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WO2001036366A1 - Method for producing phenylacetic acid esters - Google Patents

Method for producing phenylacetic acid esters Download PDF

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Publication number
WO2001036366A1
WO2001036366A1 PCT/EP2000/010322 EP0010322W WO0136366A1 WO 2001036366 A1 WO2001036366 A1 WO 2001036366A1 EP 0010322 W EP0010322 W EP 0010322W WO 0136366 A1 WO0136366 A1 WO 0136366A1
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formula
acid
hydrogenation
alkyl radical
esterification
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German (de)
French (fr)
Inventor
Karlheinz Niederreiter
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Patheon Austria GmbH and Co KG
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DSM Fine Chemicals Austria Nfg GmbH and Co KG
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Priority to AU12739/01A priority Critical patent/AU1273901A/en
Publication of WO2001036366A1 publication Critical patent/WO2001036366A1/en
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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

Definitions

  • Phenylacetic acid esters such as 4-hydroxyphenylacetic acid methyl ester, are required, inter alia, in the production of 4-hydroxyphenylacetamide, an important building block for the synthesis of the ⁇ -blocker atenolol.
  • Inhibitors, antihistamines, polymerization catalysts, diagnostic agents or liquid crystals are used
  • the phenylacetic acid esters have hitherto been prepared by hydrogenating the corresponding mandelic acid or the salt with hydrogen in the presence of a catalyst in glacial acetic acid / water mixtures, for example according to US Pat. No. 4,337,355, and subsequent esterification in the corresponding alcohol as solvent to the corresponding ester
  • J Mol Catal 75 (1992), 169-178 and 78 (1993), 9-20 describes a process variant for the preparation of phenylacetic acid esters, the phenylacetic acid esters being hydrogenated and esterified at the same time with the corresponding mandelic acid derivative with carbon monoxide in the presence of a Pd / C-HCI catalyst system can be obtained in ethanol and benzene as an additional solvent.
  • Pd / C is only a highly active catalyst in combination with HCI, so that poor results are achieved in the absence of HCI.
  • the additional solvent benzene is also according to These references are crucial for a high yield.
  • the invention accordingly relates to a process for the preparation of phenylacetic acid derivatives of the formula
  • Ar is a phenyl radical RH or C 1 -C 4 -alkyl radical which is mono- or polysubstituted by OR, NR 2 or halogen and R 'is a C 1 -C 4 -alkyl radical, by simultaneous hydrogenation and esterification of the corresponding substituted mandelic acids formula
  • phenylacetic acid esters of the formula (I) are prepared.
  • Ar denotes a phenyl radical which is mono- or polysubstituted.
  • OR or NR 2 are suitable as substituents, where R is H or —CC alkyl, or Halogen, such as F, Cl or Br.
  • the substituents can be in the o-, m- or p-position, the phenyl radical preferably having a maximum of 2 substituents and particularly preferably only one substituent.
  • Preferred substituents are the hydroxyl radical and the alkoxy radical, in which Alkoxy radical of methoxy and ethoxy rest preferred are particularly preferred, the phenyl radical is substituted only in the p-position by OH or OR or in the p-position by OH and in the m-position by OR
  • R ' in the formula (I) denotes a dC 4 -alkyl radical, a C 1 -C 2 -alkyl radical being preferred
  • Phenylacetic acid esters which can be prepared by the process according to the invention are, for example, 4-hydroxy-3-methoxyphenyless ⁇ gsauremethyl- or ethyl ester, 4-
  • Methyl or ethyl methoxyphenylacetate Preferably, methyl or ethyl 4-hydroxyphenylacetate, particularly preferably methyl 4-hydroxyphenylacetate, is prepared
  • correspondingly substituted mandelic acid compounds of the formula (II) or suitable salts thereof serve as the starting compound.
  • suitable salts thereof serve as the starting compound.
  • Na, K or NH 4 salts are suitable as salts
  • the corresponding almond acid compound of the formula (II) or its salt is hydrogenated and esterified at the same time.
  • the alcohol ROH which leads to the desired ester in the end product, is used as the solvent.
  • Methanol, ethanol, propanol or butanol are therefore preferred as alcohols methanol or ethanol are used, particularly preferably methanol is used as the solvent
  • the alcohol serves both as a solvent and as an esterifying agent, it is used in excess, based on the starting material, preferably in an amount of 2 mol to 60 mol per mol of starting material, particularly preferably from 10 to 40 mol per mol of starting material, used
  • Sulfuric acid is also required as an adjuvant for the process according to the invention.
  • the amount of sulfuric acid added depends on the starting material used, and in the case of starting material salts the excess sulfuric acid, based on the starting material, is used.
  • the preferred amount is dependent on the starting material used - educt, 0.3 to 3 mol of sulfuric acid per mol of educt. 0.5 to 2 mol of sulfuric acid per mol of educt are particularly preferably used
  • Suitable hydrogenation catalysts are conventional hydrogenation catalysts, such as transition metals from group 8 of the periodic table, such as Ni, Fe, Co, Pd or Pt catalysts or their salts, oxides or complexes, and elements from groups Ib, IIb, III , IV, V, VIb or VI Ib of the periodic table or their salts, oxides or complexes. Transition metals from group 8 of the periodic table are preferably used, a Pd catalyst, for example PdCl 2 , Pd / C, PdCl 2 -PPh3 etc. is particularly preferred, A Pd / C catalyst is particularly preferred.
  • the catalyst is added in customary amounts of about 1-10% by weight, based on the starting material
  • activated carbon can be added to the reaction mixture to facilitate the isolation of the catalyst after the end of the reaction, approximately in the amount of the catalyst
  • the process according to the invention is carried out at a hydrogen pressure of 2-10 bar, preferably at 3-6 bar and a reaction temperature of 70-150 ° C, preferably at 80-140 ° C and particularly preferably at 100-120 ° C
  • reaction mixture is constantly stirred
  • the catalyst, the sulfate formed when using a commercial acid salt and any activated carbon present are separated from the reaction solution, for example by simple filtration.
  • the remaining sulfuric acid solution is then removed by adding suitable bases, for example NaOH, KOH or NH 3 adjusted to a pH of 2 to 8, preferably 5 to 7, and filtered again.
  • suitable bases for example NaOH, KOH or NH 3 adjusted to a pH of 2 to 8, preferably 5 to 7, and filtered again.
  • the solvent, ie the alcohol is separated off from the filtrate obtained, which contains the desired phenyl acid acetic ester. This can be done, for example, by distillation or on a rotary evaporator respectively

