WO2000050381A1

WO2000050381A1 - Method for preparing 2-aminobenzophenone derivatives

Info

Publication number: WO2000050381A1
Application number: PCT/FR2000/000443
Authority: WO
Inventors: Jean-Francis Spindler; Tuan-Phat Dang; Geneviève Padilla; Jean-Roger Desmurs
Original assignee: Rhodia Chimie
Priority date: 1999-02-22
Filing date: 2000-02-22
Publication date: 2000-08-31
Also published as: FR2789990A1; AU2812500A; FR2789990B1

Abstract

The invention concerns a method for preparing 2-aminobenzophenone derivatives as well as the process intermediates, namely 2-nitrobenzophenone derivatives. The invention first concerns a method for preparing a 2-nitrobenzophenone derivative according to a selective nitration method in position 2 of a benzophenone derivative characterised in that it consists in reacting a benzophenone derivative, with a NO2+ source in the presence or in the absence of an inert organic solvent. The invention also concerns a method for preparing a 2-aminobenzophenone derivative characterised in that it consists: in a first step in performing a benzoylation reaction on a benzene compound, in the presence of a Friedel-Crafts catalyst; in a second step in performing nitration of the resulting benzophenone derivative in position 2 as described above; in a third step, in performing a catalytic hydrogenation of the nitro group into an amino group.

Description

PROCESS FOR THE PREPARATION OF 2-AMINORFNZOPHENONE DERIVATIVES.

The present invention relates to a process for the preparation of 2-aminobenzophenone derivatives. The invention also relates to the preparation of manufacturing intermediates, namely derivatives of 2-nitrobenzophenones.

Aminobenzophenone derivatives, in particular 2-amino-4,5,3 ', 4'-tetramethoxybenzophenone are products of interest as intermediate products for the manufacture of quinolines or quinazolines which have anti-inflammatory properties useful in the treatment of pain and rheumatism.

A synthetic route of 2-amino-4,5,3 ', 4'-tetramethoxybenzophenone is described in EP-A-0 839801. It consists in reacting N- (3,4-dimethoxyphenyDacetamide with acid 3 , 4-dimethoxybenzoic acid, in the presence of phosphorus oxychloride and stannic chloride then in hydrolyzing the 2-acetylamino-4,5,3 ' _I 4'-tetramethoxybenzophenone obtained.

This process requires protection of the amino function in acetyl form. In addition, it involves reagents, phosphorus oxychloride and stannic chloride which are expensive products and difficult to handle.

Furthermore, there is also the problem of the treatment of effluents due to the presence of tin which is known for its ecotoxicity.

The objective of the present invention is to provide a process more easily implemented on an industrial scale.

A first object of the invention is a process for the preparation of a 2-nitrobenzophenone derivative corresponding to formula (VI):

in which the benzene rings can be substituted, characterized in that it consists in reacting a benzophenone derivative corresponding to the general formula (IV):

in which the benzene rings can be substituted, with a source of Nθ2 ⁺ , in the presence or in the absence of an inert organic solvent.

Another subject of the invention is a process for the preparation of a 2-aminobenzophenone derivative corresponding to formula (I):

in which the benzene rings can be substituted, characterized in that it consists in carrying out the reduction by hydrogen of the nitro group of the compound of formula (VI), in the presence of a hydrogenation catalyst or using preferably a chemical reducing agent, sodium thiosulfate or hydrogen sulfide.

A preferred variant of the process of the invention and which constitutes another subject of the invention is a process for the preparation of a 2-aminobenzophenone derivative corresponding to formula (I):

in which the benzene rings can be substituted, characterized in that it consists:

in a first step, to react in the presence of a Friedel-Crafts catalyst, a benzene compound of formula (II):

in which the benzene ring can be substituted, with a compound of formula (III):

in which the benzene ring can be substituted and Y represents a halogen atom; a hydroxyl group; an R'-O- group; a group R'-COO- in which groups, R 'represents an alkyl group having from 1 to 4 carbon atoms or a phenyl group,

in a second step to carry out the nitration of the benzophenone derivative obtained in position 2, as previously described,

- In a third step, to carry out the reduction by hydrogen of the nitro group to the amino group, in the presence of a hydrogenation catalyst based on a metal from group VIII of the periodic table.

The process of the invention is much more economical because of the choice of raw materials and less polluting. In accordance with the process of the invention, a benzophenone derivative of formula (IV) is prepared by reacting a benzene compound corresponding to formula (II) with a compound of formula (III).

More specifically, the compounds of formula (II) or (III) are benzene compounds which can relate to the aromatic ring, possibly from one to four substituents symbolized by R.

As compounds preferably used in the process of the invention, use is made of benzene compounds carrying at least one electro-donor group.

The term "electron-donating group", a group as defined by HC BROWN in the work by Jerry March - Advanced Organic Chemistry, ^4th Edition, John Wiley and Sons, 1992, Chapter 9, pp. 273 - 292.

The electron donor group can be at any position of the aromatic cycle but it is preferably in position 3 and / or 4 relative to the COY group in the compound of formula (III). The preferred starting compounds of formula (II) comprise at least two electron donor groups in position 1 and 2 and those of formula (III) two electron donor groups in position 3 and 4.

