EP1208069A1 - Process for catalyzing the oxidation of organic compounds - Google Patents

Process for catalyzing the oxidation of organic compounds

Info

Publication number
EP1208069A1
EP1208069A1 EP00960420A EP00960420A EP1208069A1 EP 1208069 A1 EP1208069 A1 EP 1208069A1 EP 00960420 A EP00960420 A EP 00960420A EP 00960420 A EP00960420 A EP 00960420A EP 1208069 A1 EP1208069 A1 EP 1208069A1
Authority
EP
European Patent Office
Prior art keywords
solvent
process according
phase
reaction medium
inert aprotic
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Withdrawn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
EP00960420A
Other languages
German (de)
French (fr)
Inventor
Patrick Bernardelli
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.)
Warner Lambert Co LLC
Original Assignee
Warner Lambert Co LLC
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 Warner Lambert Co LLC filed Critical Warner Lambert Co LLC
Publication of EP1208069A1 publication Critical patent/EP1208069A1/en
Withdrawn legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B33/00—Oxidation in general
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B41/00—Formation or introduction of functional groups containing oxygen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/78—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 2
    • C07D239/80—Oxygen atoms
    • C07D239/82—Oxygen atoms with an aryl radical attached in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D243/00—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms
    • C07D243/06—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4
    • C07D243/10—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
    • C07D243/14—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines
    • C07D243/16—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines substituted in position 5 by aryl radicals
    • C07D243/18—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines substituted in position 5 by aryl radicals substituted in position 2 by nitrogen, oxygen or sulfur atoms
    • C07D243/24—Oxygen atoms

