EP2147004A2 - Verfahren zur herstellung von phosphinbutadienliganden, komplexe davon mit kupfer und deren verwendung in der katalyse - Google Patents

Verfahren zur herstellung von phosphinbutadienliganden, komplexe davon mit kupfer und deren verwendung in der katalyse

Info

Publication number
EP2147004A2
EP2147004A2 EP08737504A EP08737504A EP2147004A2 EP 2147004 A2 EP2147004 A2 EP 2147004A2 EP 08737504 A EP08737504 A EP 08737504A EP 08737504 A EP08737504 A EP 08737504A EP 2147004 A2 EP2147004 A2 EP 2147004A2
Authority
EP
European Patent Office
Prior art keywords
formula
butadiene
phosphine
group
complex
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.)
Withdrawn
Application number
EP08737504A
Other languages
English (en)
French (fr)
Inventor
Marc Taillefer
Hamid Kaddouri
Fouad Ouazzani
Armelle Ouali
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.)
Centre National de la Recherche Scientifique CNRS
Ecole Nationale Superieure de Chimie de Montpellier ENSCM
Universite Sidi Mohammed Ben Abdellah
Original Assignee
Centre National de la Recherche Scientifique CNRS
Ecole Nationale Superieure de Chimie de Montpellier ENSCM
Universite Sidi Mohammed Ben Abdellah
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
Application filed by Centre National de la Recherche Scientifique CNRS, Ecole Nationale Superieure de Chimie de Montpellier ENSCM, Universite Sidi Mohammed Ben Abdellah filed Critical Centre National de la Recherche Scientifique CNRS
Priority to EP12180417.3A priority Critical patent/EP2527350B1/de
Publication of EP2147004A2 publication Critical patent/EP2147004A2/de
Withdrawn legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/50—Organo-phosphines
    • C07F9/5045—Complexes or chelates of phosphines with metallic compounds or metals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/50—Organo-phosphines
    • C07F9/5022—Aromatic phosphines (P-C aromatic linkage)