As more specific examples of electron-donor groups, there may be mentioned in particular: a linear or branched alkyl group having from 1 to 6 carbon atoms, preferably from 1 to 4 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, - a linear or branched haloalkyl group, having from 1 to 6 carbon atoms, and from 1 to 13 halogen atoms, (preferably a fluorine atom) and preferably from 1 to 4 carbon atoms and 3 to 9 halogen atoms,

a cycloalkyl group having 3 to 8 carbon atoms, preferably a cyclohexyl group,

a linear or branched alkenyl group having from 2 to 6 carbon atoms, preferably from 2 to 4 carbon atoms, such as vinyl, allyl,

a linear or branched alkoxy group having from 1 to 6 carbon atoms, preferably from 1 to 4 carbon atoms such as the methoxy, ethoxy, propoxy, isopropoxy, butoxy radicals, a 2-oxy propionic group,

a haloalkoxy, alkoxylalkyl, alkenyloxy, cycloalkylcarbonyloxy, alkoxycarbonyloxy, alkoxycarbonylalkyoxy group having from 1 to 6 carbon atoms, preferably from 1 to 4 carbon atoms,

- a phenoxy group, - a benzyl group,

- a phenyl group,

- a hydroxyl group,

- an amino or aminocarbonyloxy group substituted by one or two alkyl groups having from 1 to 6 carbon atoms, - an alkylamide group having from 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms. Two R groups placed on two vicinal carbon atoms can form together and with the carbon atoms which carry them, a ring having 5 to 7 atoms, possibly including another heteroatom. When the number of R groups is greater than or equal to 2, two R groups and the 2 successive atoms of the aromatic ring can be linked together by an alkylene, alkenylene or alkenylidene group having from 2 to 4 carbon atoms to form a saturated heterocycle , unsaturated or aromatic having 5 to 7 carbon atoms. One or more carbon atoms can be replaced by another heteroatom, preferably oxygen or sulfur. Thus, the R groups can represent a methylenedioxy or ethylenedioxy group or a methylenedithio or ethylenedithio group.

The compounds preferably used correspond to the formulas (II) and (III) in which the electron-donor groups are alkoxy groups having from 1 to 4 carbon atoms or alkyleneoxy groups preferably, a methylenedioxy, ethylenedioxy and Y group represents a halogen atom, preferably a chlorine atom. As preferred examples of compounds corresponding to formula (II), there may be mentioned:

- 1,2-dihydroxybenzene

- 1,2-dimethoxybenzene or veratrole, - 1,2-diethoxybenzene,

- 1,2-diisopropoxybenzene

- 1-hydroxy-2-methoxybenzene,

- 1-methoxy-2-isopropoxybenzene.

As preferred examples of compounds corresponding to formula (III), there may be mentioned:

- veratric acid chloride,

- 3,4-dihydroxybenzoic acid chloride,

- 3-hydroxy-4-methoxybenzoic acid chloride,

- 4-hydroxy-3-methoxybenzoic acid chloride, - 3,4-methylenedioxybenzoic acid chloride.

The compounds of formula (III) in which Y represents a halogen atom, preferably a chlorine atom, are either commercially available or easily accessible to those skilled in the art, from the corresponding acid. Indeed, the preparation of a halide, preferably an acid chloride from the corresponding acid is a method well known to those skilled in the art which can in particular obtain it by reaction of the corresponding acid with a halodehydroxylation agent (COCI2 SOCI2, POCI3) according to the teaching of Jerry MARCH - Advanced Organic Chemistry, 4 ^th edition, John Wiley and Sons, 1992, chapter 10, pp. 437. The reaction is generally carried out at a temperature between 20 and 100 ° C. by mass or in an organic solvent, for example an amide (for example dimethylformamide).

The halodehydroxylation agent is gradually added to the reaction mixture comprising the acid and the hydracid formed during the reaction is eliminated as it is formed.

In accordance with the process of the invention, the benzoylation of the compound (II) is carried out in a first step using the compound of formula (III), in the presence of a catalyst.

A first variant of the invention consists in making use of a homogeneous catalysis by using Friedel-Crafts catalysts of organic or mineral type.

As examples of salts comprising an organic counterion, mention may in particular be made of acetate, propionate, benzoate, methanesulfonate, trifluoromethanesulfonate of metallic or metalloid elements of groups (IIIa), (IVa), (VIII), (llb), (IIIb), (IVb), (Vb) and (Vlb) of the periodic table.

As regards the salts comprising an inorganic counterion, mention may be made of chlorides, bromides, iodides, sulfates, phosphates, nitrates, oxides and similar products of the metallic or metalloid elements of the groups

(lia), (llla), (IVa), (VIII), (llb), (lllb), (IVb), (Vb) and (Vlb) of the periodic table.

In this text, reference is made below to the Periodic Table of Elements published in the Bulletin de la Société Chimique de France, No. 1 (1966).

The salts used in the process of the invention are more particularly those of the elements of group (Ma) of the periodic classification preferably, magnesium; of the group (IIIa) preferably, scandium, ryttrium and the lanthanides; preferably group (IVa), titanium, zirconium; preferably group (VIII), iron; preferably group (llb), zinc; preferably group (IIIb), boron, aluminum, gallium, indium; preferably group (IVb), tin; of the group (Vb) preferably, bismuth; of the group (Vlb) preferably tellurium. Among the inorganic salts, mention may be made of metal halides and preferably magnesium chloride, zirconium chloride, ferric chloride, zinc chloride, aluminum chloride, aluminum bromide, gallium chloride, indium chloride, stannic chloride, bismuth chloride, boron trifluoride. It is possible to generate a halide in situ and therefore, use any compound of the above elements insofar as it is associated with a halogen source.

So you can use metal or any form. They can be provided in the form of metal or oxide or in saline form, single or double salt, mineral or organic.

As mentioned above, the above elements can be provided in the form of a metal or in the form of an oxide or a hydroxide. It is possible to use a mineral salt preferably, nitrate, sulfate, oxysulfate, halide, oxyhalide, silicate, carbonate, oxalate or an organic salt preferably, acetylacetonate; alcoholate and even more preferably methylate or ethylate; carboxylate and even more preferably acetate. Mention may in particular be made of ferrous oxide, ferric oxide and gallium oxide.

As far as the halogen source is concerned, any compound capable of providing halogen ions making it possible to generate the metal or metalloid halide in situ can be used.

As examples of halogen sources, halogen may be used in molecular form; to any mineral or organic acid halide, and more particularly aliphatic carboxylic acids; to any metallic or metalloid, mineral or organic salt capable of generating a halogenated form.

