PROCESS FOR THE SAFE OZONOLYSIS OF ORGANIC COMPOUNDS IN

FLAMMABLE SOLVENTS

The invention relates to a process for the safe ozonolysis of unsaturated, organic carbon compounds having one or more olefinic or aromatic double bonds in the molecule in flammable solvents for the preparation of mono- or biscarbonyl or hydroxy compounds.

The ozonolysis of olefins gives carbonyl compounds, such as aldehydes or ketones, or, depending on the working-up conditions, the hemiacetals, acetals or ketals thereof, and hydroxy compounds, which are valuable starting materials in preparative, organic chemistry.

The preparation of carbonyl or hydroxy compounds from organic compounds which have one or more C=C double bonds as a structural element in the molecule by means of a two-stage ozonolysis and reduction process is known. It has been usual to date to use an ozone-carrying oxygen stream having an ozone content of from about 0.5 to 5% by weight in the ozonolysis step (for example EP 0 147 593; WO 02/072518).

However, as has been found the ozonolysis in a flammable solvent, such as for example, methanol, and pure oxygen as the carrier gas is unacceptable on the industrial scale for safety reasons since such mixtures can lead to explosions even when they are handled well below the flashpoint of the solvent. The absence of an explosive atmosphere above the liquid because the vapor pressure of flammable liquid at reaction temperatures is too low is not an adequate criterion for preventing ignition of the system at the interface between liquid and gas phase (e.g.: B. Plewinski and H. Hieronymus in H. Steen: Handbuch des Explosionsschutzes [Handbook of explosion protection], section 5.2 "Heterogene Systeme aus organischen Flϋssigkeiten und Sauerstoff ["Heterogeneous systems of organic liquids and oxygen"]", Wiley-VCH Verlag, Weinheim 2000.).

Proposals for inertization, i.e. reduction of the oxygen content below the limiting oxygen concentration (e.g. European Standard EN 1 127-1 , German version, European Committee for Standardization, Brussels 1997, 6th Professional Association of the Chemical Industry: guidelines for the avoidance of dangers due to explosive atmosphere (Ex-RL) or O. Fuβ, M. Molnarne, A. Schonbucher, W. Schroder; Chemie Ingenieur Technik 74, 6 (2002) 827-832), during the ozonolysis by dilution of

the ozone-containing gas stream with inert gas (N ₂ ) are known from the literature, for example from Organic Process Research & Development, 2003, 7, 155-166.

At the same time, however, the following disadvantages of this procedure are also recognized: • If ozone is produced from oxygen, very large amounts of gas are required on admixing the N ₂ .

• If ozone is produced from air and rendered inert with N ₂ , the cost-efficiency of the ozone production becomes poorer (higher specific energy demand per kg of ozone in conjunction with long reaction times due to the lower ozone concentration).

A further disadvantage arises in the recycling of the exit gas of the ozonolysis since, with such low O ₂ concentrations, the working-up of the gas stream by catalytic combustion is considerably disturbed or fails completely. An increase in volume has a disadvantageous effect on the apparatus costs. On a small scale, processes which use air as feed gas for the O ₃ production are also carried out. For example, the use of air as an oxygen source is described in DE 2713863.

However, this process likewise has some disadvantages. Thus, with the use of air as feed gas, oxides of nitrogen (N ₂ O ₅ , N ₂ O) form in the ozone generator and give rise to considerable problems on a large scale. In processes with recycling of alcoholic solvents, resulting nitric acid and nitric acid esters are enriched and rapidly lead to a safety risk. The formation of nitrous oxide (N ₂ O) is moreover problematic for environmental reasons. In large ozonolysis plants, complicated exit gas purification plants would have to constructed in this case. It was therefore an object of the present invention to provide an improved process for the ozonolysis of unsaturated, organic carbon compounds having one or more olefinic or aromatic double bonds in the molecule in reaction mixtures which can form explosive heterogeneous mixtures in contact with oxygen, which process firstly avoids the safety problems of processes to date and secondly is cost- efficient.

It has now unexpectedly been found that the disadvantages associated with the known processes can be avoided according to the present invention by a simple and economical process in which the oxygen content is reduced not to the limiting oxygen concentration which is known for many solvents but is

defined only for the homogeneous gaseous mixture of fuel and oxygen-containing gas (not complete inertization) but only below the safety concentration at which ignition and flame propagation of the heterogeneous mixture of liquid fuel and oxygen-containing gas are no longer possible at the reaction temperature but the direct use as feed gas for ozone production is still economical. At reaction temperatures, the limiting oxygen concentration for the heterogeneous mixture is substantially higher than the limiting oxygen concentration used to date for a homogeneous mixture of fuel and oxygen- containing gas.

The present invention accordingly relates to an improved process for the safe ozonolysis of unsaturated, organic carbon compounds having one or more olefinic or aromatic double bonds in the molecule in flammable solvents for the preparation of mono- or biscarbonyl or hydroxy compounds, wherein the ozonolysis is carried out with the use of an ozone-carrying inert gas/O ₂ stream, in which the oxygen concentration in the inert gas/C> ₂ stream is above the known limiting oxygen concentration of the homogeneous fuel/gas mixture and below the safety-critical limiting oxygen concentration of the heterogeneous mixture of the liquid fuel and oxygen-containing gas which is dependent on the reaction conditions and at which ignition and flame propagation no longer take place.

By means of the process according to the invention, a multiplicity of very different mono- or biscarbonyl or hydroxy compounds can be prepared.