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

Abstract

The invention relates to a method for producing phenylacetic acid derivatives of formula Ar-CH2COOR' (I), wherein Ar means a phenyl radical with one or more substitutions with OR, NR2 or halogen, R means H or a C1-C4 alkyl radical and R' means a C1-C4, by simultaneously hydrogenating and esterifying the corresponding substituted mandelic acids of formula Ar-CHOHCOOH (II), wherein Ar has the above meaning, or a suitable salts thereof. The simultaneous hydrogenation and esterification take place in a solvent in the form of an alcohol R'OH, R' being a C1-C4 alkyl radical, in the presence of sulfuric acid and a hydrogenation catalyst and hydrogen.

Description

VERFAHREN ZUR HERSTELLUNG VON PHENYLESSIGSAUREESTERN METHOD FOR THE PRODUCTION OF PHENYLIC ACETIC REESTERS

Phenylessigsaureester, wie etwa 4-Hydroxyphenylessιgsauremethylester werden unter anderem bei der Herstellung von 4-Hydroxyphenylacetamιd, einem wichtigen Baustein zur Synthese des ß-Blockers Atenolol benotigt Weiters werden diese Substanzen beispielsweise bei der Herstellung von Lipoxygenase-Inhibitoren, Elastase-Inhibitoren, Ty- rosinkinase-lnhibitoren, Antihistaminika, Polymerisationskatalysatoren, Diagnostika oder Flussigkπstalle eingesetztPhenylacetic acid esters, such as 4-hydroxyphenylacetic acid methyl ester, are required, inter alia, in the production of 4-hydroxyphenylacetamide, an important building block for the synthesis of the β-blocker atenolol. Inhibitors, antihistamines, polymerization catalysts, diagnostic agents or liquid crystals are used