As more specific examples, there may be mentioned, among others, chlorine or bromine: hydrochloric acid, hydrobromic acid; acetyl chloride; silicon chloride SiCI, halosilanes such as Mβ3SiCI,

Me ₂ SiCI ₂ , _j MeSiCI ₃ , PhMe ₂ SiCI, phosphorus chlorides PCI ₃ or PCI ₅ , sulfur chloride SCI2., Sulfuryl chloride SO ₂ CI ₂ .

As regards the organic salts, use is preferably made of the rare earth and / or bismuth salts of trifluoromethanesulfonic acid commonly known as "triflic acid".

By "rare earth" is meant the lanthanides having an atomic number from 57 to 71 and yttrium as well as scandium.

Regarding the rare earth triflate used as a catalyst, it is more particularly a rare earth chosen from lanthanides, yttrium scandium and their mixtures, preferably lanthanides such as lanthanum, cerium, praseodymium, neodymium, samarium, europium, gadolinium, terbium, dysprosium, holmium, erbium, thulium, ytterbium and lutetium and their mixtures.

In the process of the invention, the following rare earths are more particularly envisaged: lanthanum, ytterbium, lutetium and / or scandium.

Rare earth triflates are known products which are described in the literature, in particular in US-A-3,615,169. They are generally obtained by reaction of rare earth oxide and trifluoromethanesulfonic acid.

The bismuth salts of triflic acid described in patent application PCT / FR96 / 01488 can also be used in the process of the invention. In the process of the invention, it is possible to use a mass catalyst as mentioned above.

According to another implementation variant, a catalyst can be used in supported form. To this end, the support can be chosen from oxides of metals, such as aluminum, silicon and / or zirconium oxides, clays and more particularly, kaolin, talc or montmorillonite or also among coals optionally activated by a well-known treatment with nitric acid, acetylene black, or resins. The support can be in any form, for example, powder, beads, granules, extrusions, etc.

In the description, the expression “catalyst” will denote both the mass catalyst and the supported catalyst prepared according to techniques known to those skilled in the art. In accordance with the process of the invention, the benzoylation reaction of the compound of formula (II) is carried out.

The process of the invention can be carried out in an organic solvent, for example isopropyl ether, but one of the reagents can also be used as reaction solvent. It is desirable that the solvent is anhydrous.

The ratio between the number of moles of the compound of formula (II) and the number of moles of benzoylating agent [compound of formula (III)] can vary because the substrate can serve as a reaction solvent. Thus, the ratio can range from 1 to 10, preferably from 1 to 4.0. The amount of catalyst used is determined so that the ratio between the number of moles of catalyst and the number of moles of compound of formula (III) is less than 1.0 and preferably varies between 0.001 and 0 , 8, and even more preferably between 0.002 and 0.02.

The temperature at which the benzoylation reaction is carried out depends on the reactivity of the starting substrate and that of the benzoylating agent.

It is between 20 ° C and 200 ° C, preferably between 80 ° C and 120 ° C.

Generally, the reaction is carried out at atmospheric pressure but lower or higher pressures may also be suitable. It is preferred to carry out the reaction under a controlled atmosphere of inert gases such as nitrogen or rare gases, for example argon.

From a practical point of view, use is preferably made of the compound of formula (III), the catalyst and then the compound of formula (II).

After bringing the reactants into contact, the reaction mixture is brought to the desired temperature.

The duration of the reaction is a function of many parameters. Most often, it is from 1 hour to 8 hours. After the benzoylation step of the compound of formula (II), the excess reagent is eliminated and a deactivation treatment of the catalyst is then carried out, either by extraction with water or by addition of a solution of 'a basic agent, preferably ammonia or sodium carbonate or hydrogen carbonate, then filtration.

The amount of water used can vary widely. It preferably represents from 50 to 500% of the weight of the product obtained.

A variant of the invention consists in replacing the water with a basic solution, generally of soda or ammonia having a concentration preferably, between 20 and 30% by weight or of sodium carbonate or hydrogencarbonate having a concentration of 5 at 10% by weight.

The catalyst is separated, preferably by filtration.

At the end of the reaction, the desired product is obtained, namely a benzophenone derivative of formula (IV):

It is recovered according to known techniques, in particular by distillation or by recrystallization from an appropriate solvent optionally in the presence of water, preferably an alcohol, for example methanol, isopropanol or butanol; a ketone, for example methyl ethyl ketone or methyl isobutyl ketone. In the remainder of this text, the compound of formula (IV) will be referred to as

"benzophenone".

Another variant of the process of the invention consists in carrying out the benzoylation of the compound of formula (II), in the presence of a zeolitic catalyst. By "zéoϋthe" is meant a crystallized tectosilicate of natural or synthetic origin, the crystals of which result from the three-dimensional assembly of tetrahedral units of SiO-i, and TO4: T representing a trivalent element such as aluminum, gallium, boron, iron, preferably aluminum.

The aluminosiiicate zeolites are the most common. Zeolites present within the crystal lattice, a system of cavities linked together by channels of a well-defined diameter called pores.

Zeolites can have a network of one-dimensional, two-dimensional or three-dimensional channels. In the process of the invention, use may be made of a natural or synthetic zeolite.

As examples of natural zeolites which may be used, there may be mentioned, for example: chabazite, clinoptilolite, erionite, phillipsite, offerite.

Synthetic zeolites are entirely suitable for implementing the invention.

Examples of synthetic zeolites with a one-dimensional network include, among others, zeolite ZSM-4, zeolite L, zeolite ZSM-12, zeolite ZSM-22, zeolite ZSM-23, zeolite ZSM-48.

By way of examples of zeolites with a two-dimensional network preferably used, mention may be made of mordenite, ferrierite.

With regard to the zeolites with three-dimensional lattice, one can name more particularly, the zeolite β, the zeolite Y, the zeolite X, the zeolite ZSM-5, the zeolite ZSM-11, the offerite.

