EP1461304A2

EP1461304A2 - Method for obtaining 5-halogenolaevulinic acid alkyl esters

Info

Publication number: EP1461304A2
Application number: EP02790254A
Authority: EP
Inventors: Antonia Mariotti; Sven Aldenkortt
Original assignee: Individual
Current assignee: Individual
Priority date: 2001-11-23
Filing date: 2002-11-22
Publication date: 2004-09-29
Also published as: WO2003045895A3; US20050070727A1; CA2478853A1; WO2003045895A2; DE10157557A1; US7339073B2

Abstract

The invention relates to a method for obtaining a 5-bromolaevulinic acid methyl ester (or a 5-chlorolaevulinic acid methyl ester) from a bromination mixture (or a chlorination mixture) containing a 5-bromolaevulinic acid methyl ester (or a 5-chlorolaevulinic acid methyl ester) and produced by means of bromination (or chlorination) of laevulinic acid or a laevulinic acid methyl ester. The inventive method comprises the following steps: a) said bromination mixture (or chlorination mixture) is dissolved in an organic solvent or solvent mixture; b) the solution is cooled to a low temperature, preferably to a temperature which is lower than -20 °C, especially in the temperature range between -20 °C to -40 °C; c) the 5-bromolaevulinic acid methyl ester (or 5-chlorolaevulinic acid methyl ester) is crystallised out of the solution; and d) the crystalline 5-bromolaevulinic acid methyl ester (or 5-chlorolaevulinic acid methyl ester) is isolated by draining off the solution with the remaining bromination mixture (or chlorination mixture).

Description

METHOD FOR OBTAINING 5-HALOGEN LEVULINIC ACID ALKYL ESTERS

The invention relates to a method for obtaining 5-

Methyl bromolevulinate from a bromination mixture containing 5-bromolevulinic acid methyl ester, produced by bromination of levulinic acid or methyl levulinate, and 5-chloro levulinic acid alkyl esters.

In the bromination of levulinic acid with one molar equivalent of bromine in

Methanol is obtained

1. Methyl 3-bromolevulinate

2. 5-bromo levulinic acid methyl ester 3. 3,5-dibromo levulinic acid methyl ester

and as a result of the consumption of further bromine equivalents for the formation of the 3,5-dibromo levulinic acid methyl ester from (1) and / or (2)

4. the non-brominated levulinic acid methyl ester.

The quantitative ratio of the products within the bromination mixture behaves approximately as (1) :( 2) :( 3) :( 4) = 28: 56: 8: 8, with slight fluctuations depending on the reaction conditions. In general, however, the selectivity in the formation of the bromination products, for example in favor of the 5-bromolevulinic acid methyl ester, cannot be changed decisively. Roughly the same result is obtained if, instead of levulinic acid, the levulinic acid methyl ester (4) is reacted in methanol with one equivalent of bromine.

When obtaining 5-bromolevulinic acid methyl ester, one is therefore dependent on the bromination mixture mentioned. Several methods for isolating the 5-bromolevulinic acid methyl ester from the mixture are known from the prior art. In the SF McDonald publication in Can. J. Chem. 1974, 52, 3257-23258 a process is specified in which the bromine compound is obtained from the bromination mixture by double fractional distillation under high vacuum. The 5-bromolevulinic acid methyl ester is obtained in this way in a yield of 30%, based on the starting product levulinic acid, and with an impurity of approx. 2% of 3,5-dibromo-levulinic acid methyl ester.

In order to avoid an acid catalytic change in the isomer ratio, the distillation should proceed quickly and the thermal load on the

Bromination mixture can be kept as low as possible. A higher thermal load has a problem, in particular, if traces of hydrogen bromide are present, by means of which the yield is adversely changed to the disadvantage of the 5-bromolevulinic acid methyl ester. Practice has also shown that the one obtained from distillation

The amount of methyl 5-bromolevulinate in the presence of even small amounts of methyl 3,5-dibromoevulinate is considerably lower.

The process described only insufficiently fulfills the requirements for a gentle extraction of the desired ester combined with an optimal yield, since the double fractionation causes a comparatively high expenditure of time with the consequence of a high thermal load on the distillation material. If, in addition, the pressure range required for the distillation is not reached within a short period of time, the distillation time and thus the thermal load on the bromination mixture is extended.

In addition, a particular disadvantage is that the separation of the bromination products by distillation in the present process is very complex overall, since this requires double fractionation by means of a vacuum-jacketed Vigreux column. Because of the high technical effort, this method is therefore ruled out for large-scale use. In a publication by H.-J. Ha, S.-K-Lee, Y.-J. Ha, JW Park in Synth. Comm. 1994, 24 (18), 2557-2562 calls a process for the production of 5-bromolevulinic acid methyl ester, in which the desired ester is obtained from the bromination mixture by means of column chromatography. This method is disadvantageously associated with high costs, however, purification by liquid chromatography is out of the question for industrial use.

With regard to the use of 5-bromolevulinic acid methyl ester, processes for the production of 5-aminolevulinic acid hydrochloride must also be mentioned in the prior art.

According to US Pat. No. 5,907,058, a process is known in which 5-amino-levulinic acid hydrochloride is prepared by reacting methyl 5-bromolevulinic acid with sodium diformylamide in anhydrous acetonitrile to give 5-diformylamino-levulinic acid methyl ester and subsequent acidic hydrolysis of the resulting 5-diformylaminomethyl ester.

In the Z. Naturforsch. 1986, 41b, 1593 - 1594 is by E. Benedikt and H.-P. Kost discloses a process which is characterized by the following steps:

Reacting methyl 5-bromoavulinic acid with potassium phthalimide in dimethylformamide to methyl 5-phthalimidolevulinate and then acidic hydrolysis of the methyl 5-phthalimidolevulinate formed.

Finally, H.-J. Ha, S.-K-Lee, Y.-J. Ha, JW Park, in the publication already mentioned above, specified a process for the preparation of methyl 5-aminovulinic acid. This process starts from 5-bromolevulinic acid methyl ester, which was obtained by bromination of levulinic acid, and provides for the following process steps: reaction of 5-bromolevulinic acid methyl ester with sodium azide in dimethylformamide to give 5-azidolevulinic acid methyl ester and then catalytic hydrogenation and subsequent 5-hydrolysis of the resulting Aminolävulinsäuremethylesterhydrochlorids. The disadvantage of these processes is that they require the starting material in high purity. The associated high technical outlay and the high costs for the production of this product therefore mean that large-scale production of 5-aminolevulinic acid hydrochloride, as stated above, has not hitherto been profitable.