Die Herstellung der Phenylessigsaureester erfolgte bisher durch Hydrierung der entsprechenden Mandelsaure bzw des Salzes mit Wasserstoff in Gegenwart eines Katalysators in Eisessig/Wasser-Gemischen, beispielsweise gemäß US 4,337,355, und nachfolgender Veresterung im entsprechenden Alkohol als Losungsmittel zum korrespondierenden EsterThe phenylacetic acid esters have hitherto been prepared by hydrogenating the corresponding mandelic acid or the salt with hydrogen in the presence of a catalyst in glacial acetic acid / water mixtures, for example according to US Pat. No. 4,337,355, and subsequent esterification in the corresponding alcohol as solvent to the corresponding ester

Neben dem erhöhten Zeitaufwand für zwei Reaktionsschritte, musste zusatzlich die als Zwischenstufe entstehende Phenylessigsaure vor der Veresterung isoliert und gereinigt werdenIn addition to the increased time required for two reaction steps, the phenylacetic acid formed as an intermediate also had to be isolated and purified before the esterification

In J Mol Catal 75 (1992), 169-178 und 78 (1993), 9-20 ist eine Verfahrensvariante zur Herstellung von Phenylessigsaureestern beschrieben, wobei die Phenylessigsaureester durch gleichzeitige Hydrierung und Veresterung des entsprechenden Mandelsauredeπ- vates mit Kohlenmonoxid in Gegenwart eines Pd/C-HCI-Katalysatorsystems in Ethanol und Benzol als zusätzliches Losungsmittel erhalten werden Es wird darauf hingewiesen, dass Pd/C nur in Kombination mit HCI ein hochaktiver Katalysator ist, sodass in Abwesenheit von HCI nur schlechte Resultate erzielt werden Auch das zusätzliche Losungsmittel Benzol ist gemäß diesen Literaturstellen ausschlaggebend für eine hohe Ausbeute So zeigen die durchgeführten Versuche dass die Ausbeute ein Maximum erreicht, wenn das Verhältnis von Ethanol zu Benzol 1 1 betragt und dass die Ausbeute sinkt wenn der Anteil an Ethanol steigt Unerwarteterweise wurde nun gefunden, dass verschieden substituierte Phenylessigsaureester durch gleichzeitige Hydrierung und Veresterung der entsprechenden Man- delsauredeπvate auch in Abwesenheit eines zusätzlichen Losungsmittels und mit Schwefelsaure anstelle von Salzsaure in hohen Ausbeuten auf einfache und ökologische Weise erhalten werdenJ Mol Catal 75 (1992), 169-178 and 78 (1993), 9-20 describes a process variant for the preparation of phenylacetic acid esters, the phenylacetic acid esters being hydrogenated and esterified at the same time with the corresponding mandelic acid derivative with carbon monoxide in the presence of a Pd / C-HCI catalyst system can be obtained in ethanol and benzene as an additional solvent. It should be noted that Pd / C is only a highly active catalyst in combination with HCI, so that poor results are achieved in the absence of HCI. The additional solvent benzene is also according to These references are crucial for a high yield. The experiments carried out show that the yield reaches a maximum when the ratio of ethanol to benzene is 1 1 and that the yield decreases when the proportion of ethanol increases It has now been found, unexpectedly, that differently substituted phenylacetic acid esters can be obtained in high yields in a simple and ecological manner in high yields by simultaneous hydrogenation and esterification of the corresponding silicate derivatives even in the absence of an additional solvent and with sulfuric acid instead of hydrochloric acid

Gegenstand der Erfindung ist demnach ein Verfahren zur Herstellung von Phenylessig- sauredeπvaten der FormelThe invention accordingly relates to a process for the preparation of phenylacetic acid derivatives of the formula