Examples of these are mono- or biscarbonyl or hydroxy compounds of the general formula I

Q-X-B-R,

I A

I

Z

in which B is either C or S,

Z is either OH or O and A is a single bond where Z is OH and is a double bond where Z is O,

/ Q is hydrogen or the radicals -C- Ri, C-H or -C-ORi or -ORi Il \ Il

Ri being H or being an ester moiety which is derived from chiral or nonchiral, primary, secondary or tertiary alcohols,

X is a straight-chain, branched or cyclic, monovalent or divalent, aliphatic alkyl or alkylene radical having 1 to 50 C atoms or a straight-chain, branched or cyclic alkenyl having 2 to 50 C atoms and one or more double bonds, it being possible for this alkyl or alkylene radical or the alkenyl radical to be substituted by one or more groups which are inert under the reaction conditions; an optionally substituted, straight-chain, branched or cyclic aliphatic alkyl or alkylene radical or alkenyl radical having 2 to 50 C atoms, one or more of the -CH ₂ - or -CH- groups of the alkyl or alkylene or alkenyl chain being replaced by an oxygen atom, nitrogen atom, sulfur atom or -SO ₂ -group; a radical of the formula -(CH ₂ ) _m -O-CO-(CH ₂ )p, it being possible for m to be an integer from 1 to 4 and p an integer from 1 to 6; a phenyl or phenylene radical, it being possible for this phenyl or phenylene radical to be substituted by one or more groups which are inert under the reaction conditions; a monovalent or divalent alkyl arylene or alkylene arylene radical having 7 to 50 C atoms, it being possible for these radicals to be substituted by one or more groups which are inert under the reaction conditions; an optionally substituted heterocycle or an optionally substituted condensed ring system having one or more heteroatoms in the ring or a single bond between two neighboring C atoms, and

R is hydrogen, a d- to C ₂₀ -alkyl radical, -ORi or the radical

Il O or X and R together form a mono- or bicyclic radical which has 4 to 20

C atoms and 0 to 2 heteroatoms and may be mono- or polysubstituted by groups inert under the reaction conditions. Ester moiety which is derived from chiral or nonchiral alcohols is to be understood as meaning esters of primary, secondary or tertiary alcohols. Esters of primary alcohols are preferably derived from methanol, ethanol, butanol, propanol or

hexanol. Esters of secondary or tertiary alcohols are preferably derived from acyclic, monocyclic or bicyclic terpene alcohols or from acyclic, monocyclic or tricyclic sesquiterpene alcohols or di- or triterpene alcohols, which may optionally be substituted. Suitable substituents which are inert under the reaction conditions are, for example, the following groups:

Ci-C ₂ o-alkyl or alkoxy or alkylalkoxy groups, such as, for example, methyl, ethyl, isopropyl, butyl, hexyl, octyl decyl, dodecyl, methoxy, ethoxy, butoxy, hexyloxy, methoxymethyl, methoxyethyl, ethoxymethyl, ethoxyethyl, etc; nitro, halogen, hydroxyl, CN-, CONH ₂ -, carboxyl, carboxylic ester, amino, SO ₃ H groups, optionally substituted phenyl, etc.

Compounds which can be prepared are, for example benzaldehyde, 4-methylbenzaldehyde, 3,4-methylenedioxybenzaldehyde, p-nitrobenzaldehyde, p-tolualdehyde, pyridin-4-aldehyde, pyridin-2-aldehyde, nonanal, acetoxyacetaldehyde, methyl or ethyl pyruvate, ethyl α-ketobutyrate, diethyl mesoxalate, 3,3- dimethoxypropanal, 3,3-di-n-butoxypropanal, succindialdehyde, adipaldehyde, 1 ,8- octanedial, 3-thiaglutaraldehyde 3,3-dioxide, homophtalaldehyde, dimethyl 1 ,6- hexanedial-3,4-dicarboxylate, o-phthalaldehyde, 3-oxaglutaraldehyde, dimethanol hemiacetal of methyl glyoxylate, dimethanol hemiacetal of n-butyl glyoxylate, dimethanol hemiacetal of n-octyl glyoxylate, menthyl glyoxylate, borneyl glyoxylate, fenchyl glyoxylate, 8-phenylmenthyl glyoxylate, maleic acid, 2-sulfobenzoic acid, 4- nitro-2-sulfobenzoic acid, 4-nitro-2-sulfobenzaldehyde, 4-aminobenzoic acid, 4- bromobenzoic acid, terephthalic acid, 2,3-pyridinedicarboxylic acids which are unsubstituted or substituted in position 4 and/or 5 and/or 6 by Ci-C ₄ -alkyl or alkoxy, d- C ₄ -alkyl-Ci-C ₄ -alkoxy, halogen, hydroxyl or nitro, 2-acetylnicotinic acid, nopinone, hydroxymethylpyridine, methyl lactate, butyroxyacetaldehyde and amino acids, amino aldehydes or amino alcohols, for example according to WO 2005/063682, such as, for example, (R)-3-amino-3-phenyl-1-propanol, or cyclopropanecarboxylic acid derivatives, for example according to IN189318, or benzimidazole sulfoxides, for example according to WO 20051 1601 1 , etc.

Unsaturated, organic carbon compounds having one or more olefinic or aromatic double bonds in the molecule which are cleavable by ozone are suitable as starting compounds for the ozonization.

These are, for example, unsaturated compounds of the general formula Il

C

/ \

R ₃ H

i n is 0 or 1 , Qi is hydrogen or the radicals

Il Il I

C , C -CH, -C-OR ₁ ,

/ \ / \ \ Il

Ri being defined as above,

R ₂ and R ₃ , independently of one another, are hydrogen, a C ₁ - to C ₄ - alkyl radical, a phenyl or pyridyl radical which is unsubstituted or substituted by groups inert under the reaction conditions, or is a -COOR ₁ radical or a radical of the formula (CH ₂ ) _m -O-CO-(CH ₂ ) _p , it being possible for m to be an integer from 1 to 4 and p an integer from 1 to 6, or, if n is 1 and Q ₁ is the radical H

\ / C Il C / \

H R ₂ -

R ₂ and R ₃ together are a single bond between two neighboring C atoms, or are an alkylene radical having 2 to 4 C atoms if Y is an o-phenylene radical or an alkylene radical having 2 to 4 C atoms and R is a hydrogen atom, otherwise Y has the same meaning as X in formula I if n is 1 , or if n is 0, is either hydrogen or, together with R ₃ or with R ₃ and the C=C double bond, is an optionally substituted, aliphatic, araliphatic, aromatic or heteroaromatic radical having 1 to 50 C atoms which may be interrupted by oxygen, nitrogen or sulfur, or Y together with R ₃ and the C=C double bond is an optionally substituted mono- or bicyclic radical having 4 to 20 C atoms which may contain one or 2 heteroatoms from the group consisting of S, N or O,

or Y and R together form a mono- or bicyclic radical having 4 to 20 C atoms, which may be mono- or polysubstituted by groups inert under the reaction conditions and R is as defined in formula I.