We preferentially use synthetic zeolites and more particularly zeolites which are in the following forms:

- the mazzite with an Si / Ai molar ratio of 3.4,

- the zeolite L with an Si / Ai molar ratio of 1.5 to 3.5, - the mordenite with an Si / Ai molar ratio of 5 to 100, preferably from 5 to 50,

- the ferrierite with a Si / Ai molar ratio of 3 to 10,

- the offer of Si / Ai molar ratio from 4 to 8.5.

- β zeolites with an Si / Ai molar ratio greater than 8, preferably between 10 and 100, and even more preferably between 12 and 50, - Y zeolites, in particular zeolites obtained after dealumination treatment (for example hydrotreatment, washing with hydrochloric acid or treatment with S1Cl4) and mention may more particularly be made of US-Y zeolites with an Si / Al molar ratio greater than 2, preferably between 4 and 60; the zeolite X of the faujasite type with an Si / Ai molar ratio of 0.7 to 1.5,

- ZSM-5 zeolites or aluminum silicalite with Si / Ai molar ratio from 10 to 500,

- ZSM-11 zeolite with an Si / Ai molar ratio of 5 to 30.

- the mesoporous zeolite of MCM type, more particularly MCM-22 and MCM-41 with an Si / Ai molar ratio of between 10 and 100, preferably between 15 and 40.

Among all these zeolites, use is preferably made in the process of the invention of β, mordenite, or Y zeolites. The zeolites used in the process of the invention are known products described in the literature [cf. Atlas of zeolites structure types by WM Meier and DH Oison published by the Structure Commission of the International Zeolite Association (1978)]. One can use commercially available zeolites or else synthesize them according to the methods described in the literature.

We can refer to the aforementioned Atlas, and more particularly, for the preparation:

- from zeolite L to the publication by Barrer R. M. et al, Z. Kristallogr., 128. pp. 352 (1969)

- from the zeolite ZSM-12, to US patent 3,832,449 and to the article LaPierre et ai, Zeolites 5, pp. 346 (1985),

- from the zeolite ZSM-22, to the publication Kokotailo G.T. et al, Zeolites 5_, pp. 349 (1985), - from the zeolite ZSM-23, to US Pat. No. 4,076,842 and to the article Rohrman A. C. et al, Zeolites 5_, pp. 352 (1985),

- from the zeolite ZSM-48, to the work of Schlenker J. L. et al, Zeolites 5_, pp. 355 (1985),

- β zeolite, to US patent 3,308,069 and to the article Caullet P. et al, Zeolites 12, pp. 240 (1992),

- from mordenite, to the works of Itabashi et al, Zeolites fî, pp. 30 (1986),

- from zeolites X and Y respectively to patents US 2,882,244 and US 3,130,007,

- from the zeolite ZSM-5, to US patent 3,702,886 and to the article Shiralkar V. P. et al, Zeolites â, PP- 363 (1989),

- from the zeolite ZSM-11, to the work of Harrison I. D. et al, Zeolites Z. PP-21 (1987),

- the mesoporous zeolite of MCM type, in the article by Beck et al, J. Am. Chem. Soc. JJ4 (27), pp. 10834-43 (1992). The zeolite constitutes the catalytic phase. It can be used alone or mixed with a mineral matrix. In the description, the term “catalyst” will denote the catalyst produced entirely from a zeolite or from a mixture with a matrix prepared according to techniques known to those skilled in the art.

To this end, the matrix can be chosen from metal oxides, such as aluminum, silicon and / or zirconium oxides, or also from clays and more particularly, kaolin, talc or montmoriilonite.

In the catalyst, the active phase content represents from 5 to 100% of the weight of the catalyst. The catalysts can be in different forms in the process of the invention: powder, shaped products such as granules (for example, extruded or balls), pellets, which are obtained by extrusion, molding, compacting or any other type of known process. In practice, on the industrial level, it is the forms of granules or beads which have the most advantages both in terms of efficiency and in terms of ease of use.

According to the invention, the benzoylation reaction is advantageously carried out in the liquid phase comprising the compound of formula (II) and the compound of formula (III), in the presence of the catalyst.

One of the starting reagents can serve as reaction solvent but it is also possible to use an organic solvent.

An organic solvent is chosen, which is less activated than the starting substrate and which preferably dissolves it. As examples of solvents suitable for the present invention, there may be mentioned in particular aliphatic or aromatic hydrocarbons, halogenated or not, aliphatic, cycloaliphatic or aromatic ether-oxides.

As examples of aliphatic hydrocarbons, there may be mentioned more particularly paraffins such as in particular, hexane, cyclohexane, methylcyclohexane, aromatic hydrocarbons and more particularly aromatic hydrocarbons such as in particular benzene, toluene, xylenes , cumene, petroleum fractions consisting of a mixture of alkylbenzenes, in particular Solvesso®-type fractions.

With regard to aliphatic or aromatic halogenated hydrocarbons, there may be mentioned more particularly, perchlorinated hydrocarbons such as in particular tetrachlorethylene, hexachloroethane; partially chlorinated hydrocarbons such as dichloromethane, 1,2-dichloroethane, dichlorobenzene.

It is also possible to use, as organic solvents, the aliphatic, cycloaliphatic or aromatic ether-oxides and, more particularly, dipropyl ether, diisopropyl ether, dibutyie ether, methyl tert-butyl ether, dimethyl ether ethylene glycol (or glyme), dimethyl ether of diethylene glycol (or diglyme); phenyl oxide; dioxane, tetrahydrofuran (THF). As examples of aprotic, more polar organic solvents which can also be used in the process of the invention, there may be mentioned more particularly nitro compounds such as, for example, nitromethane, nitroethane, 1-nitropropane, 2- nitropropane or their mixtures, nitrobenzene; alphatic or aromatic nitriles such as acetonitrile, propionitrile, benzonitrile, benzyl cyanide; linear or cyclic carboxamides such as N, N-dimethylacetamide (DMAC), N, N-diethylacetamide, dimethylformamide (DMF), diethylformamide or 1-methyl-2-pyrrolidinone (NMP); dimethyl sulfoxide (DMSO); tetramethylenesulfone (sulfolane); hexamethylphosphotriamide (HMPT).

