EP0000518A1 - Process for the chemical resolution of racemic mandelic acid - Google Patents

Process for the chemical resolution of racemic mandelic acid Download PDF

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EP0000518A1
EP0000518A1 EP78100393A EP78100393A EP0000518A1 EP 0000518 A1 EP0000518 A1 EP 0000518A1 EP 78100393 A EP78100393 A EP 78100393A EP 78100393 A EP78100393 A EP 78100393A EP 0000518 A1 EP0000518 A1 EP 0000518A1
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mandelic acid
aminobutanol
optically active
mother liquor
acids
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EP0000518B1 (en
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Wolfgang Dr. Dannenberg
Horst Dr. Schmand
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Honeywell Riedel de Haen AG
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C59/40—Unsaturated compounds
    • C07C59/42—Unsaturated compounds containing hydroxy or O-metal groups
    • C07C59/48—Unsaturated compounds containing hydroxy or O-metal groups containing six-membered aromatic rings
    • C07C59/50—Mandelic acid

Definitions

  • the invention relates to a process for the chemical cleavage of racemic mandelic acid and the production, in particular, of D (-) - mandelic acid.
  • D (-) - mandelic acid is an important intermediate for the production of semisynthetic cephalosporins.
  • optically active amines used in the practically usable mandelic acid racemate cleavages are very expensive and moreover have relatively high molecular weights, so that the use of larger amounts is necessary.
  • the above object can be achieved by adding DL-mandelic acid in one or a mixture of a plurality of solvents from the group water, lower aliphatic alcohols and ketones with D (-) - 2-aminobutanol -. (1 ), the crystallizing diastereomeric salt is separated from the mother liquor and then the diastereomeric salts contained in crystals and mother liquor with acids or bases in each case into the optically active methods according to methods known per se Acids and D (-) - 2-aminobutanol separated.
  • D (-) - 2-aminobutanol- (1) can easily be obtained from racemic 2-aminobutanol- (1) by resolution with L (+) - tartaric acid (DE-PS 1 243 206). It shows a high resistance to racemization and can be easily cleaned by distillation.
  • 2-Aminobutanol- (1) has a comparatively low molecular weight and shows excellent dissolving properties in the solvents used for resolution. After successful cleavage, the amine used can be recovered using the usual methods and fed back into the process.
  • optically active forms of 2-aminobutanol (1) are already in use as racemate resolution reagents. However, based on the state of the art (e.g. tables of resolving agents and optical resolution), one had to expect that only bases which contain a large molecule, preferably a secondary or tertiary nitrogen atom, are suitable for the resolution of mandelic acid.
  • the optically active aminobutanol can be used in proportions between 0.5 and 1.0 equivalents. Equimolar amounts of mandelic acid and aminobutanol are preferably used, since the highest yields are achieved in this way.

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  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

1. Process for the chemical cleavage of racemic mandelic acid and for the preparation especially of D(-)-mandelic acid, which comprises reacting DL-mandelic acid in one solvent or in a mixture of several solvents of the group water, lower aliphatic alcohols and ketones with D(-)-2-aminobutanol-(1), separating the crystallizing diastereomeric salt from the mother liquor and subsequently splitting according to known methods the diastereomeric salts contained in the crystallization product and the mother liquor with acids or bases to yield each the optically active acids and D(-)-2-aminobutanol-(1).

Description

umfangreiche Umkristallisationen notwendig. Man erhält ca. 80 % Ausbeute des Diastereomeren, das nach Spaltung (+)-Mandelsäure ergibt (A. Mackenzie, J. Chem. Soc. 75 (1899) 966).extensive recrystallizations necessary. About 80% yield of the diastereomer is obtained which, after cleavage, gives (+) - mandelic acid (A. Mackenzie, J. Chem. Soc. 75 (1899) 966).

Bei der Spaltung von DL-Mandelsäure mit (+)-Phenyläthylamin unter Verwendung äquimolarer Mengen in Wasser als Lösungsmittel sind zur. Erhöhung der optischen Reinheit auch mehrere Umkristallisationen erforderlich. Es werden ca. 86 % Ausbeute an Diastereomeren erhalten, die nach Spaltung des kristallisierten Salzes (-)-Mandelsäure liefern (A. W. Ingersoll et al., J. Amer. Chem. Soc. 55 (1933) 411).In the cleavage of DL-mandelic acid with (+) - phenylethylamine using equimolar amounts in water as a solvent. Increasing the optical purity also requires several recrystallizations. Approx. 86% yield of diastereomers are obtained which, after cleavage of the crystallized salt, give (-) - mandelic acid (A. W. Ingersoll et al., J. Amer. Chem. Soc. 55 (1933) 411).