Against this background, the invention has for itself the object of specifying a process for the production of 5-bromolevulinic acid methyl ester which avoids the disadvantages mentioned, enables the said substance to be obtained in highly pure form and by means of gentle processes, has simple processes, is accordingly suitable for industrial use and leads to an inexpensive preparation of the substance mentioned and thus creates the prerequisite for an inexpensive preparation of 5-aminolevulinic acid methyl ester hydrochloride and 5-aminolevulinic acid hydrochloride. In addition, the proposed method also includes recycling the undesirable by-products that are formed.

According to the invention, this object is achieved by a method which provides the following method steps:

Dissolve the bromination mixture in an organic solvent or solvent mixture

Cooling the solution to low temperatures, preferably temperatures less than minus 20 ° C, especially from the temperature interval -20 ° to

-40 °

Crystallization of the 5-bromolevulinic acid methyl ester from the solution Isolation of the crystalline 5-bromolevulinic acid methyl ester by draining the solution with the remaining bromination mixture.

The proposed process is based on known processes for the preparation of methyl 5-bromolevulinate, in which a mixture of methyl 3-bromolevulinate, methyl 5-bromolevulinate, methyl 3,5-dibromolevulinate and methyl levulate is formed by the bromination of levulinic acid or methyl levulinate. To isolate the 5-bromolevulinic acid methyl ester from the mixture according to the present invention, it is first dissolved in an organic solvent or solvent mixture and cooled down in the subsequent process step. Temperatures are in the range of minus

Maintain 20 ° C to minus 40 ° C. The 5-bromolevulinic acid methyl ester crystallizes out in the form of colorless needles or platelets, while the other constituents of the bromination mixture remain in solution. To separate the crystallized ester from the remaining bromination mixture, the remaining solution is simply drained off.

The invention is based on the essential finding that the individual constituents of the bromination mixture show a completely different crystallization behavior in solution. This behavior has proven to be extremely selective, with a temperature range from minus 20 ° C to minus

40 ° C crystallized only 5-bromolevulinic acid methyl ester. Cooling the mixture to these temperatures thus ensures that only the bromine compound mentioned precipitates. The proposed process has a yield of 35% - 38% in relation to the starting amount of levulinic acid, the bromine product produced being of a high purity of 99%.

After isolation of the 5-bromolevulinic acid methyl ester, impurities consist of levulinic acid methyl ester and 3-bromolevulinic acid methyl ester. These two compounds do not interfere in the further synthetic route, while the 5-bromo-levulinic acid methyl ester obtained by the McDonald process (see above) is an impurity of 3,5-

Contains methyl dibromoevulinic acid ester. This connection adversely affects the further course of the reaction extremely disadvantageously and requires complex cleaning processes of the end product!

The manufacturing process according to the present invention can be described as extremely gentle, since the bromination mixture and the ester to be isolated are not exposed to any thermal loads as a result of the crystallization process. The risk of an acid catalytic change in the isomer ratio is therefore advantageously excluded. A major advantage of the method according to the invention also lies in its ex- Extremely simple processes in the production of 5-bromolevulinic acid methyl ester, which can accordingly be carried out quickly. The process steps mentioned can not only be implemented in the laboratory, but also in large-scale plants. The costs for the process plants, relative to the amount of ester produced, and the production costs incurred during production are incomparably lower than the corresponding costs for the processes according to the prior art with liquid-chromatic workup or fractional distillation under high vacuum.

Numerous organic solvents or mixtures thereof are suitable as solvents for carrying out the selective crystallization. According to the present invention, it is recommended

the solvents

Ethanol 2-propanol diisopropyl ether

or the solvent mixtures

Diethyl ether plus low or higher boiling petroleum spirit fractions t-butyl methyl ether plus petroleum spirit diethyl ether plus cyclohexane - t-butyl methyl ether plus cyclohexane.

In the laboratory tests carried out, mixtures of petroleum spirit with a boiling temperature of 30 - 50 ° C and diethyl ether or t-butyl methyl ether in a ratio of 1: 1 have proven their worth. The amounts of solvent required to carry out the process are comparatively small.

Another advantage of the method according to the invention comes into play in the problem of disposing of by-products. According to a feature of the invention it is provided that after crystallization of the remaining 5-bromo-levulinic acid methyl ester remaining residual bromination mixture. Contains this remaining mixture

1. 3-bromolevulinic acid methyl ester 2. residues of 5-bromolevulinic acid methyl ester

3. 3,5-Dibromo levulinic acid methyl ester

4. and levulinic acid methyl ester.

From this, products 1 - 3 can be converted into methyl levulinate by catalytic hydrogenation with hydrogen. For this, the mixture is in

Dissolved methanol and reduced in the presence of a hydrogenation catalyst with hydrogen at a pressure of 20 bar.

The levulinic acid methyl ester recovered in this way can then be used again as a starting product in the preparation of the bromination mixture mentioned. For this purpose, the levulinic acid methyl ester is dissolved in methanol and, as in the bromination of levulinic acid described above, reacted with elemental bromine in the bromination mixture. This reaction provides about the same mixture of isomers as in the bromination of levulinic acid. In particular, the mixture contains 5-bromolevulinic acid methyl ester in a high concentration, it can thus advantageously be used as a starting product for the process according to the invention for isolating the ester mentioned.

Palladium on activated carbon is proposed as a catalyst according to the present invention. The advantage of this catalyst is that it can be regenerated again after the hydrogenation.

Hydrogenation of the remaining bromination mixture is the only byproduct of hydrogen bromide. This product can be disposed of easily if it is converted into carbon dioxide, water and sodium bromide using sodium hydrogen carbonate. The present invention provides corresponding method steps. A cost-intensive and / or environmentally harmful disposal of by-products is not necessary when 5- Methyl bromolevulinic acid ester according to the inventive method therefore entirely.

