Zentiva K.s.

Zentiva, A.s.

Josef Jirman

Jindrich Richter

Petr Lustig

Lukas Placek

Richard Junek

Hana Petrickova

Ales Halama

Ludmila Hejtmánková

Lucie Srsnová

Hejtmankova Ludmila

A method for the manufacture of dabigatran of formula VIII, in which the product of a reaction of 4-ethylamino-3-nitrobenzoic acid chloride with ethyl-3-(pyridin-2-ylamino)propanoate, is converted to the hydrochloride using a hydrogen chloride solution producing the compound of formula III-HCl, in which the nitro group is reduced by means of a reaction with sodium dithionite, and the resulting compound of formula IV is subjected to a reaction with [(4-cyanophenyl)amino]acetic acid and oxalic acid, the product of this reaction VI-oxal is then subjected to hydrolysis and a reaction with ammonium carbonate to produce the intermediate of formula VII-HCl, which is then converted to dabigatran by means of a reaction with hexyl chloroformate. 

Method for the preparation of dabigatran

Intermediates for the preparation of dabigatran of formulae (VII-2HCl) and (VII-HCl), methods for their preparation and a method for preparation of dabigatran of formula (VIII) using these intermediates. 

Method for the preparation of dabigatran and its intermediates

A process for the preparation of (1S)-QR)-I-azabicyclo[2.2.2.]oct-3-yl 3,4-dihydro-1-phenyl-2(1H)-isoquinoline carboxylate by reacting (1S)-alkyl 1-phenyl-1,2,3,4-tetrahydro-2-isoquinoline carboxylate with 3-(R)-quinuclidol in an inert solvent, where a primary alkyl ester of the carboxylate whose alkyl length is C-Cis used and the reaction is catalyzed by a non-nucleophilic base. 

Process for the preparation of solifenacin

The invention deals with new crystalline salts of bazedoxifene, by means of which a high API quality can be achieved in a high yield.

Salts of bazedoxifene

The monosodium salt of 3-pyridyl-1-hydroxyethylidene-1,1-bisphosphonic acid in new amorphous forms, methods of preparation and a pharmaceutical formulation.

Amorphous forms of risedronate monosodium

The present invention relates to a crystalline, hydrated form of the sodium salt of 3-pyridyl-1-hydroxyethylidene-1,1-bisphosphonic acid. The hydrate contains from 6.4 up to 22 weight % of sodium and 15 up to 23 weight % of crystalline water if the sodium content is lower than 7.5 weight %, based on the whole molecule, or 4.5 up to 18 weight % of crystalline water if the sodium content is equal to or higher than 13 weight %, based on the anhydrous substance. Due to stability in humid environments, the hydrate is useful as an active substance for the treatment of diseases associated with bone resorption disorders.

Crystalline form of the sodium salt of 3-pyridyl-1-hydroxyethylidene-1,1-bisphosphonic acid

A method for obtaining antidiabetic of formula (I), wherein the method comprises condensing of a 4-derivatized phenol or phenolate of general formula (II), wherein R is an amino group-containing organic residue, selected from the group comprising a residue of the following formula &#x2014;NHR, wherein Ris hydrogen or a protecting group, which is removed before further treatment, and a residue of general formula (A), wherein Rrepresents a carboxy group either in the free acid form or in the form of a salt or ester or another functional derivative or the nitrile group CN, and M represents a hydrogen or alkali metal atom, with a pyridine base of general formula (III, wherein Z is a leaving group other than a halogen, wherein, before or after carrying out the condensation, the following operations are carried out: (a) diazotizing the amino group present in organic residue R; (b) converting the diazotised residue R into a derivative of 2-halopropionate or 2-halopropionitrile of formula (B), wherein Ris as defined above and X is a halogen; (c) cyclizing the derivative of 2-halopropionate or 2-halopropionitrile with thiourea; (d) hydrolysing the resulting imine thus giving pioglitazone of formula (I)

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Prague, Czechia

Josef Jirman