Definitions

  • Synthetic metalloporphyrins can serve favorably to mimic oxidative catalytic reactions occurring in biological systems, with the aim of producing and identifying oxidative products of drug candidates, in quantities allowing in vivo studies.
  • PCT application WO 96/08455 discloses a process for the preparation of oxidative products using various combinations of a synthetic metallopo ⁇ hyrin, a co-oxidizing reagent, and a solvent.
  • the solvent is generally a CH3CN/CH2CI2 combination.
  • the inventor has unexpectedly found that the yields of oxidative reactions involving metalloporphyrins and which can be useful for the synthesis of metabolites of organic compounds of interest could be increased in a substantial manner through the use of an inert aprotic solvent.
  • one of the objects of the present invention is a process for the oxidation of organic compounds.
  • This process comprises reacting the selected organic compound with catalytic amounts of a metalloporphyrin and of an oxidizing agent in the presence of an inert aprotic solvent and recovering the desired products obtained therefrom.
  • the process of the invention is extremely useful in pharmaceutical research and development as it can be used to perform preliminary evaluations of the metabolic processes which are likely to occur when a given compound is tested in vivo. These preliminary evaluations can be performed rapidly without having to carry out expensive and time consuming in vivo experiments.
  • the process of the present invention provides better yields of individual products than those obtained using prior art processes. In other words, the process of the present invention opens the possibility of obtaining and analyzing in a more systematic fashion a higher number of individual potential metabolites for a given selected compound on which the process is carried out.
  • the present invention therefore concerns a process for the efficient oxidative preparation of metabolites of organic compounds.
  • the invention comprises reacting an organic compound of interest with a catalytic amount of a metalloporphyrin and an oxidizing agent, in a non-reactive aprotic solvent. It also comprises recovering and identifying the desired reaction products.
  • compounds containing heteroatoms can be efficiently oxidized through the process of the invention, particularly to a higher oxidation state, and more particularly to their highest oxidation state.
  • heteroatoms such as nitrogen or sulfur
  • primary amines can be readily converted to their corresponding hydroxylamines, nitroso- or nitro- derivatives; and tertiary amines to their corresponding N-oxides.
  • C-H bonds can be conveniently hydroxylated into C-OH bonds by metallopo ⁇ hyrin- catalyzed oxidations according to this invention.
  • Examples include labile C-H bonds, such as those in benzylic positions or C-H bonds wherein the carbon atom is adjacent to a heteroatom (e.g. N, S, O, or the like). Those are particularly reactive to these conditions.
  • primary alcohols can be converted to their corresponding aldehydes; in turn aldehydes can be converted to their corresponding acids, and said acids may further undergo decarboxylation.
  • Carbon-carbon double bonds can be epoxidized by metallopo ⁇ hyrin-catalyzed oxidation according to this invention, and aromatic groups can be oxidized into corresponding phenols or quinones.
  • the main parameters involved in the process of the invention are the starting material which is usually an organic compound of interest, the reactants which usually include a metallopo ⁇ hyrin, an oxidizing agent and an inert aprotic solvent, and the reaction conditions which comprise the reaction temperature and the reaction time.
  • the starting material which is usually an organic compound of interest
  • the reactants which usually include a metallopo ⁇ hyrin, an oxidizing agent and an inert aprotic solvent
  • reaction conditions which comprise the reaction temperature and the reaction time.
  • metallopo ⁇ hyrins are described in international patent application WO 96/08455.
  • the term "metallopo ⁇ hyrin”, as used herein, refers to po ⁇ hyrin compounds of formula (I):
  • Rl, R2 and R3 independently represent hydrogen or an electron- withdrawing group such as Cl, F, Br, SO3Na, or the like,
  • R4, R5, R6, R7, R8, R9, RIO and Rl l independently represent hydrogen or an electron-withdrawing group such as Cl, F, Br, NO2, CN, SO3Na or the like,
  • R12 is Cl, acetate or the like
  • M is selected from the group consisting of iron, manganese, chromiirai, ruthenium, cobalt, copper and nickel.
  • Preferred metallopo ⁇ hyrins include tetrakis(pentafluoro-phenyl)po ⁇ hyrin Mn(I_3) chloride, herein abbreviated as Mn(TPFPP)Cl, which is the compound of formula (I) above wherein M is manganese, Rl, R2 and R3 are fluorine, R4, R5, R6, R7, R8. R9, RIO and Rl 1 are hydrogen, and R12 is chlorine.
  • Preferred metallopo ⁇ hyrins also include: tetrakis(pentafluoro-phenyl)po ⁇ hyrin Fe chloride, abbreviated as Fe(TPFPP)Cl, which is the compound of formula (I) above wherein M is iron, Rl, R2 and R3 are fluorine, R4, R5, R6, R7, R8, R9, RIO and Rl 1 are hydrogen, and R12 is chlorine;
  • Mn(TDCPP)Cl tetrakis(2,6-dichlorophenyl)po ⁇ hyrin Mn chloride, abbreviated as Mn(TDCPP)Cl, which is the compound of formula (I) above wherein M is manganese, Rl is chloride, R2, R3, R4, R5, R6, R7, R8, R9, RIO and Rl 1 are hydrogen, and R12 is chlorine;
  • Fe(TDCPP)Cl tetrakis(2,6-dichlorophenyl)po ⁇ hyrin Fe chloride, abbreviated as Fe(TDCPP)Cl, which is the compound of formula (I) above wherein M is iron, Rl is chloride, R2, R3, R4, R5, R6, R7, R8, R9, RIO and Rl 1 are hydrogen, and R12 is chlorine;
  • Fe tetrakis(2,6-dichlorophenyl)-octachloropo ⁇ hyrin chloride
  • Fe(TDCPClgP)Cl which is the compound of formula (I) above wherein M is iron, Rl is chloride, R2 and R3 are hydrogen, R4, R5, R6, R7, R8, R9, RIO and Rl 1 are chloride, and R12 is chlorine;
  • the amount of the metallopo ⁇ hyrin catalyst usually ranges between 0.5 and 10 % molar and is preferably about 1 % molar.
  • Oxidizing agents Various oxidizing agents can be used in the instant invention. It should be noted that the very nature of the oxidizing agent does not appear to be a limiting factor in the process of the present invention. The person skilled in the art can thus select the appropriate oxidizing agent among the wide variety of compounds which have been used in metallopo ⁇ hyrin- catalyzed oxidative reactions.
  • a list of possible agents includes, but is not limited to: iodosylbenzene, also known as iodosobenzene, aqueous solutions of hydrogen peroxide (concentration about 30 to 45 %), anhydrous equivalents of hydrogen peroxide such as sodium percarbonate, urea hydrogen peroxide complex or the like, potassium monopersulfate, sodium hypochlorite, tert-butyl hydroperoxide, cumene hydroperoxide, m- chloroperbenzoic acid, and magnesium monoperoxyphthalate.
  • Preferred oxidants include iodosylbenzene, any source of hydrogen peroxide, and potassium monopersulfate.
  • Oxidation using hydrogen peroxide is more efficient in the presence of a co-catalyst such as imidazole, ammonium acetate, N-hexylimidazole, amine N-oxides, tetrabutylammonium acetate, tert-butyl pyridine, pyridine, 4-methylpyridine, and 2,4,6-trimethyl-pyridine.
  • a co-catalyst such as imidazole, ammonium acetate, N-hexylimidazole, amine N-oxides, tetrabutylammonium acetate, tert-butyl pyridine, pyridine, 4-methylpyridine, and 2,4,6-trimethyl-pyridine.