Suitable substituents in turn are Ci-C ₂ o-alkyl or alkoxy or alkylalkoxy groups, such as, for example, methyl, ethyl, isopropyl, butyl, hexyl, octyl, decyl, dodecyl, methoxy, ethoxy, butoxy, hexyloxy, methoxymethyl, methoxyethyl, ethoxymethyl, ethoxyethyl, etc.; nitro, halogen, hydroxyl, CN, CONH ₂ , carboxyl, carboxylic ester, amino or SO ₃ H groups, optionally substituted phenyl, etc. Accordingly, starting materials which may be converted into the corresponding mono- or biscarbonyl or hydroxy compounds of the formula I are those compounds of the formula Il in which, for example, an aliphatic radical Y is to be understood as meaning, for example, a divalent, straight-chain or branched alkylene radical having 1 to 50, preferably 1 to 20, carbon atoms, it being possible for a -CH ₂ radical in the aliphatic chain to be replaced by oxygen, nitrogen or sulfur or by the - SO ₂ - radical. Aralkylene, alkylarylene or alkylenearylene radicals having, for example 7-50, preferably 7-20, carbon atoms are to be understood as an example of an araliphatic radical. An example of an aromatic radical is, for example, a phenylene radical and an example of a heteroaromatic radical is a divalent radical of a heterocycle, for example a mono- or bicyclic heterocycle, having one or two heteroatoms in the ring, the rings preferably being five- or six-membered. The abovementioned radicals may also be substituted by one or more groups inert under the reaction conditions, for example by alkyl, alkoxy or alkoxycarbonyl groups having in each case 1 to 10 carbon atoms, preferably having 1 to 4 carbon atoms, or by nitro groups.

Preferably, unsaturated compounds of the formula Na

H-Y ₁ -C-R

Il C

/ \ R ₃ H in which

R is defined as in formula I and R ₃ as in formula Il and Yi and R ₃ are identical and are both the radical -(CH ₂ ) _m -O-CO-(CH ₂ ) _p where m is 1 or 2 and p is 1 , 2 or 3, or

Yi together with hydrogen is a phenyl radical optionally substituted in the ortho- and/or meta- and/or para-position or an optionally substituted five- or six- membered heteroaryl radical having a heteroatom in the ring, but particularly preferably the para-nitrophenyl, p-tolyl, or 2- or 4-pyridinyl radical, or, together with the C=C double bond, is an optionally substituted mono- or bicyclic heterocycle, such as, for example, unsubstituted or substituted quinoline or indole, or in which Y ₁ and R together form a bicyclic radical having 4 to 10 C atoms which may be mono- or polysubstituted by groups inert under the reaction conditions, can be converted into the corresponding preferred carbonyl or hydroxy compounds. Examples of unsaturated compounds of the formula Na are 1 ,4- butenediol dibutyrate, para-nitro- or para-methylstyrene, 2- or 4-vinylpyridine, quinoline, 8-methylquinoline, 3-ethyl-8-methylquinoline, indole, thiophene dioxide, stilbene-2,2 ^' - disulfonic acid, 4,4 ^' -dinitrostilbene-2,2 ^' -disulfonic acid, 4,4 ^' -vinylenedianiline, 4,4 ^' - vinylenedipyridine, 4,4 ^' -stilbenedicarboxylic aid and β-pinene. Preferably, unsaturated compounds of the formula Nb

R ₄ O - C - C - R ₅ Il Il O CH ₂

in which

R ₄ is methyl or ethyl and R ₅ is methyl, ethyl or the ethoxycarbonyl radical, are also converted into the corresponding preferred carbonyl compounds. Very particularly preferably, compounds in which R ₄ and R ₅ are methyl are converted. Examples of starting compounds of the formula Nb are methyl methacrylate, ethyl alkylacrylate or diethyl methylenemalonate.

A further preferred group of starting materials for the preparation of the correspondingly preferred carbonyl compounds of the formula I are compounds of the formula Nc

R ₁ O

\

CH - CH ₂ - CH / Il

R ₁ O CH ₂

in which R ₁ is defined as in formula I. Examples of compounds of the formula Hc are 4,4-dimethoxybutene or 4,4-di-n-butoxybutene.

Furthermore, preferably compounds of the formula Nd

H Y ₂ H \ / \ /

C C Il Il

C C

/ \ / \

in which Y ₂ is an o-phenylene radical or an alkylene radical having 2 to 4 C atoms and Re and R ₇ together are a single bond between the neighboring C atoms or an alkylene radical having 2 to 4 C atoms, are converted into the correspondingly preferred dialdehydes of the formula I. Examples of the compounds of the formula Nd are naphthalene or 1 ,5-cyctooctadiene. Finally, preferably a further group of unsaturated compounds of the formula Ne

Y ₃ R

\ /

C Il

C

/ \

in which, if R and R ₃ are each H, Y ₃ and R ₈ together are an alkylene radical having 2 to 6 C atoms or the radicals

CH ₃ O O O OCH ₃ \ // W / C C I I

-CH ₂ -SO ₂ -CH ₂ -, -CH ₂ -O-CH ₂ , -CH ₂ -CH CH-CH ₂ -, or

is converted into the correspondingly preferred dialdehydes of the formula I or, if R and R ₃ are each COORi and Y ₃ and R ₈ are H, into the correspondingly preferred glyoxylic esters or their hemiacetals or monohydrates of the formula I. Examples of compounds of the formula Ne are cyclohexene, cyclooctene, cyclododecene, sulfolene, indene, dimethyl tetrahydrophthalate or 2,5-

dihydrofuran, and dimethyl or diethyl maleate, monophenyl menthyl maleate, monomenthyl, fenchyl or boneyl maleate, and analogous fumaric esters.