Die hohe Ausbeute lässt sich nur durch eine umfangreiche Aufarbeitung der insgesamt eingesetzten grossen Lösungsmittelmenge erreichen.The high yield can only be achieved by extensive work-up of the large amount of solvent used overall.

Das Verfahren zur Spaltung von DL-Mandelsäure mit (-)-Ephedrin unter Verwendung äquimolarer Mengen in Äthanol als Lösungsmittel lieferte eine Ausbeute von höchstens 85 % der Diastereomeren. Nach Spaltung des kristallisierten Salzes erhält man (-)-Mandelsäure. Zur Erhöhung der optischen Reinheit der Mandelsäure sind mehrere Umkristallisationen der Diastereomeren erforderlich. Spätere Nacharbeiten können die Ausbeuteangaben nicht bestätigen. Es werden nur 70 % Ausbeute erhalten (R. Roger, J. Chem. Soc. 1935, 1544).The process for the cleavage of DL-mandelic acid with (-) - ephedrine using equimolar amounts in ethanol as solvent gave a yield of at most 85% of the diastereomers. After the crystallized salt has been cleaved, (-) - mandelic acid is obtained. Several recrystallizations of the diastereomers are required to increase the optical purity of the mandelic acid. Subsequent rework cannot confirm the yield information. Only 70% yield is obtained (R. Roger, J. Chem. Soc. 1935, 1544).

Die Spaltungen mit Morphin, Strychnin und Cinchonidin sind nur unvollständig beschrieben. Strychnin ist ausserdem sehr giftig, so dass eine praktische Verwendung nicht in Betracht kommt.The cleavages with morphine, strychnine and cinchonidine are only partially described. Strychnine is also very toxic, so practical use is out of the question.

In den neueren Veröffentlichungen-über Racematspaltungen von DL-Mandelsäure tritt neben L-Phenylalanin immer stärker die Spaltung an optisch aktiven Polymeren durch Chro-In the more recent publications on racemate cleavages of DL-mandelic acid, in addition to L-phenylalanine, the cleavage of optically active polymers by chromium

Die Erfindung betrifft ein Verfahren zur chemischen.Spaltung racemischer Mandelsäure und Herstellung insbesondere von D(-)-Mandelsäure.The invention relates to a process for the chemical cleavage of racemic mandelic acid and the production, in particular, of D (-) - mandelic acid.

Neben der allgemeinen Verwendbarkeit von optisch aktiven Mandelsäurederivaten zur Racematspaltung von Aminen stellt die D(-)-Mandelsäure ein wichtiges Zwischenprodukt zur Herstellung halbsynthetischer Cephalosporine dar.In addition to the general applicability of optically active mandelic acid derivatives for resolving amines, D (-) - mandelic acid is an important intermediate for the production of semisynthetic cephalosporins.

Verfahren zur Spaltung von DL-Mandelsäure in die optischen Antipoden sind bekannt. Sie verlaufen über die Bildung diastereomerer Salze mit optisch aktiven Verbindungen, insbesondere mit optisch aktiven Aminen. In den "Tables of Resolving Agents and Optical Resolution", S. H. Wilen, 1972, Notre Dame, Indiana, werden Conchonin, Cinchonidin, Phenyläthylamin, Ephedrin, Strychnin und Morphin als Spaltungsreagenzien für DL-Mandelsäure aufgeführt.Methods for splitting DL-mandelic acid into the optical antipodes are known. They run through the formation of diastereomeric salts with optically active compounds, in particular with optically active amines. Conchonine, cinchonidine, phenylethylamine, ephedrine, strychnine and morphine are listed as cleavage reagents for DL-mandelic acid in the "Tables of Resolving Agents and Optical Resolution", S.H. Wilen, 1972, Notre Dame, Indiana.

Bei der Spaltung von DL-Mandelsäure mit Cinchonin unter Verwendung äquimolarer Mengen in Wasser als Lösungsmittel muss die Kristallisation des diastereomeren Salzes durch Animpfen bei einer bestimmten höheren Temperatur eingeleitet werden. Zur Erhöhung der optischen Reinheit sind matographie oder Ionenaustauscheffekte in den Vordergrund ,(G. Blaschke, Chem. Ber. 107, (1974) 237). Das jeweilige Trägermaterial ist dabei mit optisch aktiven Aminen behandelt worden. Die Spaltungen verlaufen jedoch meist en- vollständig und haben bislang noch keine technische Verwertung gefunden.When DL-mandelic acid is cleaved with cinchonine using equimolar amounts in water as the solvent, the crystallization of the diastereomeric salt must be initiated by seeding at a certain higher temperature. To increase the optical purity matography or ion exchange effects in the foreground, (G. Blaschke, Chem. Ber. 107, (1974) 237). The respective carrier material has been treated with optically active amines. However, the divisions are mostly complete and have not yet been technically exploited.