  • the metallopo ⁇ hyrin-catalyzed oxidation of the invention is performed in an inert solvent, which in fact can contain one or several solvents.
  • the term 'inert aprotic solvent' when used herein, is intended to designate any solvent or any mixture of solvents which, when evaluated in a global manner, does not react in any substantial fashion with the starting materials or with the products of the reaction. More particularly, the solvent should not react with the oxidizing agent. Furthermore, the solvent should be resistant to hydrogen abstraction.
  • this mixture usually contains a so-called “main solvent” and a “co-solvent”. It should be noted however that several solvents having similar properties could be used to form the main solvent. Similar considerations apply to an eventual mixture of co-solvents.
  • the main solvent is present in larger amounts in the solvent mixture than the co-solvent.
  • the main solvent should therefore be inert and aprotic.
  • the main solvent should have the capability to dissolve the starting material (i.e. the organic compound of interest) and the metallopo ⁇ hyrin.
  • the main solvent examples include, but are not limited to polyhalogenated aliphatic solvents such as l,l,2-trichloro-l,2,2-trifluoroethane and the like or polyhalogenated aromatic solvents such as 1,2-dichlorobenzene, 1,2,4-trichlorobenzene, pentafluorobenzene and the like.
  • Preferred polyhalogenated solvents include polyfluorinated aromatic compounds, such as trifluorotoluene (also known as benzotrifluoride) and the like. Trifluorotoluene is a most preferred solvent, which combines the capacity of dissolving a wide variety of organic compounds with a low reactivity towards oxidative conditions.
  • suitable concentrations of starting material in the chosen solvent can vary between 0.1 M and 0.5 M, preferably 0.1 M.
  • the co-solvent is present in small amounts in the mixture and is introduced to provide additional properties of interest to the overall solvent mixture, which will be useful at some point but which will not interfere in a significant manner with the reaction itself.
  • a co-solvent can be used to improve its solubility in the reaction medium.
  • a co-solvent can be used in order to improve its solubility in the reaction medium.
  • Preferred co-solvents include highly polar and poorly nucleophilic co-solvents.
  • the properties of the co-solvent should be chosen in order to minimize complex formation with the metallopo ⁇ hyrin.
  • 2,2,2-Trifluoroethanol and, particularly, 1,1,1,3,3,3-hexafluoro- propan-2-ol also called hexafluoroisopropanol or HFIP are representative examples of co- solvents that can be used in the process of this invention.
  • hexafluoroisopropanol can be useful in oxidation reactions performed with iodosylbenzene in one of the organic solvents mentioned above since this co-solvent helps dissolve this particular oxidant in the reaction medium.
  • the amount of co-solvent used to dissolve the starting material or the oxidizing agent and eventually the catalyst should be kept to relatively low levels with respect to the main solvent.
  • suitable concentrations can vary between 1 and 30%, preferably between 1 and 20% and more preferably between 1 and 10% with respect with the main solvent.
  • the co-solvent can be used in order to facilitate transfer of reactants within the reaction medium.
  • a co- solvent is used in the case where the starting material or one or several reactants leads to a reaction mixture which comprises a biphasic solution.
  • the reaction is biphasic and a water-miscible co-solvent can be used to facilitate the transfer of the oxidant in the organic phase.
  • a water-miscible co-solvent can be used to facilitate the transfer of the oxidant in the organic phase.
  • a minimal amount of co-solvent such as hexafluoroisopropanol, is preferred. This co-solvent is miscible with water and it can facilitate dissolution of the starting material.
  • the amount of co-solvent which should be used in this second embodiment usually ranges between 0.25 and 1 equivalent, preferably between 0.3 and 0.5 and is more preferably about 0.4 equivalent with respect to the starting material.
  • a phase-transfer catalyst can be used to facilitate the transfer of any of the reactants into the phase where the reaction will take place.
  • a phase-transfer catalyst can be used to facilitate the transfer of the oxidant in the organic phase.
  • phase-transfer catalysts examples include tetraalkyl ammonium salts (such as dodecyl- trimethyl-am onium bromide and the like).
  • the reaction is carried out at a temperature between about -20 °C and 100 °C, and preferably between about -10 °C and 40 °C.
  • reaction rate is then preferably performed in an ultrasound bath cooled to 0°C.
  • the duration of the reaction varies from a few minutes up to 2 h. Advancement can be monitored with TLC or HPLC analytical techniques; thus the reaction is stopped when the oxidation reaction reaches a plateau point beyond which no substantial conversion is observed.
  • the mass spectra are recorded on a Micromass Platform LC spectrometer (simple quadrupole with positive ionization electrospray).
  • the infrared spectra are recorded on a Nicolet spectrometer.
  • flash chromatography on a silica column means a method adapted from that of Still et al. (1978) J. Org. Chem. 42: 2923. The purity of elution fractions is verified before they are gathered and evaporated.
  • the terms “evaporation”, “elimination” or “concentration” of the solvents mean, possibly after desiccation on an appropriate dehydrating agent such as Na2SO4 or MgSO4, a distillation under a pressure of 25 to 50 mm Hg (3,3 to 6,7 kPa) with moderate heating in a water bath at a temperature below 30 °C.
  • EXAMPLE 1 r.y.Hat.nn of ⁇ ..aTi am (1) with indosylbenzene (PhT ) catalysed by tetrakistpp ⁇ taflnnr ⁇ - ⁇ hpny1)pn ⁇ hyrin manganese (TTT) r/hlnri e in friflnnrntnlnpnp
  • nordiazepam (2), temazepam (3), oxazepam (4), 6-chloro-4-phenyl-l- memyl-2-(l_ _ q ⁇ inazo_inone (5) and 6-chloro-4-phenyl-2-(lH)-quinazol_none (£) are formed.
  • reaction is monitored by analytical ⁇ PLC one hour after each addition: a sample, prepared with 5 ⁇ L of crude and 100 ⁇ L of a 5 mM methanolic solution of acetophenone (internal standard) diluted with 395 ⁇ L of methanol, is injected into a Nucleosil 5C18 150x4.6 mm column eluting with 50/50 methanol/water at 1 mL/min during 45 minutes. Nordiazepam (2), temazepam (2), oxazepam (4) formed are identified by comparison with authentic samples (Sigma). Their retention times are respectively 21.9, 16.7 and 13.3 min.
  • 6-Chloro-l-methyl-4-phenyl-lH-quinazolin-2-one (5) and 6-chloro-4-phenyl- lH-quinazolin-2-one (fi), respectively eluting at 25.1 and 20.5 min, are identified in a separate run by isolation and comparison of * ⁇ NMR and MS data with Felix et al (1968) J Heterocycl. Chem. 5, 731 and Sulkowski etal (1961) J. Org. Chem. 22, AA1A.
  • nordiazepam (2), temazepam (2), oxazepam (4), 6-chloro-4-phenyl-l- methyl-2-(lH)-quinazolinone (5), diazepam N-oxide (2) and nordiazepam N-oxide (8) are formed.
  • Diazepam N-oxide (2) (retention time 8.4 min) and nordiazepam N-oxide (8) (6.7 min) are identified by comparison with samples prepared from the reaction of diazepam and nordiazepam with m- chloroperbenzoic acid (cf. Ebel et al (1979) Arzneim.-Forsch. 22, 1317).