An inexpensive preparation of 5-bromolevulinic acid methyl ester according to the present invention opens up far-reaching uses for the ester mentioned. According to the invention, use is in particular provided for the production of 5-aminolevulinic acid methyl ester hydrochloride and 5-aminolevulinic acid hydrochloride therefrom. The latter compound is used both for cancer diagnosis and for the therapy of carcinomas, in particular bladder carcinomas. In addition, 5-

Aminolevulinic acid hydrochloride also used as a herbicide with a broad spectrum of activity. Since this substance occurs naturally in nature, the herbicide has the advantageous property of being biodegradable and not providing any unnatural and problematic metabolites.

So far, large-scale production of 5-aminolevulinic acid hydrochloride has failed, despite intensive efforts, due to the high costs for the production of the starting product. To date, this substance is therefore only produced in smaller quantities, with the disadvantageous consequence of high prices. One gram of the substance currently costs around 60 - 130 in the chemical trade

DM and in medical quality about 150 DM. A wide application of 5-aminolevulinic acid hydrochloride in agriculture is excluded at the currently valid prices.

The inexpensive extraction of 5-bromolevulinic acid methyl ester according to the present process thus creates the conditions for the large-scale production of 5-aminolevulinic acid hydrochloride. The use according to the invention of the 5-bromolevulinic acid methyl ester obtained by the proposed process for the preparation of 5-aminolevulinic acid hydrochloride also includes use in the processes mentioned in the prior art.

When using 5-bromolevulinic acid methyl ester for the production of 5-aminolevulinic acid hydrochloride, it is provided according to the invention in particular that the last process step for obtaining the 5-bromolevulinic acid acid methyl ester, the first process step for the preparation of 5-amino-levulinic acid hydrochloride without changing the reaction vessel.

In the usual synthesis of 5-aminolevulinic acid hydrochloride, 5-bromo-levulinic acid methyl ester is present in the liquid phase. In this form it has strong tear and skin irritating properties, so any contact with the substance should be avoided. The crystalline form of the bromination product, however, has far less stimulus properties. If the product is also left in the reaction vessel after it has crystallized out in order to carry out the subsequent processes, a priori contact with persons who:

This completely eliminates the risk of eye and skin irritation.

The proposed procedure also achieves a further advantage, which is due to the omission of storage of the 5-bromolevulinic acid methyl ester and the problems associated with it. The bromine compound tends to

Presence of traces of acid, for example hydrogen bromide, for an acid-catalyzed isomerization into the compounds 3-bromo, 3,5-dibromo and levulinic acid methyl esters. It therefore usually requires careful storage, but this is not necessary in the proposed method.

In addition, the two subsequent steps on the way from 5-bromolevulinic acid methyl ester to 5-aminolevulinic acid hydrochloride take place at already 20-25 ° C (at times even exothermic), so that no energy is required and the reaction mixtures only have to be stirred.

In an alternative, a further production method is mentioned in claim 2.

5-Bromo levulinic acid methyl ester and 5-chloro levulinic acid ester are starting compounds for the production of the pharmacologically important substance 5-aminolevulinic acid methyl ester hydrochloride.

According to the prior art, the generation of the 5-

Methyl bromolevulinic acid is classified as difficult because of the expensive distillative and chromatographic purification of the bromination mixture. The strong tear-provoking properties create the liquid 5-bromolevulinic acid methyl ester as a disadvantage. The tear-irritating property is due to the bromomethyl ketone subunit in the compound and applies generally to compounds which contain such a subunit as a structural element in the molecule (cf. e.g. BM Gaudry, A. Marquet, Organic Syntheses, Coll. Vol. 6, 193-195).

In order to eliminate the stated disadvantages of the 5-bromo compounds and to produce more stable, non-tear-irritating, storable derivatives - halogen-substituted at the C-5 position - the 5-bromo compounds or the 5-chloro or 5-iodine compounds are suitable. The 5-chloro compounds have no tear-irritating properties compared to the 5-bromine compounds because they have a chloromethyl ketone subunit instead of a bromomethyl ketone subunit. In addition, they are thermally much more stable than the bromine compounds and do not tend to acid-catalyzed isomerizations even under the conditions of distillation. This property also applies to other chloromethyl ketones (cf. E. Warnhoff, M. Rampersad, P. S. Raman, F. W. Yerhoff, Tetrahedron Lett. 1978, 19, 1659 - 1662).

The production of chlorine-substituted esters of levulinic acid at the C-5 position by direct chlorination of levulinic acid or its esters with or without organic diluent by introducing elemental chlorine has the disadvantage that, compared to bromination with elemental bromine, one has greatly reduced selectivity of the halogenation to the detriment of the desired 5-chloro compounds. For example, the chlorination of levulinic acid leads to such a greatly reduced selectivity that 3-chloro levulinic acid is obtained as the main product. In addition, undesirable polychlorination products such as 3,3-dichloro, 3,5-dichloro, 5,5-dichloro levulinic acid, as well as other unknown by-products, are produced together with unreacted levulinic acid and 5-chloroevulinic acid (cf. EP 0397048). Similarly, when trying to chlorinate levulinic acid esters under the most varied of conditions, mixtures of substances which roughly correspond to those described above are obtained. These mixtures of substances are very difficult to separate, the yields are poor and therefore unusable for further conversion. For example, chlorination of levulinic acid ethyl ester without a diluent mainly gives the 3- Chlorolevulinic acid ethyl ester. The chlorination of levulinic acid ethyl ester with sulfuryl chloride in a non-polar organic solvent mainly gives the 3-chloro levulinic acid derivative with the reverse selectivity (cf. EP 0397048).

EP 58392 describes a process for the preparation of 5-chloro levulinic acid ethyl ester, which starts from succinic acid monoethyl ester monochloride. This compound is reacted with diazomethane at -5 ° C and then worked up acidically by introducing HCl gas. In this way, the desired compound is obtained in pure form

Shape and high yield. However, the difficult handling of explosive diazomethane makes this method unsuitable for large-scale use. The same procedure is described in PL 136454. Instead of the succinic acid monoethyl ester monochloride, the corresponding methyl ester derivative is used and gives the 5-chloro levulinic acid methyl ester.