Definitions

  • the present invention relates to a process for the preparation of phosphorus butadiene phosphine ligands, their applications, especially as catalytic metal ligands used in carbon-carbon bond formation reactions and cabone-heteroatom.
  • butadiene phosphorus derivatives are known since the 1960s and are of interest in organic synthesis, because of their electrophilic character and their biological activity, including antiviral. With the development of asymmetric synthesis, butadiene phosphorus derivatives are now the subject of intensive research for their great importance in coordination chemistry by the presence in these derivatives of two ligands widely used in coordination chemistry. : the phosphine ligand, and the butadiene ligand.
  • Z. Xi et al. (Tetrahedron Lett, (2004), 45, 2427-2429) also involves an alkyne as the starting compound, alkyne which is reacted with a zirconium complex.
  • MP Teulade and P. Savignac propose a general synthesis of butadiene phosphines based on a Wittig-Homer reaction from cyclic phosphonates, and JL Cabioch and JM Denis (J. Organomet Chem., (1989), 377 (2-3), 227-
  • CONFIRMATION COPY 233 propose for their part an example of synthesis of an unsubstituted primary butadiene phosphine from the corresponding phosphonate in the presence of an aluminum salt.
  • a first object of the present invention is to provide a synthesis route suitable for the preparation of various butadiene phosphines, with acceptable yields, and whose implementation is easy, preferably with a minimum of steps, from starting compounds that are relatively common or easy to prepare.
  • the present invention firstly relates to the process for preparing a butadiene phosphine of formula (1):
  • R a and R b identical or different, preferably identical, each represents a radical independently selected from alkyl, aryl, heteroaryl, monoalkylamino, dialkylamino, alkoxy, aryloxy and heteroaryloxy; ⁇
  • R 1 , R 2 , R 3 , R 4 and R 5 are independently selected from hydrogen, a hydrocarbon radical, an aryl radical and a heteroaryl radical; said process comprising the steps of: a) contacting a phosphonium halide of formula (2) with a strong base in an aprotic polar solvent, for example tetrahydrofuran, at low temperature, generally between -70 ° C. and 0 ° C, for example -50 ° C., to give phosphonium diylide (3):
  • aprotic polar solvent for example tetrahydrofuran
  • R 1 is as defined above, Z and Z 'have definitions identical to those of R a and R b defined above, and X represents a halogen selected from fluorine, chlorine, bromine and iodine; b) which diylide (3) is reacted, in polar aprotic solvent medium, for example tetrahydrofuran, at a temperature generally between -70 ° C.
  • polar aprotic solvent medium for example tetrahydrofuran
  • halophosphine ( 4): where R a and R b are as defined above, and X 'represents a halogen atom selected from fluorine, chlorine, bromine and iodine; to lead to phosphonium ylide (5a) which undergoes rearrangement by prototropy to give phosphonium ylide (5b):
  • R 2 , R 3 , R 4 and R 5 are as defined above, to conduct, after removal of the solvent and optional purification, the butadiene phosphine (1).
  • R 4 and / or R 5 may be bonded so as to form with the carbon atom which carries them a carbocyclic or heterocyclic group having from 3 to 20 carbon atoms, saturated, unsaturated, monocyclic or polycyclic comprising two or three cycles, the adjacent cycles may be aromatic in nature,
  • the method described above can advantageously be carried out in a single reactor ("one pot"), that is to say without it is necessary to isolate all or some of the intermediaries. However, it is possible, of course and if desired, to isolate one or more of the intermediates, advantageously when they are stable.
  • the strong base used for the preparation of the phosphonium diylide (3) described above is generally a metallized base, that is to say a strong base comprising one or more metals, preferably selected from alkali metals and alkaline earth, and in particular among lithium, sodium, potassium, magnesium, calcium and barium. Strong lithiated bases are preferred, especially butyllithium.
  • the counter ion of phosphonium diylide (3) is the lithium cation.
  • Alkyl represents a saturated hydrocarbon radical, linear or branched having from 1 to 10 carbon atoms, preferably from 1 to 6 carbon atoms, and in particular the methyl, ethyl radical, the propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl and decyl radicals;
  • Aryl represents a mono or polycyclic aromatic hydrocarbon radical, and for example the phenyl radical and the naphthyl radical;
  • Heteroaryl represents a mono or polycyclic aromatic hydrocarbon radical, further comprising one or more heteroatoms, identical or different, selected from nitrogen, oxygen, sulfur, each of rings having 5 or 6 members;
  • heteroaryl radicals are pyridyl, quinolyl, imidazolyl and tetrazolyl radicals, without this list constituting any limitation;
  • Haldrocarbon radical as indicated for the radicals R 1 , R 2 , R 3 , R 4 and R 5 represents a branched, linear or cyclic hydrocarbon radical (mono- or polycyclic) containing from 1 to 20 carbon atoms , and may comprise one or more unsaturations in the form of double (s) and / or triple (s) bond (s), for example and without limitation methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, cyclohexyl, benzyl, phenyl, vinyl, allyl, and the like; in the terms “alkoxy, aryloxy, heteroaryloxy, monoalkylamino and dialkylamino", the definitions of the terms alkyl-, aryl- and heteroaryl- correspond to the generic terms defined above.
  • radicals whose definitions appear above may optionally be substituted with one or more halogen atoms, advantageously chosen from fluorine, chlorine, bromine and iodine, with one or more alkyl, alkenyl and / or linear or branched alkynyl radicals having 1 to 10 carbon atoms, with one or more hydroxyl, alkoxy, alkenyloxy, alkynyloxy, aryl, heteroaryl, amino, alkylamino, dialkylamino, carboxy, carbonyl, carbonylamino, carbonylalkylamino radicals, carbonyldialkylamino, the substituents being identical or different.
  • halogen atoms advantageously chosen from fluorine, chlorine, bromine and iodine
  • the bonds in "wavy" lines indicate that the two double bonds may be in the cis or trans configuration, that is to say that the phosphine butadiene of formula (1) may be of E or Z configuration.
  • the butadiene phosphines obtained according to the process of the invention may be specifically of Z configuration (formula (1Z)) or of configuration E (formula (1E)) or as a mixture in all proportions:
  • the E and Z isomers of phosphines obtained according to the process of the present invention may be separated, if necessary, according to conventional methods or methods known to those skilled in the art.
  • butadiene phosphines of configuration Z, or butadiene phosphines of configuration E, or mixtures of butadiene phosphine E and Z in all proportions.
  • R a and R b identical or different, each represent a radical independently selected from alkyl, including methyl, ethyl propyl, butyl; aryl, especially phenyl or naphthyl, heteroaryl, especially pyridyl or quinolyl, and preferably R a and R b are identical and each represent phenyl;
  • R 1 represents hydrogen or alkyl, especially methyl, ethyl or propyl, preferably R 1 represents hydrogen;
  • R 2 , R 3 and R 4 which are identical or different, are chosen independently from hydrogen, an alkyl radical, an aryl radical and a radical; j
  • heteroaryl in particular from hydrogen and an alkyl radical, especially methyl, ethyl or propyl
  • R 5 is chosen from hydrogen, an alkyl radical, an aryl radical and a heteroaryl radical; preferably, R 5 represents alkyl, in particular methyl, ethyl, propyl, butyl or pentyl, or represents phenyl, naphthyl, pyridyl or quinolyl.
  • the process of the invention makes it possible in particular to obtain butadiene phosphites (Z) -Ph (C 4 H 4 ) PPh 2 , (E) -Ph (C 4 H 4 ) PPh 2 , (Z) -CH 3 (C 4 H 4 ) PPh 2 and (E) -CH 3 Ph (C 4 H 4 ) PPh 2 , where Ph is phenyl.
  • the process described above makes it possible to obtain the butadiene phosphines of formula (1) from compounds which are readily available commercially, or which are easily prepared from procedures known from the literature. In addition, the low number of process steps allows easy implementation.
  • the process can advantageously be carried out in a single operation ("one pot"), that is to say without it being necessary to isolate and / or purify the synthesis intermediates.
  • the butadiene phosphines of formula (1) may quite advantageously be used as ligands of copper to form complexes.
  • butadiene phosphines are of great interest in coordination chemistry and catalysis, due to the fact that they combine two very important ligands of organometallic chemistry: conjugated dienes and phosphines.
  • the complexes according to the invention can be represented sohematically in the form Pho-Bu / Cu, where Pho-Bu represents a butadiene phosphine of formula (1) defined above, and Cu represents a copper atom. This schematic representation in no way indicates the number of moles of butadiene phosphine present relative to the number of copper atoms present.
  • a “monomeric complex” is a Pho-Bu / Cu complex which comprises a copper atom, "dimer complex”, a Pho-Bu / Cu complex which comprises two copper atoms, “trimer complex”, a complex Pho-Bu / Cu which has three copper atoms, etc.
  • the invention also relates to monomeric phenyl or methyl butadienyldiphenylphosphine / copper iodide complexes.
  • the Pho-Bu / Cu complexes defined above can be prepared according to conventional techniques known to those skilled in the art.
  • the Pho-Bu / Cu complexes can be prepared by contacting at least one butadiene phosphine, especially of formula (1) defined above, with metallic copper or a derivative of copper (copper (I) or copper (II)), for example a copper halide, such as cupric or cuprous iodide, bromide or chloride, or other derivatives, especially organo-copper compounds, for example copper acetylacetonate.
  • the reaction is generally carried out under an inert atmosphere, for example under nitrogen or argon, in an organic solvent medium, preferably an aprotic polar solvent, for example acetonitrile.
  • the complexation reaction is usually carried out at a temperature of between 0 ° C. and 80 ° C., depending on the nature of the compounds in the presence, and generally the reaction temperature is ambient temperature.