Ar-CH2COOR' (I)Ar-CH 2 COOR ' (I)

in der Ar einen ein- oder mehrfach durch OR, NR2 oder Halogen substituierten Phenyl- rest R H oder einen Cι-C4-Alkylrest und R' einen Cι-C4-Alkylrest bedeuten, durch gleichzeitige Hydrierung und Veresterung der korrespondierenden substituierten Mandelsauren der Formelin which Ar is a phenyl radical RH or C 1 -C 4 -alkyl radical which is mono- or polysubstituted by OR, NR 2 or halogen and R 'is a C 1 -C 4 -alkyl radical, by simultaneous hydrogenation and esterification of the corresponding substituted mandelic acids formula

Ar-CHOHCOOH (II)Ar-CHOHCOOH (II)

in der Ar obige Bedeutung hat, oder eines geeigneten Salzes, das dadurch gekennzeichnet ist, dass die gleichzeitige Hydrierung und Veresterung in einem Alkohol ROH, wobei R' ein Cι-C4-Alkylrest ist, als Losungsmittel, in Anwesenheit von Schwefelsaure und in Gegenwart eines Hydrierkatalysators und Wasserstoff erfolgtin the Ar has the above meaning, or a suitable salt, which is characterized in that the simultaneous hydrogenation and esterification in an alcohol ROH, where R 'is a C 1 -C 4 -alkyl radical, as a solvent, in the presence of sulfuric acid and in the presence a hydrogenation catalyst and hydrogen

Bei dem erfindungsgemaßen Verfahren werden Phenylessigsaureester der Formel (I) hergestellt In der Formel (I) bedeutet Ar einen ein- oder mehrfach substituierten Phe- nylrest Als Substituenten eignen sich OR oder NR2, mit R gleich H oder Cι-C -Alkyl, oder Halogen, wie F, Cl oder Br Die Substituenten können sich dabei in o-, m- oder p- Stellung befinden, wobei der Phenylrest bevorzugt maximal 2 Substituenten und besonders bevorzugt nur einen Substituenten aufweist Bevorzugte Substituenten sind der Hydroxylrest und der Alkoxyrest, wobei beim Alkoxyrest der Methoxy- und der Ethoxy- rest bevorzugt sind Besonders bevorzugt ist der Phenylrest nur in p-Stellung durch OH oder OR oder in p-Stellung durch OH und in m-Stellung durch OR substituiertIn the process according to the invention, phenylacetic acid esters of the formula (I) are prepared. In the formula (I), Ar denotes a phenyl radical which is mono- or polysubstituted. OR or NR 2 are suitable as substituents, where R is H or —CC alkyl, or Halogen, such as F, Cl or Br. The substituents can be in the o-, m- or p-position, the phenyl radical preferably having a maximum of 2 substituents and particularly preferably only one substituent. Preferred substituents are the hydroxyl radical and the alkoxy radical, in which Alkoxy radical of methoxy and ethoxy rest preferred are particularly preferred, the phenyl radical is substituted only in the p-position by OH or OR or in the p-position by OH and in the m-position by OR

R' bedeutet in der Formel (I) einen d-C4-Alkylrest, wobei ein Cι-C2-Alkylrest bevorzugtR ' in the formula (I) denotes a dC 4 -alkyl radical, a C 1 -C 2 -alkyl radical being preferred

Durch das erfindungsgemaße Verfahren herstellbare Phenylessigsaureester sind somit beispielsweise 4-Hydroxy-3-methoxyphenylessιgsauremethyl- oder -ethylester, 4-Phenylacetic acid esters which can be prepared by the process according to the invention are, for example, 4-hydroxy-3-methoxyphenylessιgsauremethyl- or ethyl ester, 4-

Hydroxy-phenylessigsauremethyl- oder ethylester oder 4-Hydroxy-phenylacetic acid methyl or ethyl ester or 4-

Methoxyphenylessigsauremethyl- oder ethylester Bevorzugt wird 4-Hydroxy- phenylessigsauremethyl- oder -ethylester, besonders bevorzugt der 4-Hydroxy- phenylessigsauremethylester, hergestelltMethyl or ethyl methoxyphenylacetate Preferably, methyl or ethyl 4-hydroxyphenylacetate, particularly preferably methyl 4-hydroxyphenylacetate, is prepared