A very wide range of compounds which can also contain complex structures having a very wide range of functionalities is therefore suitable for the process according to the invention. In addition to the abovementioned preferred starting compounds, compounds having complex structures, such as, for example, cephalosporins, etc., are therefore also suitable as starting material. The only precondition or limitation in the selection of the starting material is the presence of at least one double bond cleavable by ozone. The reaction, according to the invention, of the unsaturated compounds with ozone is effected in a flammable organic solvent in which the starting compounds are readily soluble, or in a solvent mixture comprising a flammable solvent or in nonflammable solvents, such as water, where the presence of the starting material, of the product or of an intermediate may lead to explosive heterogeneous systems. This is the case in particular whenever flammable, volatile components (i) are formed as byproducts, such as, for example, formaldehyde or glyoxyal, glycolaldehyde, formic acid or acetic acid, glycolic acid or glyoxylic acid, (ii) or may form by secondary reactions, such as, for example, ester or acetal hydrolysis, such as, for example, methanol, ethanol, acetone or glycol. The fire behavior of the reaction mixture can further be accelerated in a dangerous manner by peroxides and ozonides and oligomers thereof, with the result that explosive mixtures comprising allegedly harmless substances may in turn form. The process according to the invention with avoidance of explosive heterogeneous mixtures of oxygen and reaction solution is particularly valuable if the reaction solution comes into contact with catalysts, such as Pt, Pd, etc., which may lead to spontaneous ignition. Without the knowledge of the ignition behavior of the heterogeneous mixture, there is a considerable risk of explosion in these processes. It is of minor importance whether the catalysts are deliberately added (WO 2004054950, DSM) or introduced by cross-contamination. Flammable organic solvents which are suitable for the ozonolysis are, for example, alcohols, such as, for example, methanol, ethanol, propanol, butanol, etc.; carboxylic acids, such as, for example, formic acid, acetic acid or propionic acid, etc.; carboxylic esters, such as, for example, butyl acetate, etc.; hydrocarbons, such as, for example, octane, etc.; halogenated hydrocarbons, such as, for example, methylene chloride, etc.

Flammable organic solvents here also include those which are considered to be nonflammable in air but may very well burn in an oxygen atmosphere. Examples of these are methylene chloride and silicone oils.

It is also possible to use solvent mixtures comprising the abovementioned solvents.

Examples of mixtures of alcohols and halohydrocarbons or water in concentrations which, under reaction conditions, cannot form heterogeneous explosive mixtures in air but may very well do so in oxygen are 1 :1 mixtures of methanol with methylene chloride, methanol with water, ethanol with water, etc. Preferred solvents are lower branched and straight-chain aliphatic alcohols having 1 to 6 C atoms, such as methanol, ethanol, propanol, etc, use of methanol, ethanol and butanol being particularly preferred, or mixtures with halogenated and nonhalogenated hydrocarbons or with water.

In the preparation of, for example, glyoxylic ester hemiacetals of the formula I, the alcohol used as solvent is important in that this alcohol participates in the acetal formation.

The reaction with ozone can be carried out both batchwise and continuously, ozone being used in stoichiometric amounts up to a 40% excess, depending on the reactivity of the starting materials or substrates in relation to the solvent used. Stoichiometric amounts up to a 20% excess of ozone are preferably employed.

The ozonolysis can be effected at atmospheric pressure or under superatmospheric pressure. A pressure of from 1 to 60 bar abs., preferably from 1 to 16 bar abs. and particularly preferably from 1 to 5 bar abs. is preferably employed. The ozonization according to the invention is carried out at temperatures of from -70 to +80 ⁰ C, depending on starting material and/or solvent used, it being preferable to maintain a temperature of from -40 to +30 ⁰ C.

According to the invention, ozone is introduced into the reaction mixture by means of an ozone-carrying inert gas/C> ₂ stream. Those gases which are inert under the reaction conditions and which have no disadvantageous effects in the ozone preparation in the ozone generator, such as, for example, formation of byproducts or adverse effect on the energy characteristics, are preferred as inert gas.

Noble gases, such as Ar, He, Ne, etc., and CO ₂ , or other gases which are inert under the reaction conditions and which do not form any byproducts in the

ozone preparation or change the energy characteristics in a disadvantageous manner, or mixtures thereof, are preferably used.

The proportion of ozone in the stream is from 0.1 to 10% by weight, preferably from 0.5 to 5% by weight. The oxygen concentration of the inert gas/C> ₂ stream which can be used in the process according to the invention depends on the reaction parameters (temperature; pressure), the solvent used or inert gas used.

According to the invention, the oxygen concentration used is above the limiting oxygen concentration for homogeneous gas mixtures (LOC), so that no inertization in the customary sense is present, and below the safety-critical oxygen concentration for heterogeneous gas mixtures which is dependent on the reaction conditions and at which ignition and flame propagation of the heterogeneous mixture are no longer possible.