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Catalysts (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
  • Investigating Or Analyzing Non-Biological Materials By The Use Of Chemical Means (AREA)

Abstract

Oxidation of organic compounds is catalyzed by addition of a catalytic amount of a metalloporphyrin in a non-reactive aprotic solvent.

Description

PROCESS FOR CATALYZING THE OXIDATION OF ORGANIC COMPOUNDS
FIELD OF THE INVENTION
The study of drug metabolism is an important part of the very expensive drug R&D process. In humans and other mammals, many drugs are metabolized through oxidative reactions catalyzed by heme- and cytochrome-containing enzymes. Cytochrome P450 mono- oxygenases, the main enzymes involved in drug oxidative metabolism, have in their active site a heme moiety.
Synthetic metalloporphyrins can serve favorably to mimic oxidative catalytic reactions occurring in biological systems, with the aim of producing and identifying oxidative products of drug candidates, in quantities allowing in vivo studies.
PCT application WO 96/08455 discloses a process for the preparation of oxidative products using various combinations of a synthetic metallopoφhyrin, a co-oxidizing reagent, and a solvent. The solvent is generally a CH3CN/CH2CI2 combination. One of the major inconveniences of processes of this type is the fact that they frequently provide incomplete yields of the sought-after individual products as well as low conversion percentages. As a result, they can rarely be used in a reliable fashion in integrated discovery processes. In fact, their use is generally limited to experimental validation.
SUMMARY OF THE INVENTION
In accordance with the present invention, the inventor has unexpectedly found that the yields of oxidative reactions involving metalloporphyrins and which can be useful for the synthesis of metabolites of organic compounds of interest could be increased in a substantial manner through the use of an inert aprotic solvent.
Thus, one of the objects of the present invention is a process for the oxidation of organic compounds. This process comprises reacting the selected organic compound with catalytic amounts of a metalloporphyrin and of an oxidizing agent in the presence of an inert aprotic solvent and recovering the desired products obtained therefrom. The process of the invention is extremely useful in pharmaceutical research and development as it can be used to perform preliminary evaluations of the metabolic processes which are likely to occur when a given compound is tested in vivo. These preliminary evaluations can be performed rapidly without having to carry out expensive and time consuming in vivo experiments. Furthermore, the process of the present invention provides better yields of individual products than those obtained using prior art processes. In other words, the process of the present invention opens the possibility of obtaining and analyzing in a more systematic fashion a higher number of individual potential metabolites for a given selected compound on which the process is carried out.
DETAILED DESCRIPTION OF THE INVENTION
The present invention therefore concerns a process for the efficient oxidative preparation of metabolites of organic compounds. The invention comprises reacting an organic compound of interest with a catalytic amount of a metalloporphyrin and an oxidizing agent, in a non-reactive aprotic solvent. It also comprises recovering and identifying the desired reaction products.
As mentioned previously, several drugs are metabolized through oxidative reactions. The process of the instant invention is therefore applied favorably to organic compounds of interest possessing one or several functional groups which will react to oxidation conditions. Some of these functional groups are described below but as the skilled person will readily appreciate, the list provided is not intended to be exhaustive. In fact, the process of the invention can be used on any organic compound which can be oxidized in some way by enzymes involved in drug oxidative metabolism.
Preferably, compounds containing heteroatoms, such as nitrogen or sulfur, can be efficiently oxidized through the process of the invention, particularly to a higher oxidation state, and more particularly to their highest oxidation state. For example, primary amines can be readily converted to their corresponding hydroxylamines, nitroso- or nitro- derivatives; and tertiary amines to their corresponding N-oxides.
Also, C-H bonds can be conveniently hydroxylated into C-OH bonds by metallopoφhyrin- catalyzed oxidations according to this invention. Examples include labile C-H bonds, such as those in benzylic positions or C-H bonds wherein the carbon atom is adjacent to a heteroatom (e.g. N, S, O, or the like). Those are particularly reactive to these conditions. In this manner, primary alcohols can be converted to their corresponding aldehydes; in turn aldehydes can be converted to their corresponding acids, and said acids may further undergo decarboxylation.
Through the process of the invention, secondary alcohols can be converted to their corresponding ketones.
Carbon-carbon double bonds can be epoxidized by metallopoφhyrin-catalyzed oxidation according to this invention, and aromatic groups can be oxidized into corresponding phenols or quinones.
The main parameters involved in the process of the invention are the starting material which is usually an organic compound of interest, the reactants which usually include a metallopoφhyrin, an oxidizing agent and an inert aprotic solvent, and the reaction conditions which comprise the reaction temperature and the reaction time. Each of these parameters will be discussed in further detail below.
Metalloporphyrins
Synthetic metallopoφhyrins are described in international patent application WO 96/08455. The term "metallopoφhyrin", as used herein, refers to poφhyrin compounds of formula (I):
wherein:
Rl, R2 and R3 independently represent hydrogen or an electron- withdrawing group such as Cl, F, Br, SO3Na, or the like,
R4, R5, R6, R7, R8, R9, RIO and Rl l independently represent hydrogen or an electron-withdrawing group such as Cl, F, Br, NO2, CN, SO3Na or the like,
R12 is Cl, acetate or the like,
M is selected from the group consisting of iron, manganese, chromiirai, ruthenium, cobalt, copper and nickel.
Preferred metallopoφhyrins include tetrakis(pentafluoro-phenyl)poφhyrin Mn(I_3) chloride, herein abbreviated as Mn(TPFPP)Cl, which is the compound of formula (I) above wherein M is manganese, Rl, R2 and R3 are fluorine, R4, R5, R6, R7, R8. R9, RIO and Rl 1 are hydrogen, and R12 is chlorine.
Preferred metallopoφhyrins also include: tetrakis(pentafluoro-phenyl)poφhyrin Fe chloride, abbreviated as Fe(TPFPP)Cl, which is the compound of formula (I) above wherein M is iron, Rl, R2 and R3 are fluorine, R4, R5, R6, R7, R8, R9, RIO and Rl 1 are hydrogen, and R12 is chlorine;
tetrakis(2,6-dichlorophenyl)poφhyrin Mn chloride, abbreviated as Mn(TDCPP)Cl, which is the compound of formula (I) above wherein M is manganese, Rl is chloride, R2, R3, R4, R5, R6, R7, R8, R9, RIO and Rl 1 are hydrogen, and R12 is chlorine;
tetrakis(2,6-dichlorophenyl)poφhyrin Fe chloride, abbreviated as Fe(TDCPP)Cl, which is the compound of formula (I) above wherein M is iron, Rl is chloride, R2, R3, R4, R5, R6, R7, R8, R9, RIO and Rl 1 are hydrogen, and R12 is chlorine;