Als Ausgangsverbindung dienen die entsprechend substituierten Mandelsaureverbin- dungen der Formel (II) oder geeignete Salze davon Als Salze kommen dabei beispielsweise Na-, K- oder NH4-Salze in FrageThe correspondingly substituted mandelic acid compounds of the formula (II) or suitable salts thereof serve as the starting compound. For example, Na, K or NH 4 salts are suitable as salts

Bei dem erfindungsgemaßen Verfahren wird die entsprechende Mandelsaureverbin- dung der Formel (II) oder deren Salz gleichzeitig hydriert und verestert Als Losungsmittel dient dabei der Alkohol ROH, der zum gewünschten Ester im Endprodukt fuhrt Als Alkohole eignen sich demanch Methanol, Ethanol, Propanol oder Butanol Bevorzugt werden Methanol oder Ethanol eingesetzt, besonders bevorzugt wird Methanol als Losungsmittel verwendetIn the process according to the invention, the corresponding almond acid compound of the formula (II) or its salt is hydrogenated and esterified at the same time. The alcohol ROH, which leads to the desired ester in the end product, is used as the solvent. Methanol, ethanol, propanol or butanol are therefore preferred as alcohols methanol or ethanol are used, particularly preferably methanol is used as the solvent

Da der Alkohol sowohl als Losungsmittel als auch als Veresterungsmittel dient, wird er im Uberschuss, bezogen auf das Edukt, eingesetzt Bevorzugte wird er in einer Menge von 2 mol bis 60 mol pro mol Edukt, besonders bevorzugt von 10 bis 40 mol pro mol Edukt, verwendetSince the alcohol serves both as a solvent and as an esterifying agent, it is used in excess, based on the starting material, preferably in an amount of 2 mol to 60 mol per mol of starting material, particularly preferably from 10 to 40 mol per mol of starting material, used

Für das erfindungsgemaße Verfahren wird weiters Schwefelsaure als Hilfsstoff benotigt Die Menge an zugesetzter Schwefelsaure hangt dabei vom eingesetzten Edukt ab, wobei im Falle von Edukt-Salzen die Schwefelsaure im Uberschuss, bezogen auf das Edukt, eingesetzt wird Die bevorzugte Menge betragt, in Abhängigkeit vom eingesetz- ten Edukt, 0,3 bis 3 mol Schwefelsaure pro mol Edukt Besonders bevorzugt werden 0,5 bis 2 mol Schwefelsaure pro mol Edukt verwendetSulfuric acid is also required as an adjuvant for the process according to the invention. The amount of sulfuric acid added depends on the starting material used, and in the case of starting material salts the excess sulfuric acid, based on the starting material, is used. The preferred amount is dependent on the starting material used - educt, 0.3 to 3 mol of sulfuric acid per mol of educt. 0.5 to 2 mol of sulfuric acid per mol of educt are particularly preferably used

Als Katalysator eignen sich übliche Hydrierkatalysatoren, wie etwa Übergangsmetalle der Gruppe 8 des Periodensystems, wie Ni-, Fe-, Co-, Pd-, oder Pt-Katalysatoren oder deren Salze, Oxide oder Komplexe, sowie Elemente der Gruppen Ib, llb, III, IV, V, VIb oder VI Ib des Periodensystems oder deren Salze, Oxide oder Komplexe Bevorzugt werden Ubergangsmetalle der Gruppe 8 des Periodensystems eingesetzt, besonders bevorzugt wird ein Pd-Katalysator, beispielsweise PdCI2, Pd/C, PdCI2-PPh3 u s w , verwendet Besonders bevorzugt ist ein Pd/C-Katalysator Der Katalysator wir in üblichen Mengen von etwa 1 -10Gew%, bezogen auf das Edukt zugesetztSuitable hydrogenation catalysts are conventional hydrogenation catalysts, such as transition metals from group 8 of the periodic table, such as Ni, Fe, Co, Pd or Pt catalysts or their salts, oxides or complexes, and elements from groups Ib, IIb, III , IV, V, VIb or VI Ib of the periodic table or their salts, oxides or complexes. Transition metals from group 8 of the periodic table are preferably used, a Pd catalyst, for example PdCl 2 , Pd / C, PdCl 2 -PPh3 etc. is particularly preferred, A Pd / C catalyst is particularly preferred. The catalyst is added in customary amounts of about 1-10% by weight, based on the starting material

