungles

Gabriele Roidl

Gerald Mehltretter

Mark Henderson

Robert Baffi

Julia Volkel

Verena Gisin

Richard Breitschuh

Stefan Kaiser

Philipp Wyser

Stefan Burckhardt

Christian Müller

Philipp Schmidt

Christian Mueller

The present disclosure provides a method that efficiently produces (6R)-tetrahydrobiopterin of Formula I in high yield and purity. The method includes the step of hydrolyzing diacetylbiopterin to biopterin under basic conditions in a biphasic mixture comprising an organic phase and an aqueous phase. After substantially complete hydrolysis of diacetylbiopterin, the aqueous phase containing biopterin can be separated from the organic phase containing most of the organic impurities, which avoids the time-consuming step of isolating biopterin as a solid. The aqueous solution containing biopterin is stereoselectively hydrogenated to (6R)-tetrahydrobiopterin under basic conditions and high hydrogen pressure in the presence of a metal catalyst (e.g., a platinum catalyst). To improve the purification of an acid addition salt of (6R)-tetrahydrobiopterin (e.g., (6R)-tetrahydrobiopterin dihydrochloride), any residual salts (e.g., sodium salts) in the aqueous solution after the hydrogenation reaction can be removed by contacting the aqueous solution with an ion (e.g., cation) exchange resin or column. Alternatively, removal of residual salts from the aqueous solution can be omitted if an organic amine (e.g., diethylamine or triethylamine) rather than an inorganic base is used in the hydrolysis and/or hydrogenation reactions. 

Method of synthesizing tetrahydrobiopterin

From compounds of formula II wherein Rand Rare independently of one another H, C&#x2013;Calkyl, C&#x2013;Chalogenalkyl, C&#x2013;Calkoxy, C&#x2013;Calkoxy-C&#x2013;Calkyl, or C&#x2013;Calkoxy-C&#x2013;Calkyloxy, Ris C&#x2013;Calkyl, Ris C&#x2013;Calkyl, and Ris C&#x2013;Calkyl, C&#x2013;Chydroxyalkyl, C&#x2013;Calkoxy-C&#x2013;C-alkyl, C&#x2013;Calkanoyloxy-C&#x2013;Calkyl, C&#x2013;Caminoalkyl, C&#x2013;Calkylamino-C&#x2013;C-alkyl, C&#x2013;C-dialkylamino-C&#x2013;C-alkyl, C&#x2013;C-alkanoylamido-C&#x2013;C-alkyl, HO(O)C&#x2014;C&#x2013;C-alkyl, C&#x2013;Calkyl-O&#x2014;(O)C&#x2014;C&#x2013;Calkyl, HN&#x2014;C(O)&#x2014;C&#x2013;Calkyl, C&#x2013;Calkyl-HN&#x2014;C(O)&#x2014;C&#x2013;Calkyl or (C&#x2013;Calkyl)N&#x2014;C(O)&#x2014;C&#x2013;C-alkyl, Ris C&#x2013;Calkyl, Ris C&#x2013;Calkyl or C&#x2013;Calkoxy, or Rand Rtogether are tetramethylene, pentamethylene, 3-oxa-1,5-pentylene or &#x2014;CHCHO&#x2014; substituted, if necessary, with C&#x2013;C-Alkyl, phenyl or benzyl, it is possible&#x2014;through halolactonization, azidation of the halogen group, ring opening with an amine R&#x2014;NH, and reduction of the azide group to form the amino group&#x2014;to prepare compounds of formula I wherein Ris C&#x2013;Calkyl, C&#x2013;Chydroxyalkyl, C&#x2013;Calkoxy-C&#x2013;Calkyl, C&#x2013;Calkanoyloxy-C&#x2013;Calkyl, C&#x2013;Caminoalkyl, C&#x2013;Calkylamino-C&#x2013;Calkyl, C&#x2013;Cdialkylamino-C&#x2013;C-alkyl, C&#x2013;Calkanoylamido-C&#x2013;Calkyl, HO(O)C&#x2014;C&#x2013;Calkyl, C&#x2013;Calkyl-O&#x2014;(O)C&#x2014;C&#x2013;Calkyl, HN&#x2014;C(O)&#x2014;C&#x2013;Calkyl, C&#x2013;Calkyl-HN&#x2014;C(O)&#x2014;C&#x2013;Calkyl or (C&#x2013;Calkyl)&#x2014;N&#x2014;C(O)&#x2014;C&#x2013;Calkyl. If 2(S),7(R)-diastereomer of formula II is used, the 2(S),4(S),5(S),7(S)-diastereomer of formula Ia is obtained in a high degree of purity.