  • the complex is generally obtained in the form of a precipitate which is isolated from the reaction medium according to techniques known per se, by for example by filtration, and optionally recrystallization in a solvent, advantageously identical to that used for the complexation reaction.
  • the Pho-Bu / Cu complex may advantageously be prepared in situ in the reaction medium of the reaction catalyzed by the Pho-Bu / Cu complex. Such an alternative is illustrated in the following examples of arylation (Examples C).
  • the copper / phosphine butadiene complexes find an application quite suitable as a catalyst system for carbon-carbon bond formation reactions (CC) or carbon-heteroatom (C-HE) according to the so-called Ulimann method (F. Ullmann and H. Kipper, Ber., Chem., Ges., 1095, 38, 2120-2126).
  • Ulimann method F. Ullmann and H. Kipper, Ber., Chem., Ges., 1095, 38, 2120-2126.
  • the copper-catalyzed Ullmann reaction is one of the most used methods in the industry because of the attractive cost of copper, compared with the costs of other noble metals such as palladium, ruthenium, and others.
  • the present invention relates to a process for creating a carbon-carbon (CC) bond or a carbon-heteroatom (C-HE) bond by reacting a compound carrying a grouping. starting with a nucleophilic compound carrying a carbon atom or a heteroatom (HE) capable of substituting for the leaving group, thus creating a CC or C-HE bond, in which process the reaction is carried out in the presence of a effective amount of a catalyst system comprising at least one copper / phosphine butadiene complex.
  • a catalyst system comprising at least one copper / phosphine butadiene complex.
  • YR 0 represents a compound carrying a leaving group Y
  • RQ represents a nucleophilic compound, R being the residue of said nucleophilic compound, and Q being a carbon atom or a heteroatom (HE) which can substitute for said leaving group Y.
  • an arylation reaction is carried out by reacting an aromatic compound carrying a leaving group with a nucleophilic compound.
  • a vinylation or alkynation reaction is carried out by reacting respectively a compound comprising a double bond or a triple bond in the ⁇ position of a leaving group, with a compound nucleophile.
  • Arylation is used in its broad sense, since it is contemplated the implementation of an unsaturated compound bearing a leaving group which is either unsaturated aliphatic type or aromatic carbocyclic or heterocyclic type. 2 1
  • nucleophilic compound an organic hydrocarbon compound which is acyclic as well as cyclic or polycyclic and the characteristic of which is to comprise at least one atom carrying a free doublet, which may or may not comprise a charge, and of preferably a nitrogen, oxygen, sulfur, boron or phosphorus atom, or comprises a carbon atom which can donate its pair of electrons.
  • the nucleophilic compound comprises at least one carrier atom of a free doublet which can be provided by a functional group and / or a carbanion.
  • N-H N N-N - N-N-C N-H
  • -N C- N ⁇ CN, N (CN) 2 " ; P (CN) 2 “ ; C (CN) 3 “ ; C (CN) 2 NO “ ; NCO “ NCS “ ; NSO “ CNO “ ;
  • the nucleophilic compound comprises at least one nitrogen atom carrying a free doublet included in a saturated, unsaturated or aromatic ring; the cycle generally comprises from 3 to 8 atoms.
  • the counterion is generally a metal cation, such as an alkali metal, preferably lithium, sodium or potassium, or an alkaline earth metal, preferably calcium, or the remainder of an organometallic compound, such as that especially magnesian or zincic.
  • a first advantage of the process of the invention is to carry out the reaction at moderate temperature.
  • Another advantage is to be able to use a wide range of coupling agents, in particular arylation agents, nucleophiles, not only iodides, but also bromides, chlorides or triflates, especially iodides. of aryl, aryl bromides, aryl chlorides or aryl triflates.
  • Another advantage of the method of the invention is to use catalysis by copper rather than palladium or nickel, that is to say a less toxic catalyst and providing a further advantage of the point of contact. economic view.
  • a first category of substrates (nucleophilic compounds) to which the process of the invention applies comprises nitrogenous organic derivatives and more particularly primary or secondary amines; hydrazine or hydrazone derivatives; amides; sulfonamides; urea derivatives; heterocyclic derivatives, preferably nitrogenous and / or sulfurized.
  • the primary or secondary amines may be represented by the general formula (Ia):
  • R 11 and R 12 which are identical or different, are chosen from hydrogen, a hydrocarbon radical (1 to 20 carbon atoms, as defined above), an aryl radical, a heteroaryl radical, and from any one of any two or several of the aforementioned groups, it being understood that at most one of the groups R 11 and R 12 represents the hydrogen atom.
  • the amines used preferentially correspond to the formula (la) in which R 11 and R 12 , which may be identical or different, represent a Ci-Ci 5 , preferably Ci-Ci 0 , alkyl group, a cycloalkyl group or a cycloalkyl group. C 3 -C 8, preferably C 5 or C 6, or an aryl or arylaikyle group C 6 to C 2.
  • R 11 and R 12 groups there may be mentioned C 1 -C 4 alkyl, phenyl, naphthyl or benzyl groups.
  • formula (Ia) amines mention may be made of aniline, N-methylaniline, diphenylamine, benzylamine and dibenzylamine.
  • the present invention does not exclude the presence of one or more unsaturations in the hydrocarbon chain (s), such as one or more double and / or triple bonds, which may be conjugated or not conjugated.
  • the hydrocarbon chain (s) may also be interrupted by one or more heteroatoms (for example oxygen, sulfur, nitrogen, phosphorus), and / or by a non-reactive functional group, such as for example -CO-.
  • the amino group can in the form of anions.
  • the counterion is then a metal cation, preferably an alkali metal cation, and more preferably sodium or potassium. Examples of such compounds include sodium or potassium amide.
  • the hydrocarbon chain may optionally carry one or more substituents, as indicated above, and in particular atoms, groups or radicals chosen from halogen, ester, amino or alkyl and / or arylphosphine, insofar as they do not interfere with each other. not.
  • the acyclic aliphatic groups, linear or branched, saturated or unsaturated, may optionally carry a cyclic substituent.
  • the term "ring" refers to a saturated, unsaturated or aromatic carbocycic or heterocyclic ring.
  • the acyclic aliphatic group may be linked to the ring by a valence bond, a heteroatom or a functional group such as oxy, carbonyl, carboxyl, sulfonyl, etc.
  • cyclic substituents it is possible to envisage cycloaliphatic, aromatic or heterocyclic, in particular cycloaliphatic, substituents comprising 6 carbon atoms in the ring or benzenes, these cyclic substituents being themselves optionally carrying any substituent in the measurement. where they do not interfere with the reactions involved in the process of the invention.
  • C 1 -C 4 alkyl, alkoxy groups may be mentioned.
  • cycloalkylalkyl groups for example, cyclohexylalkyl or arylalkyl groups preferably C 7 to C 2 , especially benzyl or phenylethyl.
  • the groups R 11 and R 12 can also represent, independently of one another, a saturated carbocyclyl group or comprising 1 or 2 unsaturations in the ring, generally in C 3 to C 8) preferably to 6 carbon atoms in the IC
  • cycle said cycle being substitutable.
  • Preferred examples of this type of group include cyclohexyl groups optionally substituted, especially with linear or branched alkyl groups having from 1 to 4 carbon atoms.
  • the groups R 11 and R 12 may represent, independently of one another, an aromatic hydrocarbon group, and in particular a benzene group having the general formula (FO:
  • W represents a group selected from alkyl, d-C ⁇ linear or branched alkoxy, linear Ci-C 6 branched or alkylthio CRC-6 linear or branched, -NO 2, -CN, halogen, and CF 3.
  • the aromatic hydrocarbon group can therefore be substituted.
  • W illustrates certain types of preferred substituents but the enumeration is not limiting.
  • R 11 and R 12 may also represent, independently of one another, a polycyclic aromatic hydrocarbon group with the rings which can form between them o / ffro-condensed, ortho- and peri-condensed systems. There may be mentioned more particularly a naphthyl group, said cycle being able to be substituted.
  • R 11 and R 12 may also represent, independently of each other, a polycyclic hydrocarbon group consisting of at least 2 saturated and / or unsaturated carbocycles or at least 2 carbocycles of which only one of them is aromatic and forming between them ortho- or ortho- and peri-condensed systems.
  • the rings are C 3 to C 8 , preferably C 6 . More specific examples include the bomyl group or the tetrahydronaphthalene group.
  • R 11 and R 12 may also represent, independently of one another, a saturated, unsaturated or aromatic heterocyclic group, comprising in particular 5 or 6 atoms in the ring, including one or two heteroatoms such as nitrogen (not substituted by a hydrogen atom), sulfur and oxygen; the carbon atoms of this heterocycle may also be substituted.
  • R 11 and R 12 may also represent a polycyclic heterocyclic group defined as either a group consisting of at least two aromatic or non-aromatic heterocycles containing at least one heteroatom in each ring and forming between them ortho- or ortho-ortho systems.
  • groups R 11 and R 12 of heterocyclic type there may be mentioned inter alia, furyl, thienyl, isoxazolyl, furazanyl, isothiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrannyl, phosphino and quinolyl groups groups. , naphthyridinyl, benzopyranyl, benzofuranyl.
  • nucleophilic compounds that may be used in the process of the invention are, for example, the hydrazine derivatives corresponding to formula (Ib):
  • R 13 and R 14 identical or different, have the meaning given for R 11 and R 12 in the formula (la), and at most one of the groups R 3 and R 4 represents the hydrogen atom.
  • the groups R 13 and R 14 are more particularly an alkyl group of C 1 to C 15 , preferably C 1 to C 10, a cycloalkyl group. from C 3 to C 8 , preferably C 5 or C 6 , an aryl or arylalkyl group of C 12 to C 12. More preferably, R 13 and R 14 represent a C 1 to C 4 alkyl, phenyl, benzyl or naphthyl.
  • nucleophiles that may be mentioned include oximes and hydroxylamines, which may be represented by the general formulas (Ic) and (Id) respectively:
  • R 15 and R 16 which are identical or different, have the definitions given for R 11 and R 12 in the formula (Ia), and at most one of the groups R 15 and
  • R 16 represents the hydrogen atom.
  • R 17 has the definitions given for R 11 or R 12 in the formula (la), the hydrogen atom excepted;
  • R 18 is chosen from the hydrogen atom, a linear or branched, saturated or unsaturated acyclic aliphatic group and a saturated or unsaturated monocyclic or polycyclic carbocyclic group; as well as from any sequence of two or more of said groups.
  • Preferred examples of oximes or hydroxylamines of the formulas (Ic) and (Id), respectively, are those for which R 15, R 16 and R 17 are alkyl to C 5, preferably -C do; C 3 -C 8 cycloalkyl, preferably C 5 or C 6 cycloalkyl; or C 6 -C 12 aryl or arylalkyl.
  • groups R 15 , R 16 and R 17 mention may be made of C 1 -C 4 alkyl, phenyl, naphthyl or benzyl groups.
  • R 18 it is preferably C 1 -C 4 alkyl or benzyl.
  • nucleophilic compounds of the hydrazine type which may be represented by the following formula (Ic): in which :
  • R 19 , R 20 and R 21 identical or different, have the definitions given for R 11 and R 12 in the formula (la); - R 21 represents the hydrogen atom or a protective group G; and at least one of R 19 , R 20 and R 21 is not hydrogen; or R 19 and R 20 may together form, and with the nitrogen atom which carries them, a saturated, unsaturated or aromatic monocyclic or polycyclic C 3 -C 2 O heterocyclic group.
  • Preferred hydrazines of formula (Ic) above are those in which R 19 and R 20 , which may be identical or different, represent C 1 to C 15 alkyl, preferably C 10 alkyl; C 3 -C 8 cycloalkyl, preferably C 5 or C 6 ; or aryl or arylalkyl C 6 -C 2. More preferably, the hydrazines are those of formula (Ic), in which R 19 and R 20 , which are identical or different, represent C 1 -C 4 alkyl, phenyl, benzyl or naphthyl.
  • R 19 and R 20 may be connected together, so as to form, with the nitrogen atom which carries them, a saturated, unsaturated or aromatic monocyclic or polycyclic C 3 -C 2 O heterocyclic group, comprising two or three o-condensed rings, i.e., at least two rings which have two carbon atoms in common.
  • the number of atoms of each ring may preferably vary between 3 and 6.
  • R 19 and R 20 together form a cyclohexane or fluorenone ring.
  • R 21 preferably represents hydrogen, alkyl (preferably C 1 -C 12 ), alkenyl or alkynyl (preferably C 2 -C 12 ), cycloalkyl (preferably C 3 -C 12 ), aryl or arylalkyl (preferably C 6 -C 12 ). More preferably, R 21 represents a hydrogen atom or a C 1 -C 4 alkyl group.
  • Such protecting groups are well known in the art, and mention may be made of the commonly used protecting groups, such as, for example, acyl (acetyl, benzoyl), BOC (butoxycarbonyl), CBZ (carbobenzoxy), FMOC (trifluoromethyloxycarbonyl) groups. or MSOC (methanesulfenyl-2-ethoxycarbonyl).
  • acyl acetyl, benzoyl
  • BOC butoxycarbonyl
  • CBZ carboxycarbonyl
  • FMOC trifluoromethyloxycarbonyl
  • MSOC methanesulfenyl-2-ethoxycarbonyl
  • R 22 , R 23 and R 24 identical or different, have the definitions given for R 11 and R 12 in the formula (la); at most one of the groups R 22 and R 23 represents the hydrogen atom; or R 22 and R 23 together with the nitrogen atom carrying them may form a saturated, unsaturated or aromatic monocyclic or polycyclic C 3 -C 20 carbocyclic or heterocyclic group.
  • Preferred examples of hydrazones of formula (If) above are those in which R 22 and R 23 , which are identical or different, represent C 1 -C 5 alkyl, preferably C 1 -C 10 alkyl. ; cycloalkyl C 3 -C 8, preferably C 5 or C 6; or aryl or arylalkyl C 6 -C 2.
  • examples of hydrazones of formula (If) are those in which R 22 and R 23 , which may be identical or different, represent C 1 -C 4 alkyl, phenyl, benzyl or naphthyl.
  • R 22 and R 23 may together form, and with the nitrogen atom which carries them, a carbocyclic or heterocyclic C 3 -C 2 O, monocyclic or polycyclic, saturated, unsaturated or aromatic, group comprising two or three o / tfto-condensed cycles.
  • the number of atoms of each ring may vary, preferably between 3 and 6.
  • R 22 and R 23 together form a cyclohexane or fluorenone ring.
  • R 24 preferably represents the hydrogen atom, an alkyl (preferably C 1 -C 12 ), alkenyl or alkynyl (preferably C 2 -C 12 ) group, cycloalkyl (preferably C 3 -C 12 ), aryl or arylalkyl (preferably C 6 -C 12 ). More preferably, R 24 represents a hydrogen atom or a C 1 -C 4 alkyl group.
  • the invention also relates to compounds of amide type which more particularly correspond to the formula (Ig):
  • R 25 -NH-CO-R 26 (Ig) wherein R 25 and R 26 have the meaning given for R 11 and R 12 in formula (Ia).
  • Examples of compounds of formula (Ig) include oxazolidin-2-one, benzamide and acetamide.
  • Examples of compounds of formula (Ih) include tosylhydrazide.
  • urea derivatives such as guanidines and which may be represented by formula (Ii): in said formula (Ii) 1, the groups R 29 , which are identical or different, have the meaning given for R 11 and R 12 in formula (Ia).
  • compounds of formula (Ii) include N, N, N ', N'-tetramethylguanidine.
  • RAA represents the hydrogen atom or the residue of an amino acid, preferably the hydrogen atom; a linear or branched alkyl CRCI 2 optionally bearing a functional group; C 6 -C 12 aryl or arylalkyl; or a functional group, preferably a hydroxyl group;
  • R 30 and R 31 have the given definitions R 11 and R 12 in the formula
  • R h represents the hydrogen atom; a metal cation, preferably an alkali metal cation; or a C 1 -C 12 hydrocarbon group, preferably C 1 -C 12 alkyl.
  • RAA in formula (Ij) above represents alkyl, optionally containing a functional group, for example -OH, -NH 2 , -CO-NH 2 , -NH-CNH-, -HN-C (O) -NH 2 , -COOH, -SH, -S-CH 3 , or an imidazole, pyrrole, or pyrazole group.
  • a functional group for example -OH, -NH 2 , -CO-NH 2 , -NH-CNH-, -HN-C (O) -NH 2 , -COOH, -SH, -S-CH 3 , or an imidazole, pyrrole, or pyrazole group.
  • Examples of such amino acids include glycine, cysteine, aspartic acid, glutamic acid, histidine. oo
  • Nucleophilic substrates quite well adapted to the implementation of the process of the invention are heterocyclic derivatives comprising at least one nucleophilic atom such as a nitrogen atom, sulfur or phosphorus.
  • R 32 identical or different, represent (s) the substituents of the cycle; n represents the number of substituents on the cycle.
  • the invention is particularly applicable to monocyclic heterocyclic compounds corresponding to formula (Ik) in which A represents a heterocycle, saturated or unsaturated, or aromatic containing in particular 5 or 6 atoms in the ring which may comprise 1 or 3 heteroatoms such as nitrogen, sulfur and oxygen atoms and at least one of which is a nucleophilic atom such as NH or S.
  • A may also represent a polycyclic heterocyclic compound defined as consisting of at least 2 aromatic or non-aromatic heterocycles containing at least one heteroatom in each ring and forming between them ortho- or ortho- and peri-condensed systems or a group constituted by at least one aromatic or non-aromatic carbocycle and at least one aromatic or non-aromatic heterocycle forming between them ortho- or ortho- and peri-condensed systems. It is also possible to start from a substrate resulting from the concatenation of a saturated, unsaturated or aromatic heterocycle as mentioned above and of a saturated, unsaturated or aromatic carbocycle.
  • carbocycle one preferably means a cycloaliphatic or aromatic ring having 3 to 8 carbon atoms, preferably 6.
  • the carbon atoms of the heterocycle may optionally be substituted, in their entirety or for a part of them only by R32 groups.
  • n is preferably 0, 1, 2, 3 or 4, more preferably n is 0 or 1.
  • the group or groups R32 which may be identical or different, preferably represent one of the following groups:
  • a linear or branched alkyl group of C 1 to C 6 preferably of C 1 to C 4 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl;
  • a linear or branched alkoxy or thioether group from C 1 to C 6, preferably from C 1 to C 4, such as the methoxy, ethoxy, propoxy, isopropoxy or butoxy groups, an alkenyloxy group, preferably an allyloxy group or a phenoxy group; ; a cyclohexyl, phenyl or benzyl group;
  • a group or a function such as hydroxyl, thiol, carboxyl, ester, amide, formyl, acyl, aroyl, amide, urea, isocyanate, thioisocyanate, nitrile, azide, nitro, sulfone, sulfonic, halogen, pseudohalogen or trifluoromethyl.
  • the present invention is particularly applicable to compounds of formula (Ik) wherein the R32 group or groups more particularly represent an alkyl or alkoxy group. More particularly, the optionally substituted residue A represents one of the following rings: a monocyclic heterocycle comprising one or more heteroatoms
  • a bicycle comprising a carbocycle and a heterocycle comprising one or more heteroatoms:
  • a tricycle comprising at least one carbocycle or a heterocycle comprising one or more heteroatoms:
  • heterocyclic compounds it is preferred to use those which have the formula (Ik) in which A represents a ring such as imidazole, pyrazole, triazole, pyrazine, oxadiazole, oxazole, tetrazole, indole, pyrrole, phthalazine, pyridazine. , oxazolidine.
  • A represents a ring such as imidazole, pyrazole, triazole, pyrazine, oxadiazole, oxazole, tetrazole, indole, pyrrole, phthalazine, pyridazine. , oxazolidine.
  • nucleophilic compounds which may also be used in the process of the invention, mention may also be made of the alcohol or thiol type compounds which may be represented by the following formula (Im) :
  • R 33 represents a hydrocarbon group having from 1 to 20 atoms and has the meaning given for R 11 or R 12 in formula (Ia); and Z represents a group of OM 1 or SM 1 type in which M 1 represents a hydrogen atom or a metal cation, preferably an alkali metal cation.
  • R33 represents a hydrocarbon group having 1 to 20 carbon atoms which may be a linear or branched, saturated or unsaturated acyclic aliphatic group; a saturated, unsaturated or aromatic, monocyclic or polycyclic carbocyclic or heterocyclic group; or any sequence of two or more of the aforementioned groups.
  • R33 preferably represents a linear or branched saturated acyclic aliphatic group preferably having from 1 to 12 carbon atoms, and more preferably from 1 to 4 carbon atoms.
  • the invention does not exclude the presence of unsaturation on the hydrocarbon chain such as one or more double and / or triple bonds which may or may not be conjugated.