Gegebenenfalls kann dem Reaktionsgemisch noch Aktivkohle zur leichteren Isolierung des Katalysators nach Beendigung der Reaktion etwa in der Menge des Katalysators zugesetzt werdenIf necessary, activated carbon can be added to the reaction mixture to facilitate the isolation of the catalyst after the end of the reaction, approximately in the amount of the catalyst

Das erfindungsgemaße Verfahren wird bei einem Wasserstoffdruck von 2 -10 bar, bevorzugt bei 3 - 6 bar und einer Reaktionstemperatur von 70-150°C, bevorzugt bei 80- 140°C und besonders bevorzugt bei 100-120°C durchgeführtThe process according to the invention is carried out at a hydrogen pressure of 2-10 bar, preferably at 3-6 bar and a reaction temperature of 70-150 ° C, preferably at 80-140 ° C and particularly preferably at 100-120 ° C

Wahrend der gleichzeitigen Hydrierung und Veresterung wird das Reaktionsgemisch standig gerührtDuring the simultaneous hydrogenation and esterification, the reaction mixture is constantly stirred

Nach Beendigung der Reaktion wird der Katalysator, das bei Verwendung eines Man- delsauresalzes entstandene Sulfat und die gegebenenfalls vorhandene Aktivkohle von der Reaktionslosung, beispielsweise durch einfache Filtration, abgetrennt Die verbleibende schwefelsaure Losung wird sodann durch Zugabe geeigneter Basen, beispielsweise von NaOH, KOH oder NH3 auf einen pH-Wert von 2 bis 8, bevorzugt von 5 bis 7, eingestellt und erneut filtriert Vom erhaltenen Filtrat, das den gewünschten Phenylsau- reessigester enthalt, wird das Losungsmittel, d h der Alkohol, abgetrennt Dies kann beispielsweise durch Destillation oder am Rotationsverdampfer erfolgenAfter the reaction has ended, the catalyst, the sulfate formed when using a commercial acid salt and any activated carbon present are separated from the reaction solution, for example by simple filtration. The remaining sulfuric acid solution is then removed by adding suitable bases, for example NaOH, KOH or NH 3 adjusted to a pH of 2 to 8, preferably 5 to 7, and filtered again. The solvent, ie the alcohol, is separated off from the filtrate obtained, which contains the desired phenyl acid acetic ester. This can be done, for example, by distillation or on a rotary evaporator respectively

Durch das erfindungsgemaße Verfahren werden die gewünschten Phenylsaureessige- ster auf einfache und ökologische Weise in hohen Ausbeuten von über 90% erhalten Beispiel 1The process according to the invention gives the desired phenylacetic acid esters in a simple and ecological manner in high yields of over 90% example 1

