Egis Gyogyszergyar Zrt.

Egis Gyogyszergyar Rt.

Gábor Berecz

Gyula Simig

Zoltán Varga

Balázs Volk

László Szlávik

Gábor Németh

Adrienn Keszthelyi

Beatrix Bali

Daniel Ulej

Kálmán Nagy

Gyula Lukács

Bálint Nyulasi

Mátyás Milen

András Mravik

Györgyi Vereczkeyné Donáth

János Szulágyi

Gyuláné Körtvélyessy

György Clementis

József Reiter

László Pongó

Péter Slégel

László Koncz

Mária TÓTHNÉ Lauritz

Róbert Gudor

János Levente HÉDER

Ede László MÁRVÁNYOS

Balázs Peregi

Method for the production of formula (I) lumateperone or its acid addition salts so that the enantiomer compound with stereochemistry 6bR,10aS is separated form the cis racemate using resolution and the formula (II) stereoisomer is alkylated with 4-halo-4'-fluoro butyrophenone (X=I, Br, Cl) to produce the formula (I) lumateperone, or optionally its acid addition salt. The object of the invention also relates to the amorphous form of the morphologically uniform p-toluenesulfonic acid salt of lumateperone and to the naphthalene-2-sulfonic acid salt of lumateperone, to the 1:2 stoichiometry salt of lumateperone formed with naphthalene-2-sulfonic acid.

Method for the production of lumateperone and its salts

The invention relates to a process for the preparation of 3-{2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl}-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one of the Formula (I), and pharmaceutically acceptable acid addition salts thereof by subjecting the oxime of the Formula (II), to ring-closure in the presence of an alkali hydroxide, alkali carbonate or alkali-Calkoxide in an inert organic solvent, converting the base of the Formula I thus obtained into an acid addition salt or setting free the base of the Formula I from an acid addition salt thereof which comprises reacting a halogen derivative of the general Formula (XIV), (wherein Hal is halogen) with piperidine oxime derivative of the Formula (V), or an acid addition salt thereof in the presence of a base, and using by the ring-closure of the oxime of the Formula II formed a C-alkanol as inert solvent. The process of the present invention enables the economical preparation of a product having a purity suitable for pharmaceutical purposes.

Process for the preparation of 3-{2-'4- (6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyllethyl}-6,7,8,9-tetrahydro-2-methyl-4h-pyrido&#x2032;1,2-methyl-4h-pyrido&#x2032;,2-a!pyrimidin-4-one

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Budapest, Hungary

Gábor Berecz