The safety-critical oxygen concentration for heterogeneous gas mixtures which is dependent on the reaction conditions and at which ignition and flame propagation are no longer possible can be determined by simple ignition experiments in which the ignitability of the solvent used is investigated at different temperatures and pressures in inert gas/C> ₂ mixtures having different O ₂ concentrations and different inert gas composition. The experiments then give a maximum oxygen concentration at which ignitability and flame propagation no longer take place, so that safe operation can be effected under the chosen reaction conditions, and at the same time sufficiently efficient operation of the ozone generator is ensured when the inert gas, for example argon, is admixed before the O ₃ generator. Thus, it is possible to show in experiments that, for example, for methanol as solvent at -20 ⁰ C and 2 bar, the maximum oxygen concentration is from 20 mol% of O ₂ to 35% of O ₂ , depending on the composition of the inert gas components. This concentration also permits direct use of, for example, an Ar/O ₂ stream as feed gas for the ozone production. The ozone production is promoted thereby. A low specific energy consumption per kg of ozone is present. As a result, firstly a sufficiently high safety level is achieved and secondly many disadvantages of complete inertization are absent.

The gas composition according to the invention permits both single use of the ozone-containing gas mixture and recycling of the ozonolysis exit gas.

In the case of single contacting, it is possible to use both air and nitrogen-free gas mixtures, such as, for example, oxygen/argon/carbon dioxide mixtures.

On recycling the ozonolysis exit gas and on a larger industrial scale, it is possible, particularly, in the case of danger of enrichment of nitrates and organic NOx compounds, for example through recycling of the solvent, substantially to limit the losses due to the low solubility of argon in the reaction mixture by choosing argon as the main component of the gas mixture. Argon also does not interfere in the gas workup and forms no byproducts in the ozone generator, as is known, for example, with the use of air, due to the formation of oxides of nitrogen.

Argon therefore remains in the gas circulation and may scarcely be replaced, which is reflected in the low costs. The proportions of argon which are present as an impurity in the oxygen are enriched in the gas circulation and therefore lead to a further reduction of the costs. Figure 1 shows an exemplary gas circulation for ozonolysis processes.

The inert gas/O ₂ stream is preferably introduced into the ozone generator as feed gas for ozone production. If appropriate, the gas stream is then cooled to reaction temperature. Thereafter, the ozonolysis is effected either continuously or batchwise in a suitable ozonolysis apparatus, for example in a stirred vessel, in a bubble column or in one or more columns, by the cocurrent or countercurrent method. After the ozonolysis, the ozonolysis exit gas is worked up, said gas first being fed, if appropriate, through one or more immersion containers and then fed to the catalytic combustion. The proportion of flammable solvent vapors which is discharged with the gas stream is converted into CO ₂ in the catalytic combustion. The CO ₂ formed remains, if appropriate, in the gas circulation, with the result that the required amount of continuously added inert gas is reduced.

Oxygen and, if appropriate, argon, and other inert gases, are preferably added to the inert gas/0 ₂ stream before or after the catalytic combustion, so that the oxygen consumption due to the conversion to ozone and subsequently into peroxidic reaction products, and the inert gas consumption owing to low solubility of the reaction solution, are replaced and the oxygen concentration is kept constant below the safety-critical oxygen concentration dependent on the reaction conditions.

Thereafter, the gas stream is, if appropriate, washed and dried before it is passed again into the ozone generator.

For the use of, for example, Ci-C ₈ -alcohols, such as, for example, methanol or ethanol, the fact that the catalytic combustion of the alcohol results in the formation of CO ₂ which can remain as inert gas in the gas circulation, further increasing the cost-efficiency of the process, is particularly advantageous. The catalytic hydrogenation of the ozonolysis products which follows the ozonization is carried out according to the prior art, for example according to WO 02/072518. For the practical procedure, for example, a suspension of the catalyst in the alcohol used in stage a) in the ozonization, preferably in methanol or ethanol, very preferably in methanol, is initially introduced into a hydrogenation reactor and the solution obtained in the ozonization is fed in continuously by means of a regulatable metering apparatus. During the addition of the ozonolysis solution at the beginning and in the course of the hydrogenation, it should be ensured that, through the amount of peroxide-containing ozonization products fed in, the peroxide content recognized as being advantageous is not exceeded in the hydrogenation solution. Owing to the low concentration of peroxide-containing ozonization products during the actual hydrogenation process, the ratio of catalyst to substrate to be reduced is constantly advantageous over the entire duration of the hydrogenation, so that a rapid reduction is ensured even with the economical use of the catalyst. In this way, the poisoning otherwise to be observed at high peroxide concentrations and the associated loss of activity of the catalyst are also prevented.

Overall, however, large amounts of ozonization products can be reductively cleaved in a relatively small volume by the continuous feed, with the result that concentrated solutions are obtained in the final stage of the process and, in addition to the solvent itself, time and costs are also reduced during the removal of the solvents by distillation during working-up.

Example 1 : Investigations into the safety-critical oxygen concentration for O? gas mixtures a) Laboratory experiment in MeOH - pure O ₂ stream A thermostatable autoclave which was resistant to explosion pressure and was provided with pressure and temperature sensors and with a powerful ignition apparatus (exploding wire) was filled with methanol and oxygen. The ignition wire was positioned directly above the liquid surface, a small distance away. After cooling to - 25°C, a pressure of 1 bar abs. was set and the liquid phase was ignited. A very rapid pressure and temperature increase occurred. It was thus possible to show that the

heterogeneous system of liquid MeOH in a pure O ₂ stream is an explosion hazard below the flashpoint. The system liquid MeOH/oxygen was therefore not used subsequently. b) Laboratory experiment in MeOH - pure O ₂ stream at elevated pressure

The ignition vessel from example 1 a was filled with methanol and oxygen. After cooling to -25°C, the pressure was adjusted to 2 bar abs. The liquid phase was ignited with the aid of an ignition wire having a direct effect on the liquid surface. A very rapid pressure and temperature increase occurred, with the result that it was possible to show that the system MeOH at -25°C in a pure O ₂ stream is not suitable even at pressures of 2 bar abs. and the associated increase in the flashpoint, but can lead to explosions. Example 2: Use of air instead of O? a) A pressure-resistant ignition vessel from example 1 was filled with cold methanol and dry synthetic air. After cooling to -25°C, the pressure was 1 bar abs.