  • the hydrocarbon chain may optionally be interrupted by a heteroatom, a functional group or may carry one or more substituents.
  • R33 may also represent a saturated or unsaturated carbocyclic group preferably having 5 or 6 carbon atoms in the ring; a saturated or unsaturated heterocyclic group comprising in particular 5 or 6 atoms in the ring including 1 or 2 heteroatoms such as nitrogen, sulfur, oxygen or phosphorus; a carbocyclic or heterocyclic aromatic group, monocyclic, preferably phenyl, pyridyl, furyl, pyranyl, thiophenyl, thienyl, phospholyl, pyrazolyl, imidazolyl, pyrrolyl; or a carbocyclic or heterocyclic aromatic group, polycyclic, condensed or not, preferably naphthyl.
  • R33 comprises a cycle, it can also be substituted.
  • the nature of the substituent can be any as long as it does not interfere with the main reaction.
  • the number of substituents is generally at most 4 per cycle but most often equal to 1 or 2.
  • the invention also relates to the case where R33 comprises a chain of aliphatic and / or cyclic, carbocyclic and / or heterocyclic groups.
  • An acyclic aliphatic group may be linked to a ring by a valence bond, a heteroatom or a functional group such as oxy, carbonyl, carboxy, sulfonyl, etc.
  • cycloalkylalkyl groups for example, cyclohexylalkyl or aralkyl groups having 7 to 12 carbon atoms, especially benzyl or phenylethyl.
  • the invention also contemplates a chain of carbocyclic and / or heterocyclic groups and more particularly a chain of phenyl groups separated by a valence bond or an atom or functional group such as oxygen, sulfur, sulpho, sulphonyl, carbonyl, carbonyloxy, imino, carbonylimino, hydrazo, alkylene (C1-C10, preferably C1-C6) -diimino.
  • a chain of carbocyclic and / or heterocyclic groups and more particularly a chain of phenyl groups separated by a valence bond or an atom or functional group such as oxygen, sulfur, sulpho, sulphonyl, carbonyl, carbonyloxy, imino, carbonylimino, hydrazo, alkylene (C1-C10, preferably C1-C6) -diimino.
  • acyclic aliphatic group saturated or unsaturated, linear or branched may optionally carry a cyclic substituent.
  • ring is meant a saturated, unsaturated or aromatic carbocyclic or heterocyclic ring.
  • D represents the remainder of an aromatic, monocyclic or polycyclic carbocyclic group or a divalent group consisting of any chain of two or more monocyclic aromatic carbocyclic groups;
  • R 34 represents one or more substituents, identical or different
  • Z represents a group of OM 1 or SM 1 type in which M 1 represents a hydrogen atom or a metal cation, preferably an alkali metal cation;
  • - n 1 represents 0, 1, 2, 3, 4 or 5.
  • m represents a number equal to 0, 1 or 2, the symbols R 34 and n ', which are identical or different, having the meaning given above;
  • R 34 represents a hydrogen atom, a hydroxyl group, a -CHO group, a -NO 2 group, a linear or branched alkyl or alkoxy group containing from 1 to 6 carbon atoms, preferably from 1 to 4 carbon atoms; carbon, and more preferably methyl, ethyl, methoxy or ethoxy;
  • - W symbolizes a valency bond, an alkylene or alkylidene group having 1 to 4 carbon atoms, or an oxygen atom; m is 0 or 1;
  • n 0, 1 or 2;
  • p 0 or 1.
  • radical D corresponds to the formula (Fn) in which m and n 'are equal to 0, such as phenol or thiophenol;
  • residue D has the formula (Fn) in which m is equal to 0 and n 1 is equal to 1, such as hydroquinone, pyrocatechol, resorcinol, alkylphenols, alkylthiophenols, alkoxyphenols, salicylic aldehyde, para-hydroxybenzaldehyde, methyl salicylate, para-hydroxybenzoic acid methyl ester, chlorophenols, nitrophenols, para-acetamidophenol;
  • residue D corresponds to the formula (Fn) in which m is equal to 0 and n 1 is equal to 2, such as dialkylphenols, vanillin, isovanilline, 2-hydroxy-5-acetamidobenzaldehyde, 2-hydroxy-5-propionamidobenzaldehyde, 4-allyloxybenzaldehyde, dichlorophenols, methylhydroquinone, chlorohydroquinone; those in which the residue D has the formula (Fn) in which m is 0 and n 1 is equal to 3, such as 4-bromovanillin, 4-hydroxy-vanillin, trialkylphenols, 2,4 6-trinitrophenol, 2,6-dichloro-4-nitrophenol, trichlorophenols, dichlorohydroquinones, or 3,5-dimethoxy-4-hydroxybenzaldehyde;
  • radical D corresponds to the formula (Fn) in which m is equal to 1 and n 'is greater than or equal to 1, such as dihydroxynaphthalene, 4-methoxynaphth-1-ol, 6-bromonaphth- 2-ol;
  • nucleophilic compounds belonging to totally different families and which may be used in the process of the invention, mention may be made of compounds containing phosphorus, as well as compounds containing phosphorus and phosphorus. nitrogen, preferably those having the following formulas:
  • - cycloalkyl C 5 -C 6 alkyl substituted by u or more alkyl Ci-C 4 alkoxy groups or -C 4; phenylalkyl, the aliphatic portion of which has 1 to 6 carbon atoms;
  • phenyl substituted with one or more C 1 -C 4 alkyl groups or C 1 -C 4 alkoxy groups, or with one or more halogen atoms.
  • tricyclohexylphosphine trimethylphosphine, triethylphosphine, tri- ⁇ -butylphosphine, tris-butylphosphine, tri-terf-butylphosphine, tribenzylphosphine, dicyclohexylphénylphosphine triphenylphosphine, dimethylphenylphosphine, diethylphenylphosphine, di-tert-butylphenylphosphine.
  • Other compounds that may be used in the process of the invention are hydrocarbon derivatives comprising a nucleophilic carbon.
  • Mention may more particularly be made of malonate anions comprising a group -OC-HC-COO-.
  • Mention may be made of malonate alkyl anions of formula (Ir):
  • R 37 OOC-HC ⁇ (R 38) -COO-R '37 (Ir) wherein: - R 37 and R 37, identical or different, represent an alkyl group containing from 1 to 12 atoms, preferably from 1 at 4 atoms;
  • R 38 is selected from the hydrogen atom; C 1 -C 12 alkyl; C 5 -C 6 cycloalkyl; C 5 -C 6 cycloalkyl substituted with one or more C 1 -C 4 alkyl or C 1 -C 4 alkoxy; phenyl; phenyl substituted by one or more C 4 alkyl, alkoxy or -C 4 or one or more halogen; phenylalkyl, the aliphatic part of which contains from 1 to 6 carbon atoms.
  • malonitrile and malodinitrile anions comprising a group R 37 -OOC-HC ⁇ (R 38 ) -CN or NC-HC - CN respectively, in which R 37 and R 38 have the meanings given. previously.
  • R 11 in formula (la) also represents a metal cation, preferably an alkaline cation, and even more preferably lithium, sodium or potassium.
  • acetonitrile cyanobenzene, optionally bearing one or more substituents on the benzene ring or the ethanal cyanohydrin CH 3 CH (OH) CN.
  • the acetylenide compounds which can be represented by the formula (Is), can also be used in the process of the invention:
  • R 39 -C ⁇ C- (ls) in said formula is of any kind and in particular the meaning given for R 11 in the formula (la), the counter-ion is a metal cation, preferably sodium or potassium.
  • the counter-ion is a metal cation, preferably sodium or potassium.
  • acetylide or diacetylide of sodium or potassium may be mentioned.
  • nucleophilic compounds As other classes of nucleophilic compounds that can be used in the process of the invention, mention may be made of the compounds of secane type and their derivatives, which can be represented by the following formula (It):
  • R 40 has the meaning given for R 11 in formula (la);
  • R 41 represents an alkyl group having 1 to 12 carbon atoms, preferably 1 to 4 atoms.
  • the preferred compounds are those which correspond to the formula (It) in which R 40 represents an alkyl group having from 1 to 12 carbon atoms, a cycloalkyl group having 5 or 6 carbon atoms and an aryl group having 6 or 12 carbon atoms, or a nitrogen heterocycle having 5 or 6 atoms. It may also be mentioned as nucleophilic compounds, those comprising a carbanion and whose counterion is a metal and corresponding to the following formulas:
  • a phenylalkyl group whose aliphatic part contains from 1 to 6 carbon atoms;
  • a phenyl group A phenyl group substituted by one or more alkyl radicals having from 1 to 4 carbon atoms or alkoxy having from 1 to 4 carbon atoms or by one or more halogen atoms; or
  • a saturated, unsaturated or aromatic heterocyclic group preferably comprising 5 or 6 atoms and comprising, as heteroatom (s), sulfur, oxygen or nitrogen;
  • the groups R '42 and R " 42 represent a hydrogen atom or a group such as R 42 , two of the groups R 42 , R' 42 and R" 42 may be joined together to form a saturated, unsaturated carbocycle or heterocycle or aromatic having preferably 5 or 6 carbon atoms;
  • M 2 represents a metallic element of group (IA) of the periodic table of elements
  • M 3 represents a metallic element of groups (HA) and (HB) of the periodic table of elements;
  • Xi represents a chlorine or bromine atom;
  • v is the valence of the metal M 3 ; and
  • w is 0 or 1.
  • R 42 , R '42 and R " 42 are advantageously a C 1 -C 4 alkyl group, a cyclohexyl or phenyl group, or said groups may form a benzene, cyclopentadiene, pyridine or thiophene ring.
  • nucleophilic compounds it is possible to use boronic acids or their derivatives, and more particularly to those corresponding to the following formula (Iv):
  • R 43 represents a carbocyclic or heterocyclic, aromatic, monocyclic or polycyclic group; and - T 1 and T 2 , which may be identical or different, represent a hydrogen atom, a linear or branched, saturated or unsaturated aliphatic group having from 1 to 20 carbon atoms or an R 43 group.
  • the boronic acid or its derivative has formula (Iv) in which the group R 43 represents a carbocyclic or heterocyclic aromatic group.
  • R 43 can take the meanings previously given for D in the formula (Im-i).
  • R 43 is more particularly a carbocyclic group such as phenyl, naphthyl or a heterocyclic group such as pyrrolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, 1,3-thiazolyl, 1,3,4-thiadiazolyl or thienyl.
  • the aromatic ring may also be substituted.
  • the number of substituents is generally at most 4 per cycle but most often 1 or 2.
  • R 32 of formula (Ik) for examples of substituents.
  • the preferred substituents are alkyl or alkoxy groups having 1 to 4 carbon atoms, an amino group, a nitro group, a cyano group, a halogen atom or a trifluoromethyl group.
  • T 1 and T 2 which may be identical or different, they more particularly represent a hydrogen atom or an acyclic aliphatic group, linear or branched, having from 1 to 20 carbon atoms, saturated or comprising one or more unsaturations in the form of double (s) and / or triple (s) link (s) on the chain, preferably from 1 to 3 unsaturations, which are preferably single or conjugated double bonds.
