CZ2002452A3 - Catalytic oxidation process of organic compounds - Google Patents

Abstract

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

Description

Catalytic process of oxidation of organic compounds

Technical field

The invention relates to the oxidation of organic compounds in the presence of a catalytic amount of metal porphyrin in a non-reactive aprotic solvent.

BACKGROUND OF THE INVENTION

Studying drug metabolism is an important part of a very costly drug research and development process. Many drugs are metabolized in human and mammalian organisms through oxidative reactions catalyzed by enzymes containing heme and cytochrome. Cytochrome P450 monooxygenases, the major enzymes involved in the oxidative metabolism of drugs, have a hernia role in their active sites.

Synthetic metal porphyrins can successfully mimic the oxidation catalytic reactions occurring in biological systems in order to generate and identify the oxidation products of drug candidates in an amount allowing in vivo studies.

PCT application WO 96/08455 showed a method for preparing oxidation products using various combinations of synthetic metal porphyrin, an oxidizing agent and a solvent. The solvent is generally a combination of acetonitrile and dichloromethane. One of the main drawbacks of this method is that it often provides insufficient yields of the desired individual products as well as a low degree of conversion. The result of this ^; is that these methods can rarely be reliably used in integrated discovery processes. In fact, their use is limited to experimental confirmation.

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SUMMARY OF THE INVENTION

In accordance with the present invention, the inventor has unexpectedly found that in the presence of metal porphyrins, the yields of oxidation reactions, which may be useful for the synthesis of metabolites of relevant organic compounds, can be substantially increased by the use of an inert aprotic solvent.

Thus, one object of the present invention is a process for oxidizing organic compounds. The method comprises reacting the selected organic compound with a catalytic amount of metal porphyrins and an oxidizing agent in the presence of an inert aprotic solvent and isolating the desired products thus obtained.

The method of the invention is extremely useful for pharmaceutical research and development since it can be used to make preliminary assessments of the metabolic processes that are considered in vivo testing of a given compound. These preliminary assessments can be performed directly without the need for expensive and time consuming in vivo experiments. Further, the process of the present invention gives better yields of individual products than the prior art methods. In other words, the method of the present invention opens up the possibility of more systematically obtaining and analyzing a plurality of individual potential metabolites of a given selected compound to which the method is applied.

DETAILED DESCRIPTION OF THE INVENTION

The present invention thus provides a process for the efficient oxidative preparation of metabolites of organic compounds. The invention involves the reaction of a relevant organic compound with a catalytic amount of metal porphyrins and with an 'oxidizing agent' in a non-reactive aprotic solvent. It also includes isolation and identification of the desired reaction products.

As mentioned, many drugs are metabolized by oxidative reactions. The process of the invention is therefore preferably applicable to relevant organic compounds having one or more functional groups that react under oxidizing conditions. Some of these functional groups are described below, but one skilled in the art will readily appreciate that this listing is not intended to be exhaustive. The method of the invention can in fact be applied to any organic compound that can be oxidized in some way by enzymes involved in the oxidative metabolism of the drug.

Compounds containing heteroatoms such as nitrogen or sulfur can best be effectively oxidized by the process of the invention, especially to higher oxidation states and especially to their highest oxidation states. For example, primary amines can be easily converted to the corresponding hydroxylamines, nitroso or nitro derivatives and tertiary amines to the corresponding N-oxides.

By means of metal-porphyrin-catalyzed oxidation, C-H bonds to C-OH bonds can also be hydroxylated without difficulty according to the invention. Examples of labile C-H bonds include, for example, bonds at benzyl positions or C-H bonds, wherein the carbon atom binds to the heteroatom (eg, N, S, O, and the like). These bonds are particularly reactive under these conditions. This is how you can. convert primary alcohols to the corresponding aldehydes, the aldehydes can in turn be converted to the corresponding acids, and the acids can further undergo decarboxylation.

By the method of the invention, the secondary alcohols can be converted to the corresponding ketones.

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According to the invention, carbon-carbon double bonds can be epoxidized and aromatic groups can be oxidized to the corresponding phenols or quinones.

