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WO2006063861A1 - Procédé d'obtention de la cizolirtine et de ses énantiomères - Google Patents

Procédé d'obtention de la cizolirtine et de ses énantiomères Download PDF

Info

Publication number
WO2006063861A1
WO2006063861A1 PCT/EP2005/013827 EP2005013827W WO2006063861A1 WO 2006063861 A1 WO2006063861 A1 WO 2006063861A1 EP 2005013827 W EP2005013827 W EP 2005013827W WO 2006063861 A1 WO2006063861 A1 WO 2006063861A1
Authority
WO
WIPO (PCT)
Prior art keywords
process according
ligand
formula
mol
zinc
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/EP2005/013827
Other languages
English (en)
Inventor
Antoni Torrens Jover
Helmut H. Buschmann
Stefan Dahmen
Matthias Lormann
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Esteve Pharmaceuticals SA
Original Assignee
Laboratorios del Dr Esteve SA
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from EP04380266A external-priority patent/EP1671953A1/fr
Application filed by Laboratorios del Dr Esteve SA filed Critical Laboratorios del Dr Esteve SA
Priority to EP05822912A priority Critical patent/EP1838678A1/fr
Publication of WO2006063861A1 publication Critical patent/WO2006063861A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms

Definitions

  • the present invention refers to a process for the asymmetric addition to a pyrazolcarbaldehyde with a phenyl zinc reagent in the presence of a chiral ligand. Said process allows the preparation of known intermediates of formula (II), which thereafter can yield, by O-alkylation, the desired enantiomers of the pharmaceutically active compound Cizolirtine.
  • the present invention is directed to a process for the preparation of an enantiomerically enriched compound of formula (II):
  • Diphenylzinc and triphenylborane are relatively expensive reagents. Therefore, stable complexes of aryl boranes are preferred. Especially triphenylborane ammonia complex, which can readily be prepared from commercially available triphenylborane sodium hydroxide complex, has proven very suitable. Additionally, commercially available and stable 2-aminoethyl diphenylborinate can also be employed. Preferably, the phenyl-boron reagent is triphenylborane ammonia complex.
  • a variable that can affect the enantioselectivity of the addition reaction is the ratio of borane reagent versus diethylzinc (when the phenyl zinc reagent is obtained from these compounds).
  • N,S-ligands are employed, preferably , those of formula VII
  • Typical ligands to be used in this addition reaction are the following compounds, their enantiomers, or derivatives thereof:
  • SD286 -2-piperidinyl- 1,1,2- ti ⁇ phenylethanol
  • ligand (V) catalyst (VI) wherein n is 0 or 1 and R"' is phenyl, ethyl or methyl.
  • This zinc alkoxide complex (VI) is the active catalyst in the addition reaction which subsequently coordinates with the pyrazolcarbaldehyde in such a way that it induces the enantioselective addition of the phenyl group to said aldehyde.
  • the concentration of the aldehyde in the reaction is preferably low, such as between 0.01 molar and 2 molar, more preferably between 0.1 and 1 molar and most preferably at about 0.1 molar. Although in some cases it has been seen that enantioselectivity increases at lower concentrations, this is not suitable for a technical process. In these cases a proper balance between enantioselectivity and adequate concentrations has to be found.
  • the process of the invention can be carried out at temperatures between -40 and
  • the process of the invention can also comprise the presence of additives, for example in order to improve the enantioselectivity by scavenging or complexing Lewis- acidic zinc salts present in the reaction or formed as products.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

La présente invention décrit un procédé de synthèse d'un alcool précurseur de la Cizolirtine, la (±)-2-[phény(1-méthyl-1H-pyrazol-5-yl)méthoxy]-N,N-diméthyléthanamine ainsi que de ses énantiomères. Ledit procédé comprend l'addition asymétrique d'un réactif de type organométallique phénylé sur un pyrazolcarbaldéhyde en présence d'un ligand chiral, afin d'obtenir des alcools chiraux. Lesdits alcools chiraux sont ensuite O-alkylés, pour aboutir à la formation de Cizolirtine ou de ses énantiomères.
PCT/EP2005/013827 2004-12-17 2005-12-16 Procédé d'obtention de la cizolirtine et de ses énantiomères Ceased WO2006063861A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
EP05822912A EP1838678A1 (fr) 2004-12-17 2005-12-16 Procédé d'obtention de cizolirtine et de ses énantionmères

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
EP04380266.9 2004-12-17
EP04380266A EP1671953A1 (fr) 2004-12-17 2004-12-17 Procédé d'obtention de Cizolirtine et de ses énantionmères
US11/041,637 US7109349B2 (en) 2004-12-17 2005-01-24 Process for obtaining Cizolirtine and its enantiomers
US11/041,637 2005-01-24
EP05077140.1 2005-09-20
EP05077140 2005-09-20

Publications (1)

Publication Number Publication Date
WO2006063861A1 true WO2006063861A1 (fr) 2006-06-22

Family

ID=36001075

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2005/013827 Ceased WO2006063861A1 (fr) 2004-12-17 2005-12-16 Procédé d'obtention de la cizolirtine et de ses énantiomères

Country Status (2)

Country Link
EP (1) EP1838678A1 (fr)
WO (1) WO2006063861A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010123999A3 (fr) * 2009-04-21 2011-02-24 Auspex Pharmaceuticals, Inc. Modulateurs 1-méthylpyrazole de la substance p, du peptide apparenté au gène de la calcitonine, des récepteurs adrénergiques et/ou des récepteurs 5-ht

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1029852A1 (fr) * 1997-08-04 2000-08-23 Laboratorios Del Dr. Esteve, S.A. Procede permettant d'obtenir des enantiomeres de cis-olirtine

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1029852A1 (fr) * 1997-08-04 2000-08-23 Laboratorios Del Dr. Esteve, S.A. Procede permettant d'obtenir des enantiomeres de cis-olirtine

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
JENS RUDOLPH, FRANK SCHMIDT, CARSTEN BOLM: "Highly Enantioselective Synthesis of Secondary Alcohols using Triphenylborane", ADV. SYNTH. CATAL., vol. 346, 2004, pages 867 - 872, XP002326590 *
TAKANORI SHIBATA, HIROSHI MORIOKA, TADAKATSU HAYASE, KAORI CHOJI, KENSO SOAI: "Highly Enantioselective Catalytic Asymmetric Automultiplication of Chiral Pyrimidyl Alcohol", J. AM. CHEM. SOC., vol. 118, 1996, pages 471 - 472, XP002326589 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010123999A3 (fr) * 2009-04-21 2011-02-24 Auspex Pharmaceuticals, Inc. Modulateurs 1-méthylpyrazole de la substance p, du peptide apparenté au gène de la calcitonine, des récepteurs adrénergiques et/ou des récepteurs 5-ht

Also Published As

Publication number Publication date
EP1838678A1 (fr) 2007-10-03

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