  • T 1 and T 2 preferably represent an alkyl group having 1 to 10 carbon atoms, preferably 1 to 4 carbon atoms, or an alkenyl group having 2 to 10 carbon atoms, preferably a vinyl group or 1-methylvinyl.
  • T 1 and T 2 may furthermore have the meanings given for R 43 and in particular any cycle may also carry a substituent as described above.
  • R 43 preferably represents a phenyl group. It will not be departing from the scope of the present invention to use derivatives of boronic acids such as anhydrides and esters and more particularly alkyl esters having 1 to 4 carbon atoms. Examples of arylboronic acids that may be mentioned include benzeneboronic acid, 2-thiopheneboronic acid, 3-thiopheneboronic acid, 4-methylbenzeneboronic acid and 3-methylthiophene-2-boronic acid.
  • 3-aminobenzeneboronic acid the acid 3-aminobenzeneboronic hemisulfate, 3-fluorobenzeneboronic acid, 4-fluorobenzeneboronic acid, 2-formylbenzeneboronic acid, 3-formylbenzeneboronic acid, 4-formylbenzeneboronic acid, 2-methoxybenzeneboronic acid, 3-methoxybenzeneboronic acid, A-methoxybenzeneboronic acid, 4-chlorobenzeneboronic acid, 5-chlorothiophene-2-boronic acid, benzo [b] furan-2-boronic acid, 4-carboxybenzeneboronic acid, 2-acid, 4,6-trimethylbenzeneboronic acid, 3-nitrobenzeneboronic acid, 4- (methylthio) benzeneboronic acid, 1-naphthalenboronic acid, 2-naphthalenboronic acid, 2-methoxy-1-naphthalenboronic acid, 3-chloro-4-fluorobenzeneboronic acid, 3-
  • nucleophilic compounds are in no way limiting and any type of nucleophilic compound can be envisaged.
  • a -CC or -C-HE- bond (where HE represents O, S, P, N, Si, B, and the like) can be created by reaction.
  • a nucleophilic compound such as those which have just been defined above, with a compound carrying a leaving group, in particular a compound comprising an unsaturated bond located at the ⁇ position of a leaving group.
  • R 0 represents a hydrocarbon group containing from 2 to 20 carbon atoms and optionally has at least one unsaturation (double or triple bond) located in the ⁇ position of a leaving group Y, or is a carbocyclic and / or heterocyclic, aromatic, monocyclic or polycyclic group.
  • R 0 represents a hydrocarbon group containing from 2 to 20 carbon atoms and optionally has at least one unsaturation (double or triple bond) located in the ⁇ position of a leaving group Y, or is a carbocyclic and / or heterocyclic, aromatic, monocyclic or polycyclic group.
  • R 0 represents an aliphatic hydrocarbon group optionally comprising a double bond and / or a triple bond in the ⁇ position of the leaving group or a cyclic hydrocarbon group comprising an unsaturation bearing the leaving group;
  • R 0 represents a carbocyclic and / or heterocyclic, aromatic, monocyclic or polycyclic group
  • Y represents a leaving group, preferably a halogen atom or a sulphonic ester group of formula -OSO 2 -R 6 , wherein R ⁇ is a hydrocarbon group.
  • R e is a hydrocarbon group of any nature.
  • Y is a leaving group, it is interesting from an economic point of view that R e is of a simple nature, and more particularly represents a linear or branched alkyl group having from 1 to 4 carbon atoms, preferably a methyl or ethyl group; but it may also represent for example a phenyl or tolyl group or a trifluoromethyl group.
  • the preferred group is a triflate group, which corresponds to a group R e representing a trifluoromethyl group.
  • a bromine or chlorine atom is preferably chosen.
  • the compounds of formula (II) particularly targeted according to the process of the invention can be classified into three groups:
  • R 44 , R 45 and R 46 which are identical or different, represent a hydrogen atom or a hydrocarbon group having from 1 to 20 carbon atoms which may be a saturated or unsaturated, linear or branched aliphatic group; a saturated, unsaturated or aromatic, monocyclic or polycyclic carbocyclic or heterocyclic group; any chain of aliphatic (s) and / or carbocyclic (s) and / or heterocyclic (s) groups as mentioned above; and
  • R 44 has the meaning given in formula (IIa).
  • Y represents a leaving group as previously defined; (31) the compounds of aromatic type which are subsequently designated by
  • Haloaromatic compound and which can be represented by the formula (II):
  • E symbolizes the remainder of a ring forming all or part of a carbocyclic and / or heterocyclic, aromatic, monocyclic or polycyclic system;
  • R 47 which may be identical or different, represent substituents on the ring; Y represents a leaving group as defined above; and n "represents the number of substituents on the ring.
  • the invention applies to unsaturated compounds corresponding to formulas (IIa) and (Hb), in which R 44 preferably represents a linear or branched, saturated acyclic aliphatic group, preferably having from 1 to 12 carbon atoms. .
  • R 44 preferably represents a linear or branched, saturated acyclic aliphatic group, preferably having from 1 to 12 carbon atoms.
  • the invention does not exclude the presence of another unsaturated bond on the hydrocarbon chain, such as a triple bond or one or more double bonds, which may or may not be conjugated.
  • the hydrocarbon chain may be optionally interrupted by a heteroatom (for example, oxygen or sulfur) or by a functional group, to the extent that it does not react, and there may be mentioned in particular a group such as especially -CO-.
  • the hydrocarbon chain may optionally carry one or more substituents insofar as they do not react under the reaction conditions, and there may be mentioned in particular a halogen atom, a nitrile group or a trifluoromethyl group.
  • the acyclic aliphatic group, saturated or unsaturated, linear or branched may optionally carry a cyclic substituent.
  • ring is meant a saturated, unsaturated or aromatic carbocyclic or heterocyclic ring.
  • the acyclic aliphatic group may be linked to the ring by a valence bond, a heteroatom or a functional group, such as oxy, carbonyl, carboxy, sulfonyl, etc.
  • cyclic substituents it is possible to envisage cycloaliphatic, aromatic or heterocyclic, in particular cycloaliphatic, substituents comprising 6 carbon atoms in the ring, or benzene substituents, these cyclic substituents themselves being optionally carrying any substituent. in that they do not interfere with the reactions involved in the process of the invention.
  • alkyl or alkoxy groups having 1 to 4 carbon atoms may be mentioned.
  • R 44 may also represent a carbocyclic group, saturated or unsaturated, preferably having 5 or 6 carbon atoms in the ring, preferably cyclohexyl; a heterocyclic group, saturated or unsaturated, in particular containing 5 or 6 atoms in the cycle, of which 1 or 2 heteroatoms such as nitrogen, sulfur and oxygen atoms; an aromatic carbocylic group, monocyclic, preferably phenyl, or polycyclic condensed or not, preferably naphthyl.
  • R 45 and R 46 they preferably represent a hydrogen atom or an alkyl group having 1 to 12 carbon atoms, a phenyl group or an aralkyl group having 7 to 12 carbon atoms, preferably a benzyl group.
  • R 44 , R 45 and R 46 are more particularly a hydrogen atom, or R 44 represents a phenyl group and R 45 and R 46 represent an atom. hydrogen.
  • R 34 and R 35 may also represent a functional group, insofar as they do not interact in the coupling reaction.
  • functional groups there may be mentioned amido, ester, ether, cyano groups.
  • compounds corresponding to formulas (IIa) and (Hb) there may be mentioned in particular chloride or vinyl bromide or ⁇ -bromo- or ⁇ -chlorostyrene, or bromoalkyne or iodoalcyne.
  • the invention applies in particular to the haloaromatic compounds corresponding to formula (IIc) in which E is the residue of a cyclic compound, preferably having at least 4 atoms in the ring, preferably 5 or 6, optionally substituted, and representing at least one of the following cycles:
  • An aromatic carbocycle, monocyclic or polycyclic that is to say. a compound consisting of at least 2 aromatic carbocycles and forming between them ortho- or ortho- and ⁇ -fused systems or a compound consisting of at least 2 carbocycles of which only one of them is aromatic and forming between they are ortho- or ortho- and ⁇ -condensed systems;
  • a monocyclic aromatic heterocycle comprising at least one of the heteroatoms P, O, N and / or S, or a polycyclic aromatic heterocycle, that is to say a compound constituted by at least 2 heterocycles containing at least one heteroatom in each cycle of which at least one of the two rings is aromatic and forming between them ortho- or ortho- and p-condensed systems; or a compound consisting of at least one carbocycle and at least one heterocycie of which at least one of the rings is aromatic and forming between them ortho- or ortho- and per-condensed systems;
  • the optionally substituted residue E preferably represents the residue of an aromatic carbocycle, such as benzene, of an aromatic bicycle comprising two aromatic carbocycles, such as naphthalene, or a partially aromatic bicycle comprising two carbocycles of which one is aromatic, such as 1,2,3,4-tetrahydro-naphthalene.
  • E can represent the rest of a heterocycie insofar as it is more electrophilic than the compound corresponding to the formula (Ik).
  • an aromatic heterocycie such as furan, pyridine; an aromatic bicycle comprising an aromatic carbocycle and an aromatic heterocycea, such as benzofuran, benzopyridine; a partially aromatic bicycle comprising an aromatic carbocycle and a heterocycie, such as methylenedioxybenzene; an aromatic bicycle comprising two aromatic heterocycles, such as 1,8-naphthylpyridine; a partially aromatic bicycle comprising a carbocycle and an aromatic heterocycie, such as 5,6,7,8-tetrahydroquinoline.
  • haloaromatic compound of formula (IIc) in which E represents an aromatic nucleus, preferably a benzene or naphthalenic nucleus.
  • the aromatic compound of formula (IIc) may carry one or more substituents.
  • R 47 may also represent a saturated, unsaturated or aromatic heterocycle comprising 5 or 6 atoms and comprising sulfur, oxygen and / or nitrogen, as heteroatom (s).
  • heteroatom s
  • n is equal to 0, 1, 2, 3 or 4, preferably equal to 1 or 2.
  • Examples of compounds corresponding to formula (IIc) that may be mentioned include para-chlorotoluene, para-bromoanisole and para-bromotrifluorobenzene.
  • the amount of the compound carrying a leaving group of formula (II), preferably of formula (IIa) or (Hb) or (IIc), used is generally expressed relative to the amount of the nucleophilic compound is can vary in large proportions; generally it is close to stoichiometry.
