KR20020024323A - Process for Catalyzing the Oxidation of Organic Compounds - Google Patents

Abstract

A catalytic amount of metal porphyrin is added in the nonreactive aprotic solvent to catalyze the oxidation reaction of the organic compound.

Description

Process for Catalyzing the Oxidation of Organic Compounds

Drug metabolism studies are an important part of expensive drug R & D. Many drugs in humans and other mammals are metabolized via oxidation reactions catalyzed by heme- and cytochrome-containing enzymes. Cytochrome P-450 monoxide, a major enzyme involved in drug oxygenation metabolism, has a heme moiety in its active site.

Synthetic metal porphyrins can be preferably used to mimic the oxidation catalysis that occurs in biological systems for the purpose of preparing and identifying oxidation products of candidate drugs, which largely allow for in vivo studies.

PCT Application WO 96/08455 describes a process for preparing oxidation products using various combinations of synthetic metal porphyrins, co-oxidants and solvents. The solvent is generally a CH ₃ CN / CH ₂ Cl ₂ combination. One of the major inconveniences of this method is that this method often results in lower yields as well as incomplete yield of each product required. Thus, the method is rarely used reliably in an integrated discovery process. In practice, the use of these methods is generally limited to validation experiments.

<Overview of invention>

In accordance with the present invention, it has been unexpectedly found that the yield of oxidation reactions using metal porphyrins that can be useful in the synthesis of metabolites of organic compounds of interest can be significantly increased by using inert aprotic solvents.

Therefore, one of the objects of the present invention is a method of oxidizing an organic compound. The method involves reacting the selected organic compound with a catalytic amount of metal porphyrin and an oxidant in the presence of an inert aprotic solvent and recovering the desired product thus obtained.

The method of the present invention is very useful for pharmaceutical research and development since the method of the present invention can be used to perform a preliminary assessment of metabolic processes that are likely to occur when a given compound is tested in vivo. This preliminary assessment can be performed quickly without expensive and time consuming in vivo experiments. In addition, the process of the present invention provides a better yield than the yield of each product obtained using the methods of the prior art. In other words, the method of the present invention offers the possibility of obtaining and analyzing a greater number of possible individual metabolites in a more systematic manner for any selected compound on which the method is performed.

The present invention therefore relates to a process for the efficient oxidation of the metabolites of organic compounds. The present invention involves reacting an organic compound of interest with a catalytic amount of metal porphyrin and an oxidant in an unreactive aprotic solvent. It also includes recovering and identifying the desired reaction product.

As mentioned above, various drugs are metabolized through oxidation reactions. Thus, the process of the present invention is preferably used for organic compounds of interest having from one to several functional groups that will react to oxidizing conditions. Some of these functional groups are described below, but those skilled in the art will readily appreciate that they are not limited to the list provided. Indeed, the methods of the present invention can be used with any organic compound that can be oxidized in any way by enzymes involved in drug oxidative metabolism.

Preferably, compounds containing heteroatoms such as nitrogen or sulfur can be oxidized effectively, in particular in the high oxidation state and more particularly in the highest oxidation state, via the process of the invention. For example, primary amines can be readily converted to their corresponding hydroxylamine, nitroso- or nitro-derivatives, and tertiary amines can be readily converted to their corresponding N-oxides.

In addition, C-H bonds can be conveniently hydroxylated to C-OH bonds by oxidation catalyzed by metal porphyrins according to the present invention. Examples include labile C-H bonds, such as C-H bonds where the benzyl position or carbon atom is adjacent to heteroatoms (eg, N, S, O, etc.). They are particularly reactive to these conditions. In this way, the primary alcohol can be converted to its corresponding aldehyde, and then the aldehyde can be converted to its corresponding acid, in which the decarboxylation reaction can also proceed.

Through the process of the invention, the secondary alcohol can be converted to its corresponding ketone.

Carbon-carbon double bonds can be epoxidized by metal porphyrin-catalyzed oxidation reactions according to the invention, and aromatic groups can be oxidized to the corresponding phenols or quinols.

The main parameters involved in the process of the present invention are reaction conditions, including the starting materials, usually metalporphyrins, usually metalporphyrins, oxidants and inert aprotic solvents, and reaction temperatures and reaction times, which are usually the organic compounds of interest. Each of these parameters will be discussed further below.