The main parameters relating to the process of the invention are the starting material, which is usually the organic compound to be studied, the reactants, which usually include a metal porphyrin, an oxidizing agent and an inert aprotic solvent, and reaction conditions including temperature and reaction time. Each of these parameters will be discussed in more detail below.

Metal porphyrins

Synthetic metal porphyrins are described in International Patent Application WO 96/08455. The term "metallic porphyrin, as used herein, refers to porphyrin compounds of formula (I):

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R 1, R 2 and R 3 independently represent hydrogen or an electrophilic group such as Cl, F, Br, SO ₃ Na or the like,

R 4, R 5, R 6, R 7, R 8, R 9, R 10 and R 11 independently represent hydrogen or an electrophilic group such as Cl, F, Br, NO 2, CN, SO ₃ Na or the like,

R 12 is Cl, acetate or the like,

M is selected from the group consisting of iron, manganese, chromium, ruthenium, cobalt, copper and nickel.

Preferred metal porphyrins include tetrakis (pentafluorophenyl) porphyrin Mn (III) chloride, further abbreviated as Mn (TPFPP) Cl, which is a compound of formula (I) above, wherein M is manganese, R1, R2 and R3 are fluoro, R4, R 5, R 6, R 7, R 8, R 9, R 10 and R 11 are hydrogen and R 12 is chlorine.

Preferred metal porphyrins also include:

tetrakis (pentafluorophenyl) porphyrin Fe chloride, abbreviated as Fe (TPFPP) Cl, which is a compound of the above formula (I) wherein M is iron, R1, R2 and R3 are fluorine, R4, R5, R6, R7, R8 R 9, R 10 and R 11 are hydrogen and R 12 is chloro;

tetrakis (2, β-dichlorophenyl) porphyrin Mn chloride, abbreviated Mn (TDCPP) Cl, which is a compound of the above formula (I) wherein M is manganese, R1 is chloride, R2, R3, R4, R5, R6, R7 R8, R9, R10 and R11 are hydrogen and R12 is chloro;

tetrakis (2,6-dichlorophenyl) porphyrin Fe chloride, abbreviated

Fe (TDCPP) Cl which is a compound of the above formula (I) wherein M is iron, R1 is chloride, R2, R3, R4, R5, R6, R7, R8,

R 9, R 10 and R 11 are hydrogen and R 12 is chloro;

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99 99 9999 99 9999 tetrakis (2,6-dichlorophenyl) octachlorporphyrin Fe chloride, abbreviated as Fe (TDCPClsP) Cl, which is a compound of the above formula (I) wherein M is iron, R1 is chloride, R2, R3 are hydrogen, R 4, R 5, R 6, R 7, R 8, R 9, R 10 and R 11 are chloride and R 12 is chlorine;

the compound Mn ((Cl ₂ Ph) ₄ (NO ₂ ) P) Cl with the above formula (I), wherein M is manganese, R 1 is chloride, R 4 is NO ₂ , R ₂ , R 3, R 5, R 6, R 7,

R 8, R 9, R 10 and R 11 are hydrogen and R 12 is chloro;

the compound Mn ((Cl ₂ Ph) ₄ (NO ₂ ) ₂ P) Cl, with the above formula (I), wherein M is manganese, R 1 is chloride, R 5 and R 6 are NO ₂ , R 2, R 3, R 4,

R 7, R 8, R 9, R 10 and R 11 are hydrogen and R 12 is chlorine.

The amount of metal porphyrin catalyst is usually between 0.5 and 10 mole%, and is preferably about 1 mole%.