tetrakis(2,6-dichlorophenyl)-octachloropoφhyrin chloride Fe, abbreviated as Fe(TDCPClgP)Cl, which is the compound of formula (I) above wherein M is iron, Rl is chloride, R2 and R3 are hydrogen, R4, R5, R6, R7, R8, R9, RIO and Rl 1 are chloride, and R12 is chlorine;
the compound Mn((Cl2Ph)4 (NO2)P)Cl, of formula (I) above wherein M is manganese, Rl is chloride, R4 is NO2, R2, R3, R5, R6, R7, R8, R9, RIO, and Rl 1 are hydrogen, and R12 is chlorine;
the compound Mn((Cl2Ph)4(NO2)2P)Cl, of formula (I) above wherein M is manganese, Rl is chloride, R5 and R6 are NO2, R2, R3, R4, R7, R8, R9, RIO and Rl l are hydrogen, and R12 is chlorine.
The amount of the metallopoφhyrin catalyst usually ranges between 0.5 and 10 % molar and is preferably about 1 % molar.
Oxidizing agents Various oxidizing agents can be used in the instant invention. It should be noted that the very nature of the oxidizing agent does not appear to be a limiting factor in the process of the present invention. The person skilled in the art can thus select the appropriate oxidizing agent among the wide variety of compounds which have been used in metallopoφhyrin- catalyzed oxidative reactions. A list of possible agents includes, but is not limited to: iodosylbenzene, also known as iodosobenzene, aqueous solutions of hydrogen peroxide (concentration about 30 to 45 %), anhydrous equivalents of hydrogen peroxide such as sodium percarbonate, urea hydrogen peroxide complex or the like, potassium monopersulfate, sodium hypochlorite, tert-butyl hydroperoxide, cumene hydroperoxide, m- chloroperbenzoic acid, and magnesium monoperoxyphthalate. Preferred oxidants include iodosylbenzene, any source of hydrogen peroxide, and potassium monopersulfate.
Oxidation using hydrogen peroxide is more efficient in the presence of a co-catalyst such as imidazole, ammonium acetate, N-hexylimidazole, amine N-oxides, tetrabutylammonium acetate, tert-butyl pyridine, pyridine, 4-methylpyridine, and 2,4,6-trimethyl-pyridine. For a review, see "State of the art in the development of biomimetic oxidation catalysts" Rocha Gonsalves, A.M.; Pereira, M.M. J Mol. Catal. A: Chem. 1996, 113, 209.
Solvent
The metallopoφhyrin-catalyzed oxidation of the invention is performed in an inert solvent, which in fact can contain one or several solvents. The term 'inert aprotic solvent', when used herein, is intended to designate any solvent or any mixture of solvents which, when evaluated in a global manner, does not react in any substantial fashion with the starting materials or with the products of the reaction. More particularly, the solvent should not react with the oxidizing agent. Furthermore, the solvent should be resistant to hydrogen abstraction.
In the case of a mixture of solvents, this mixture usually contains a so-called "main solvent" and a "co-solvent". It should be noted however that several solvents having similar properties could be used to form the main solvent. Similar considerations apply to an eventual mixture of co-solvents.
The main solvent is present in larger amounts in the solvent mixture than the co-solvent.
In fact, it is the main solvent that confers its overall properties to the global solvent mixture, which will then play a key role in the process of the invention. The main solvent should therefore be inert and aprotic.
To the extent possible, the main solvent should have the capability to dissolve the starting material (i.e. the organic compound of interest) and the metallopoφhyrin.
Examples of the main solvent include, but are not limited to polyhalogenated aliphatic solvents such as l,l,2-trichloro-l,2,2-trifluoroethane and the like or polyhalogenated aromatic solvents such as 1,2-dichlorobenzene, 1,2,4-trichlorobenzene, pentafluorobenzene and the like. Preferred polyhalogenated solvents include polyfluorinated aromatic compounds, such as trifluorotoluene (also known as benzotrifluoride) and the like. Trifluorotoluene is a most preferred solvent, which combines the capacity of dissolving a wide variety of organic compounds with a low reactivity towards oxidative conditions.
Although the skilled person can determine by routine experiments the optimal amount of main solvent to be used in each individual case, suitable concentrations of starting material in the chosen solvent can vary between 0.1 M and 0.5 M, preferably 0.1 M.
The co-solvent is present in small amounts in the mixture and is introduced to provide additional properties of interest to the overall solvent mixture, which will be useful at some point but which will not interfere in a significant manner with the reaction itself.
In a first embodiment of the process of the present invention, if any of the organic compound of interest or the oxidizing agent is not soluble in the main solvent, a co-solvent can be used to improve its solubility in the reaction medium.
For example, if the starting material is not soluble in trifluorotoluene or in any main solvent available, a co-solvent can be used in order to improve its solubility in the reaction medium. Preferred co-solvents include highly polar and poorly nucleophilic co-solvents. Preferably, the properties of the co-solvent should be chosen in order to minimize complex formation with the metallopoφhyrin. 2,2,2-Trifluoroethanol and, particularly, 1,1,1,3,3,3-hexafluoro- propan-2-ol (also called hexafluoroisopropanol or HFIP) are representative examples of co- solvents that can be used in the process of this invention. More particularly, hexafluoroisopropanol, can be useful in oxidation reactions performed with iodosylbenzene in one of the organic solvents mentioned above since this co-solvent helps dissolve this particular oxidant in the reaction medium.
The amount of co-solvent used to dissolve the starting material or the oxidizing agent and eventually the catalyst should be kept to relatively low levels with respect to the main solvent. Although the skilled person can determine by routine experiments the optimal amount of co-solvent to be used in each individual case, suitable concentrations can vary between 1 and 30%, preferably between 1 and 20% and more preferably between 1 and 10% with respect with the main solvent.
In a second embodiment of the process of the present invention, the co-solvent can be used in order to facilitate transfer of reactants within the reaction medium. For instance, a co- solvent is used in the case where the starting material or one or several reactants leads to a reaction mixture which comprises a biphasic solution.
For example, in the case where the oxidant is used as an aqueous solution, the reaction is biphasic and a water-miscible co-solvent can be used to facilitate the transfer of the oxidant in the organic phase. A minimal amount of co-solvent, such as hexafluoroisopropanol, is preferred. This co-solvent is miscible with water and it can facilitate dissolution of the starting material.
The amount of co-solvent which should be used in this second embodiment, as expressed in catalytic amounts, usually ranges between 0.25 and 1 equivalent, preferably between 0.3 and 0.5 and is more preferably about 0.4 equivalent with respect to the starting material.