Metal porphyrin

Synthetic metal porphyrins are described in international patent application WO 96/08455. As used herein, the term "metal porphyrin" means a porphyrin compound of formula (I)

In the formula,

R1, R2 and R3 independently represent hydrogen or an electron withdrawing group such as Cl, F, Br, SO ₃ Na, etc.,

R4, R5, R6, R7, R8, R9, R10 and R11 independently represent hydrogen or electron aspirator such as Cl, F, Br, NO ₂ , CN, SO ₃ Na, etc.,

R12 is Cl, acetate and the like,

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

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

In addition, preferred compounds include

Tetrakis (pentafluoro-), a compound of Formula I wherein M is iron, R1, R2 and R3 are fluorine, R4, R5, R6, R7, R8, R9, R10 and R11 are hydrogen and R12 is chlorine Phenyl) porphyrin Fe chloride (Fe (TPFPP) Cl);

Tetrakis (2,6-dichloro), a compound of Formula I wherein M is manganese, R 1 chlorine, R 2, R 3, R 4, R 5, R 6, R 7, R 8, R 9, R 10 and R 11 are hydrogen and R 12 is chlorine Phenyl) porphyrin Mn chloride (Mn (TDCPP) Cl);

Tetrakis (2,6-) is a compound of Formula I wherein M is iron, R 1 is chlorine, R 2, R 3, R 4, R 5, R 6, R 7, R 8, R 9, R 10 and R 11 are hydrogen and R 12 is chlorine Dichlorophenyl) porphyrin Fe chloride (Fe (TDCPP) Cl);

Tetrakis, a compound of Formula I wherein M is iron, R 1 is chlorine, R 2 and R 3 are hydrogen, R 4, R 5, R 6, R 7, R 8, R 9, R 10 and R 11 are chlorine, and R 12 is chlorine , 6-dichlorophenyl) -octachloroporphyrin chloride Fe (Fe (TDCPCl ₈ P) Cl);

Mn is a compound of Formula I wherein M is manganese, R 1 is chlorine, 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 chlorine Cl ₂ Ph) ₄ (NO ₂ ) P) Cl; And

Mn is a compound of Formula (I) wherein M is manganese, R 1 is chlorine, 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 Cl ₂ Ph) ₄ (NO ₂ ) ₂ P) Cl.

The amount of metal porphyrin catalyst is usually 0.5 to 10 mol%, with about 1 mol% being preferred.

Oxidant

Various oxidants can be used in the present invention. It should be appreciated that the nature of the oxidant does not act as a limiting factor in the process of the present invention. One skilled in the art can therefore select a suitable oxidant from a wide range of compounds used in metalporphyrin-catalyzed oxidation reactions. Possible oxidizing agents include: iodosilbenzene (also known as iodosobenzene), aqueous hydrogen peroxide solution (concentration about 30 to 45%), anhydrous equivalents of hydrogen peroxide, such as sodium percarbonate, urea hydrogen peroxide complex, potassium monopersulfate, sodium hippo Chlorite, tert-butyl hydroperoxide, cumin hydroperoxide, m-chlorobenzoic acid and manganese monoperoxyphthalate. Preferred as oxidants are iodosilbenzene, optional hydrogen peroxide and potassium monopersulfate.

Oxidation reactions using hydrogen peroxide include imidazole, ammonium acetate, N-hexylimidazole, amine N-oxide, tetrabutylammonium acetate, tert-butyl pyridine, pyridine, 4-methylpyridine and 2,4,6-trimethyl More effective in the presence of a promoter such as pyridine. "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.

menstruum

The metal porphyrin-catalyzed oxidation of the present invention is carried out in an inert solvent and may actually comprise one or more solvents. As used herein, the term “inert aprotic solvent” means any solvent or any mixture of solvents which, when assessed broadly, does not react in any substantial way with the starting materials or products of the reaction. More specifically, the solvent should not react with the oxidant. In addition, hydrogen should not be removed from the solvent.

When solvents are used in mixtures, these mixtures usually comprise so-called "main solvent" and "cosolvent". However, it should be recognized that various solvents with similar properties can be used to form the main solvent. The same applies to the final mixture of the cosolvent.

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

Indeed, imparting overall properties to the comprehensive solvent mixture is the main solvent and will play an important role in the process of the invention. The main solvent must therefore be inert and aprotic.

As far as possible the main solvent should be able to dissolve the starting material (eg the organic compound of interest) and the metal porphyrin.