The ignitability was tested several times with the aid of an ignition wire having a direct effect on the liquid surface. A pressure or temperature increase occurred in none of the ignition experiments, so that it was possible to show that the system comprising MeOH in air does not lead to explosions about 35°C below the flashpoint, even in the presence of a strong ignition source. b) On the basis of this finding, 4 liters of a methanolic solution of 900 g (6.2 mol) of dimethyl maleate (DMM) were initially introduced into a laboratory apparatus for contacting gas and liquid, consisting of a reaction column, bottom vessel for gas-liquid separation, external liquid circulation with circulation pump and heat exchanger, and were cooled to a temperature of -25°C.

A dry synthetic air stream of 2.5 m ³ (S.T.P.)/h was fed into an ozone generator from Ozonia. At a power of 1200 W and a pressure of 2.5 bar (abs.), 73 g/h of ozone are produced at a concentration of 29 g/m ³ (S. T. P.) and passed in with quantitative control at the top of the reaction column at a pressure of 1 bar abs. A sample of the ozone gas stream was analyzed for oxides of nitrogen and gave 1500 ppm of N ₂ O ₅ . The reaction conversion of the ozone was determined with the aid of an ozone monitor by analysis of the gas stream separated off from the bottom vessel and was virtually complete.

After 4.13 h, the gas feed was stopped and the remaining DMM content of the reaction solution was determined as 2 g/l by gas chromatography. Altogether, 300 g (6.3 mol) of O ₃ were reacted.

The reaction solution contained 3.5 g/l of nitric acid and 4.2 g/l of methyl nitrate. c) Final investigation of the reaction mixture obtained for ignitability:

The ignition vessel described in example 1 a was filled with the reaction mixture thus obtained and dry synthetic air. After cooling to -25°C, the pressure was 1 bar abs. The ignitability of the mixture was tested several times with the aid of an ignition wire having a direct effect on the liquid surface. A pressure or temperature increase did not occur in any of the ignition experiments, so that it was possible to show that the heterogeneous peroxide solution/air system is also not explosive at -25°C.

Example 3: Use of a CO?/O? gas mixture a) A pressure-resistant ignition vessel from example 1 was filled with cold methanol and a mixture of 36 mol% of O ₂ and 64 mol% of CO ₂ . After cooling to - 25°C, the pressure was 1 bar abs. The ignitability was tested several times with the aid of an ignition wire having a direct effect on the liquid surface. A pressure or temperature increase did not occur in any of the ignition experiments, so that an ozonolysis could be carried out in the system. b) 4 liters of a methanolic solution of 900 g (6.2 mol) of dimethyl maleate DMM were initially introduced into the laboratory apparatus from example 2 and cooled to a temperature of -25°C.

2.5 m ³ (S.T.P.yh of a dry mixture of 36 mol% of O ₂ and 64 mol% of CO ₂ were fed into the ozone generator. At a power of 1200 W and a pressure of 2.5 bar (abs.), 85.7 g/h of ozone were produced at a concentration of 34.3 g/m ³ (S. T. P.) and passed in with quantitative control at the top of the reaction column at a pressure of 1 bar abs. The reaction conversion of the ozone was determined with the aid of an ozone monitor by analysis of the gas stream separated off from the bottom vessel and was virtually complete.

After 3.50 h, the gas feed was stopped and the remaining DMM content of the reaction solution was determined as 2 g/l by gas chromatography. Altogether, 300 g (6.3 mol) of O ₃ were reacted. c) Determination of the ignitability of the reaction mixture thus obtained:

A pressure-resistant ignition vessel with pressure and temperature recording was filled with the reaction mixture thus obtained and a mixture of 36 mol% of O ₂ and 64 mol% of CO ₂ . After cooling to -25°C, the pressure was 1 bar abs. The ignitability of the mixture was tested several times with the aid of an ignition wire having a direct effect on the liquid surface. A pressure or temperature increase did not occur in any of the ignition experiments.

Example 4: Use of an Ar/O? gas mixture a) A pressure-resistant ignition vessel from example 1 was filled with cold methanol and a mixture of 20 mol% of O ₂ and 80 mol% of Ar. After cooling to -

25°C, the pressure was 1 bar abs. The ignitability was tested several times with the aid of an ignition wire having a direct effect on the liquid surface. A pressure or temperature increase did not occur in any of the ignition experiments, so that an ozonolysis was carried out in the system. b) 4 liters of a methanolic solution of 900 g (6.2 mol) of dimethyl maleate DMM were initially introduced into the laboratory apparatus from example 2 and cooled to a temperature of -25°C.

2.5 m ³ (S.T.P.yh of a dry mixture of 20 mol% of O ₂ and 80 mol% of Ar were fed into the ozone generator. At a power of 1200 W and a pressure of 2.5 bar (abs.), 96 g/h of ozone were produced at a concentration of 38.4 g/m ³ (ST. P.) and passed in with quantitative control at the top of the reaction column at a pressure of 1 bar abs. The reaction conversion of the ozone was determined with the aid of an ozone monitor by analysis of the gas stream separated off from the bottom vessel and was virtually complete. After 3.13 h, the gas feed was stopped and the remaining DMM content of the reaction solution was determined as 2 g/l by gas chromatography.

Altogether, 300 g (6.3 mol) of O ₃ were reacted. c) A pressure-resistant ignition vessel with pressure and temperature recording was filled with the reaction mixture thus obtained and a mixture of 20 mol% of O ₂ and 80 mol% of Ar. After cooling to -25 ⁰ C, the pressure was 1 bar abs. The ignitability of the mixture was tested several times with the aid of an ignition wire having a direct effect on the liquid surface. A pressure or temperature increase did not occur in any of the ignition experiments.