Oxidizing agents

Various oxidizing agents can be used in the present invention. It should be noted that the intrinsic nature of the oxidizing agent is not a limiting factor in the process of the present invention. A person skilled in the art can therefore select a suitable oxidizing agent from a wide variety of compounds that have been used for metal porphyrin catalysed oxidation reactions. The list of possible reagents includes, but is not limited to: iodosylbenzene, also known as iodosobenzene, aqueous hydrogen peroxide solutions (concentration around 30-45%), anhydrous equivalents of hydrogen peroxide such as sodium percarbonate, urea complex with hydrogen peroxide or the like, potassium monopersulfate , sodium hypochlorite, tert-butyl hydroperoxide, cumene hydroperoxide, m-chloroperbenzoic acid and monoperoxy · 4 · · · »4 4 4 4 4 4 4 4 4 4 4 4 4 ··· · · · · · · · · · · · · Magnesium phthalate. Preferred oxidants are iodosylbenzene, any source of hydrogen peroxide, and potassium monopersulfate.

Oxidation with hydrogen peroxide is more effective in the presence of a co-catalyst such as imidazole, ammonium acetate, N-hexylimidazole, N-amine oxides, tetrabutylammonium acetate, tert-butylpyridine, pyridine, 4-methylpyridine and 2,4,6-trimethylpyridine. For a review, see Rocha Gonsalves, A. M. and Pereira, Μ. M .: „State of Art in the Development of Biomimetic Oxidation Catalysts J. Mol. Catal. A: Chem. 1996,

113, 209.

Solvent

The metal porphyrin-catalyzed oxidation of the invention is carried out in an inert solvent, which may in fact contain one or more solvents. As used herein, the term "inert aprotic solvent" refers to any solvent or mixture of solvents which, when evaluated overall, does not react in any substantial way with the starting materials or reaction products. In particular, the solvent should not react with the oxidizing agent. In addition, the solvent should be resistant to hydrogen cleavage.

If it is a mixture of solvents, it usually contains a so-called "main solvent and" co-solvent. However, it should be noted that various solvents having similar properties can be used as the main solvent. The same applies to the final co-solvent mixtures.

The major solvent is present in the solvent mixture in a greater amount than the cosolvent.

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Indeed, the predominant properties of the overall solvent mixture impart the principal solvent, which will therefore play a key role in the process of the invention. The main solvent should therefore be inert and aprotic.

The main solvent should be able to dissolve the starting material (eg the study organic substance) and the metal porphyrin, as much as possible.

Examples of the principal solvent include, but are not limited to, polyhalogen aliphatic solvents such as 1,1,2-trichloro-1,2,2-trifluoroethane and the like or polyhalogen aromatic solvents such as 1,2-dichlorobenzene, 1,2,4trichlorobenzene. , pentafluorobenzene and the like. Preferred polyhalogen solvents include polyfluoro aromatic compounds such as trifluorotoluene (also known as benzotrifluoride) and the like. The most preferred solvent is trifluorotoluene, which combines the ability to dissolve a wide variety of organic compounds with low reactivity to oxidation conditions.

Although one skilled in the art can determine by routine experimentation the optimum amount of main solvent to be used in each individual case, suitable concentrations of the starting material in the chosen solvent may be between 0.1 M and 0.5 M, preferably 0.1 M.

The cosolvent is present in the mixture in small amounts and is added to provide the total solvent mixture with the additional properties needed that will be useful at a certain point in time, but which will not significantly interfere with the reaction itself.

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In a first particular embodiment of the process of the invention, the cosolvents can be used to improve solubility in the reaction medium if any of the studied organic compound or oxidizing agent is not soluble in the main solvent.

For example, if the starting material is not soluble in trifluorotoluene or in any available major solvent, a cosolvent may be used to increase its solubility in the reaction medium. Preferred co-solvents are highly polar and weakly nucleophilic co-solvents. The properties of the cosolvent should preferably be selected so as to minimize the formation of a complex with the metal porphyrin. 2,2,2-Trifluoroethanol and especially 1,1,1,3,3,3-hexafluoropropan-2-ol (also called hexafluoropropanol or HFIP) are representative examples of cosolvents that can be used according to the process of the invention. In particular, hexafluoroisopropanol can be useful in the oxidation reaction carried out with iodosylbenzene in one of the above-mentioned organic solvents, since this co-solvent helps to dissolve this particular oxidizing agent in the reaction medium.