The preferred solvents are: dichloroethane, dichlorobenzene, dimethyl ether of ethylene glycol (or glyme), dimethyl ether of diethylene glycol (or digiyme), dioxane. It is also possible to use a mixture of organic solvents.

Preferably, the starting substrate is used as the reaction solvent.

As mentioned above, the compound of formula (II) is reacted with the compound of formula (III), optionally in the presence of a reaction solvent as defined and in the presence of a zeolitic catalyst.

The ratio between the number of moles of compound of formula (II) and the number of moles of compound of formula (III) can vary because the substrate can serve as a reaction solvent. Thus, the ratio can range from 1 to 10, and is preferably between 0.5 and 4.0. The amount of catalyst which is used in the process of the invention can vary within wide limits.

When the process is carried out batchwise, the catalyst can represent, by weight relative to the compound of formula (II), from 0.01 to 50%, preferably from 5 to 25%. However, if the process is carried out continuously, for example by reacting a mixture of the compound of formula (II) and the compound of formula (III) on a fixed bed of catalyst, these catalyst / compound ratios of formula (II) do not make sense and at a given time, one can have an excess weight of catalyst compared to the starting compound of formula (II).

As regards the quantity of organic solvent used, it is generally chosen such that the ratio between the number of moles of organic solvent and the number of moles of compound of formula (II) varies, preferably, between 0 and 100 and even more preferably between 0 and 50.

The temperature at which the benzoylation reaction is carried out depends on the reactivity of the starting substrate and that of the compound of formula (III).

It is between 20 ° C and 200 ° C, preferably between 80 ° C and 120 ° C. Generally, the reaction is carried out at atmospheric pressure, but lower or higher pressures may also be suitable. We work under autogenous pressure when the reaction temperature is higher than the boiling point of the reactants and / or products.

From a practical point of view, the process can be carried out batchwise or continuously. According to the first variant, there are no constraints with regard to the use of the reagents. They can be entered in any order.

The other variant of the invention consists in carrying out the reaction continuously, in a tubular reactor comprising the solid catalyst placed in a fixed bed.

The compound of formula (II) and the compound of formula (III) can be introduced separately or as a mixture into the reactor.

Said mixture is passed over a catalytic bed comprising at least one zeolite and then the reaction mixture from the catalytic bed is subjected to recirculation on a catalytic bed, in a number of times sufficient to obtain the desired substrate conversion rate.

Benzoylation of a compound of formula (II) on a zeolite catalytic bed with recirculation of the reaction mixture is a technique described in PCT / FR 97/01066 published under the number WO 97/48665 which is incorporated by reference in the present application .

The reaction mixture passes through the catalytic bed, preferably from bottom to top and at its outlet is returned to the reagent mixing zone in order to be recycled a number of times sufficient to obtain the desired conversion rate of the substrate, preferably, greater than 20%, and even more preferably between 50 and 100%. The substrate conversion rate is defined as the ratio between the number of moles of substrate transformed over the number of moles of substrate introduced.

The linear speed of the liquid flow on the catalytic bed advantageously varies between 0.1 and 10 cm / s, preferably between 0.1 and 5 cm / s. The residence time of the material flow on the catalytic bed varies, for example, between 15 min and 10 h, and preferably between 30 min and 5 h.

At the end of the reaction, a liquid phase is recovered comprising the compound of formula (IV) which can be recovered in a conventional manner, by distillation, by draining or by recrystallization from an appropriate solvent, for example water, alcohols or ketones , after prior removal of excess reagents.

According to the process of the invention, the next step is the nitration of the compound of formula (IV).

To this end, said compound is reacted with a source of N0 ₂ ⁺ . Thus, it is possible to start with nitrogen dioxide NO, nitrogen anhydride N2O3, nitrogen peroxide N2O4, nitrogen oxide NO associated with an oxidizing agent such as, for example, nitric acid, nitrogen dioxide or oxygen. In the case where the reagent is gaseous under the reaction conditions, it is bubbled into the medium.

Nitrous acid, nitrosyl sulphate or nitrose or a nitrous salt, preferably an alkali metal salt, and even more preferably sodium associated with an oxidizing agent, preferably acid, may also be used. nitric. It is also possible to use alkyl nitrites associated with an oxidizing agent and more particularly those corresponding to formula (V):

R _a - ONO (V) in said formula (V), R _a represents a linear or branched alkyl group having from 1 to 12 carbon atoms, preferably from 1 to 4 carbon atoms. The amount of NO ₂ ⁺ source is at least equal to the stoichiometric amount of compound of formula (IV). Thus, the ratio between the number of moles of NO ₂ ⁺ source and the number of moles of benzophenone is advantageously between 1.0 and 1.2.

However, it is possible to use a catalytic amount such that the abovementioned ratio is between 0.01 and 0.1 by combining the source of Nθ2 ⁺ with nitric acid.

Use is preferably made of a concentrated nitric acid solution having a preferred concentration of between 70 and 99%.

It is therefore possible to use a concentrated nitric acid at 99%, in the absence of solvent.

The amount of nitric acid is chosen such that the ratio between the number of moles of nitric acid and the number of moles of benzophenone is between 1 and 4, preferably between 2 and 4.

A variant of the process of the invention consists in using a sulfonitric mixture (mixture of nitric acid and sulfuric acid comprising from 50 to 98% by weight of nitric acid). In this case, the reaction can then be carried out in the absence or in the presence of an organic solvent.

In fact, the nitration reaction is advantageously carried out in an organic solvent which is inert under the reaction conditions. An aprotic, polar or apolar organic solvent is used. We choose, preferably, aprotic and polar.