Preparation of N-substituted 2,7-dialkyl-4-hydroxy-5-amino-8-aryl-octanoyl amides

From compounds of formula IIwherein Rand Rare independently of one another H, C&#x2013;Calkyl, C&#x2013;Chalogenalkyl, C&#x2013;Calkoxy, C&#x2013;Calkoxy-C&#x2013;Calkyl, or C&#x2013;Calkoxy-C&#x2013;Calkyloxy, Ris C&#x2013;Calkyl, Ris C&#x2013;Calkyl, and Ris C&#x2013;Calkyl, C&#x2013;Chydroxyalkyl, C&#x2013;Calkoxy-C&#x2013;C-alkyl, C&#x2013;Calkanoyloxy-C&#x2013;Calkyl, C&#x2013;Caminoalkyl, C&#x2013;Calkylamino-C&#x2013;C-alkyl, C&#x2013;C-dialkylamino-C&#x2013;C-alkyl, C&#x2013;C-alkanoylamido-C&#x2013;C-alkyl, HO(O)C&#x2014;C&#x2013;C-alkyl, C&#x2013;Calkyl-O&#x2014;(O)C&#x2014;C&#x2013;Calkyl, HN&#x2014;C(O)&#x2014;C&#x2013;Calkyl, C&#x2013;Calkyl-HN&#x2014;C(O)&#x2014;C&#x2013;Calkyl or (C&#x2013;Calkyl)N&#x2014;C(O)&#x2014;C&#x2013;C-alkyl, Ris C&#x2013;Calkyl, Ris C&#x2013;Calkyl or C&#x2013;Calkoxy, or Rand Rtogether are tetramethylene, pentamethylene, 3-oxa-1,5-pentylene or &#x2014;CHCHO&#x2014; substituted, if necessary, with C&#x2013;C-Alkyl, phenyl or benzyl, it is possible&#x2014;through halolactonization, azidation of the halogen group, ring opening with an amine R&#x2014;NH, and reduction of the azide group to form the amino group&#x2014;to prepare compounds of formula Iwherein Ris C&#x2013;Calkyl, C&#x2013;Chydroxyalkyl, C&#x2013;Calkoxy-C&#x2013;Calkyl, C&#x2013;Calkanoyloxy-C&#x2013;Calkyl, C&#x2013;Caminoalkyl, C&#x2013;Calkylamino-C&#x2013;Calkyl, C&#x2013;Cdialkylamino-C&#x2013;C-alkyl, C&#x2013;Calkanoylamido-C&#x2013;Calkyl, HO(O)C&#x2014;C&#x2013;Calkyl, C&#x2013;Calkyl-O&#x2014;(O)C&#x2014;C&#x2013;Calkyl, HN&#x2014;C(O)&#x2014;C&#x2013;Calkyl, C&#x2013;Calkyl-HN&#x2014;C(O)&#x2014;C&#x2013;Calkyl or (C&#x2013;Calkyl)&#x2014;N&#x2014;C(O)&#x2014;C&#x2013;Calkyl. If 2(S), 7(R)-diastereomer of formula II is used, the 2(S), 4(S), 5(S), 7(S)-diastereomer of formula Iais obtained in a high degree of purity.

Production of N-substituted 2,7-dialkyl-4-hydroxy-5-amino-8-arly-octanoylamides

Coupling of nucleophiles, vinyl compounds or CO with water, alcohols or amines to organic compounds

A process for the preparation of primary aromatic carboxamides by the carbonylation of an aromatic compound, which contains at least one leaving group, with carbon monoxide, in the presence of a homogeneous or heterogeneous Pd catalyst and at least stoichiometric amounts of an amidation agent at elevated temperatures, which is characterized in that a primary carboxamide or a primary urethane is used as the amidation agent, and the reaction is carried out in the presence of an acylation catalyst.

Process for the preparation of aromatic carboxylic acid amides

Process for the preparation of trifluoromethyl acetophenone

This invention relates to a novel advantageous process for the stereoselective preparation of 2-hydroxy-4-phenylbutyrates (HPB esters) and of their precursors. This is done by starting from readily accessible &agr;-unsaturated &agr;-hydroxy-&ggr;-keto esters which can be prepared by Claisen condensation.

Process for the preparation of HPB esters

A process for the production of a fluorescent whitening agent of formula: ##STR1## in which X and Z are as defined herein, comprising A) rearranging a hydrazobenzene compound having the formula: ##STR2## in which Z is as defined herein, to produce in situ a compound having the formula: ##STR3## B) diazotising the compound of formula (3) to produce a compound having the formula: ##STR4## in which Z has its previous significance and G.sub.1 is a counter ion; and C) reacting the compound of formula (4) with 2 moles of a compound having the formula: ##STR5## in which X and n have their previous significance, in the presence of an inorganic or organic palladium salt, or a mixture thereof, as catalyst-precursor, to produce a compound having the formula (1).

Process

The present invention provides a process for the production of a compound of formula: ##STR1## in which X and Y, independently, are hydrogen, halogen, NO.sub.2, CF.sub.3, CN, C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 alkoxy, COO--C.sub.1 -C.sub.4 alkyl, CO--C.sub.1 -C.sub.4 alkyl, NH--(C.sub.1 -C.sub.4 alkyl), N(C.sub.1 -C.sub.4 alkyl).sub.2, NH(C.sub.1 -C.sub.4 alkyl-OH), N(C.sub.1 -C.sub.4 alkyl-OH).sub.2, COOH or SO.sub.3 H or an ester or amide thereof, or COOM or SO.sub.3 M in which M is Na, K, Ca, Mg, ammonium, mono-, di-, tri- or tetra-C.sub.1 -C.sub.4 alkylammonium, mono-, di- or tri-hydroxyalkylammonium or ammonium that is di- or tri-substituted with a mixture of C.sub.1 -C.sub.4 alkyl and C.sub.1 -C.sub.4 hydroxyalkyl groups;

Process for the preparation of substituted 3-aminobenzonitriles

Growing community of inventors

Möhlin, Switzerland

Adriano Indolese