The amount of co-solvent used to dissolve the starting material or oxidizing agent and optionally the catalyst should be kept at relatively low levels relative to the main solvent. Although one of ordinary skill in the art can determine by routine experimentation the optimum amount of co-solvent to be used in each individual case, suitable concentrations may be between 1 and 30%, preferably between 1 and 20% and more preferably between 1 and 10% relative to the main solvent.

In a second particular embodiment of the process of the invention, the co-solvent may be used to facilitate the transfer of reactants within the reaction medium. For example, a cosolvent will be used. · · · · • · · · · · · · · · »·» · »·»

ΦΦΦΦ ΦΦΦ ΦΦΦΦ ΦΦΦΦ rea rea ved ved případě ΦΦΦΦ ΦΦΦΦ případě případě případě případě in the case where the starting material or one or more reactants results in a reaction mixture comprising a two-phase solution.

For example, when the oxidizing agent is used as an aqueous solution, the reaction mixture is biphasic and the water-miscible cosolvents can then be used to facilitate the transfer of the oxidant to the organic phase. A minimum amount of co-solvent, for example hexafluoropropanol, is preferred. This co-solvent is miscible with water and may aid in the dissolution of the starting material.

The amount of co-solvent to be used in the second embodiment, expressed in catalytic amounts, is usually between 0.25 and 1 equivalent, preferably between 0.3 and 0.5, and most preferably about 0.4 equivalent to the starting material.

In order to facilitate the transfer of any of the reactants to the phase in which the reaction will take place, a phase transfer catalyst may be used as an alternative to this second process of the invention. For example, if an oxidant is used in the form of an aqueous solution, a phase transfer catalyst may be used to facilitate the transfer of the oxidant to the organic phase.

Exemplary phase transfer catalysts are tetraalkyl ammonium salts (e.g., dodecyltrimethylammonium bromide and the like). The amount of phase transfer catalyst to be used in this second embodiment, expressed as a catalytic amount, is usually between 0.05 and 0.5 equivalents, preferably about 0.1 equivalents with respect to the starting material.

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Temperature and reaction time

The reaction is carried out at a temperature between about -20 ° C and 100 ° C, and preferably between about -10 ° C and 40 ° C.

However, one of ordinary skill in the art would note that ultrasound can be used to increase the reaction rate. The reaction is therefore preferably carried out in an ultrasonic bath cooled to 0 ° C.

In general, the reaction time is between a few minutes and up to two hours. The progress of the reaction can be monitored by TLC or HPLC analysis techniques and thus the reaction can be stopped when the oxidation reaction reaches a point beyond which substantial changes are no longer observed.

DETAILED DESCRIPTION OF THE INVENTION

The following examples illustrate embodiments of the process of the invention without limiting the invention.

The purity, identity and physico-chemical characteristics of the prepared products are determined as follows:

purity was verified by reverse phase analytical HPLC on a Merck Lachrom instrument and the measured Rf values were reported for the eluent used;

- the identity of the products obtained from the proposed structures is verified by means of their spectra from proton nuclear magnetic resonance and mass spectroscopy.

¹ H NMR spectra were recorded at 400 MHz on a Bruker instrument, and the compounds were dissolved in deuterochloroform with tetramethylsilane as an internal standard. The nature of the signals, their chemical shifts in ppm, the number of protons they represent and their exchange capacity with _D2 0 is recorded.

Mass spectra are recorded on a Micromass Platform LC (single quadrupole electron scattering ionization) spectrometer. Infrared spectra are recorded on a Nicolet spectrometer.

The phrase "flash chromatography on silica" means a method taken from Still et al. (1978) J. Org. Chem. 43, 2923. The purity of the elution fractions is verified before they are collected and evaporated.

The terms " evaporation, " removal or " solvent concentration " mean possibilities ranging from drying on a suitable dehydrating agent such as Na ₂ SO ₄ or MgSO ₄ to distillation at 25 to 50 mm Hg (3.3 to 6.7 kPa) to heating in a water bath at a temperature below 30 ° C.

