Chinoin Gyogyszer Es Vegyeszeti Termekek Gyara Rt.

Chinoin Pharmaceutical and Chemical Works Private Company Ltd.

Chinoin Zrt

Euroapi Hungary Limited Liability Company

István Lászlófi

Zsuzsanna Kardos

Irén Hortobágyi

Gábor Havasi

László Takács

Péter Buzder-Lantos

Imre Juhász

József Molnár

Ágnes Nagyné Borkó

Imre Rozsumberszki

Zoltán Bischof

Ádám Bódis

Tibor Kiss

Tamás Altsach

Tamás Bán

Zoltán Varga

Andrea Sántáné Csutor

Ervin Vajda

Csaba Váradi

Ibolya Fekete

Imola Ritz

László Fónagy

Ildikó Meleg

Judit Póti

Mariusz Kertész

Róbertné Tormási

Kornélia Horváth

The present invention relates to a process for the preparation of a chiral prostaglandin enol intermediate of formula 1, comprising the steps of: separating a compound of formula 16-(R,S)-10 into its diastereomers by fractional crystallisation, reducing the 15-oxo group of the compound of formula 16-(R)-10, thereby obtaining a compound of formula 15-(R,S), 16-(R)-11, followed by removing the protecting group of the compound of formula 15-(R,S), 16-(R)-11, and isolating the compound of formula 1, and optionally, crystallizing the compound of formula 1. Optionally, the undesired isomer formed during fractional crystallization can be epimerized and further amount of the desired isomer can be recovered from the resulting mixture. The present invention also provides novel intermediates useful in the process. The invention further relates to a process for fractional crystallization of the compound of formula 16-(R,S)-10.

Process for the preparation of a chiral prostaglandin enol intermediate and intermediate compounds useful in the process

Treprostinil is a synthetic prostacyclin derivative with thrombocyte aggregation inhibitory and vasodilatory activity. Treprostinil can be administered in subcutaneous, intravenous, inhalable, or oral forms. Disclosed is a method for the preparation of treprostinil of formula I and its amorphous form, anhydrate form, monohydrate form, and polyhydrate form salts with bases. In the disclosed method, the chiral center in the 3-hydroxyoctyl substituent is formed at the end of the synthesis, so that the method is robust and well scalable. Also disclosed are treprostinil intermediates and the preparation of the intermediates.

Process for the preparation of treprostinil

The invention relates to a robust and reproducible process for the preparation of polymorph form B of treprostinil diethanolamine salt, comprising the following steps: a. treprostinil is dissolved in methanol, b. to the solution of step a) diethanolamine or its methanol solution is added, c. the reaction mixture of step b) is agitated till dissolution, d. when salt formation is completed in step c), first portion of an aprotic solvent is added to the solution, e. the solution of step d) is filtered to remove insoluble impurities, f. the filtrate of step e) is seeded with polymorph form B of treprostinil diethanolamine salt, g. to the crystal suspension obtained in step f) a second portion of the aprotic solvent is added, h. the suspension of step g) is agitated until crystallisation is completed, i. the crystals are separated, washed and dried.

Process for the preparation of polymorph form B of treprostinil diethanolamine salt

Treprostinil is a synthetic prostacyclin derivative with thrombocyte aggregation inhibitory and vasodilatory activity. Treprostinil can be administered in subcutaneous, intravenous, inhalable, or oral forms. Disclosed is a method for the preparation of treprostinil of formula I and its amorphous form, anhydrate form, monohydrate form, and polyhydrate form salts with bases. In the disclosed method, the chiral center in the 3-hydroxyoctyl substituent is formed at the end of the synthesis, so that the method is robust and well scalable. Also disclosed are treprostinil intermediates and the preparation of the intermediates. 

The invention provides a new enzimatic process for the preparation of chiral carboxylic acids, their salts and acid derivatives of the general formula (I) by enzymatic hydrolysis of racemic carboxylic acid ester of the general formula (II) and optionally subsequent esterification or acylation.

Process for the preparation of triple-bond-containing optically active carboxylic acids, carboxylate salts and carboxylic acid derivatives

The invention provides a stable epoprostenol sodium and a process for the preparation this pharmaceutically active ingredient.

Process for the preparation of epoprostenol sodium of enhanced stability

A process of preparing compounds of general formula I, by cuprate coupling of a vinyl cuprate of general formula II with a protected enone of general formula IV to produce a compound of general formula (V) removing the protecting groups of the compound of general formula (V) and purifying the compound of general formula (I) by chromatography; wherein the vinyl cuprate of formula (II) is prepared by reacting a vinyl stannane of formula III with copper halide CuX and alkyllithium R1Li and wherein an excess of the alkyllithium is decomposed before the said coupling reaction.

Process for the preparation and purification of misoprostol

The subject of the invention is a process for the preparation of Latanoprostene bunod of formula (I) with a purity higher than 95% where chromatography is used applying normal phase gravity silica gel column chromatography where the used silica gel is irregular silica gel or spherical silica gel an as eluent and eluent mixture consisting of an apolar and a polar solvent is used and if desired, contamination of the purified compound of formula I arising from the solvents are removed by silica gel filtration chromatography.

Preparation of latanoprostene bunod of desired, pre-defined quality by gravity chromatography

The subject of the invention is a novel process for the preparation of Carboprost tromethamine salt where alkylation the enone of the general formula (II) is carried out in the presence of a chiral auxiliary in aprotic solvent with a Grignard reagent. The methyl ester epimers of formula (VII) are separated by gravity silica gel chromatography and the salt formation is carried out by using solid tromethamine base. 

Process for the preparation of carboprost and its tromethamine salt

The invention provides a new process for the preparation of optically active Beraprost of formula (I) starting from racemic Beraprost alkyl ester through hydrolysis, enantiomer esterification, preparation of diacyl-Beraprost ester diastereomers and their separation and hydrolysis. 

Process for the preparation of optically active Beraprost

Treprostinil is a synthetic prostacyclin derivative with thrombocyte aggregation inhibitory and vasodilatory activity. Treprostinil can be administered in subcutaneous, intravenous, inhalable, or oral forms. Disclosed is a method for the preparation of treprostinil of formula I and its amorphous form, anydrate form, monohydrate form, and polyhydrate form salts with bases. In the disclosed method, the chiral center in the 3-hydroxyoctyl substituent is formed at the end of the synthesis, so that the method is robust and well scalable. Also disclosed are treprostinil intermediates and the preparation of the intermediates.

The subject of the invention is process for the preparation of the prostaglandin amides of the general formula I, 

Processes for the preparation of prostaglandin amides

The subject of the invention is process for the preparation of the prostaglandin amides of the general formula I, &#x2014;where in the formula the bonds marked with dotted lines may be single or double bonds, in the case of double bounds at positions 5,6 and 13,14 they may be in cis or in trans orientation, Q stands for a hydroxyl-group and Z stands for a hydroxyl- or oxo-group, Rand Rindependently represent hydrogen atom or a straight or branched Calkyl- or aralkyl-group, optionally substituted with &#x2014;ONOgroup, or an aralkyl- or aryl-group, which contains heteroatom, Rrepresents a straight or branched, saturated or unsaturated Chydrocarbon group, or a Calkylcycloalkyl- or cycloalkyl-group, or an optionally with alkyl group or halogen atom substituted phenyl-, Calkylaryl- or hetaryl-group, Y represents (CH)group or 0 atom or S atom, and where n=0-3. 

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Budapest, Hungary

István Lászlófi