Examples of the main solvent include polyhalogenated aliphatic solvents such as 1,1,2-trichloro-1,2,2-trifluoroethane or 1,2-dichlorobenzene, 1,2,4-trichlorobenzene, penta Polyhalogenated aromatic solvents such as fluorobenzene, and the like. The polyhalogenated solvent is preferably a polyfluorinated aromatic compound such as trifluorotoluene (also known as benzotrifluoride). Most preferred as the solvent is trifluorotoluene, which can also dissolve various organic compounds which are low in reactivity to oxidizing conditions.

Although the skilled person can determine the optimum amount of main solvent used in each case by general experiments, the suitable concentration of starting material in the selected solvent can vary from 0.1 M to 0.5 M, with 0.1 M being preferred.

Cosolvents are present in small amounts in the mixture and impart useful additional properties to the overall solvent mixture, which in some ways will be useful but will not significantly interfere with the reaction itself.

In a first embodiment of the process of the invention, when any organic compound or oxidant of interest is not soluble in the main solvent, a co-solvent can be used to improve the solubility in the reaction medium.

For example, when the starting material is not dissolved in trifluorotoluene or any possible main solvent, cosolvents can be used to improve the solubility in the reaction medium. Cosolvents are preferred which are very polar and extremely nucleophilic. Preferably, the properties of the cosolvent should be chosen to minimize complex formation with the metal porphyrin. 2,2,2-trifluoroethanol and, in particular, 1,1,1,3,3,3-hexafluoropropan-2-ol (also called hexafluoroisopropanol or HFIP) can be used in the process of the invention It is an example of a typical cosolvent. More specifically, hexafluoroisopropanol may be useful for the oxidation reaction with iodosilbenzene in one of the above organic solvents, as this cosolvent helps to dissolve this particular oxidant in the reaction medium.

The amount of the starting material or oxidant and finally the cosolvent used to dissolve the catalyst should be kept at a significantly lower level than the main solvent. The skilled person can determine the optimum amount of cosolvent used in each case by routine experimentation, but suitable concentrations are within 1 to 30%, preferably 1 to 20%, more preferably 1 to 10% relative to the main solvent. Can vary from.

In a second embodiment of the process of the invention, a cosolvent may be used to facilitate delivery of the reactants in the reaction medium. For example, cosolvents may be used where the starting materials or one or more reactants result in a reaction mixture comprising an ideal solution.

For example, when the oxidant is used as an aqueous solution, the reactants are ideal, and the water miscible cosolvent can be used to promote the delivery of the oxidant to the organic phase. Preference is given to using a minimum amount of cosolvent, such as hexafluoroisopropanol. Such cosolvents are water miscible and can promote dissolution of the starting material.

The amount of cosolvent to be used in the second embodiment, expressed in catalytic amounts, is usually in the range of 0.25 to 1 equivalent, preferably 0.3 to 0.5 equivalent, more preferably about 0.4 equivalent to the starting material.

As an alternative to the second embodiment of the present invention, a phase transfer catalyst may be used to facilitate delivery of any reactants to the phase in which the reaction will occur. For example, when an oxidant is used in an aqueous solution, a phase transfer catalyst can be used to promote the delivery of the oxidant to the organic phase.

Examples of phase transfer catalysts are tetraalkyl ammonium salts (eg dodecyltrimethyl-ammonium bromide and the like). The amount of phase transfer catalyst that should be used in the second embodiment, expressed in catalytic amounts, is usually in the range of 0.05 to 0.5 equivalents, more preferably about 0.10 equivalents relative to the starting material.

Reaction temperature and time

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

However, the skilled person should recognize that sonication can increase the reaction rate. The reaction is then preferably carried out in an ultrasonic bath cooled to 0 ° C.

In general, the reaction time varies from a few minutes to two hours. Since the reaction can be monitored by TLC or HPLC analysis, the reaction is stopped when the oxidation reaction reaches below the plateau point where no substantial conversion is observed.

The following examples illustrate the implementation of the method of the invention without limiting the invention.

The purity, identity and physico-chemical properties of the product produced are as described below:

Purity was confirmed by analytical reversed phase HPLC on a Merck Lachrom apparatus, and the observed Rf is the value for the eluent used.

The identity of the product obtained with the proposed structure was confirmed by proton nuclear magnetic resonance spectra and mass spectrometry.