Example 1

Oxidation of diazepam U) with iodosylbenzene (PhIO) catalyzed by tetrakis (pentafluorophenyl) porphyrin manganese (III) chloride in trifluorotoluene.

During this reaction, nordiazepam (2), temazepam (3), oxazepam (4), 6'-chloro-4-phenyl-1-methyl-2- (1H) -quinazoline (5) and 6-chloro-4-phenyl are formed -2- (177) -quinazoline (6).

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To 240 µL of a solution containing 25 pmol of diazepam (1 in trifluorotoluene) was added 10 µL of a 25 mM solution of 5,10,15,20 tetrakis (pentafluorophenyl) -21H, 23β-porphyrin manganese (III) chloride (0.25 pmol, 1 mol%) A portion of iodosylbenzene (3.times.5.5 mg, 3.times.25 pmol, 3 equivalents) was added to the resulting solution with stirring three times, one hour at a time, and the reaction was monitored by analytical HPLC for one hour after each addition: sample prepared with 5 µL of raw material and 100 µL of a 5 mM methanol solution of acetophenone (internal standard) diluted with 395 µL of methanol, is loaded onto a 150x4.6 mm column packed with Nucleosil 5C18 and eluted with 50/50 methanol / water at 1 mL / min for 45 minutes. Nordiazepam (2), temazepam (3) and oxazepam (4) are identified by comparison with authentic samples (Sigma), with retention times of 21.9, 16.7 and 13.3 min. 1-methyl-2- (1H) -quinazoline (5) and 6-chloro-4-phenyl-2- (1H) -quinazoline (6) eluting at 25.1 and 20.5 min, are identified in a separate run by isolating and comparing ¹ H NMR and.

9 9 9 999 9 · 9 ·· ·· 9 «9999 99 9999 data by Felix et al. (1968), J. Heterocycl. Chem. 5, 731 and

Sulkowski et al. (1962) J. Org. Chem. 27, 4424.

The yields of the reaction products are shown in the following table:

PhIO (equiv.) Products obtained: yield (%) 1 2 3 4 5 6 1 31 19 Dec 12 3 4 0 2 5 17 6 7 11 4 3 1 9 2 5 10 3

The results of a prior art reaction using a 1: 1 dichloromethane / acetonitrile solvent are shown below:

PhIO (equiv.) Products obtained: yield (%) 1 2 3 1 86 1 1 2 83 1 2 3 79 1 2

A comparison of the two result sets implies that the use of a solvent such as trifluorotoluene, instead of a conventional mixture of dichloromethane and acetonitrile, results in better diazepam conversion and more products with significantly better yields.

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Example 2

Oxidation of diazepam (1) with 30% aqueous hydrogen peroxide solution catalyzed by tetrakis (pentafluorophenyl) porphyrin manganese (III) chloride in trifluorotoluene.

This reaction is much more effective in the presence of a catalytic amount of imidazole (Battioni et al (1988) J. Am. Chem. Soc. 110, 8462) and ammonium acetate (Thellend et al (1994) J. Chem.

Soc., Chem. Comm., 1035).

During this reaction, nordiazepam (2), temazepam (3), oxazepam (4), 6-chloro-4-phenyl-1-methyl-2- (1H) -quinazoline (5), diazepam N-oxide (7), and Nordiazepam N-oxide (8j.