Example 5: Use of an Ar/CO?/O? gas mixture a) A pressure-resistant ignition vessel from example 1 was filled with cold methanol and a mixture of 28 mol% of O ₂ , 20 mol% of CO ₂ and 52 mol% of Ar. After cooling to -25°C, the pressure was 1 bar abs. The ignitability was tested several times with the aid of an ignition wire having a direct effect on the liquid surface. A pressure or temperature increase did not occur in any of the ignition experiments, so that an ozonolysis was carried out in the system. b) 4 liters of a methanolic solution of 900 g (6.2 mol) of dimethyl maleate DMM were initially introduced into the laboratory apparatus from example 2 and cooled to a temperature of -25°C.

2.5 m ³ (S.T.P.yh of a dry mixture of 28 mol% of O ₂ , 20 mol% of CO ₂ and 52 mol% of Ar were fed into the ozone generator. At a power of 1200 W and a pressure of 2.5 bar (abs.), 142 g/h of ozone were produced at a concentration of 56.8 g/m ³ (S. T. P.) and passed in at the top of the reaction column. The reaction conversion of the ozone was determined with the aid of an ozone monitor by analysis of the gas stream separated off from the bottom vessel and was virtually complete.

After 2.1 h, the gas feed was stopped and the remaining DMM content of the reaction solution was determined as 2 g/l by gas chromatography. Altogether, 300 g (6.3 mol) of O ₃ were reacted. c) A pressure-resistant ignition vessel with pressure and temperature recording was filled with the reaction mixture thus obtained and a mixture of 28 mol% of O ₂ , 20 mol% of CO ₂ and 52 mol% of Ar. After cooling to -25 ⁰ C, the pressure was 1 bar abs. The ignitability of the mixture was tested several times with the aid of an ignition wire having a direct effect on the liquid surface. A pressure or temperature increase did not occur in any of the ignition experiments.

Example 6: Recycling of the ozonolvsis exit gas a) A pressure-resistant ignition vessel from example 1 was filled with cold methanol and a mixture of 28 mol% of O ₂ , 20 mol% of CO ₂ and 52 mol% of Ar. After cooling to -25°C, the pressure was 2 bar abs. The ignitability was tested several times with the aid of an ignition wire having a direct effect on the liquid surface. A pressure or temperature increase did not occur in any of the ignition experiments, so that an ozonolysis was carried out in the system. b) A pressure-resistant ozonolysis apparatus for contacting gas and liquid, consisting of a reaction column, bottom vessel for gas-liquid separation, external

liquid circulation with circulating pump and heat exchanger, was provided with a gas circulation for recycling the exit gas. The gas circulation consisted of a catalytic combustion for removing solvent residues in the exit gas and a compressor, a gas work-up and an ozone generator. The bottom vessel of the reaction column was filled with 4 liters of a methanolic solution of 900 g (6.2 mol) of dimethyl maleate (DMM) and cooled to a temperature of -25°C.

The gas circulation was filled with a gas comprising 28 mol% of O ₂ , 20 mol% of CO ₂ and 52 mol% of Ar at 2.5 bar (abs.). This circulation gas was circulated at a gas flow rate of 2.5 m ³ (S.T.P.)/h. At an ozone generator power of 1200 W, 142 g/h of ozone were produced at a concentration of 56.8 g/m ³ (S. T. P.) and were completely consumed in the reaction column, a stationary pressure gradient of 2.5 bar (abs.) in the ozone generator and 2.0 bar (abs.) in the ozonolysis apparatus resulting. After 1.8 h, the DMM content of the reaction solution had fallen to 40 g/l. Methanolic DMM solution having a concentration of 225 g/l was now fed in at a rate such that the DMM concentration determined by gas chromatography was kept constant at 40 g/l in the reaction solution discharged continuously at the same rate. In this way, a further 3600 g of DMM were reacted. The resulting reaction solution was stored under cool conditions and subjected in a 2nd step to a further continuous ozonolysis. For this purpose, the first 4 I of this reaction solution were reacted as in the 1st step with ozone-containing gas until the DMM concentration had fallen to 2 g/l. Thereafter, the remainder of the reaction solution was fed in at a rate such that, with uninterrupted introduction of ozone gas, the DMM concentration was kept constant at 2-3 g/l. In this way, altogether 1550 g (32 mol) of O ₃ and 4500 g (31 mol) of

DMM were reacted. c) A pressure-resistant ignition vessel from example 1 was filled with the reaction mixture thus obtained and a mixture of 28 mol% of O ₂ , 20 mol% of CO ₂ and 52 mol% of Ar. After cooling to -25°C, the pressure was 2 bar abs. The ignitability was tested several times with the aid of an ignition wire having a direct effect on the liquid surface. A pressure or temperature increase did not occur in any of the ignition experiments.

Example 7: Preparation of ortho-phthalaldehyde a) A pressure-resistant ignition vessel from example 1 was filled with cold methanol and a mixture of 21 mol% of O ₂ , 20 mol% of CO ₂ and 59 mol% of Ar. After cooling to -15°C, the pressure in the ignition vessel was 2 bar abs. The ignitability was tested several times with the aid of an ignition wire having a direct effect on the liquid surface. A pressure or temperature increase did not occur in any of the ignition experiments, so that ozonolysis could be carried out in the system. b) In the laboratory apparatus from example 6, 4 liters of a methanolic solution of 256 g (2 mol) of naphthalene were cooled to a temperature of -15°C. The gas circulation was filled with a gas comprising 21 mol% of O ₂ , 20 mol% of CO ₂ and 59 mol% of Ar at 2.5 bar (abs.). The circulation gas was circulated at a gas flow rate of 2.5 m ³ (S.T.P.yh. At an ozone generator power of 1200 W, 104 g/h of ozone were produced at a concentration of 41.6 g/m ³ (S. T. P.) and reacted in the reaction column. The reaction conversion of the ozone was determined with the aid of an ozone monitor by analysis of the gas stream separated off in the bottom vessel and was virtually complete.