  • the ratio between the number of moles of the leaving group carrying compound and the number of moles of the nucleophilic compound varies most often between 0.1 and 2.0, preferably between 0.5 and 1.5, more preferably between 0.8 and 1, 2, and more preferably between 0.9 and 1, 1.
  • the nucleophilic compound which preferably corresponds to formulas (la) to (Iv)
  • a compound carrying a leaving group which preferably corresponds to formula (II).
  • a catalyst system comprising a copper / butadiene phosphine complex as defined according to the invention.
  • catalytic systems that may be used, mention may be made of those comprising at least one copper / phosphine butadiene complex, such as those defined above under the name generic Pho-Bu / Cu, that is to say complexes of copper with at least one butadiene phosphine of formula (1) according to the invention.
  • the Pho-Bu / Cu complex can be prepared in situ in the reaction medium of the coupling reaction.
  • the total amount of butadiene copper / phosphine complex catalyst used in the process of the invention expressed as the molar ratio between the number of moles of complex expressed in copper, and the number of moles of carrier compound.
  • a leaving group generally varies between 0.001 and 0.5, preferably between 0.01 and 0.1.
  • the invention does not exclude that copper is associated with a small amount of another metal element designated by M.
  • the metal element M is chosen from group (VIII), (IB) and (HB) of the periodic table of elements, as defined above. Examples of metals M 1 include silver, palladium, cobalt, nickel, iron and / or zinc.
  • a mixture comprising palladium and copper is used.
  • the palladium may be provided as a finely divided metal or as an inorganic derivative such as an oxide or hydroxide. It is possible to use a mineral salt preferably, nitrate, sulfate, oxysulfate, halide, oxyhalide, silicate, carbonate, or an organic derivative, preferably cyanide, oxalate, acetylacetonate; alkoxide and even more preferably methylate or ethylate; carboxylate and even more preferably acetate.
  • complexes in particular chlorinated or cyanized palladium and / or alkali metal complexes, preferably sodium, potassium or ammonium.
  • compounds which can be used for the preparation of the catalysts of the invention mention may in particular be made of bromide of palladium (II), palladium (II) chloride, palladium (II) iodide, palladium (II) cyanide, hydrated palladium (II) nitrate, palladium (II) oxide, sulfate palladium (II) dihydrate, palladium (II) acetate, palladium (II) propionate, palladium (II) butyrate, palladium benzoate.
  • nickel (II) halides such as chloride, bromide or nickel iodide (II); nickel sulphate (ll); nickel carbonate (II); salts of organic acids comprising from 1 to 18 carbon atoms such as in particular acetate, propionate
  • nickel (II) complexes such as nickel (II) acetylacetonate, nickel (II) dibromo-bis- (triphenylphosphine), nickel (II) dibromo-bis (bipyridine); nickel complexes (O) such as nickel bis (cycloocta-1,5-diene) (O), nickel bis-diphenylphosphinoethane (O).
  • derivatives based on iron or zinc generally in the form of oxide, hydroxides or salts such as halides, preferably chloride, nitrates and sulphates.
  • the amount of the metal element M represents less than 50%, preferably less than 25, advantageously less than 10 mol% relative to the number of moles of copper. More preferably, it implements a catalyst in the form of a complex with a butadiene phosphine comprising only copper.
  • a base whose function is to trap the leaving group.
  • the bases suitable for the process of the invention can be characterized by their pKa, which is advantageously at least greater than or equal to 2, preferably between 4 and 30.
  • the pKa is defined as the ionic dissociation constant of the acid / base pair, when the water is used as a solvent.
  • a base having a pKa as defined by the invention reference may be made, inter alia, to the Handbook of Chemistry and Physics, 66 th edition, pp. D-161 and D-162.
  • mineral bases such as carbonates, hydrogencarbonates, phosphates or hydroxides of alkali metals, preferably of sodium, of potassium, of cesium, or of alkaline earth metals, of preferably calcium, barium or magnesium.
  • alkali metal hydrides preferably sodium hydride or alkali metal alkoxides, preferably sodium or potassium, and more preferably sodium methoxide, ethylate or tert-butoxide.
  • Organic bases such as tertiary amines and, more particularly, triethylamine, tri-n-propylamine, tri-n-butylamine, methyldibutylamine, methyl-dicyclohexylamine and ethyldi-isopropylamine are also suitable.
  • the alkali metal carbonates are preferably chosen.
  • the amount of base used is such that the ratio between the number of moles of base and the number of moles of the compound carrying the leaving group preferably varies between 1 and 4, preferably around 2.
  • the coupling reaction, in particular arylation or vinylation or alkynation, conducted according to the invention is most often conducted in the presence of an organic solvent.
  • An organic solvent is preferably used, which does not react under the conditions of the reaction.
  • types of solvents used in the process of the invention use is preferably made of a polar organic solvent and preferably an aprotic polar organic solvent.
  • Nonlimiting examples of solvents that can be used in the process of the invention are chosen from: linear or cyclic carboxamides such as N, N-dimethylacetamide (DMAC), N, N-diethylacetamide, dimethylformamide (DMF), diethylformamide or 1-methyl-2-pyrrolidinone (NMP); dimethylsulfoxide (DMSO); hexamethylphosphotriamide (HMPT); tetramethylurea; nitro compounds such as nitromethane, nitroethane, 1-nitropropane, 2-nitropropane or their mixtures, nitrobenzene; aliphatic or aromatic nitriles such as acetonitrile, propionitrile, butanenitrile, iso-butanenitrile, pentanenitrile, 2-methylglutaronitrile, adiponitrile; tetramethylene sulfone (sulfolane); organic carbonates such as dimethylcarbonate, di-isopropylcarbonate, di
  • the preferred solvents are carboxamides, such as DMF, acetonitrile, DMSO, NMP and DMAC.
  • the amount of organic solvent to be used is determined according to the nature of the chosen organic solvent. It is determined so that the concentration of the leaving group carrying compound in the organic solvent is preferably between 5% and 40% by weight.
  • the nucleophilic compound and / or the carrier group carrying the leaving group may be used as solvent (s) for the reaction, in which case it is not necessary to add an additional solvent to the reaction medium.
  • C-HE according to the process of the invention is generally conducted at a temperature which is advantageously between 0 ° C. and 200 ° C., preferably between 20 ° C. and 170 ° C., and even more preferably between
  • Said reaction is generally carried out at atmospheric pressure, but higher pressures of up to 10 bar may also be used.
  • the butadiene copper / phosphine complex catalyst system is charged, the nucleophilic compound, preferably of formula (Ia) to (IV), the base, the compound carrying the leaving group, preferably of formula (II), preferably still of formula (IIa), (Hb) or (IIc), and optionally the organic solvent.
  • the reaction medium is then brought to the desired temperature.
  • the compound obtained is recovered according to the conventional techniques used, in particular by crystallization in an organic solvent.
  • organic solvents used in the crystallization step there may be mentioned in particular aliphatic or aromatic hydrocarbons, halogenated or not, carboxamides and nitriles. There may be mentioned in particular cyclohexane, toluene, dimethylformamide, acetonitrile. Examples of embodiments of the invention are given below. These examples are given for information only, and are not limiting in nature.
  • Example A-1 Cinnamic Butadiene Phosphine Ph (C 4 H 4 ) PPh 2
  • IR (KBr): v (cm "1) 3020 F, 3010 m, 1620 m, 1570 m, 1470 m, 1430 FF 1 1300 f, 1250 f, 1180 m, 1090 F, 1020 F 1980 F, 950 F, 690 FF.
  • Example A-1-2 Cinnamic Butadiene Phosphine (E) -Ph (C 4 H 4 ) PPh 2
  • IR (KBr): ⁇ (cm- 1 ) 3040 F, 3010 F, 1640 F, 1580 F, 1470 F, 1430 FF, 139 O, 1190 F, 1115 F, 1090 m, 1030 m, 980 FF, 850 m, 7.20 F, 690 FF.
  • the general procedure was followed using 2.4 mL (29.22 mmol) of crotonic aldehyde (frans-2-butanal).
  • the two isomers are separated on a column of alumina with a hexane / dichloromethane (97/3) eluent mixture.
  • Example A-2-1 Crotonic Butadiene Phosphine (Z) -CH 3 (C 4 H 4 ) PPh 2
  • IR (CCl 4 ): v (cm- 1 ) 3060 F, 3040 F, 3000 F 1 2915 F 1 1690 FF, 1580 F, 1560 m, 1480 F 1 1430 FF 1 1370 m, 130O f 1 1100 m, 1030 F, 990 F, 950 F, 930 m, 820 F, 730 FF, 690 FF.
  • Example A-2-2 Crotonic Butadiene Phosphine (E) -CH 3 (C 4 H 4 ) PPh 2
  • the metal salt When the metal salt is liquid, it is added after the solvent using a syringe.
  • Example B-1 Phosphine Cinnamic (Z) / CuI Complex
  • IR (KBr): ⁇ (cm -1 ) 3066 ff, 3023 ff, 1618m, 1595f, 1576m, 1478m, 1446m, 1431f, 1420F, 1364f, 1303m, 1180f, 1156m. , 1096 m, 1066 m, 987 F, 943 F, 755 m, 740 FF, 732 FF, 711 FF, 697 FF, 627 m, 616 F.
  • phosphine-butadiene ligands are bound to copper only by the phosphorus doublet. Double bonds do not interfere in coordination.
  • the third ligand is iodine.
  • IR (KBr): ⁇ (cm-1) 3060 ff, 3000 ff, 2900 ff, 1640 m, 1560 f, 1540 f, 1480 m
  • the copper salt, the butadiene phosphine (ligand), the nucleophile and the base are successively introduced into a 35 ml Schluk tube, purged three times with vacuum-nitrogen cycles.
  • the arylating agent and then the solvent (acetonitrile) are then added using syringes.
  • the reaction is brought to the desired temperature and stirred at this temperature for the time indicated.
  • Example C-2 Arylation of 1,3-dimethylphenol
  • the general procedure (acetonitrile, 82 ° C, 12 hours or 30 hours in the case of bromobenzene) was followed using 9.52 mg (0.05 mmol) CuI 1 copper iodide 31.4 mg (0.1 mmol) of the cinnamic butadiene phosphine (Z) of Example A-1-1, 91, 62 mg (0.75 mmol) of dimethylphenol, 212 mg (1 mmol) of potassium phosphate (K 3 PO 4 ), 56 ⁇ l (0.5 mmol) of iodobenzene (53 ⁇ l of bromobenzene) and 500 ⁇ l of acetonitrile.
  • the oil obtained after treatment (dichloromethane / water extraction) was purified by chromatography on a silica column (eluent: hexane). Yield: 89 mg of colorless oil (90%).
  • Example C-3 Arylation of ethyl cyanoacetate