The 5-chloro levulinic acid alkyl esters are starting compounds for the production of other substances and are further reacted by nucleophilic substitution of the halogen atom. In addition to alkali imides and alkali azides, tertiary amines are suitable nucleophiles. The tertiary amine hexamethylenetetraamine (urotropin) is used as a cheap and commercially available nucleophilic reagent for introducing the amino group, for. B. in bromomethyl ketones (see N. Blazevic, D. Kolbah, B. Berlin, V. Sunjic, F. Kajfez, Synthesis, 1979, 161-176).

The reaction of 5-chloro levulinic acid methyl ester with urotropin yields 5-urotropium levulinic acid methyl ester chloride, a quaternary ammonium salt of the levulinic acid methyl ester, which was prepared for the first time in connection with this invention and was converted directly to 5-aminolevulinic acid hydrochloride. WO 02 / 32852A2 describes the production of 5-urotropium

Levulinic acid esters from 5-bromolevulinic acid esters (chain lengths of the alkyl radical of the ester group C1-C5) and their conversion to 5-aminolevulinic acid hydrochloride by acid hydrolysis. A disadvantage of this process description is that ammonium chloride and ammonium bromide are present as inorganic impurities in the end product 5-aminolevulinic acid is likely to be in the form of both the hydrochloride and the hydrobromide. Ammonium salts as impurities are very difficult to separate from the end product - 5-aminolevulinic acid hydrochloride / 5-aminolevulinic acid hydrobromide, so that the tasks for obtaining 5-aminolevulinic acid hydrochloride in a purity required for medical purposes are difficult to solve according to this process description.

Against this background, the method proposed in claim 2 for the production of 5-chloro levulinic acid esters is specified.

The proposed process is based on known processes for the preparation of 5-bromolevulinic acid esters, in which a mixture of 5-bromo-, 3-bromo-, 3-bromo-,

3,5-dibromo levulinic acid ester and the non-brominated levulinic acid ester are formed.

The bromination products are mixed with an organic solvent from an alcohol / water mixture, which is worked up after the aqueous work-up

Receives bromination step, extracted and then the extract at temperatures between 20-25 ° C and the boiling point of the solvent in question with sodium chloride or with saturated, aqueous sodium chloride solution, advantageously in the presence of a phase transfer catalyst. In this reaction step, the bromine atoms in the bromine esters are replaced by chlorine atoms. This exchange takes place in a relatively short time in a gentle and quantitative manner. The resulting mixture of chloro levulinic acid esters no longer has any tear-provoking properties. The bromine or chlorohalogen exchange in the pure bromolevulinic acid or alkyl chlorovulinic acid esters produced can in principle also take place with fluorine and iodine. The bromine / chlorine exchange can also be carried out with the undissolved bromination mixture under the conditions of phase transfer catalysis. A very suitable organic solvent for the bromine / chlorine exchange has been found to be non-toxic and harmless ethyl acetate, which can also be regenerated and returned to the synthesis cycle. Solvents that are difficult or immiscible with water are suitable for the phase transfer-catalyzed halogen exchange Moreover:

Esters such as For example: butyl acetate, amyl acetate - alcohols such as B .:

Butanol pentanol isobutanol ether such as E.g .: - Di-n-butyl ether etc.

Diisopropyl ether Diisoamyl ether Methyl tert-butyl ether Aliphatic and aromatic hydrogen halides such as. B. (These solvents are only suitable for bromine / chlorine exchange, but not for bromine or

Chlorine / iodine or fluorine exchange) methylene chloride tetrachlorethylene carbon tetrachloride - 1,1-dichloroethane

The following quaternary ammonium salts and quaternary phosphonium compounds may be mentioned as examples of phase transfer catalysts:

- tetrabutylammonium bromide - tetrabutylammonium chloride

- Tetrabutylammonium iodide Benzyl trimethylammonium bromide

- Tetrabutylammonium hydrogen sulfate benzyldimethyl-n-dodecylammonium bromide - Trioctyl-methylammonium chloride (Adogen 464)

- ethyl trioctyl phosphonium bromide

- Hexadecyl tributylphosphonium bromide Phase transfer catalysts based on polymer

The process is superior to all previous processes with regard to the large-scale production of 5-chloro levulinic acid alkyl esters. The proportion of 5-chloro levulinic acid alkyl ester produced in the mixture is> 56%. The only by-products are the 3-chloro levulinic acid esters (<28% share), the 3,5-dichloro levulinic acid esters (approx. 8% share) and unreacted levulinic acid esters (approx. 8% share).

The bromination step and the subsequent one

Bromine / chlorine exchange are carried out without changing the reaction vessel.

After drying and distilling off the solvent used from the chlorination mixtures, the residue is fractionally distilled. Compared to the bromination products, the corresponding chlorination products have significantly lower boiling points. The 3-chloroevulinic acid esters, together with the unreacted levulinic acid esters, always form the lead of the distillation, followed by the 5-chloroevulinic acid esters in the 2nd fraction. The higher chlorination products have a relatively high boiling point compared to the monochlorination products and form the third fraction. The mass balance of distillate to the distillation material used is always> 90%. The fractional distillation is carried out under vacuum, which in the sense of the present invention means that the process is carried out under reduced pressure. The yield (based on levulinic acid or levulinic acid ester used) of 5-

Chloro levulinic acid methyl ester after distillation is at least 50% (purity> 98%).

The sequence of the halogenation reactions takes into account, on the one hand, that the bromination of the starting compound is more selective than its chlorination. On the other hand, the mixture of chlorinated levulinic acid ester compounds present after quantitative halogen exchange is more stable compared to the present bromination mixture against acid-catalytic isomerization, because the chlorination products have significantly lower boiling points and so that the triggering of a thermally induced evolution of hydrogen chloride from the 3,5-dichloro compound is avoided.

With regard to the synthesis of 5-aminolevulinic acid hydrochloride from the 5-chloro levulinic acid methyl ester, there is an essential advantage compared to the homologous bromine compound in that in the case of a reaction with sodium azide and other nitrogen nucleophiles, they are used in the form of their sodium salts (e.g. imides) are produced, only sodium chloride (table salt) as an inorganic by-product. Sodium chloride is practically insoluble in organic solvents. This means that this by-product can be removed by simple filtration and the resulting product can be fed directly to the subsequent step with practically no inorganic contamination. With regard to the use of 5-aminolevulinic acid hydrochloride in the medical field, this is of great importance insofar as no other inorganic impurity than in the product produced in this way

Sodium chloride may be present, e.g. B. in the case of traces of sodium bromide would lead to more complex analysis.