¹ H NMR spectra were recorded at 400 MHz with a Brueker apparatus by dissolving the compound in deuterium substituted chloroform with tetramethylsilane as internal standard. The properties of the signal, its chemical shift (ppm), the number of protons and exchange capacity with D ₂ O are shown.

Mass spectra were recorded on a Micromass Platform LC spectrometer (simple quadrupole by cationized electrospray). Infrared spectra were recorded on a Nicolet spectrometer.

"Flash chromatography on silica columns" is described in Still et al. (1978) J. Org. Chem. 43: 2923]. The purity of the eluting fraction was checked before it was collected and evaporated.

"Evaporation", "removal" or "concentration" of the solvent is preferably 25 to 50 mmHg (3.3 to 6.7 kPa), followed by drying with a suitable dehydrating agent such as Na ₂ SO ₄ or MgSO ₄ , followed by moderate heating in a water bath below 30 ° C. It means to evaporate under pressure.

Example 1

Diazepam with iodosylbenzene (PhIO) catalyzed by tetrakis (pentafluorophenyl) porphyrin manganese (III) chloride in trifluorotoluene ( One Oxidation of

During this reaction, nordiazepam ( 2 ), themazepane ( 3 ), oxazepam ( 4 ), 6-chloro-4-phenyl-1-methyl-2- (1H) -quinazolinone ( 5 ) and 6-chloro 4-phenyl-2- (1H) -quinazolinone ( 6 ) was formed.

10 μl of a 25 mM solution of 5,10,15,20-tetrakis (pentafluorophenyl) -21H, 23H-porphyrin manganese (III) chloride (0.25 μmol, 1 mol%) in trifluorotoluene was added to trifluoro To 240 μl of a solution containing 25 μmol diazepam ( 1 ) in toluene was added. To the resulting stirred solution was added iodosylbenzene (3 × 5.5 mg, 3 × 25 μmol, 3 equiv) in three portions every hour. The reaction was monitored by analytical HPLC every hour after each addition: 1 ml of a sample prepared with 100 μl of methanolic solution of 5 mM acetophenone (internal standard) diluted with 5 μl of crude compound and 395 μl of methanol (internal standard). Scanning was performed on a Nucleosil 5C18 150 × 4.6 mm column eluting with 50/50 methanol / water at / min. Nordiazepam ( 2 ), temazepam ( 3 ), and oxazepam ( 4 ) formed were identified by comparison with reference samples (Sigma). Their retention times were 21.9, 16.7 and 13.3 minutes, respectively. 6-chloro-1-methyl-4-phenyl-1H-quinazolin-2-one ( 5 ) and 6-chloro-4-phenyl-1H-quinazolin-2-one ( 6 ) eluting at 25.1 and 20.5 minutes, respectively. ) Is isolated and analyzed separately and ¹ H NMR and MS data are reported in Felix et al. (1968) J. Heterocycl. Chem. 5, 731 and Sulkowski et al. (1962) J. Org. Chem. 27, 4424].

The yield of the product obtained from the reaction is shown in the table below.

PhIO (equivalent) Product Obtained: Yield (%) One 2 3 4 5 6 One 31 19 12 3 4 0 2 5 17 6 7 11 4 3 One 9 2 5 10 3

The results from the reactions performed in 1: 1 CH ₂ Cl ₂ / CH ₃ CN, representative solvent conditions of the prior art, are shown in the table below.

PhIO (equivalent) Product obtained: yield (%) One 2 3 One 86 One One 2 83 One 2 3 79 One 2

Comparison of the two sets of results shows that the conversion of diazepam is better by using a solvent such as trifluorotoluene in place of typical dichloromethane / acetonitrile, and more products are formed in significantly better yields.

Example 2

Diazepam by 30% aqueous hydrogen peroxide solution catalyzed with tetrakis (pentafluorophenyl) porphyrin manganese (II) chloride in trifluorotoluene ( One Oxidation of

This reaction is 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) -quinazolinone ( 5 ), diazepam N-jade Seed ( 7 ) and nordiazepam N-oxide ( 8 ) were formed.

