AU776140B2 - Process for catalyzing the oxidation of organic compounds - Google Patents

Description

WO 01/10797 PCTIEP00/07726 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 monooxygenases, 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 metalloporphyrin, a co-oxidizing reagent, and a solvent. The solvent is generally a CH 3

CN/CH

2 C1 2 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.

la Accordingly, a first aspect of the present invention provides a process for the oxidation of a benzodiazepine derivative, said process comprising reacting the benzodiazepine derivative to be oxidized with a reaction medium comprising a metalloporphyrin and an oxidizing agent in a polyhalogenated aromatic solvent, and recovering and identifying the desired reaction products.

A second aspect of the present invention provides a benzodiazepine derivative when oxidized according to the process of the first aspect of the present invention defined above.

[R:\LIBA]6568.ac:NJC WO 01/10791 pCT/EPOO/07726 -2- 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 viva. 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 prepar-ation 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 identiflring 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 anmines can be readily converted to their corresponding hydroxylanines, 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 metalloporphyrincatalyzed oxidations according to this invention. Examples include labile C-H bonds, such as WO 01/10797 PCT/EP00/07726 -3those in benzylic positions or C-H bonds wherein the carbon atom is adjacent to a heteroatom 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 metalloporphyrin-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 metalloporphyrin, 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 metalloporphyrins are described in international patent application WO 96/08455.

The term "metalloporphyrin". as used herein, refers to porphyrin compounds of formula WO 01/10797 PCTIEPOO/07726 -4- R3 R2 R2 R1 R6 R4 NR7 R1 R1 R R1- 3 N N R2 R1 l R1 R2 R11 R8 R1iR R2 R2 R3 wherein: Ri, R2 and R3 independently represent hydrogen or an eleclron-withdrawing group such as Cl, F, Br, SO 3 Na, or the like, R4, R5, R6, R7, R8, R9, RIO and RI I independently represent hydrogen or an electron-wvithdrawing group such as Cl, F, Br, N0 2 CN, SO 3 Na or the like, R12 is Cl, acetate or the like, M is selected from the group consisting of iron, manganese, chromium, ruthenium, cobalt, copper and nickel.

Preferred metalloporphyrins include tetrakis(pentafluoro-phenyl)porphyrin Mn(lfl) chloride, herein abbreviated as Mn(TPFPP)C1, which is the compound of formula (I) above wherein M is manganese, RI, R2 and R3 are fluorine, R4, R5, R6, R7, R8, R9, RIO and R 11 are hydrogen, and RI12 is chlorine.

Prefer-red metalloporphyrins also include: tetrakis(pentafluoro-phenyl)porphyrin Fe chloride, abbreviated as Fe(TPFPP)Cl, which is the compound of formula above wherein M is iron, RI, R2 and R3 are fluorine, R4, R6, R7, R8, R9, RIO0 and R 11 are hydrogen, and R 12 is chlorine; tetrakis(2,6-dichiorophenyl)porphyrin Mn chloride, abbreviated as Mn(TDCPP)CI, which WO 01/10797 PCT/EP00/07726 is the compound of formula above wherein M is manganese, RI is chloride, R2, R3, R4, R5, R6, R7, R8, R9, RIO and R11 are hydrogen, and R12 is chlorine; tetrakis(2,6-dichlorophenyl)porphyrin Fe chloride, abbreviated as Fe(TDCPP)Cl, which is the compound of formula above wherein M is iron, RI is chloride, R2, R3, R4, R5, R6, R7, R8, R9, RIO and RI I1 are hydrogen, and R12 is chlorine; tetrakis(2,6-dichlorophenyl)-octachloroporphyrin chloride Fe, abbreviated as Fe(TDCPC 8 lP)CI, which is the compound of formula above wherein M is iron, Ri is chloride, R2 and R3 are hydrogen, R4, R5, R6, R7, R8, R9, RO1 and R11 are chloride, and R12 is chlorine; the compound Mn((C1 2 Ph) 4

(NO

2 )P)C1, of formula above wherein M is manganese, RI is chloride, R4 is N02, R2, R3, R5, R6, R7, R8, R9, RIO, and R11 are hydrogen, and R12 is chlorine; the compound Mn((Cl 2 Ph) 4

(NO

2 2 P)CI, of formula above wherein M is manganese, RI is chloride, R5 and R6 are NO 2 R2, R3, R4, R7, R8, R9, RI 0 and R 11 are hydrogen, and R12 is chlorine.

The amount of the metalloporphyrin 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 metalloporphyrincatalyzed 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- WO 01/10797 PCT/EP00/07726 -6chloroperbenzoic 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, Pereira, M.M. J. Mol. Catal. A: Chem. 1996, 113,209.

Solvent The metalloporphyrin-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 the organic compound of interest) and the metalloporphyrin.