In this context, it is noteworthy that the 5-chloro levulinic acid methyl ester from the chlorination mixture, which is obtained from the bromination mixture of levulinic acid or methyl levulinic acid in methanol and subsequent bromine / chlorine exchange, is obtained in a gentle manner, as has already been described for the 5-bromolevulinic acid methyl ester, selectively obtained from the chlorination mixture by low-temperature crystallization. The procedure is the same as in the case of the 5-

Methyl bromolevulinate using the same solvents and solvent mixtures at a temperature of minus 20 - minus 40 ° C. The desired 5-chloro levulinic acid methyl ester is obtained in 35-38% yield and a purity of> 98%. Impurities are 3-chloro levulinic acid methyl ester and unreacted levulinic acid methyl ester.

The 5-chloro levulinic acid esters of the alcohols of chain lengths C2-C4 cannot be obtained by low-temperature crystallization, since no crystallization occurs under these conditions. The same also applies to the corresponding bromination mixtures of 5-bromolevulinic acid esters which are prepared from the alcohols of chain lengths C2-C4. Small amounts of 5-chloro levulinic acid methyl ester, 3-chloro levulinic acid methyl ester and unreacted levulinic acid ester always form the forerun of the distillations. These compounds can be converted quantitatively into the levulinic acid esters by catalytic hydrogenation with hydrogen in the presence of a hydrogenation catalyst and a non-nucleophilic tertiary amine (for trapping the hydrochloric acid formed) and can thus be returned to the bromination step. The hydrogenation catalyst used, preferably palladium on activated carbon according to the invention, can be regenerated. The alcohol in question, which forms the ester residue, is expediently used as the solvent. Only amine hydrochloride is formed as a by-product.

The solvents used can be regenerated. The catalytic hydrogenation of the by-products to the levulinic acid esters offers one possibility

Recover raw materials and return them to the synthesis cycle. Alternatively, the 3-chloro compounds can be introduced into other synthetic routes so that costly disposal of the by-products can be avoided. Solvent and catalyst can be regenerated, only the hydrochloride of a tertiary amine has to be disposed of. The synthesis is based on cheap levulinic acid or its esters, which is available in large quantities on the market and on an industrial scale, e.g. B. can be made from waste paper (see E. S. Oson, M. R. Kjelden, A. J. Schlag, R. K. Sharma, ACS Symposium Series 2001, 784, 51-63). Higher 5-chloro levulinic acid esters can be easily and almost quantitatively

Obtain the yield by standard methods by transesterification of the 5-chloro levulinic acid methyl ester and 5-chloro levulinic acid methyl ester with the corresponding alkanols by standard methods. By ester hydrolysis of the 5-chloro levulinic acid esters, the 5-chloro levulinic acid can be produced in high yields using standard methods. Further details, features and advantages of the invention can be found in the following part of the description. This section describes manufacturing examples carried out in the laboratory.

Example 1: Preparation of 5-bromolevulinic acid methyl ester from levulinic acid

In a three-necked flask with mechanical stirrer, reflux condenser, internal thermometer and dropping funnel, a solution of levulinic acid (600 g; 5.17 mol) in 2400 ml of commercially available methanol was dripped at 20-25 ° C. within 15 min. Bromine (826.2 g, 5.17 mol). The internal temperature rose to 60 ° C within 1.5 h. The solution then turned from deep red to orange within 2 minutes. At this point the reaction is complete (H NMR control). 2500 ml of water were added, the separated, yellow oil was separated off, and the remaining solution was extracted with

Dichloromethane (3 x 300 ml), combined the organic extracts with the oil, washed with saturated aqueous sodium hydrogen carbonate solution (3 x 200 ml), saturated aqueous sodium chloride solution (3 x ~ 200 ml), dried with sodium sulfate, the solvent was distilled i. Vak. and obtained a pale yellow oil consisting of 3-bromo-levulinic acid methyl ester (1) (28%), 5-bromo-levulinic acid methyl ester (2) (56%), 3,5-dibromo-levulinic acid methyl ester (3) (8%) and levulinic acid methyl ester (4) (8%) passed. The product composition was determined by H-NMR spectroscopy by integrating the 5-CH ₂ protons (2, 3) and the 5-CH ₃ protons (1, 4), the sum of the proton signal integrals being set equal to 100%.

Organic solvents such as diethyl ether, t-butyl methyl ether and chloroform are also suitable for the extraction. The best results were achieved with chloroform, dichloromethane and ethyl acetate.

A mixture of diethyl ether / petroleum ether (30-50 ° C.) 1: 1 (4000 ml) was added to the bromination mixture and the mixture was cooled to -20 ° C. to -

40 C. Colorless needles or platelets crystallized out of the mixture within 2 h. The supernatant solution was decanted and the crystals were digested with a mixture of diethyl ether / petro- cooled to -20 ° C. Leumbenzin (30 - 50 C) 1: 1 (1000 ml), decanted the supernatant solution and received 400 g (37%) 5-bromolevulinic acid methyl ester in the form of colorless

Needles or flakes with a melting point of 12 - 15 C.

Ethanol, 2-propanol, diisopropyl ether and t-butyl methyl ether / petroleum ether (30 - 50 C) 1: 1 are also suitable as solvents for the crystallization. Instead of the low-boiling petroleum spirit fraction, the higher-boiling fractions and cyclohexane can also be used in combination with the specified esters. The best results were achieved with the solvent mixture described in the instructions.