As an alternative to this second embodiment of the invention, a phase-transfer catalyst can be used to facilitate the transfer of any of the reactants into the phase where the reaction will take place. For instance, when the oxidant is used as an aqueous solution, a phase-transfer catalyst can be used to facilitate the transfer of the oxidant in the organic phase.
Examples of phase-transfer catalysts include tetraalkyl ammonium salts (such as dodecyl- trimethyl-am onium bromide and the like). The amount of phase-transfer catalyst which should be used in this second embodiment, as expressed in catalytic amounts, usually ranges between 0.05 and 0.5 equivalent and is more preferably about 0.10 equivalent with respect to the starting material.
Temperature and duration of the reaction The reaction is carried out at a temperature between about -20 °C and 100 °C, and preferably between about -10 °C and 40 °C.
The skilled person should note however that sonication can be used to increase the reaction rate. The reaction is then preferably performed in an ultrasound bath cooled to 0°C.
Generally, the duration of the reaction varies from a few minutes up to 2 h. Advancement can be monitored with TLC or HPLC analytical techniques; thus the reaction is stopped when the oxidation reaction reaches a plateau point beyond which no substantial conversion is observed.
Without limiting the invention, the following examples illustrate the implementation of the processes of the invention.
The purity, identity and physico-chemical characteristics of the products prepared are determined as follows:
- the purity is verified by analytical reverse-phase HPLC on a Merck Lachrom apparatus and the Rf observed is given for the eluent used;
- the identity of the products obtained with the proposed structures is verified by their proton nuclear magnetic resonance spectrum and by mass spectrometry.
The *H NMR spectra are recorded at 400 MHz on a Brϋker instrument, the compounds being dissolved in deuterochloroform with tetramethylsilane as internal standard. The nature of the signals, their chemical shifts in ppm, the number of protons they represent and their exchange capacity with D2O are noted.
The mass spectra are recorded on a Micromass Platform LC spectrometer (simple quadrupole with positive ionization electrospray). The infrared spectra are recorded on a Nicolet spectrometer.
The phrase "flash chromatography on a silica column" means a method adapted from that of Still et al. (1978) J. Org. Chem. 42: 2923. The purity of elution fractions is verified before they are gathered and evaporated. The terms "evaporation", "elimination" or "concentration" of the solvents mean, possibly after desiccation on an appropriate dehydrating agent such as Na2SO4 or MgSO4, a distillation under a pressure of 25 to 50 mm Hg (3,3 to 6,7 kPa) with moderate heating in a water bath at a temperature below 30 °C.
EXAMPLE 1 r.y.Hat.nn of ■..aTi am (1) with indosylbenzene (PhT ) catalysed by tetrakistppπtaflnnrπ- ρhpny1)pnφhyrin manganese (TTT) r/hlnri e in friflnnrntnlnpnp
During this reaction, nordiazepam (2), temazepam (3), oxazepam (4), 6-chloro-4-phenyl-l- memyl-2-(l_ _ qιιinazo_inone (5) and 6-chloro-4-phenyl-2-(lH)-quinazol_none (£) are formed.
To 240 μL of a solution containing 25 μmol of diazepam (1) in trifluorotoluene is added 10 μL of a 25 mM solution of 5,10,15,20-tefraMsφentafluorophenyl)-21H,23H-poφhyrin manganese (HI) chloride (0.25 μmol, 1 mol%) in trifluorotoluene. To the resulting stirring solution is added 3 times a portion of iodosylbenzene (3x5.5 mg, 3x25 μmol, 3 equiv.), one every hour. The reaction is monitored by analytical ΗPLC one hour after each addition: a sample, prepared with 5 μL of crude and 100 μL of a 5 mM methanolic solution of acetophenone (internal standard) diluted with 395 μL of methanol, is injected into a Nucleosil 5C18 150x4.6 mm column eluting with 50/50 methanol/water at 1 mL/min during 45 minutes. Nordiazepam (2), temazepam (2), oxazepam (4) formed are identified by comparison with authentic samples (Sigma). Their retention times are respectively 21.9, 16.7 and 13.3 min. 6-Chloro-l-methyl-4-phenyl-lH-quinazolin-2-one (5) and 6-chloro-4-phenyl- lH-quinazolin-2-one (fi), respectively eluting at 25.1 and 20.5 min, are identified in a separate run by isolation and comparison of *Η NMR and MS data with Felix et al (1968) J Heterocycl. Chem. 5, 731 and Sulkowski etal (1961) J. Org. Chem. 22, AA1A.
Yields of products from the reaction are shown in the following table:
Results form the reaction performed in 1:1 CH2CI2/CH3CN, solvent conditions representative of the state of the art, are shown below:
Comparison of both sets of results implies that the use of a solvent such as trifluorotoluene instead of the classical dichloromethane/acetonitrile leads to better diazepam conversion, and formation of a higher number of products in significantly better yields. EXAMPLE 2:
Oxidation of diazepam (1 ) with a 30% aqueous solution nf hydrogen peroviHe r.atalyyerl hy tetraVis(ρentaf ιnropheny1)pnφhyrin manganese (TTT) chloride in frifluorotohiene
This reaction is more efficient in the presence of catalytic amounts of imidazole (Battioni et al (1988) J Am. Chem. Soc. ilϋ, 8462) and ammonium acetate (Thellend et al (1994) J. Chem. Soc., Chem. Comm., 1035).
During this reaction, nordiazepam (2), temazepam (2), oxazepam (4), 6-chloro-4-phenyl-l- methyl-2-(lH)-quinazolinone (5), diazepam N-oxide (2) and nordiazepam N-oxide (8) are formed.
To 240 μL of a solution containing 25 μmol of diazepam (1) in trifluorotoluene is added 10 μL of a 25 mM solution of 5,10,15,20-tefralds( entafluorophenyl)-21H,23H-poφhyrin manganese (Ut) chloride (0.25 μmol, 1 mol%) and l,l,l,3,3,3-hexafluoro-2-propanol (1.1 μL, 10.4 μmol, 0.4 equiv.) in trifluorotoluene. To the resulting stirring solution is added dropwise an aqueous solution of 30% hydrogen peroxide (2.6 μL, 25 μmol, 1 equiv.), imidazole (6.5 μL of a 1 M aqueous solution, 6.5 μmol, 0.25 equiv.) and ammonium acetate (25 μL of a 1 M aqueous solution, 25 μmol, 1 equiv.) over two hours. Thirty minutes after the addition, the reaction is monitored by analytical HPLC in the same manner as in Example 1. One equivalent of 30%) aqueous hydrogen peroxide (2.6 μL, 25 μmol, 1 equiv.) is then added every 10 minutes until 15 equivalents of oxidant are used. The reaction is monitored after the addition of 2, 5, 10 and 15 equiv. of hydrogen peroxide. Diazepam N-oxide (2) (retention time 8.4 min) and nordiazepam N-oxide (8) (6.7 min) are identified by comparison with samples prepared from the reaction of diazepam and nordiazepam with m- chloroperbenzoic acid (cf. Ebel et al (1979) Arzneim.-Forsch. 22, 1317).
Yields of products from the reaction are shown in the following table:
H202 Products obtained: Yield (%)
(equiv.) 1 2 2 4 5 2 &
1 71 4 7 0 1 5 0
2 58 8 10 1 1 9 1
5 41 10 13 1 3 10 1
10 26 10 12 2 5 8 2
15 19 10 14 2 8 6 2
Results form the analogous reaction performed in 1:1 CH2CI2/CH3CΝ, instead of trifluorotoluene and hexafluoroisopropanol as co-solvent, are shown below:
When the oxidation is performed with hydrogen peroxide in a biphasic system, better diazepam conversion and yields in products are obtained with trifluorotoluene in the presence of hexafluoroisopropanol in place of the dichloromethane/acetonitrile solvent system.
Preliminary results from additional experiments currently underway confirm the efficacy of the process of the invention for the oxidation of compounds with relatively different structural parameters.