As more specific examples of organic solvents, there may be mentioned aliphatic halogenated hydrocarbons and more particularly, perchlorinated hydrocarbons such as in particular tetrachlorethylene, hexachloroethane; partially chlorinated hydrocarbons such as 1,2-dichloromethane 1,2-dichloroethane.

1,2-dichloromethane is the preferred solvent. As regards the concentration of the benzophenone substrate in the reaction medium, it is preferably between 0.2 and 3 mol / l and preferably between 0.3 and 1.5 mol / l.

The reaction is advantageously carried out at a temperature between -5 ° C and 10 ° C and under an atmosphere of inert gases. From a practical point of view, the benzophenone of formula (IV) and the organic solvent are charged, then when the reaction temperature is reached by cooling, the nitration agent, source Nθ2 ⁺ optionally nitric or sulfonitric acid, is gradually added.

The reaction advantageously lasts between 3 and 10 hours. At the end of the reaction, the desired product corresponding to formula (VI) is obtained essentially in the organic phase:

The compound of formula (VI) is subsequently called "nitro benzophenone". At the end of the reaction, the product is recovered in a conventional manner after neutralization of the residual acid using a conventional basic agent (sodium hydroxide).

The product can be used directly in the next step or purified by draining or by recrystallization from a suitable solvent, for example of the alcohol type. In accordance with the process of the invention, the reduction of the nitro group to the amino group is carried out in the third step.

A reduction can be carried out using a chemical reducing agent such as sodium thiosulfate or hydrogen sulfide.

The reduction is generally carried out in the presence of a stoichiometric quantity of reducing agent and at ambient temperature (most often between 15 and 25 ° C.).

Another reduction method consists in carrying out a hydrogenation in the presence of the conventional hydrogenation catalysts. As preferred catalysts, metals from group VIII of the periodic table are used, preferably noble metals, cobalt or nickel.

Thus, it is possible to use a finely divided noble metal, from group VIII of the periodic table of elements such as platinum, palladium, rhodium, iridium, ruthenium or osmium.

Said metal can be provided in a finely divided form or else deposited on a support. As examples of supports, mention may be made of carbon, acetylene black, silica, alumina, zirconia, chromium oxide, bentonite, etc. The metal can be deposited on the support in metallic form or well in the form of a compound which will be reduced to metal in the presence of hydrogen. Among other things, it is possible to use an oxide of one of the aforementioned noble metals.

The preferred metals are platinum and palladium, preferably deposited on carbon black.

Preferably, the platinum and / or palladium is deposited on a support. Generally, it is deposited at a rate of 0.5% to 5% of the weight of the catalyst.

The amount of hydrogenation catalyst used, expressed by weight of catalyst per weight of compound of formula (VI) can vary, for example, between 0.5 and 20%, preferably between 0.5 and 5%.

Other hydrogenation catalysts which are quite suitable for the process of the invention are Raney nickel and Raney cobalt.

Commercial forms of Raney nickel are used which can contain the conventional impurities found in this type of catalyst, namely chromium, iron and / or aluminum, without disadvantage.

In this case, the amount of hydrogenation catalyst used, expressed by weight of catalyst per weight of compound of formula (VI) can vary, for example, between 1 and 10%, preferably between 3 and 6%.

The catalyst can be used in the form of a powder, pellets or else granules.

The process of the invention is carried out at a temperature chosen from a temperature range from 10 ° C to 120 ° C and chosen more particularly between 20 ° C and 80 ° C.

The reaction takes place under hydrogen pressure ranging from a pressure slightly higher than atmospheric pressure to a pressure of several tens of bars. Advantageously, the hydrogen pressure varies between 1 and 50 bars and more preferably between 3 and 10 bar. The reaction is continued until the consumption of hydrogen is stopped.

The hydrogenation reaction is carried out in the liquid phase. An organic solvent is therefore used. An organic solvent is chosen, which is less activated than the starting substrate and which preferably dissolves it.

An inert solvent can be used under the conditions of the reaction of the invention. Thus, it is possible to use saturated aliphatic or cycloaliphatic hydrocarbons such as hexane or cyclohexane, or aromatic hydrocarbons such as benzene, toluene, xylenes; halogenated aliphatic or aromatic hydrocarbons such as dichloromethane, chlorobenzene; alcohols such as methanol, ethanol, propanol, cyclohexanol; esters such as ethyl acetate, butyl acetate; polyol esters or ethers such as tetraethylene glycol diacetate; ethers such as ethylene glycol dimethyl ether (or glyme), or diethylene glycol dimethyl ether (or diglyme).

A mixture of these solvents can be used.

The preferred solvents are methanol, ethanol, dichloromethane and their mixtures. The concentration by weight of the benzophenone entered by volume of solvent is between 10% and 75% and preferably between 15% and 50%.

In practice, the process according to the invention can be carried out by introducing the nitrated benzophenone, the catalyst and the solvent into an inert autoclave, then, after the usual purges, by feeding the autoclave with an adequate hydrogen pressure. ; the contents of the autoclave are then brought under stirring to the appropriate temperature until absorption ceases. The pressure in the autoclave can be kept constant for the duration of the reaction by virtue of a reserve of gaseous mixture, which supplies it at the selected pressure. At the end of the reaction, the autoclave is cooled and degassed. The reaction mixture is recovered and the catalyst separated according to conventional solid / liquid separation techniques.

The expected compound of formula (I) is obtained.

One recovers it in a conventional manner. For example, the hydrogenation catalyst can be separated by filtration and then the organic solvent is distilled.

The compound of formula (I) can be recrystallized from a suitable solvent or mixture of solvents, for example water / ethanol and then dried by example under reduced pressure in 10 and 15 mm of mercury. The crude product can also be purified by draining.

The process of the invention is particularly well suited to the preparation of 2-amino-4,5,3 ', 4'-tetramethoxybenzophenone which is illustrated in the example which follows.