Example 2: Preparation of 5-bromolevulinic acid methyl ester from levulinic acid methyl ester

In a three-necked flask with a reflux condenser, mechanical stirrer, internal thermometer and dropping funnel, the mixture was added dropwise at 20-25 ° C. to a mixture of levulinic acid methyl ester (5 g, 38.4 mmol) and 30 ml of commercially available methanol within 15 min bromine (6.14 g, 38.4 mmol) and the mixture was stirred at 20 - 25 ° C. After 1.5 h the reaction temperature rose to 35 ° C. The reaction solution decolorized within 2 min. from deep red to orange and the

The temperature dropped again to 20 - 25 C. The reaction was finished at this point. 100 ml of water were added, the oil was separated off, the supernatant solution was extracted with dichloromethane (2 × 30 ml), the organic phases were combined with the oil, washed with saturated, aqueous sodium hydrogencarbonate solution (2 × 20 ml) and saturated, aqueous sodium chloride solution (2 x 20 ml), dried with sodium sulfate, the solvent was distilled i. Vak. and obtained 7.56 g of a pale yellow oil consisting of 3-bromolevulinic acid methyl ester (28%), 5-bromolevulinic acid methyl ester (56%), 3,5-dibromolevulinic acid methyl ester (8%) and levulinic acid methyl ester (8%). A 1: 1 (50 ml) mixture of diethyl ether / petroleum spirit (30-50 ° C.) was added to the bromination mixture and the mixture was cooled to -20 ° C. to -40 ° C. Colorless needles or platelets crystallized out of the mixture within 2 h. The supernatant solution was decanted and the crystals were digested to -20 C-cooled mixture of diethyl ether / petroleum ether (30 - 50 C) 1: 1 (20 ml), decanted the supernatant solution and received 2.9 g (36%) of methyl 5-bromate in the form of colorless needles or platelets with a melting point of 12 - 15 ° C.

Example 3: Preparation of levulinic acid methyl ester from a bromination mixture of 3-bromo levulinic acid methyl ester, 5-bromo levulinic acid methyl ester, 3,5-dibromo levulinic acid methyl ester and levulinic acid methyl ester with a composition according to example 1 after crystallization of the 5-bromo levulinic acid methyl ester

The solvent of the bromination mixture from the crystallization according to Example 1 was i. Vak. distilled and a mixture of 3-bromolevulinic acid methyl ester (61%), 5-bromolevulinic acid methyl ester (23%), 3.5-

Dibromo levulinic acid methyl ester (8%) and levulinic acid methyl ester (8%). 5 g of the mixture were dissolved in 20 ml of commercially available methanol, a hydrogenation catalyst was added (palladium on activated carbon) and the mixture was hydrogenated

Introducing hydrogen at a pressure of 20 bar for 5 h at 20-25 C. Monitoring of the hydrogenation showed that the reaction had proceeded quantitatively after 5 h (H and C NMR spectra) and that, apart from hydrogen bromide, only levulinic acid methyl ester had formed , 20 ml of water were added, the mixture was extracted with dichloromethane (3 × 20 ml), the combined organic phases were washed with saturated aqueous sodium bicarbonate solution (3 × 10 ml), saturated aqueous sodium chloride solution (3 × 10 ml) and dried with sodium sulfate , distilled the solvent and the residue i. Vak. and received 2.5 g (80%) of pure levulinic acid methyl ester. The product obtained in this way can be used for the preparation of methyl 5-bromolevulinate according to Example 2. A working up by distillation is not absolutely necessary, so that the crude product after removal of the largest

Part of hydrogen bromide can be directly returned to the bromination step as a crude product.

Example 4: Preparation of 5-chloro levulinic acid methyl ester, 5-chloro levulinic acid ethyl ester, 5-chloro levulinic acid propyl ester, 5- Butyl chlorovulinic acid ester from bromination mixtures of the corresponding bromination products by phase-transfer-catalyzed bromine / chlorine exchange. General procedure for the preparation of 5-chloro levulinic acid methyl, ethyl, propyl and n-butyl esters.

In a three-necked flask with reflux condenser, mechanical stirrer, internal thermometer and dropping funnel, 1 mol of bromine was added to a solution of 1 mol of levulinic acid or 1 mol of levulinic acid ester in 400 ml of the corresponding alcohol, which forms the alkyl radical of the ester, which had been cooled to 10 ° C. The mixture was then stirred with slow heating to 20-25 ° C. until the initially dark red mixture had turned yellow to orange. The reaction is complete at the time of decolorization. 400 ml of water were then added and the oil which separated out and the aqueous solution were extracted with a total of 200 ml of ethyl acetate. The aqueous phase was separated off, 1000 ml of saturated aqueous sodium chloride solution were added to the organic phase, and 10 g of trioctyl-methylammonium chloride were added. The reaction mixture was stirred at 20-25 ° C. or with gentle boiling until no more bromination products were present (TLC, ¹ H NMR). Possibly. the sodium chloride solution was replaced by a fresh solution. The organic phase was separated off, washed with 100 ml of water, dried with sodium sulfate and the solvent was distilled i. Vak. The residue was fractionally distilled in vacuo at 10 mm over a claisen bridge (with the exception of the 5-chlorobutyl ester, the boiling point of which is approximately 158 ° C. at a pressure of 10 mm). You always took one

Lead containing the unreacted levulinic acid ester and the 3-chloro ester and little of the desired 5-chloro levulinic acid ester. The 5-chloro levulinic acid ester is in the main barrel. There was little 5-chloro levulinic ester and 3,5-dichloro levulinic ester in the distillate sump ( ¹ H-NMR).

To produce 5-chloro levulinic acid n-butyl ester, in deviation from the general instructions, the bromination mixture was washed acid-free with water and the butanolic solution was fed directly to the bromine / chlorine exchange step with phase transfer catalysis. On- finally, the procedure was as described in the general regulation. Distillation was carried out at a negative pressure of 5 x 10 ^'2 mm.

Example 5: Preparation of 5-chloro levulinic acid methyl ester from a mixture of 3-chloro, 5-chloro, 3,5-dichloro levulinic acid ester and

Levulinic acid methyl ester with a composition corresponding to the remaining chlorination mixture after the low-temperature crystallization

A chlorination mixture of the levulinic acid methyl ester was prepared according to the procedure in Example 4. The solvent was distilled in vacuo. The ratio of 5-chloro levulinic acid methyl ester: 3,5-dichloro levulinic acid methyl ester: 3-chloro levulinic acid methyl ester: levulinic acid methyl ester corresponded to that of the corresponding bromination products from Example 1 and was determined analogously by NMR spectroscopy by integrating the corresponding proton signals.

Diethyl ether / petroleum ether (30-50 ° C.) 1: 1 (800 ml) was added to the crude product mixture and the mixture was cooled to -20 ° C. to -40 ° C. Colorless needles crystallized from the mixture within 4 h. The supernatant solution was decanted, the crystals were digested with a mixture of diethyl ether / petroleum ether (30-50 ° C.) 1: 1 (200 ml) cooled to -20 ° C. and 62 g (38%) of colorless needles with melting point 8- 13 ° C. The solvents additionally listed in Example 1 can also be used as solvents for the crystallization. The NMR spectroscopic

Data of the product corresponded to the data obtained for the methyl 5-chlorovulinate from Example 4. The purity of the product produced in this way is> 98%.

