公开(公告)号：WO2019086434A1

公开(公告)日：2019-05-09

申请号：PCT/EP2018/079675

申请日：2018-10-30

Applicant: PROCOS S.P.A.

Inventor： DONNOLA, Monica ,  MOSSOTTI, Matteo ,  BARBERO, Mauro ,  ROLETTO, Jacopo ,  PAISSONI, Paolo

IPC: C07D453/02

CPC classification number: C07D453/02

Abstract: The present invention discloses a process for the preparation of 2-benzhydryl-3-quinuclidinone (1). (I). The process of the invention allows to obtain the intermediate 2-benzhydryl-3-quinuclidinone (1) by reaction of 2-benzylidene-3-quinuclidinone (2) with the Grignard reagent phenylmagnesium halide, in particular chloride or bromide, in the presence of catalytic amounts of copper (I) salts. Taking advantage of the high efficiency of the catalytic system of the copper (I) salts, 2-benzhydryl-3-quinuclidinone (1) is obtained in higher yields than those of the known processes. Advantageously, since the amounts of copper (I) salts are catalytic, the latter can easily be removed from the reaction mixture, and the process is carried out in the presence of solvents less toxic and expensive than those used in the state of the art.

公开(公告)号：WO2020254580A1

公开(公告)日：2020-12-24

申请号：PCT/EP2020/067105

申请日：2020-06-19

Applicant: PROCOS S.P.A.

Inventor： DONNOLA, Monica ,  BAROZZA, Alessandro ,  ROLETTO, Jacopo ,  PAISSONI, Paolo

IPC: C07D233/22 ,  A61K31/415

Abstract: 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.

公开(公告)号：EP4071139A1

公开(公告)日：2022-10-12

申请号：EP22170802.7

申请日：2020-06-19

Applicant: Procos S.p.A.

Inventor： DONNOLA, Monica ,  BAROZZA, Alessandro ,  ROLETTO, Jacopo ,  PAISSONI, Paolo

IPC: C07D233/22 ,  A61K31/415

Abstract: 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.

公开(公告)号：EP3704116A1

公开(公告)日：2020-09-09

申请号：EP18800538.3

申请日：2018-10-30

Applicant: Procos S.p.A.

Inventor： DONNOLA, Monica ,  MOSSOTTI, Matteo ,  BARBERO, Mauro ,  ROLETTO, Jacopo ,  PAISSONI, Paolo

IPC: C07D453/02

公开(公告)号：EP3986869A1

公开(公告)日：2022-04-27

申请号：EP20736584.2

申请日：2020-06-19

Applicant: Procos S.p.A.

Inventor： DONNOLA, Monica ,  BAROZZA, Alessandro ,  ROLETTO, Jacopo ,  PAISSONI, Paolo

IPC: C07D233/22 ,  A61K31/415