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Biochemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Molecular Biology (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
EP08737504A 2007-04-20 2008-04-21 Verfahren zur herstellung von phosphinbutadienliganden, komplexe davon mit kupfer und deren verwendung in der katalyse Withdrawn EP2147004A2 (de)

Priority Applications (1)

Application Number Priority Date Filing Date Title
EP12180417.3A EP2527350B1 (de) 2007-04-20 2008-04-21 Verfahren zur Herstellung von Liganden vom Typ Butadien-Phosphine, ihre mit Kupfer verbundenen Komplexe und ihre Anwendungen in der Katalyse

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
FR0702878A FR2915200B1 (fr) 2007-04-20 2007-04-20 Procede de preparation de ligands de type phosphines butadieniques,leurs complexes avec le cuivre,et leurs applications en catalyse
PCT/IB2008/000984 WO2008129407A2 (fr) 2007-04-20 2008-04-21 Procede de preparation de ligands de type phosphines butadieniques, leurs complexes avec le cuivre, et leurs applications en catalyse

Related Child Applications (1)

Application Number Title Priority Date Filing Date
EP12180417.3A Division EP2527350B1 (de) 2007-04-20 2008-04-21 Verfahren zur Herstellung von Liganden vom Typ Butadien-Phosphine, ihre mit Kupfer verbundenen Komplexe und ihre Anwendungen in der Katalyse

Publications (1)

Publication Number Publication Date
EP2147004A2 true EP2147004A2 (de) 2010-01-27

Family

ID=38695561

Family Applications (2)

Application Number Title Priority Date Filing Date
EP12180417.3A Not-in-force EP2527350B1 (de) 2007-04-20 2008-04-21 Verfahren zur Herstellung von Liganden vom Typ Butadien-Phosphine, ihre mit Kupfer verbundenen Komplexe und ihre Anwendungen in der Katalyse
EP08737504A Withdrawn EP2147004A2 (de) 2007-04-20 2008-04-21 Verfahren zur herstellung von phosphinbutadienliganden, komplexe davon mit kupfer und deren verwendung in der katalyse

Family Applications Before (1)

Application Number Title Priority Date Filing Date
EP12180417.3A Not-in-force EP2527350B1 (de) 2007-04-20 2008-04-21 Verfahren zur Herstellung von Liganden vom Typ Butadien-Phosphine, ihre mit Kupfer verbundenen Komplexe und ihre Anwendungen in der Katalyse

Country Status (4)

Country Link
US (2) US20100121076A1 (de)
EP (2) EP2527350B1 (de)
FR (1) FR2915200B1 (de)
WO (1) WO2008129407A2 (de)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8652203B2 (en) 2010-09-23 2014-02-18 Cardiaq Valve Technologies, Inc. Replacement heart valves, delivery devices and methods

Family Cites Families (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE19522293A1 (de) * 1995-06-20 1997-01-02 Bayer Ag Neue Bisphospine als Katalysatoren für asymmetrische Reaktionen
DE10112067A1 (de) * 2001-03-12 2002-09-19 Basf Ag Verfahren zur Herstellung von 2,7-Dimethyl-2,4,6-octarienal-monoacetalen
CN100482344C (zh) * 2001-04-12 2009-04-29 罗狄亚化学公司 亲核取代用催化剂、它的合成、包含它的组合物以及它的用途
FR2838441B1 (fr) 2002-04-11 2005-07-01 Rhodia Chimie Sa Composes presentant un role catalytique dans les echanges de substitutions nucleophiles et procede de synthese de ces composes
US6759554B2 (en) * 2001-04-24 2004-07-06 Massachusetts Institute Of Technology Copper-catalyzed formation of carbon-heteroatom and carbon-carbon bonds
FR2833947B1 (fr) * 2001-12-20 2004-02-06 Rhodia Chimie Sa Procede d'arylation ou de vinylation d'un compose nucleophile
FR2840303B1 (fr) 2002-05-31 2005-07-15 Rhodia Chimie Sa Procede d'arylation ou de vinylation ou d'alcylynation d'un compose nucleophile
US20050234239A1 (en) * 2002-03-31 2005-10-20 Marc Taillefer Method of forming a carbon-carbon or carbon-heteroatom linkage
DE10254809A1 (de) * 2002-11-22 2004-06-03 Basf Ag Verfahren zur Herstellung von Carotinoiden
FR2859205B1 (fr) * 2003-08-28 2006-02-03 Rhodia Chimie Sa Procede de formation d'une liaison carbone-carbone ou carbone-heteroatome
US6894191B1 (en) * 2003-12-10 2005-05-17 Council Of Scientific And Industrial Research Process for the preparation of arylamines

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO2008129407A2 *

Also Published As

Publication number Publication date
WO2008129407A3 (fr) 2009-01-29
FR2915200B1 (fr) 2009-07-03
FR2915200A1 (fr) 2008-10-24
US20130165667A1 (en) 2013-06-27
WO2008129407A2 (fr) 2008-10-30
US20100121076A1 (en) 2010-05-13
EP2527350B1 (de) 2015-06-03
EP2527350A1 (de) 2012-11-28
US8674125B2 (en) 2014-03-18

Similar Documents

Publication Publication Date Title
US9861971B2 (en) Catalytic system for cross-coupling reactions
FR2840303A1 (fr) Procede d'arylation ou de vinylation ou d'alcylynation d'un compose nucleophile
US20100197969A1 (en) Use of phosphonium salts in coupling reactions and process for their manufacture
CA2487475A1 (fr) Procede de formation d'une liaison carbone-carbone ou carbone-heteroatome
EP1456151A1 (de) Verfahren zur herstellung einer kohlenstoff-kohlenstoff oder kohlenstoff-heteroatombindung
EP2197889B1 (de) Verwendung von cyclovinylphosphin/kupfer-komplexen als arylierungskatalysatoren
EP2527350B1 (de) Verfahren zur Herstellung von Liganden vom Typ Butadien-Phosphine, ihre mit Kupfer verbundenen Komplexe und ihre Anwendungen in der Katalyse
US9162953B2 (en) Iron-copper co-catalyzed process for carbon-carbon or carbon-heteroatom bonding
JP2006282587A (ja) ３−アミノフェニルアセチレンの製造方法
WO2005023731A2 (fr) Procede de formation d'une liaison carbone-carbone ou carbone-heteroatome.
JP2019011286A (ja) ホスフィン化合物及びこれを配位子とするカップリング用触媒
EP1753707A1 (de) Verfahren zur verringerung einer funktionellen gruppe in einer oxidierten form
Kleijn et al. Efficient recycling of fluorous versions of highly enantioselective S, N-chelated zinc aminoarene thiolate catalysts for the 1, 2-addition of diethylzinc to benzaldehydes
FR2854890A1 (fr) Procede de formation d'une liaison carbone-heteroatome
WO2011101604A1 (fr) Procede de preparation de composes chimiques d'interet par substitution nucleophile aromatique de derives d'acides carboxyliques aromatiques portant au moins un groupement electroattracteur
FR2884249A1 (fr) Procede de preparation de beta-aminoesters ou alpha-, beta-diaminoesters derives de la serine

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 20091113

AK Designated contracting states

Kind code of ref document: A2

Designated state(s): AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MT NL NO PL PT RO SE SI SK TR

AX Request for extension of the european patent

Extension state: AL BA MK RS

17Q First examination report despatched

Effective date: 20100816

GRAP Despatch of communication of intention to grant a patent

Free format text: ORIGINAL CODE: EPIDOSNIGR1

DAX Request for extension of the european patent (deleted)
STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN

18D Application deemed to be withdrawn

Effective date: 20121117