Die in den praktisch nutzbaren Mandelsäure-Racematspaltungen eingesetzten optisch aktiven Amine sind sehr teuer und haben ausserdem relativ hohe Molekulargewichte, so dass der Einsatz grösserer Mengen notwendig wird.The optically active amines used in the practically usable mandelic acid racemate cleavages are very expensive and moreover have relatively high molecular weights, so that the use of larger amounts is necessary.

Es bestand daher die Aufgabe, für die Racematspaltung von DL-Mandelsäure ein billiges Spaltungsmittel mit möglichst niedrigem Molgewicht und hohem Wirkungsgrad bereitzustellen.It was therefore the task of the resolution of DL-mandelic a cheap Spaltun g smittel low molecular weight as possible and provide high efficiency.

Das Prinzip der Racematspaltung durch fraktionierte Kristallisation diastereomerer Salze ist dem Fachmann bereits bekannt. Die fraktioniert kristallisierten Salze sind leicht hydrolysierbar und das gewünschte Enantiomere wird unter Ausnutzung der Säure-Basen-Eigenschaften der Partner von der optisch aktiven Hilfsverbindung getrennt. Eine Voraussage darüber, welche-Verbindungen besonders gute Trennungsergebnisse liefern, ist nicht möglich (G. L. Eliel, Stereochemie der Kohlenstoffverbindungen, Weinheim 1966, S. 60 ff).The principle of racemate resolution by fractional crystallization of diastereomeric salts is already known to the person skilled in the art. The fractionally crystallized salts are easily hydrolyzable and the desired enantiomer is separated from the optically active auxiliary compound using the partners' acid-base properties. It is not possible to predict which compounds will give particularly good separation results (G.L. Eliel, Stereochemie derarbonverbindungen, Weinheim 1966, p. 60 ff).

Es wurde nun überraschend gefunden, dass die genannte Aufgabe dadurch gelöst werden kann, dass man DL-Mandelsäure in einem oder einer Mischung mehrer Lösungsmittel aus der Gruppe Wasser, niedere aliphatische Alkohole und Ketone mit D(-)-2-Aminobutanol-.(1) umsetzt, das auskristallisierende diastereomere Salz von der Mutterlauge abtrennt und anschliessend die in Kristallisat und Mutterlauge enthaltenen diastereomeren Salze mit Säuren oder Basen nach an sich bekannten Methoden jeweils in die optisch aktiven Säuren und D(-)-2-Aminobutanol auftrennt.It has now surprisingly been found that the above object can be achieved by adding DL-mandelic acid in one or a mixture of a plurality of solvents from the group water, lower aliphatic alcohols and ketones with D (-) - 2-aminobutanol -. (1 ), the crystallizing diastereomeric salt is separated from the mother liquor and then the diastereomeric salts contained in crystals and mother liquor with acids or bases in each case into the optically active methods according to methods known per se Acids and D (-) - 2-aminobutanol separated.

D(-)-2-Aminobutanol-(1) lässt sich leicht aus dem racemischen 2-Aminobutanol-(1) durch Racematspaltung mit L(+)-Weinsäure gewinnen (DE-PS 1 243 206). Es zeigt eine hohe Racemisierungsbeständigkeit und kann ohne grossen Aufwand durch Destillation gereinigt werden. 2-Aminobutanol-(1) hat ein vergleichsweise niedriges Molekulargewicht und zeigt ausgezeichnete Lösungseigenschaften in den zur Racematspaltung verwendeten Solventien. Nach erfolgreicher Spaltung kann das eingesetzte Amin nach den üblichen Methoden zurückgewonnen und dem Prozess erneut zugeführt werden. D (-) - 2-aminobutanol- (1) can easily be obtained from racemic 2-aminobutanol- (1) by resolution with L (+) - tartaric acid (DE-PS 1 243 206). It shows a high resistance to racemization and can be easily cleaned by distillation. 2-Aminobutanol- (1) has a comparatively low molecular weight and shows excellent dissolving properties in the solvents used for resolution. After successful cleavage, the amine used can be recovered using the usual methods and fed back into the process.