Claims

1) A process for the oxidation of a selected organic compound, said process comprising reacting the selected organic compound to be oxidized with a reaction medium comprising a metallopoφhyrin and an oxidizing agent in an inert aprotic solvent and recovering and identifying the desired reaction products.
2) Process according to claim 1, wherein the inert aprotic solvent is a polyhalogenated aliphatic or aromatic solvent.
3) Process according to claim 2, wherein the inert aprotic solvent is a polyhalogenated aromatic solvent.
4) Process according to claim 3, wherein the solvent is trifluorotoluene.
5) Process according to claim 1, wherein said reaction medium comprises an inert aprotic main solvent and a co-solvent capable of increasing the solubility of the selected organic compound in the reaction medium. 6) Process according to claim 5, wherein said co-solvent is a polar and poorly nucleophilic solvent.
7) Process according to claim 6, wherein said co-solvent is 2,2,2-trifluoroethanol or 1 , 1 , 1 ,3 ,3 ,3 -hexafluoro-propan-2-ol.
8) Process according to claim 5, wherein the concentration of the co-solvent ranges between 1 and 30%.
9) Process according to claim 1, wherein said reaction medium comprises a biphasic solution.
10) Process according to claim 9, wherein said reaction medium comprises an inert aprotic main solvent and a co-solvent having the capability of transferring the selected organic compound from one phase to the other.
11) Process according to claim 10, wherein the co-solvent is hexafluoroisopropanol.
12) Process according to claim 9, wherein said reaction medium includes a first aqueous phase comprising the oxidizing agent and a second organic phase comprising the selected organic compound and a metallopoφhyrin in an inert aprotic solvent. 13) Process according to claim 12, wherein said second phase comprises an inert aprotic main solvent and a co-solvent having the capability of transferring the oxidizing agent from one phase to the other.
14) Process according to claim 13, wherein said co-solvent is water-miscible.
15) Process according to claim 13, wherein said co-solvent is 1,1,1,3,3,3-hexafluoro-propan- 2-ol.
16) Process according to claim 9, which comprises introducing a phase-transfer catalyst into the reaction medium, said phase-transfer catalyst having the capability of allowing the transfer of reactants from one phase to the other.
17) Process according to claim 16, wherein the phase-transfer catalyst is a tetraalkyl ammonium salt.
18) Process according to claim 17, wherein the tetraalkyl ammonium salt is dodecyl- trimethyl-ammonium bromide.
EP00960420A 1999-08-10 2000-08-09 Process for catalyzing the oxidation of organic compounds Withdrawn EP1208069A1 (en)

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
US14807999P 1999-08-10 1999-08-10
US148079P 1999-08-10
US15010199P 1999-08-20 1999-08-20
US150101P 1999-08-20
PCT/EP2000/007726 WO2001010797A1 (en) 1999-08-10 2000-08-09 Process for catalyzing the oxidation of organic compounds

Publications (1)

Publication Number Publication Date
EP1208069A1 true EP1208069A1 (en) 2002-05-29

Family

ID=26845496

Family Applications (1)

Application Number Title Priority Date Filing Date
EP00960420A Withdrawn EP1208069A1 (en) 1999-08-10 2000-08-09 Process for catalyzing the oxidation of organic compounds

Country Status (17)

Country Link
EP (1) EP1208069A1 (en)
JP (1) JP2003506419A (en)
KR (1) KR20020024323A (en)
CN (1) CN1367769A (en)
AU (1) AU776140B2 (en)
BR (1) BR0013018A (en)
CA (1) CA2380851A1 (en)
CZ (1) CZ2002452A3 (en)
HK (1) HK1047428A1 (en)
HU (1) HUP0202521A2 (en)
IL (1) IL147452A0 (en)
MX (1) MXPA02001388A (en)
PL (1) PL356156A1 (en)
RU (1) RU2002103336A (en)
TR (1) TR200200330T2 (en)
WO (1) WO2001010797A1 (en)
YU (1) YU4902A (en)

