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).

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• Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
• Investigating Or Analyzing Non-Biological Materials By The Use Of Chemical Means (AREA)

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• 2000
  • 2000-08-09 BR BR0013018-4A patent/BR0013018A/pt not_active IP Right Cessation
  • 2000-08-09 KR KR1020027001738A patent/KR20020024323A/ko not_active Application Discontinuation
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  • 2000-08-09 CA CA002380851A patent/CA2380851A1/en not_active Abandoned
  • 2000-08-09 TR TR2002/00330T patent/TR200200330T2/xx unknown
  • 2000-08-09 AU AU72738/00A patent/AU776140B2/en not_active Ceased
  • 2000-08-09 EP EP00960420A patent/EP1208069A1/en not_active Withdrawn
  • 2000-08-09 YU YU4902A patent/YU4902A/sh unknown
  • 2000-08-09 CN CN00811067A patent/CN1367769A/zh active Pending
  • 2000-08-09 WO PCT/EP2000/007726 patent/WO2001010797A1/en not_active Application Discontinuation
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• 2002
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