91 ,70g (440,5mmol) 4-Hydroxymandelsaurenatπumsalz Monohydrat wurden zusammen mit 6, 10g Aktivkohle, 6, 10g Pd/C (5%) Katalysator, 65,28g (642,3mmol) Schwefelsaure und 492g (15,4mol) Methanol 6 Stunden bei 4 bar Wasserstoffdruck und 1 10°C gerührt Nach Beendigung der Reaktion wurde der Katalysator, die Aktivkohle und das entstandene, in Methanol schwer lösliche, Natriumsalz von der Reaktionslosung abfiltriert Die verbleibende schwefelsaure Losung wurde mit 40%ιger NaOH auf pH 6 gestellt und erneut filtriert Vom Fittrat wurde sodann das Methanol am Rotationsverdampfer abgezogen Ausbeute an 4-Hydroxyphenylessιgsauremethylester > 90% 91.70 g (440.5 mmol) of 4-hydroxymandelic acid sodium salt monohydrate were combined with 6, 10 g of activated carbon, 6, 10 g of Pd / C (5%) catalyst, 65.28 g (642.3 mmol) of sulfuric acid and 492 g (15.4 mol) of methanol 6 Hours at 4 bar hydrogen pressure and 110 ° C. After the reaction had ended, the catalyst, the activated carbon and the sodium salt formed, which was sparingly soluble in methanol, were filtered off from the reaction solution. The remaining sulfuric acid solution was adjusted to pH 6 with 40% NaOH and again filtered from the Fittrat, the methanol was then removed on a rotary evaporator. Yield of methyl 4-hydroxyphenylacetate> 90%

Claims

Patentansprücheclaims 1 Verfahren zur Herstellung von Phenylessigsaurederivaten der Formel1 Process for the preparation of phenylacetic acid derivatives of the formula Ar-CH2COOR' (I)Ar-CH 2 COOR ' (I) in der Ar einen ein- oder mehrfach durch OR, NR2 oder Halogen substituierten Phe- nylrest, R H oder einen Cι-C4-Alkylrest und R' einen Cι-C4-Alkylrest bedeuten, durch gleichzeitige Hydrierung und Veresterung der korrespondierenden substituierten Mandelsaureπ der Formelin which Ar is a phenyl radical which is mono- or polysubstituted by OR, NR 2 or halogen, RH or a C 1 -C 4 -alkyl radical and R 'is a C 1 -C 4 -alkyl radical, by simultaneous hydrogenation and esterification of the corresponding substituted mandelic acid of the formula Ar-CHOHCOOH (II)Ar-CHOHCOOH (II) in der Ar obige Bedeutung hat, oder eines geeigneten Salzes, dadurch gekennzeichnet, dass die gleichzeitige Hydrierung und Veresterung in einem Alkohol ROH, wobei R' ein Cι-C4-Alkylrest ist, als Losungsmittel, in Anwesenheit von Schwefelsaure und in Gegenwart eines Hydrierkatalysators und Wasserstoff erfolgtin the Ar has the above meaning, or a suitable salt, characterized in that the simultaneous hydrogenation and esterification in an alcohol ROH, where R 'is a C 1 -C 4 -alkyl radical, as a solvent, in the presence of sulfuric acid and in the presence of a hydrogenation catalyst and hydrogen occurs Verfahren nach Anspruch 1 dadurch gekennzeichnet, dass Phenylessigsaureester der Formel (I) in der Ar einen ein- oder zweifach durch OR substituierten Pheπylrest und R H oder einen Cι-C -Alkylrest bedeuten, hergestellt werdenA method according to claim 1, characterized in that phenylacetic acid esters of the formula (I) in which Ar is a phenyl radical which is mono- or disubstituted by OR and R H or a -CC alkyl radical are prepared Verfahren nach Anspruch 1 , dadurch gekennzeichnet, dass 4-Hydroxy-3- methoxyphenylessigsauremethyl- oder -ethylester, 4-Hydroxy- phenylessigsauremethyl- oder -ethylester oder 4-Methoxyphenylessιgsauremethyl- oder -ethylester hergestellt werdenA method according to claim 1, characterized in that 4-hydroxy-3-methoxyphenylacetic acid, methyl or ethyl ester, 4-hydroxy-phenylacetic acid, methyl or ethyl ester or 4-methoxyphenylacetic acid, methyl or ethyl ester are prepared Verfahren nach Anspruch 1 , dadurch gekennzeichnet, dass als Salz der substituierten Mandelsauren der Formel (II) ein Na-, K- oder NH4-Salz verwendet wird Verfahren nach Anspruch 1 , dadurch gekennzeichnet, dass der Alkohol ROH in einer Menge von 2 bis 60 mol pro mol Mandelsaureverbindung der Formel (II) eingesetzt wirdA method according