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2807032B1 (en) * 2000-03-29 2003-04-18 Warner Lambert Co MODIFICATION OF CHEMOSLECTIVITY DURING THE OXIDATION OF NITROGEN ORGANIC COMPOUNDS
CN102503860A (en) * 2011-11-14 2012-06-20 武汉大学 Synthetic method of 1, 3-two substituted ureas and carbamate
PT107020B (en) * 2013-06-21 2015-07-09 Univ Aveiro PROCESS FOR THE PRODUCTION OF INDIGO AND ITS DERIVATIVES
CN115197170A (en) * 2021-04-09 2022-10-18 中国科学院上海有机化学研究所 Method for preparing epoxy dodecane from cyclododecene

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
IT1217608B (en) * 1988-05-17 1990-03-30 Istituto Guido Donegami Spa PROCESS FOR THE PREPARATION OF EPOXY
DD291748A5 (en) * 1990-02-01 1991-07-11 Bitterfeld Chemie PROCESS FOR PREPARING ALLYL HYDROXYLATED TERPENOIDES OF HYDROCARBONS
US5760216A (en) * 1994-09-15 1998-06-02 Abbott Laboratories Use of synthetic metalloporphyrins for preparation and prediction of drug metabolites

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO0110797A1 *

Also Published As

Publication number Publication date
AU7273800A (en) 2001-03-05
TR200200330T2 (en) 2003-02-21
CN1367769A (en) 2002-09-04
RU2002103336A (en) 2003-09-20
MXPA02001388A (en) 2004-07-16
YU4902A (en) 2004-09-03
CA2380851A1 (en) 2001-02-15
AU776140B2 (en) 2004-08-26
BR0013018A (en) 2002-04-16
IL147452A0 (en) 2002-08-14
WO2001010797A1 (en) 2001-02-15
KR20020024323A (en) 2002-03-29
JP2003506419A (en) 2003-02-18
HK1047428A1 (en) 2003-02-21
PL356156A1 (en) 2004-06-14
HUP0202521A2 (en) 2002-10-28
CZ2002452A3 (en) 2002-05-15

Similar Documents

Publication Publication Date Title
JP5373764B2 (en) Novel opiate reduction using catalytic hydrogen transfer reaction
Imada et al. Flavin‐catalyzed oxidation of amines and sulfides with molecular oxygen: biomimetic green oxidation
Largeron et al. A Metalloenzyme‐Like Catalytic System for the Chemoselective Oxidative Cross‐Coupling of Primary Amines to Imines under Ambient Conditions
Itoh et al. Synthesis of 2-arylbenzothiazoles from 2-aminobenzenethiol and aryl aldehydes catalyzed by scandium triflate
US6815543B1 (en) Process for catalyzing the oxidation of organic compounds
Kraïem et al. Hydrogen peroxide/dimethyl carbonate: a green system for epoxidation of N-alkylimines and N-sulfonylimines. One-pot synthesis of N-alkyloxaziridines from N-alkylamines and (hetero) aromatic aldehydes
Choukairi Afailal et al. Dearomative syn-dihydroxylation of naphthalenes with a biomimetic iron catalyst
Zhang et al. Dearomatization reaction of β-naphthols with disulfurating reagents
Park et al. β‐Aminosulfonyl Fluorides via Water‐Accelerated N‐Heterocyclic Carbene Catalysis
AU776140B2 (en) Process for catalyzing the oxidation of organic compounds
JPH07206865A (en) New porphyrin and its synthesis from dipyrromethane compound and aldehyde
JPH07206735A (en) Oxidizing method for alkane with new porphyrin synthesized from dipyrromethane and aldehyde
Choukairi Afailal et al. Manganese‐Catalyzed Enantioselective Dearomative Epoxidation of Naphthalenes with Aqueous Hydrogen Peroxide
Caputo et al. Synthesis of α‐Imino Amidines and 2, 3‐Diamino Indolenines Using a One‐Pot Graphene Oxide‐Catalyzed Process
Kang et al. Silver-catalyzed cross-dehydrogenative coupling of benzoxazine-2-ones with resorcinol
Cai et al. N-Aryl/heteroaryl oxaziridines: from photochemical synthesis to reactivity investigation in heteroatom transfer reactions
WO2014152737A1 (en) Selective modification of organic compounds in the presence of amines and/or sulfides
Jia et al. Catalytic oxidation of alcohols to aldehydes and ketones with ferric nitrate nonahydrate/trifluoroacetic acid via mechanochemical reaction
US6878821B2 (en) Modifying chemoselectivity during oxidation of nitrogen compounds
Gonsalves et al. 5, 10, 15, 20-Tetrakisaryl-and 2, 3, 7, 8, 12, 13, 17, 18-octahalogeno-5, 10, 15, 20-tetrakisarylporphyrins and their metal complexes as catalysts in hypochlorite epoxidations
d'A et al. Metalloporphyrin catalytic oxidations of hydrocarbons by H2O2
Beng et al. Site-selective, catalytic, and diastereoselective sp 3 C–H hydroxylation and alkoxylation of vicinally functionalized lactams
Jain et al. [Bmim] BF4-immobilized rhenium-catalyzed highly efficient oxygenation of aldimines to oxaziridines using solid peroxides as oxidants
Chen et al. Theoretical guidance and feedback on the design, preparation, and efficient catalytic oxidation of novel imidazole-modified iron porphyrin catalysts
CN119735549B (en) A method for the synthesis of 3-nitropyrazole catalyzed by metalloporphyrin

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: 20020311

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AT BE CH CY DE DK ES FI FR GB GR IE IT LI LU MC NL PT SE

AX Request for extension of the european patent

Free format text: AL PAYMENT 20020311;LT PAYMENT 20020311;LV PAYMENT 20020311;MK PAYMENT 20020311;RO PAYMENT 20020311;SI PAYMENT 20020311

RAP1 Party data changed (applicant data changed or rights of an application transferred)

Owner name: WARNER-LAMBERT COMPANY LLC

17Q First examination report despatched

Effective date: 20030325

GRAP Despatch of communication of intention to grant a patent

Free format text: ORIGINAL CODE: EPIDOSNIGR1

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: 20050330

REG Reference to a national code

Ref country code: HK

Ref legal event code: WD

Ref document number: 1047428

Country of ref document: HK