Example 6: Catalytic hydrogenation of the low-temperature crystallization residue from Example 5 - Regeneration of levulinic acid methyl ester The solvent of the mixture from the crystallization according to Example 5 was i. Vak. Distilled and obtained a mixture consisting of 3-chloro levulinic acid methyl ester (63%), 5-chloro levulinic acid methyl ester (21%), 3,5-dichloro levulinic acid methyl ester (8%) and levulinic acid methyl ester (8%). 5 g of the mixture were dissolved in 20 ml of commercially available methanol, a hydrogenation catalyst (palladium on activated carbon) and 2.45 g of triethylamine were added and the mixture was hydrogenated in the presence of hydrogen at a pressure of 20 bar at 20-25 ° C. The reaction was complete after 5 h ( ¹ H-NMR). The catalyst was filtered, the solvent was distilled i. Vac., Gave 20 ml

Ethyl acetate, the solid was filtered, the solvent was distilled again i. Vak. and recovered the levulinic acid methyl ester in 2.96 g (95%) yield. The ester was purified by distillation.

Example 7: Exemplary transesterification of 5-chloro levulinic acid methyl ester with 1-propanol

10 g of 5-chloro levulinic acid methyl ester were dissolved in 50 ml of 1-propanol, 0.5 ml of conc. Sulfuric acid and refluxed the mixture for 3 hours. Then methanol and 1-propanol were distilled i. Vak., Took up the residue in dichloromethane, washed the organic phase with saturated, aqueous sodium hydrogen carbonate solution and water and obtained 5.4 g (quantitative) of pure 5-chloro levulinic acid propyl ester. The NMR data were identical to the data of the substance from Example 4.

Example 8: Exemplary implementation of the 5-chloro levulinic acid ester with sodium azide to the 5-azidolevulinic acid ester. General instructions for the preparation of 5-azidolevulinic acid methyl, ethyl, propyl and n-butyl esters

1 g of the 5-chloro levulinic acid methyl ester was dissolved in 3 ml of commercially available acetone, 1 molar equivalent of sodium azide was added and the reaction mixture was stirred at 20-25 ° C. for 10 h. The precipitated sodium chloride was filtered off and the solvent was distilled i. Vak. The 5-azidolevulinic acid ester was obtained in quantitative yield and a purity of> 99% in the form of yellow to deep yellow oils. There were no by-products.

Example 9: Exemplary Catalytic Reduction of 5-

Azidolevulinic acid esters to the 5-aminolevulinic acid ester hydrochlorides as intermediates and subsequent acidic hydrolysis of the intermediates to form 5-aminolevulinic acid hydrochloride. General instructions for the preparation and hydrolysis of 5-aminolevulinic acid ester hydrochlorides with alkyl residues of chain lengths C1-C3 as intermediates by catalytic hydrogenation and subsequent acidic hydrolysis to 5-aminolevulinic acid hydrochloride

1 g of azidolevulinic acid ester was dissolved in 10 ml of alcohol (corresponding to the alkyl radical of the ester) / hydrochloric acid in water (2 mol / l) and the mixture was treated with a hydrogenation catalyst (palladium on activated carbon). The mixture was hydrogenated under the introduction of hydrogen at a pressure of 1-6 bar for 3 hours. Monitoring of the hydrogenation showed that the hydrogenation had ended quantitatively after 3 h ( ¹ H-NMR). The hydrogenation is carried out by a

Temperature increase accompanied up to 35 ° C. If the reaction temperature drops again to 20-25 ° C, the reaction is complete ( ¹ H-NMR). The catalyst was filtered, the alcohol was distilled i. Vac., Added a little activated carbon and 10 ml of aqueous hydrochloric acid (6 mol / l) to the pale yellow residue and heated the reaction mixture under reflux for 5 h. The activated carbon was filtered, the aqueous hydrochloric acid and the alcohol formed during the hydrolysis were distilled, and an almost colorless, viscous residue was obtained. 20 ml of 2-propanol were added to the residue while stirring. After a minute, a white, crystalline solid suddenly precipitated out. The solid was filtered with a glass suction filter, washed with a little 2-propanol, the crystals dried i. Vak. and obtained with 85-90% colorless crystals with melting point 150-151 ° C, which consisted of pure 5-aminolevulinic acid hydrochloride.

Adapting the batch to 75 g of 5-azido-levulinic acid ester used led to the same result. The physical and spectroscopic see data matched data known from the literature (see H.-J. Ha, S.- K. Lee, Y.-J. Ha, JW Park, Synth. Comm. 1994, 24, 2557-2562).

Example 10: Exemplary reaction of the 5-chloro levulinic acid esters with hexamethylenetetramine (urotropin) to the 5-urotropinium levulinic acid ester chlorides as intermediate and subsequent acidic hydrolysis to 5-aminolevulinic acid hydrochloride

General instructions for the preparation and hydrolysis of methyl, ethyl, propyl and n-butyl ester of 5-urotropinium levulinate followed by acidic hydrolysis to 5-aminolevulinic acid hydrochloride

5 g of 5-chloro levulinic acid alkyl ester were dissolved in 50 ml of ethanol, the equimolar amount of hexamethylenetetramine (urotropin) was added and the mixture was stirred at 20-25 ° C. for 2 h. Then 10 ml of conc. Hydrochloric acid and heated the reaction mixture under reflux for 2 h. The precipitated ammonium chloride was filtered off, distilled alcohol and volatile formaldehyde diethyl acetal i. Vak. and got a yellow to brown residue. The residue was dissolved in methanol and the 5-aminolevulinic acid hydrochloride was precipitated

Form of a white, fine crystalline solid by adding ether. The solid was filtered and, after drying, i. Vak. 75 - 85% pure 5-aminolevulinic acid hydrochloride with mp. 150 - 151 ° C. The NMR data are identical to the data given in the literature (cf. see H.-J. Ha, S.-K. Lee, Y.-J. Ha, JW Park, Synth. Comm. 1994, 24, 2557-2562).