to claim 1, characterized in that a Na, K or NH 4 salt is used as the salt of the substituted almond acids of the formula (II) A method according to claim 1, characterized in that the alcohol ROH is used in an amount of 2 to 60 mol per mol of almond acid compound of the formula (II) Verfahren nach Anspruch 1 , dadurch gekennzeichnet, dass die Schwefelsaure in einer Menge von 0,3 bis 3 mol pro mol Mandelsaureverbindung der Formel (II) eingesetzt wirdA method according to claim 1, characterized in that the sulfuric acid is used in an amount of 0.3 to 3 mol per mol of mandelic acid compound of the formula (II) Verfahren nach Anspruch 1 , dadurch gekennzeichnet, dass als Hydrierkatalysator Ni- , Fe-, Co-, Pd-, oder Pt-Katalysatoren oder deren Salze, Oxide oder Komplexe eingesetzt werdenA method according to claim 1, characterized in that Ni, Fe, Co, Pd, or Pt catalysts or their salts, oxides or complexes are used as the hydrogenation catalyst Verfahren nach Anspruch 7, dadurch gekennzeichnet, dass als Hydrierkatalysator Pd- Katalysatoren oder deren Salze, Oxide oder Komplexe eingesetzt werdenA method according to claim 7, characterized in that Pd catalysts or their salts, oxides or complexes are used as the hydrogenation catalyst Verfahren nach Anspruch 1 , dadurch gekennzeichnet, dass die gleichzeitige Hydrierung und Veresterung bei einer Temperatur von 70 bis 150°C und einem Druck von 2 bis 10 bar durchgeführt wirdA method according to claim 1, characterized in that the simultaneous hydrogenation and esterification is carried out at a temperature of 70 to 150 ° C and a pressure of 2 to 10 bar Verfahren nach Anspruch 1 , dadurch gekennzeichnet, dass nach beendeter Hydrierung und Veresterung der Katalysator und das bei Verwendung eines Mandelsau- resalzes der Formel (II) anfallende Sulfat abgetrennt werden, die verbleibende schwefelsaure Losung durch Zugabe einer Base auf einen pH-Wert zwischen 2 und 8 eingestellt und filtriert wird, anschließend vom Filtrat der Alkohol ROH abgetrennt und der gewünschte Phenylessigsaureester der Formel (I) erhalten wird A method according to claim 1, characterized in that after the hydrogenation and esterification has ended, the catalyst and the sulfate obtained when using an almond acid salt of the formula (II) are separated off, the remaining sulfuric acid solution by adding a base to a pH between 2 and 8 is adjusted and filtered, then the alcohol ROH is separated from the filtrate and the desired phenylacetic acid ester of the formula (I) is obtained
PCT/EP2000/010322 1999-11-17 2000-10-20 Method for producing phenylacetic acid esters Ceased WO2001036366A1 (en)

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AU12739/01A AU1273901A (en) 1999-11-17 2000-10-20 Method for producing phenylacetic acid esters

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ATA1935/99 1999-11-17
AT193599 1999-11-17

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007009590A1 (en) * 2005-07-18 2007-01-25 Dsm Ip Assets B.V. Process for the preparation of phenolic compounds

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4337355A (en) * 1980-06-20 1982-06-29 Nippon Gohsei Kagaku Kogyo Kabushiki Kaisha Process for preparing 4-hydroxyphenylacetic acid
WO1997038963A1 (en) * 1996-04-18 1997-10-23 E.I. Du Pont De Nemours And Company Process for the manufacture of alkyl 2-(6-methoxy-naphthyl)propionates

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4337355A (en) * 1980-06-20 1982-06-29 Nippon Gohsei Kagaku Kogyo Kabushiki Kaisha Process for preparing 4-hydroxyphenylacetic acid
WO1997038963A1 (en) * 1996-04-18 1997-10-23 E.I. Du Pont De Nemours And Company Process for the manufacture of alkyl 2-(6-methoxy-naphthyl)propionates

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007009590A1 (en) * 2005-07-18 2007-01-25 Dsm Ip Assets B.V. Process for the preparation of phenolic compounds

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