This example is given by way of illustration and without limitation. In the examples, the following compounds are defined by the formulas (I) to (IV), (VI): - (I): 2-amino-4, 5, 3 ', 4'-tetramethoxybenzophenone.

- (II): veratrole

- (III): 3,4-dimethoxybenzoyl chloride

- (IV): 3, 3 ', 4, 4'-tetramethoxybenzophenone.

- (VI): 2-nitro-4, 5, 3 ', 4'-tetramethoxybenzophenone.

Example 1

1 - Benzoylation reaction

The acid chloride (III) (12.03 g; 58.8 mmol), iron chloride (0.195 g; 0.186 mmol) and then the veratrole (II) (17.1 g; 123 mmol) are charged to the reactor. ). The mixture is heated with stirring for 3 hours at 120 ° C.

At the end of the reaction, the reaction mixture is cooled to 80 ° C. and isopropanol is added (35 ml for 58.8 mmol of compound (III)).

Benzophenone (IV) is recovered by filtration at 15 ° C from the isopropyl suspension. The isolated solid is dried at 80 ° C. under 15 mm of mercury to constant weight.

The isolated yield of benzophenone (IV) is 87%.

The melting point is 143.5 ° C.

The purity of the benzophenone (IV) is 99.6% by weight. z - Nitration reaction

Benzophenone (IV) (5.01 g; 16.6 mmol) and 1,2-dichloroethane (48.7 g per 16.6 mmol of (IV)) are charged to the reactor. The mixture is cooled with stirring to -5 ° C.

Sodium nitrite (27 mg) and 98% sulfuric acid (120 mg) are added to the medium with stirring at -5 ° C.

Then poured, in 30 minutes, nitric acid (2 g; 31, 6 mmol) while cooling to -5 ° C. At the end of the reaction, the reaction mixture is poured into 70 g of water at 5 ° C.

After decantation, the organic phase is recovered and then washed to a pH of 8 using a solution of potassium hydrogen carbonate.

After evaporation of the 1,2 dichloroethane, the crude nitro benzophenone (VI) is collected with a purity of 95% by weight.

The isolated yield is 85%.

3 - Reduction reaction

11 g of 95% ethanol, Raney 50 nickel (0.3 g), dichloromethane (12.6 g) and crude benzophenone (VI) (2 g; 5.47 mmol) are loaded into the reactor. .

The reactor is placed under absolute hydrogen pressure (excess hydrogen) of 760 mm of mercury and the reaction mixture is heated at 50 ° C for 4 hours.

At the end of the reaction, the catalyst is separated by filtration. The crude aminobenzophenone (I) is obtained after evaporation of the solvents.

The titer of the crude product recovered is 95% by weight.

The isolated yield is 86%.

Claims

1 - Process for the preparation of a 2-nitrobenzophenone derivative corresponding to formula (VI):

in which the benzene rings can be substituted, with a source of NO2 "^" , in the presence or in the absence of an inert organic solvent.

2 - Process according to claim 1 characterized in that the source of NO ₂ ⁺ is nitrogen dioxide O2, nitrogen anhydride N2O3, nitrogen peroxide

N2O4, nitrogen oxide NO associated with an oxidizing agent such as nitric acid, nitrogen dioxide or oxygen.

3 - Process according to claim 1 characterized in that the source of NU2 ⁺ is nitrous acid, a nitrosyl sulfate or nitrose or a nitrous salt, preferably an alkali metal salt, and even more preferably sodium , an alkyl nitrite: said source being associated with an oxidizing agent, preferably nitric acid.

4 - Method according to one of claims 2 and 3 characterized in that the amount of Nθ2 ⁺ source is such that the ratio between the number of moles of NO ₂ ⁺ source and the number of moles of benzophenone is between 1, 0 and 1.2. 5 - Method according to one of claims 2 and 3 characterized in that the amount of Nθ2 ⁺ is such that ie ratio between the number of moles of Nθ2 ⁺ source and the number of moles of benzophenone is between 0.01 and 0.1.

6 - Process according to claim 1 characterized in that the source of NU2 ⁺ is nitric acid or a sulfonitric mixture.

7 - A method according to claim 6 characterized in that the amount of nitric acid is chosen such that the ratio between the number of moles of nitric acid and the number of moles of benzophenone is between 1 and 4, preferably, between 2 and 4.

8 - Method according to one of claims 1 to 7 characterized in that the nitration reaction takes place in in an organic solvent, preferably aprotic and polar, and more preferably an aliphatic or aromatic halogenated hydrocarbon.

9 - Method according to one of claims 1 to 8 characterized in that the nitration reaction is carried out at a temperature between - 5 ° C and 10 ° C.

10 - Process according to claim 1 characterized in that the compound of formula (IV) is obtained by reacting in the presence of an effective amount of a benzoylation catalyst, a benzene compound of formula (II):

in which the benzene ring can be substituted, with a compound of formula (III):

in which the benzene ring can be substituted and Y represents a halogen atom; a hydroxyl group; an R'-O- group; a group R'-COO- in which groups, R 'represents an alkyl group having from 1 to 4 carbon atoms or a phenyl group. 11 - Method according to claim 10 characterized in that the compounds of formula (II) and (III) can be carriers on their aromatic cycle of 1 to 4 electron donor groups R.