Claims

1. A process for the production of 5-bromolevulinic acid methyl ester (or 5-chloro levulinic acid methyl ester) from a bromination mixture (or chlorine mixture), or chlorine mixture, (or chlorine) produced by bromination (or chlorination) of levulinic acid or methyl ester, or 5-bromolevulinic acid methyl ester (or 5-chlorovulinic acid methyl ester) by the following process steps a) dissolving the bromination mixture (or chlorination mixture) in an organic solvent or solvent mixture b) cooling the solution to low temperatures, preferably temperatures less than minus 20 ° C., in particular from the temperature interval -20 ° to -40 °, c) crystallization of the 5-bromolevulinic acid methyl ester (or 5-

Chloro levulinic acid methyl ester) from solution d) isolation of the crystalline methyl 5-bromo levulinic acid (or 5-chloro levulinic acid methyl ester) by draining off the solution with the remaining bromination mixture (or chlorination mixture).

2. A process for the recovery of 5-chloro levulinic acid alkyl ester from a bromination mixture produced by bromination of levulinic acid or alkyl levulinate and containing 5-bromo levulinic acid alkyl ester, characterized by the following process steps a) halogen exchange by reaction of the bromination mixture with an alkali metal chloride in the presence of a phase transfer catalyst. b) Isolation of the 5-chloro levulinic acid alkyl ester by fractional distillation under vacuum.

3. The method according to claim 2, characterized in that the alkyl is a methyl or ethyl compound.

4. A process for the production of 5-bromolevulinic acid methyl ester according to claim 1, characterized in that - preferably as an organic solvent Ethanol and / or 2-propanol and / or diisopropyl ether and as a solvent mixture preferably - diethyl ether plus low or higher boiling petroleum spirit fractions and / or

- t-Butyl methyl ether plus petroleum ether and / or diethyl ether plus cyclohexane and / or

- t-Butyl methyl ether plus cyclohexane is used.

5. A process for the production of 5-bromo levulinic acid methyl ester according to claim 1 or 4, characterized in that said residual bromination mixture is converted into methyl levulinate by catalytic hydrogenation with hydrogen and the levulinic acid methyl ester thus obtained is preferably brominated into said 5-bromo levulinic acid methyl ester containing bromination mixture is transferred.

6. A process for the production of 5-bromolevulinic acid methyl ester according to claim 5, characterized in that palladium on activated carbon is used as the catalyst.

7. A process for the production of methyl 5-bromoavulinate according to claim 5 or 6, characterized in that the hydrogen bromide formed in the hydrogenation is converted into carbon dioxide, water and sodium bromide by means of sodium hydrogen carbonate.

8. Use of the 5-bromolevulinic acid methyl ester obtained according to one of claims 1 and claims 4-7, characterized in that it is used for the preparation of 5-aminolevulinic acid hydrochloride.

9. A process for the production of 5-bromolevulinic acid methyl ester according to claim 1, characterized in that the first process step for the production of 5-aminolevulinic acid hydrochloride without changing the reaction vessel follows immediately after the production of 5-bromolevulinic acid methyl ester.

10. A process for the production of 5-chloro levulinic acid alkyl ester by halogen exchange according to claim 2, characterized in that

- The bromination mixtures produced by extraction with solvent which are difficult or impossible to mix with water, e.g.

Ethyl acetate, to be separated from the aqueous phase,

- The organic phase is mixed with an aqueous, preferably saturated alkali metal chloride solution

- the exchange of bromine for chlorine in the presence of a phase transfer catalyst such as Trioctyl-methylarnmonium chloride is carried out.

11. The method according to claim 10, characterized in that the brominating step and the subsequent bromine / chlorine exchange is carried out without changing the reaction vessel, using an organic solvent which is lighter in terms of water.

12. A process for the production of 5-chloro levulinic acid alkyl ester according to claim 10 or 11, characterized in that

- The 3-chloro levulinic acid alkyl ester trapped in the fractional distillation can be converted back into the starting substance levulinic acid alkyl ester by catalytic hydrogenation with hydrogen - and the recovered levulinic acid alkyl ester together with the non-halogenated levulinic acid alkyl ester is again fed to a halogenation.

13. A process for the production of 5-chloroevulinic acid alkyl ester according to claim 12, characterized in that - Palladium on activated carbon is used as a catalyst.

14. Use of the 5-chloro levulinic acid alkyl ester obtained according to claim 2 and the claims 10-13, characterized in that they are used for the production of 5-urotropinium levulinic acid alkyl ester chloride or 5-azidolevulinic acid alkyl ester.

15. Use of the 5-urotropinium levulinic acid alkyl ester chlorides obtained according to claim 14, characterized in that they are used for the production of 5-aminolevulinic acid hydrochloride.

16. A process for the production of 5-chloro levulinic acid alkyl ester according to claim 2, characterized in that

- 5-Chloro levulinic acid alkyl ester with longer-chain ester alkyl radicals is carried out by transesterification of the 5-chloro levulinic acid methyl ester and / or 5-chloro levulinic acid ethyl ester with longer chain alkanols.

17. Use of the 5-chloro levulinic acid alkyl ester obtained according to claim 2 and that obtained according to claims 10-12, characterized in that from these by reaction with alkali fluorides or alkali iodides in the presence of a phase transfer catalyst the corresponding pure 5-fluoro- or 5- Alkyl iodolevulinic acid ester can be obtained.

18. Use according to claim 2 and according to claims 10-12 and 16 obtained 5-chloro levulinic acid alkyl ester, characterized in that - these are converted into 5-chloro levulinic acid by ester hydrolysis.

19. Use of the 5-bromolevulinic acid methyl ester prepared according to claim 1, characterized in that this can be converted into the corresponding pure 5-chloro, 5-iodo and 5-fluorolevulinic acid methyl ester by reaction with alkali metal chlorides, iodides and fluorides in the presence of a phase transfer catalyst.

20. Use of the 5- produced according to claim 14

Is azidolevulinic acid alkyl ester, characterized in that they can be used for the production of 5-aminolevulinic acid alkyl ester hydrochlorides.

21. Use of the 5-azidolevulinic acid alkyl esters prepared according to claim 14, characterized in that they can be used in a manner known per se for the production of 5-aminolevulinic acid hydrochloride.