5,10,15,20-tetrakis (pentafluorophenyl) -21H, 23H-porphyrin manganese (III) chloride (0.25 μmol, 1 mol%) and 1,1,1,3,3 in trifluorotoluene 10 μl of a 25 mM solution of, 3-hexafluoro-2-propanol (1.1 μl, 10.4 μmol, 0.4 equiv) was added to 240 μl of a solution containing 25 μmol of diazepam ( 1 ) in trifluorotoluene. To the resulting stirred solution, 30% hydrogen peroxide (2.6 μl, 25 μmol, 1 equivalent), imidazole (6.5 μl, 6.5 μmol, 0.25 equivalent) and ammonium acetate (25 μl, 25 μmol, 1 equivalent) in 1 M aqueous solution An aqueous solution of was added dropwise over 2 hours. 30 minutes after addition, the reaction was monitored by analytical HPLC in the same manner as in Example 1. One equivalent of 30% hydrogen peroxide (2.6 μl, 25 μmol, 1 equiv) was then added every 10 minutes until 15 equivalents of oxidant was used. The reaction was monitored after the addition of 2, 5, 10 and 15 equivalents of hydrogen peroxide. Diazepam N-oxide ( 7 ) (retention time 8.4 minutes) and Nordiazepam N-oxide ( 8 ) (6.7 minutes) were identified by comparison with samples prepared from the reaction of diazepam and nordiazepam with m-chloroperbenzoic acid. (Compare Ebel et al. (1979) Arzneim.-Forsch. 29, 1317).

The yield of the product obtained from the reaction is shown in the table below.

H ₂ O ₂ (equivalent) Product obtained: yield (%) One 2 3 4 5 7 8 One 71 4 7 0 One 5 0 2 58 8 10 One One 9 One 5 41 10 13 One 3 10 One 10 26 10 12 2 5 8 2 15 19 10 14 2 8 6 2

The results from similar reactions performed in 1: 1 CH ₂ Cl ₂ / CH ₃ CN instead of trifluorotoluene and hexafluoroisopropanol as cosolvents are shown in the table below.

H ₂ O ₂ (equivalent) Product obtained: yield (%) One 2 3 7 One 84 One One 2 2 77 2 One 3 5 74 5 3 6 10 74 6 7 7 15 74 5 9 7

When the oxidation reaction with hydrogen peroxide in the above system was carried out, better diazepam conversion and product yield were obtained by trifluorotoluene in the presence of hexafluoroisopropanol instead of dichloromethane / acetonitrile solvent system.

Preliminary results from further ongoing experiments confirm the effect of the process of the invention on the oxidation reaction of compounds with significantly different structural parameters.

Claims (18)

A method of oxidation of a selected organic compound, comprising reacting the selected organic compound with a reaction medium comprising metal porphyrin and an oxidant in an inert aprotic solvent to recover and identify the desired reaction product. The method of claim 1 wherein the inert aprotic solvent is a polyhalogenated aliphatic or aromatic solvent. The method of claim 2 wherein the inert aprotic solvent is a polyhalogenated aromatic solvent. The method of claim 3 wherein the solvent is trifluorotoluene. The method of claim 1, wherein the reaction medium comprises an inert aprotic main solvent and a cosolvent capable of increasing solubility in the reaction medium of the selected organic compound. The method of claim 5, wherein said cosolvent is polar and extremely nucleophilic solvent. The method of claim 6, wherein the cosolvent is 2,2,2-trifluoroethanol or 1,1,1,3,3,3-hexafluoro-propan-2-ol. The method of claim 5 wherein the concentration of cosolvent is in the range of 1 to 30%. The method of claim 1, wherein the reaction medium comprises an ideal solution. 10. The method of claim 9, wherein the reaction medium comprises a main solvent that is inert aprotic and a cosolvent having the ability to transfer selected organic compounds from one phase to another. The method of claim 10, wherein the cosolvent is hexafluoroisopropanol. 10. The process of claim 9, wherein the reaction medium comprises a second organic phase comprising a metal porphyrin and an organic compound selected from a first aqueous phase and an inert aprotic solvent comprising an oxidizing agent. 13. The method of claim 12, wherein said second phase comprises a cosolvent having the ability to transfer an inert aprotic main solvent and an oxidant from one phase to another. The method of claim 13, wherein the cosolvent is water miscible. The method of claim 13, wherein the cosolvent is 1,1,1,3,3,3-hexafluoro-propan-2-ol. The method of claim 9, comprising introducing a phase transfer catalyst into the reaction medium having the ability to deliver the reactants from one phase to another. The method of claim 16, wherein the phase transfer catalyst is a tetraalkyl ammonium salt. 18. The method of claim 17, wherein the tetraalkyl ammonium salt is dodecyltrimethyl-ammonium bromide.