12 - Method according to one of claims 10 and 11 characterized in that the electro-donor group (s) are chosen from:

a linear or branched alkyl group having from 1 to 6 carbon atoms, preferably from 1 to 4 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, - a linear or branched haloalkyl group, having from 1 to 6 carbon atoms, and from 1 to 13 halogen atoms, (preferably a fluorine atom) and preferably from 1 to 4 carbon atoms and 3 to 9 atoms halogen,

a cycloalkyl group having from 3 to 8 carbon atoms, preferably a cyclohexyl group, a linear or branched alkenyl group having from 2 to 6 carbon atoms, preferably from 2 to 4 carbon atoms, such as vinyl, allyle,

- a linear or branched alkoxy group having from 1 to 6 carbon atoms, preferably from 1 to 4 carbon atoms such as the methoxy, ethoxy, propoxy, isopropoxy, butoxy radicals, a 2-oxy propionic group, - a haloalkoxy group , alkoxylalkyle, alkenyloxy, cycloaikylcarbonyloxy, alkoxycarbonyloxy, alkoxycarbonylalkyoxy having from 1 to 6 carbon atoms, preferably from 1 to 4 carbon atoms,

- a phenoxy group,

- a benzyl group, - a phenyl group,

- a hydroxyl group,

an amino or aminocarbonyloxy group substituted by one or two alkyl groups having from 1 to 6 carbon atoms,

an alkylamide group having from 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms.

13 - Process according to claim 12 characterized in that two R groups and the 2 successive atoms of the aromatic ring can be linked together by an alkylene, alkenylene or alkenylidene group having from 2 to 4 carbon atoms to form a saturated heterocycle, unsaturated or aromatic having 5 to 7 carbon atoms, preferably a methylenedioxy or ethylenedioxy group or a methylenedithio or ethylenedithio group. 14 - Method according to one of claims 10 to 13 characterized in that the compounds used correspond to formula (II) and (III) in which the electron donor groups are alkoxy groups having from 1 to 4 atoms carbon or alkyleneoxy groups preferably, a methylenedioxy group, ethylenedioxy and Y represents a halogen atom, preferably a chlorine atom.

15 - Method according to one of claims 10 to 14 characterized in that the compound of formula (II) is chosen from: - 1, 2-dihydroxybenzene

- 1, 2-dimethoxybenzene or veratrole,

- 1, 2-diethoxybenzene,

- 1,2-diisopropoxybenzene

- 1-hydroxy-2-methoxybenzene, - 1-methoxy-2-isopropoxybenzene.

- and the compound of formula (III) is chosen from:

- veratric acid chloride,

- 3,4-dihydroxybenzoic acid chloride,

- 3-hydroxy-4-methoxybenzoic acid chloride, - 4-hydroxy-3-methoxybenzoic acid chloride,

- 3,4-methylenedioxybenzoic acid chloride.

16 - Method according to one of claims 10 to 15 characterized in that the compound of formula (III) in which Y is a halogen atom, preferably a chlorine atom is obtained by reaction of the corresponding acid with a halodehydroxylation agent (COCI ₂ SOCI ₂ , POCI3).

17 - Method according to one of claims 10 to 16 characterized in that according to the first step, reacting the compound of formula (II) and the compound of formula (III), in the presence of a Friedel catalyst- Crafts.

18 - Process according to claim 17 characterized in that the catalyst is a salt comprising an organic counterion, preferably acetate, propionate, benzoate, methanesulfonate, trifluoromethanesulfonate of the metallic or metalloid elements of the groups ( llla), (IVa), (Vlll), (llb), (lllb), (IVb), (Vb) and (Vlb) of the Periodic Table of the Elements, preferably a rare earth or bismuth trifluoromethanesulfonate. 19 - Process according to claim 17 characterized in that the catalyst is a salt comprising an inorganic counterion, preferably chloride, bromide, iodide, sulfate, oxide and analogous products of the metallic or metalloid elements of the groups (IIa) , (llla), (IVa), (Vlll), (llb), (lllb), (IVb), (Vb) and (Vlb) of the Periodic Table of the Elements.

20 - Process according to claim 10 characterized in that the catalyst is chosen from metal halides and preferably magnesium chloride, aluminum chloride, aluminum bromide, ferric chloride, stannic chloride, trifluoride boron.

21 - Method according to one of claims 19 and 20 characterized in that the catalyst is generated in situ by using any metallic or metalloid compound associated with a halogen source.

22 - Method according to one of claims 17 to 21 characterized in that the catalyst is in supported form.

23 - Process according to claim 10 characterized in that the catalyst is a zeolite.

24 - Process according to claim 23 characterized in that the zeolite is a β, Y zeolite or a mordenite in acid form.

25 - Method according to one of claims 10 to 24 characterized in that the temperature at which the benzoylation reaction is carried out is between 20 ° C and 200 ° C, preferably between 80 ° C and 120 ° C .

26 - Process for the preparation of a 2-aminobenzophenone derivative corresponding to formula (I):

in which the benzene rings can be substituted, characterized in that it consists in carrying out the reduction by hydrogen of the nitro group of the compound of formula (VI), in the presence of a catalyst hydrogenation or preferably using a chemical reducing agent, sodium thiosulfate or hydrogen sulfide.

27 - A method according to claim 26 characterized in that one carries out the hydrogenation of nitro benzophenone, in the presence of a catalyst based on a metal from group Vlll of the periodic table, preferably a noble metal, cobalt or nickel.

28 - Process according to claim 26 characterized in that the hydrogenation catalyst is Raney nickel.

29 - Method according to one of claims 26 to 28 characterized in that the temperature at which the hydrogenation reaction is carried out is chosen between 10 ° C and 120 ° C, preferably between 20 ° C and 80 ° C.

30 - Method according to one of claims 26 to 29 characterized in that the hydrogenation is carried out in the liquid phase, in the presence or not of an organic solvent.

31 - Method according to one of claims 27 to 30 characterized in that one recovers the compound of formula (I) obtained according to conventional separation techniques.

32 - Process for the preparation of a 2-aminobenzophenone derivative corresponding to formula (I):

in which the benzene ring can be substituted, with a compound of formula (III):

in a second step to carry out the nitration of the benzophenone derivative obtained in position 2, as previously described in one of claims 1 to 9,

in a third step, to carry out the reduction by hydrogen of the nitro group to the amino group, in the presence of a hydrogenation catalyst based on a metal from group Vlll of the periodic table.

33 - Use of the process described in one of claims 1 to 32 for the preparation of 2-amino-4,5,3 ', 4'-tetramethoxybenzophenone.