Examples of the main solvent include, but are not limited to polyhalogenated aliphatic solvents such as 1,1,2-trichloro-1,2,2-trifluoroethane and the like or polyhalogenated WO 01/10797 PCT/IEP00/07726 -7aromatic 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 metalloporphyrin. 2,2,2-Trifluoroethanol and, particularly, 1,1,1,3,3,3-hexafluoropropan-2-ol (also called hexafluoroisopropanol or HFIP) are representative examples of cosolvents 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 WO 01/10797 PCT/EP00/07726 -8with 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 cosolvent 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 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 dodecyltrimethyl-ammonium 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 OC and 100 OC, and preferably between about -10 °C and 40 °C.

The skilled person should notc however that sonication can be used to increase the reaction rate. The reaction is then preferably performed in an ultrasound bath cooled to WO 01/10797 PCT/EP00/07726 -9- 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.

FXAMPLES

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 1 H NMR spectra are recorded at 400 MHz on a Brilker 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 D 2 0 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. 43: 2923. The purity of elution fractions is verified before they are gathered and evaporated.

WO 0 1/10797 PCTIEP00107726 The terms "evaporation", "elimination" or "concentration" of the solvents mean, possibly after desiccation on an appropriate dehydrating agent such as Na 2

SO

4 or MgSO 4 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 Oxifintinn nf izapn with indnqylh -n7p-ne (Pub) C-Atgdyzed tby tkijitfmirgk, phenyl)pcirhyi zpigrn I! chlaririp in rifluinrtnhiene During this reaction, nordiazepam temazepam oxazepani 6-chloro-4-phenyl-lmethyl-2-(LH)-quinazolinone and 6 -chloro-4-phenyl-2-(1R)-quinazolinone are formed.

N 0 0 0 Mn(TPFPP)CI

_OH

0- -N PhIO C1 -N C1 PhCF 3 2 3 A O H 4

H~

N 0 N To 240 pLL of a solution containing 25 pznol of diazepanm in trifluorotoluene is added pL of a 25 mM solution of SlOlS, 2 -tetdks(pentafluorophenyl)-2lH,23Hporphyrin manganese (In) chloride (0.25 pmnol, 1 mol%/) in trifluorotoluene. To the resulting stirring solution is added 3 times a portion of iodosylbenzene (3x5.5 mg, 3x25 4mxol, 3 equiv.), one every hour. The reaction is monitored by analytical I{PLC one hour after each addition: a WO 01/10797 PCT/EP00/07726 -11sample, prepared with 5 pL of crude and 100 iL of a 5 mM methanolic solution of acetophenone (internal standard) diluted with 395 pL of methanol, is injected into a Nucleosil 5C18 150x4.6 mm column eluting with 50/50 methanol/water at 1 mL/min during minutes. Nordiazepam temazepam oxazepam formed are identified by comparison with authentic samples (Sigma). Their retention times are respectively 21.9, 16.7 and 13.3 min. 6-Chloro-1-methyl-4-phenyl- 1H-quinazolin-2-one and 6-chloro-4-phenyl- 1H-quinazolin-2-one respectively eluting at 25.1 and 20.5 min, are identified in a separate run by isolation and comparison of 1H NMR and MS data with Felix et al (1968) J.

Heterocycl. Chem. 5, 731 and Sulkowski et al (1962) J. Org. Chem. 22, 4424.

Yields of products from the reaction are shown in the following table: PhlO Products obtained: Yield (equiv.) 1 2 3 4 5 6 1 31 19 12 3 4 0 2 5 17 6 7 11 4 3 1 9 2 5 10 3 Results form the reaction performed in 1:1 CH 2 Cl 2

/CH

3 CN, solvent conditions representative of the state of the art, are shown below: PhlO Products obtained: Yield (equiv.) 1 2 3 1 86 1 1 2 83 1 2 3 79 1 2 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.

WO 01/10797 PCTIEPOO/07726 -12- EXAMPLE 2: Owitintinn nf di7epnm with a 1fO/n aqneniim snlitinn of hy.drngern pDrrnide rt1yriad hy ttetm~ki(pe-,ntfl1nmpen41) rhyrn mnninege (Hi) chloride in triflimrnzonilen Mhs reaction is more efficient in the presence of catalytic amounts of imidazole (Battioni et al (1988) J Am Chem. Soc. 1M11 8462) and ammonium acetate (Thellend et al (1994) J Chemn. Soc., Chem. Comm., 1035).

During th-is reaction, nordiazepamn temazepam oxazepam 6-chloro-4-phenyl-1niethyl-2-(1H)-quinazolinone diazepam N-oxide and nordiazepam N-oxide are formed.

