Procos S.p.a.

Alessandro Barozza

Jacopo Roletto

Paolo Paissoni

Monica Donnola

Matteo Mossotti

Luigi Bogogna

Lavinia Cicione

Fabio Garavaglia

Matteo Colombo

Disclosed is a process for the synthesis of lofexidine of formula (I) and the hydrochloride salt thereof (II), from ethyl 2-(2,6-dichlorophenoxy)propionate (III) and ethylenediamine in the presence of tetravalent titanium alkoxides, preferably titanium isopropoxide, in an apolar solvent such as toluene. A further object of the present invention is a process for the preparation of the intermediate ethyl 2-(2,6-dichlorophenoxy)propionate (III) from 2,6-dichlorophenol and ethyl 2-chloropropionate in the presence of a polar aprotic solvent and an alkali or alkaline earth carbonate salt, preferably potassium carbonate. Both processes are more cost-effective and more easily industrially scalable than the known procedures, thus enabling the active ingredient to be obtained with high yields at a limited cost.

Process for the synthesis of lofexidine

Disclosed is a process for the synthesis of Pirfenidone (1) from 5-methyl-2(1H)-pyridinone and chlorobenzene in the presence of a catalytic system consisting of a copper salt and an organic ligand, in the presence of a base.  The process exploits the high efficiency of the catalytic system consisting of copper(I) salt and an organic ligand in the presence of an inorganic base in the N-amidation reaction of chlorobenzene, a cheap reagent also usable as solvent in this case; reaction conditions at high temperatures, at atmosphere pressure or higher, produce a reaction with good yields.

Process for the synthesis of pirfenidone

Disclosed is a process for the synthesis of chlorzoxazone (1) from 4-chloro-2-aminophenol and ethyl chloroformate in the presence of a base.  The process is particularly advantageous because it uses ethyl chloroformate instead of triphosgene, a highly dangerous reagent that releases phosgene and must be handled with extremely strict procedures to guarantee the safety of operators in industrial facilities. Ethyl chloroformate allows the possibility of working with a number of solvents, including water. The yield and purity of the product obtained are very high.

Process for the synthesis of chlorzoxazone

A process for the preparation of Dalfampridine (1), 4-aminopyridine, starting from 4-pyridinecarbonitrile using a one-pot procedure.  Said process is carried out with no need for isolating intermediates and is particularly advantageous as far as environment, yields, productivity and purity of the resulting product are concerned, both in the reaction mixture and in the isolated crystal.

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Nosate, Italy

Alessandro Barozza