After 2.1 h, the naphthalene content of the reaction solution had fallen to 2 g/l. 220 g (4.6 mol) of O ₃ were reacted. c) A pressure-resistant ignition vessel from example 1 was filled with the reaction mixture thus obtained and a mixture of 21 mol% of O ₂ , 20 mol% of CO ₂ and 59 mol% of Ar. After cooling to -15°C, the pressure was 2 bar abs. The ignitability was tested several times with the aid of an ignition wire having a direct effect on the liquid surface. A pressure or temperature increase did not occur in any of the ignition experiments, with the result that it was possible to show that even the peroxide- containing ozonolysis solution was not explosive under the chosen reaction conditions. d) The solution obtained in the ozonolysis was fed via the metering vessel into a hydrogen-filled hydrogenation reactor, into which a suspension of 1.5 g of Pt catalyst in 0.5 I of methanol was initially introduced, at a metering such that the peroxide content in the hydrogenation reactor was not more than 0.01 mol/l in the course of the entire hydrogenation. The hydrogen consumed was continuously replenished with pressure control. Over the entire hydrogenation period, a temperature of 30 ⁰ C ± 2°C was maintained by cooling and a pH of from 2 to 4 by addition of methanolic sodium hydroxide solution. As soon as the hydrogenation reactor was full, hydrogenated solution was removed continuously via an immersed frit in order to keep the level approximately constant. The metering of the peroxide solution was not

interrupted during this procedure. After the end of the hydrogenation, a content of 220 g (1.64 mol, 82.1 % of theory) of ortho-phthalaldehyde was determined by gas chromatographic analysis. The solution was adjusted to pH 1 with H ₂ SO ₄ for working up. After 4 hours, the acetalization was complete. The methanolic acetal solution was added dropwise to excess alkali solution and the methanol was distilled off simultaneously. The acetal was extracted twice from the reaction mixture with MTBE and the solvent was removed in a Rotavapor. A residue of 293 g of ortho- phthalaldehyde dimethyl acetal remained, corresponding to 81.4% of the theory.

Example 8: Ozonolvsis in methanol/water (analogous to example 09 from EP 1 481

959): a) In an ignition experiment analogous to example 1 , a mixture of

10% of methanol in water (flashpoint 57°C) was ignited in an oxygen atmosphere at

5°C and a pressure and temperature increase was registered, with the result that it was shown that even dilute aqueous solutions of flammable organic compound are still fire hazards in pure oxygen.

After reduction of the oxygen content of 50% by dilution with nitrogen, the pressure or temperature increase was no longer observed within the ignition experiment. b) Carrying out the ozonolysis:

2.7 g of 2-allyphenol were dissolved in 275 ml of methanol/water

(10%) in a simple ozonolysis apparatus without gas recycling. The ozone generator was fed with a gas stream comprising 50% of O ₂ and 50% of N ₂ . Altogether, 0.96 g of ozone was produced and was reacted in the ozonolysis apparatus. The reaction mixture was then heated to 60 ⁰ C for 5 h, and extracted with twice 100 ml of ethyl acetate, and the combined organic extracts were dried over sodium sulfate. After the solution had concentrated, 2.8 g of hydroxyphenyl acetic acid

(93% of theory) were obtained.

A subsequent comparison for the production of 0.96 g of ozone with pure O ₂ as feed gas showed virtually no difference in the specific energy demand with the use of the same ozone generator.

Example 9: Ozonolysis in acetic acid and in the presence of transition metal catalyst as process-inherent ignition sources (analogous to example 2 from EP 1 362 840): a) In an ignition experiment analogous to example 1 , acetic acid (flashpoint 40 ⁰ C) was ignited in an oxygen atmosphere at 16°C and a strong pressure and temperature increase was registered, with the result that it was shown that a heterogeneous mixture of acetic acid and oxygen, is still explosive 24°C below the flashpoint.

The ignition experiment was repeated several times with air instead of oxygen. No pressure or temperature increase was now observable. b) 34.1 g of 4-bromotoluene and 0.24 g of manganese(ll) acetate were dissolved in 200 ml of acetic acid in a simple ozonolysis apparatus without gas recycling and were cooled to 16°C. The ozone generator was fed with air. Altogether 20 g of ozone were produced and were reacted in the ozonolysis apparatus. The analysis of the reaction mixture gave 98% selectivity in the conversion to 4- bromobenzoic acid and an unconverted residue of < 0.1% of 4-bromotoluene.

Example 10: Ozonolvsis of chiral substrates (analogous to example 01 from WO 2005/06382):

(R)-4-Amino-4-phenyl-1-butene (0.04 mol) was dissolved in 200 ml of methanol in a simple ozonolysis apparatus without gas recycling and was cooled to - 20 ⁰ C. The ozone generator was fed continuously with air, as in example 2. A concentration of 20 g/m ³ (ST. P.) of ozone was produced and was completely reactive in the ozonolysis apparatus. After the end of the ozonolysis, the reaction solution was added dropwise over the course of 10 min to 100 ml of an ice-cooled methanolic sodium borohydride solution (0.9 mol/l). The reaction solution was then warmed to room temperature and 10 ml of water were added in order to decompose excess sodium borohydride. After the solvent had been distilled off, the residue was extracted several times with dichloromethane and the combined organic phases were dried over sodium sulfate and filtered. After the solvent had been distilled off, 0.37 mol of (R)-3- amino-3-phenyl-1-propanol (melting point 73-74°C) were obtained in 99% enantiomeric excess (93% yield).

Examples 1 1-19

The results of known ozonolyses of further starting materials in a manner analogous to examples 1 to 7 are summarized in the table below.

K>

*) Result of the ignition experiment (as in example 1 to 7) of the solvent and the reaction solution under reaction conditions.