H ₂ O ₂

Mn (TPFPP) Cl imid., AcONH ₄ HFIP PhCF ₃

9 · «9 9 9 · * 9 9 9 9 * * * * 9 9 9 9 9 9 9 9 9 9 9 9 «··

To 240 µL of a solution containing 25 pmol of diazepam (1) in trifluorotoluene was added 10 µL of a 25 mM solution of 5,10,15,20 / tetrakis (pentafluorophenyl) -21H, 23H-porphyrin manganese (III) chloride (0.25 pmol, 1). mol%) and 1,1,1,3,3,3-hexafluoro-2-propanol (1.1 µL, 10.4 pmol, 0.4 equiv) in trifluorotoluene. To the resulting solution was added dropwise an aqueous solution of 30% hydrogen peroxide (2.6 µL, 25 pmol, 1 equiv.), Imidazole (6.5 µL of 1 M aqueous solution, 6.5 pmol, 0.25 equiv.) Dropwise with stirring. ) and ammonium acetate (25 µL of 1 M aqueous solution, 25 pmol, 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 pmol, 1 equiv) is then added every 10 minutes until 15 equivalents of oxidant are used. The reaction is monitored by addition of 2, 5, 10 and 15 equivalents 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 by reaction of diazepam and nordiazepam with m-chloroperbenzoic acid (cf. Ebel et al.) (1979), Arzneim-Forsch. 29, 1317).

The yields of the reaction products are shown in the following table:

H2O2 (equiv.) 1 Products obtained: yield (%) 8 2 3 4 5 7 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 Dec 19 Dec 10 14 2 8 6 2

Results from an analogous reaction carried out in a 1: 1 mixture of dichloromethane and acetonitrile instead of trifluorotoluene and ₁₇ ............... ₁₇ ............... .

hexafluorisoprapanol as cosolvents are shown below:

h ₂ 0 ₂ (eq) Products obtained: yield (%) 1 2 3 7 1 84 1 1 2 2 77 2 1 3 5 74 5 3 6 10 74 6 7 7 15 Dec 74 5 9 7

If oxidation is carried out with peroxide. hydrogen in a biphasic system, yielding better diazepam conversion and higher yields of trifluorotoluene products in the presence of hexafluoroisopropanol instead of the dichloromethane-acetonitrile solvent system.

Preliminary results of further recent experiments confirm the efficacy of the method of the invention for the oxidation of compounds with relatively different structural parameters.

Claims (16)

PATENT CLAIMS CLAIMS 1. A process for oxidizing an organic compound comprising reacting an organic compound to be oxidized with a reaction medium comprising a metal porphyrin and an oxidizing agent in an inert aprotic solvent selected from a polyhalogen aliphatic or aromatic solvent and obtaining and identifying the desired reaction products under the condition wherein the inert aprotic solvent is not dichloromethane, dichloroethane or trichloroethane. The process of claim 1, wherein the inert aprotic solvent is a polyhalogen aromatic solvent. The process of claim 2, wherein the solvent is trifluorotoluene. The process of claim 1 wherein the reaction medium comprises an inert aprotic main solvent and a cosolvent capable of increasing the solubility of the organic compound in the reaction medium. The method of claim 4, wherein said co-solvent is a polar and weakly nucleophilic solvent. The process of claim 5, wherein said solvent is 2,2,2-trifluoroethanol or 1,1,1,3,3,3-hexafluoro-propan-2-ol. The method of claim 4, wherein the co-solvent concentration is in the range of 1 to 30%. 8. The process of claim 1 wherein the reaction medium comprises a biphasic solution. 9. The process of claim 8 wherein said reaction medium comprises an inert aprotic main solvent and a cosolvent having the ability to transfer the organic compound from one phase to another. 9 99 99 99 99 99 99 9 · »9 · 8 ·« 99 99 9 «9 9 • 9 9 99 9999 The process according to claim 9, hexafluoroisopropanol. where the cosolvent is The process of claim 8, wherein the reaction medium comprises a first aqueous phase oxidizing agent and a second organic phase an organic compound and a metal porphyrin in an aprotic solvent. The composition of claim 1, wherein said containing is inert 12. The method of claim 11 wherein said second phase comprises an inert aprotic solvent and a cosolvent having the ability to transfer the oxidizing agent from one phase to the other. The method of claim 12, wherein the co-solvent is water miscible. The method of claim 12, wherein the co-solvent is 1,1,1,3,3,3-hexafluoro-propan-2-ol. Process according to claim 8, characterized in that a phase transfer catalyst, a phase transfer catalyst capable of transferring the reactants from one phase to the other, is used in the reaction medium. The process of claim 15, wherein the phase transfer catalyst is a tetraalkyl ammonium salt. The process of claim 16, wherein the tetraalkyl ammonium salt is dodecyl-trimethylammonium bromide.