N H202 H0 Nn(TPFPP)CI N- _OH) imid., AcONH 4 C1 N C1 ZHFIP PhCF 3 2 3 N- N N 0 Ci 1 N CN 0 7 8 To 240 pL of a solution containing 25 jpimot of diazepamn in trifluorotoluene is added pLL of a 25 mM solution of 5,lO,lS,20-tetakis(pentafluorophenyl)-21H,23H-porphyrin manganese (Ml) chloride (0.25 umnol, I mol%) and 1,1,1,3,3,3-hexafluoro-2-propano (1.1 WO 01/10797 PCT/EP00/07726 -13pL, 10.4 pmol, 0.4 equiv.) in trifluorotoluene. To the resulting stirring solution is added dropwise an aqueous solution of 30% hydrogen peroxide (2.6 IiL, 25 pmol, 1 equiv.), imidazole (6.5 pL of a 1 M aqueous solution, 6.5 tpmol, 0.25 equiv.) and ammonium acetate pL of a 1 M aqueous solution, 25 1 gmol, 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 piL, 25 nmol, I 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 (6.7 min) are identified by comparison with samples prepared from the reaction of diazepam and nordiazepam with mchloroperbenzoic acid (cf Ebel et al (1979) Arzneim.-Forsch. 1317).

Yields of products from the reaction are shown in the following table: H11202 Products obtained: Yield (equiv.) 1 2 3 4 5 2 8 1 71 4 7 0 1 5 0 2 58 8 10 1 1 9 1 41 10 13 1 3 10 1 26 10 12 2 5 8 2 19 10 14 2 8 6 2 Results form the analogous reaction performed in 1:1 CH 2 CI2/CH 3 CN, instead of trifluorotoluene and hexafluoroisopropanol as co-solvent, are shown below:

H

2 0 2 Products obtained: Yield (equiv.) 1 2 a 2 1 84 1 1 2 2 77 2 1 3 74 5 3 6 74 6 7 7 74 5 9 7 WO 01/10797 PCTIEP00/07726 -14- 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 (15)

1. A process for the oxidation of a benzodiazepine derivative, said process comprising reacting the benzodiazepine derivative to be oxidized with a reaction medium comprising a metalloporphyrin and an oxidizing agent in a polyhalogenated aromatic solvent, and recovering and identifying the desired reaction products.

2. The process according to claim 1, wherein the solvent is trifluorotoluene.

3. The process according to claim 1 or claim 2, wherein said reaction medium comprises the polyhalogenated aromatic solvent and a co-solvent capable of increasing the solubility of the organic compound in the reaction medium.

4. The process according to claim 3, wherein said co-solvent is a polar and poorly nucleophilic solvent. The process according to claim 4, wherein said co-solvent is 2,2,2- trifluoroethanol or 1,1,1,3,3,3-hexafluoro-propan-2-ol.

6. The process according to any one of claims 3 to 5, wherein the concentration 15 of the co-solvent ranges between 1 and

7. The process according to any one of claims 1 to 6, wherein said reaction S. medium comprises a biphasic solution.

8. The process according to claim 7, wherein said reaction medium comprises the polyhalogenated aromatic solvent and a co-solvent having the capability of 20 transferring the organic compound from one phase to the other.

9. The process according to claim 8, wherein the co-solvent is •hexafluoroisopropanol.

10. The process according to claim 7, wherein said reaction medium includes a first aqueous phase comprising the oxidizing agent and a second organic phase *o 25 comprising the organic compound and a metalloporphyrin in the polyhalogenated aromatic solvent. *se

11. The process according to claim 10, wherein said second phase comprises the polyhalogenated aromatic solvent and a co-solvent having the capability of transferring the oxidizing agent from one phase to the other.

12. The process according to claim 11, wherein said co-solvent is water-miscible.

13. The process according to claim 11 or claim 12, wherein said co-solvent is 1,1,1,3,3,3-hexafluoro-propan-2-ol.

14. The process according to claim 7, 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. [R:\LIBA]6568.doc:NJC 16 The process according to claim 14, wherein the phase-transfer catalyst is a tetraalkyl ammonium salt.

16. The process according to claim 15, wherein the tetraalkyl ammonium salt is dodecyl-trimethyl-ammonium bromide.

17. A process for the oxidation of a benzodiazepine derivative, said process comprising reacting the benzodiazepine derivative to be oxidized with a reaction medium comprising a metalloporphyrin and an oxidizing agent in a polyhalogenated aromatic solvent, and recovering and identifying the desired reaction products, substantially as hereinbefore described with reference to anyone of the Examples. 1o 18. A benzodiazepine derivative when oxidized according to the process claimed in any one of claims 1 to 17. Dated 9 July, 2004 Warner-Lambert Company Patent Attorneys for the Applicant/Nominated Person 15 ISPRUSON FERGUSON S *d. [R:\LIBA]6568.doc:NJC