EP1461304A2 - Procede d'obtention d'un ester alkylique d'acide 5-halogenolevulique - Google Patents

Procede d'obtention d'un ester alkylique d'acide 5-halogenolevulique

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Publication number
EP1461304A2
EP1461304A2 EP02790254A EP02790254A EP1461304A2 EP 1461304 A2 EP1461304 A2 EP 1461304A2 EP 02790254 A EP02790254 A EP 02790254A EP 02790254 A EP02790254 A EP 02790254A EP 1461304 A2 EP1461304 A2 EP 1461304A2
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EP
European Patent Office
Prior art keywords
levulinic acid
methyl ester
ester
acid methyl
chloro
Prior art date
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Application number
EP02790254A
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German (de)
English (en)
Inventor
Antonia Mariotti
Sven Aldenkortt
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Individual
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Individual
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Publication of EP1461304A2 publication Critical patent/EP1461304A2/fr
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
    • C07C67/317—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by splitting-off hydrogen or functional groups; by hydrogenolysis of functional groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • C07C67/03—Preparation of carboxylic acid esters by reacting an ester group with a hydroxy group
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
    • C07C67/307—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by introduction of halogen; by substitution of halogen atoms by other halogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • C07C67/48—Separation; Purification; Stabilisation; Use of additives
    • C07C67/52—Separation; Purification; Stabilisation; Use of additives by change in the physical state, e.g. crystallisation

Definitions

  • the invention relates to a method for obtaining 5-
  • 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.
  • 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 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.
  • the proposed method also includes recycling the undesirable by-products that are formed.
  • this object is achieved by a method which provides the following method steps:
  • 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.
  • 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
  • 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
  • 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%.
  • 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-
  • 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.
  • 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
  • products 1 - 3 can be converted into methyl levulinate by catalytic hydrogenation with hydrogen.
  • the mixture is in
  • 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.
  • 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.
  • 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.
  • 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.
  • 5-aminolevulinic acid methyl ester hydrochloride 5-aminolevulinic acid hydrochloride therefrom.
  • the latter compound is used both for cancer diagnosis and for the therapy of carcinomas, in particular bladder carcinomas.
  • 5-aminolevulinic acid methyl ester hydrochloride 5-aminolevulinic acid hydrochloride
  • 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.
  • 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.
  • 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:
  • 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
  • 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.
  • 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).
  • 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.
  • 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).
  • 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
  • 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.
  • 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).
  • 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.
  • 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-,
  • the bromination products are mixed with an organic solvent from an alcohol / water mixture, which is worked up after the aqueous work-up
  • 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
  • phase transfer catalysts The following quaternary ammonium salts and quaternary phosphonium compounds may be mentioned as examples of phase transfer catalysts:
  • 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 residue 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 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.
  • 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.
  • 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.
  • Sodium chloride may be present, e.g. B. in the case of traces of sodium bromide would lead to more complex analysis.
  • 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
  • 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
  • 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.
  • 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.
  • 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.
  • 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-
  • 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.
  • 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
  • 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
  • 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.
  • 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%).
  • Example 7 Exemplary transesterification of 5-chloro levulinic acid methyl ester with 1-propanol
  • Example 8 Exemplary implementation of the 5-chloro levulinic acid ester with sodium azide to the 5-azidolevulinic acid ester.
  • 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
  • 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.
  • 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

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Crystallography & Structural Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

L'invention concerne un procédé d'obtention d'ester méthylique d'acide 5-bromolévulique (ou d'ester méthylique d'acide 5-chlorolévulique) à partir d'un mélange de bromation (ou d'un mélange de chloration) obtenu par bromation (ou chloration) d'acide lévulique ou d'ester méthylique d'acide lévulique, contenant de l'ester méthylique d'acide 5-bromolévulique (ou de l'ester méthylique d'acide 5-chlorolévulique). Ce procédé comprend les étapes suivantes : a) dissolution du mélange de bromation (ou du mélange de chloration) dans un solvant organique ou dans un mélange de solvants organiques ; b) refroidissement de la solution jusqu'à une basse température, de préférence à une température inférieure à - 20° C, en particulier comprise dans l'intervalle - 20° C à - 40° C ; c) recristallisation de l'ester méthylique d'acide 5-bromolévulique (ou de l'ester méthylique d'acide 5-chlorolévulique) à partir de la solution ; et d) isolement de l'ester méthylique cristallin d'acide 5-bromolévulique (ou de l'ester méthylique d'acide 5-chlorolévulique) par évacuation de la solution avec le mélange de bromation (ou le mélange de chloration) résiduel.
EP02790254A 2001-11-23 2002-11-22 Procede d'obtention d'un ester alkylique d'acide 5-halogenolevulique Withdrawn EP1461304A2 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
DE10157557 2001-11-23
DE10157557A DE10157557A1 (de) 2001-11-23 2001-11-23 Verfahren zur Gewinnung von 5-Bromlävulinsäuremethylester
PCT/DE2002/004302 WO2003045895A2 (fr) 2001-11-23 2002-11-22 Procede d'obtention d'un ester alkylique d'acide 5-halogenolevulique

Publications (1)

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EP1461304A2 true EP1461304A2 (fr) 2004-09-29

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US (1) US7339073B2 (fr)
EP (1) EP1461304A2 (fr)
CA (1) CA2478853A1 (fr)
DE (1) DE10157557A1 (fr)
WO (1) WO2003045895A2 (fr)

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KR101963430B1 (ko) * 2017-07-03 2019-03-28 제너럴바이오(주) 메틸 5-브로모레불리네이트 제조방법 및 이를 이용한 5-아미노레불린산 헥실 에스테르 하이드로클로라이드 제조방법
CN113416142B (zh) * 2021-06-22 2022-10-18 邯郸市赵都精细化工有限公司 一种5-ala中间体5-溴乙酰丙酸酯的制备方法

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US3275504A (en) * 1964-11-23 1966-09-27 Crown Zellerbach Corp Method for controlling microbiological organisms with compositions comprising halogenated levulinic acid and derivatives
US3708194A (en) * 1971-05-24 1973-01-02 A Amit Vehicle safety apparatus
DE3915094A1 (de) * 1989-05-09 1991-01-10 Hoechst Ag Verfahren zur herstellung von 2-mercapto-4-methyl-1,3-thiazol-5-yl-essigsaeure und deren ester
JP3270596B2 (ja) * 1993-10-28 2002-04-02 三井化学株式会社 アリルブロミド類の製造方法
US5725265A (en) * 1997-01-16 1998-03-10 Baber; Jeff Air bag system for vehicle bumpers
US5907058A (en) * 1998-07-29 1999-05-25 Midwest Research Institute Synthesis of an acid addition salt of delta-aminolevulinic acid from 5-bromo levulinic acid esters
DE19918202A1 (de) * 1999-04-22 2000-10-26 Bayer Ag Sicherheitsstoßfänger
US6583317B1 (en) * 2000-10-18 2003-06-24 Midwest Research Institute Synthesis of acid addition salt of delta-aminolevulinic acid from 5-bromo levulinic acid esters

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Title
See references of WO03045895A2 *

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US7339073B2 (en) 2008-03-04
WO2003045895A3 (fr) 2003-09-18
US20050070727A1 (en) 2005-03-31
CA2478853A1 (fr) 2003-06-05
DE10157557A1 (de) 2003-06-05
WO2003045895A2 (fr) 2003-06-05

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