Die optisch aktiven Formen von 2-Aminobutanol-(1) sind bereits als Racematspaltungsreagenzien in Gebrauch. Man musste jedoch auf Grund des Standes der Technik (z.B. Tables of Resolving Agents and Optical Resolution) erwarten, dass nur Basen, die ein grosses Molekül, bevorzugt ein sekundäres oder tertiäres Stickstoffatom, enthalten, für die Racemattrennung der Mandelsäure geeignet sind..The optically active forms of 2-aminobutanol (1) are already in use as racemate resolution reagents. However, based on the state of the art (e.g. tables of resolving agents and optical resolution), one had to expect that only bases which contain a large molecule, preferably a secondary or tertiary nitrogen atom, are suitable for the resolution of mandelic acid.

Im vorliegenden Fall ist es überraschend, dass nach der erfindungsgemässen Umsetzung eine Gesamtausbeute von ca 90 % an reinem optisch aktivem Mandelat erhalten werden kann, und zwar weitgehend unabhängig vom verwendeten Lösungsmittel.In the present case, it is surprising that a total yield of approximately 90% of pure optically active mandelate can be obtained after the reaction according to the invention, largely independently of the solvent used.

Bei Wahl der geeigneten Konzentration ist es möglich, ein diastereomeres Salzpaar zur Ausfällung zu bringen, das bereits ohne Umkristallisation eine hohe, für die Weiterverarbeitung geeignete optische Reinheit aufweist.If the appropriate concentration is selected, it is possible to precipitate a diastereomeric salt pair which has a high optical purity suitable for further processing even without recrystallization.

Bei Einsatz von D(-)-2-Aminobutanol-(1) kristallisiert aus Wasser, niederen Alkanolen und Ketonen wie z.B. Aceton, das (-).(-)-Salzpaar. Bedingungen für ausreichende Reinheit und Ausbeuten über 90 % können durch Variation der

Figure imgb0001
When using D (-) - 2-aminobutanol- (1), the (-). (-) - salt pair crystallizes from water, lower alkanols and ketones such as acetone. Conditions for sufficient purity and yields above 90% can be varied by
Figure imgb0001

Eine Reihe von Versuchen mit verschiedenen Lösungsmitteln und nach Zusammensetzung und Konzeatration unterschiedlichen Lösungsmittelgemischen ergab, dass unterschiedliche Konzentrationen Veränderungen in Ausbeute und optischer Reinheit des diastereomeren Salzpaares bewirken. Eine für das jeweilige Lösungsmittel günstigste Konzentration lässt sich durch Experimente eingrenzen. Wasser als Verdünnungsmittel der Alkanole senkt allgemein die Ausbeuten, nimmt aber wenig Einfluss auf die Diastereomereninheit der Salze.A series of tests with different solvents and different solvent mixtures according to composition and concentration showed that different concentrations cause changes in the yield and optical purity of the diastereomeric salt pair. A concentration that is most favorable for the respective solvent can be limited by experiments. Water as a diluent for the alkanols generally lowers the yields, but has little influence on the diastereomeric unit of the salts.

Zur Racematspaltung der DL-Mandelsäure kann das optisch aktive Aminobutanol in Anteilen zwischen 0,5 und 1,0 Äquivalenten eingesetzt werden. Bevorzugt werden äquimolare Mengen von Mandelsäure und Aminobutanol verwendet, da auf diese Weise die höchsten Ausbeuten erzielt werden.For the resolution of DL-mandelic acid, the optically active aminobutanol can be used in proportions between 0.5 and 1.0 equivalents. Equimolar amounts of mandelic acid and aminobutanol are preferably used, since the highest yields are achieved in this way.

Die bei den oben erwähnten Versuchen erhaltenen Produkte wurden zur Reinigung des kristallisierten Salzes mit 5 - 20 ml Äthanol gewaschen. Durch mehrfache Umkristallisationen wurde [α]

Figure imgb0002
= -80,3° als höchste optische Drehung des kristallinen diastereomeren Salzes gemessen. Salze mit spezifischen Drehungen von mindestens -79,0° ergaben nach der sauren Spaltung eine optisch aktive D(-)-Mandelsäure von mindestens 96,5% optischer Reinheit [α]
Figure imgb0003
 = -152,3°)The products obtained in the experiments mentioned above were washed with 5-20 ml of ethanol to purify the crystallized salt. Through multiple recrystallizations, [α]
Figure imgb0002
 = -80.3 ° measured as the highest optical rotation of the crystalline diastereomeric salt. Salts with specific rotations of at least -79.0 ° gave an optically active D (-) - mandelic acid of at least 96.5% optical purity after the acidic cleavage [α]
Figure imgb0003
 = -152.3 °)

Zur Berechnung der optischen Reinheit der Mandelsäure wurden die in der Literatur gefundenen höchsten spezifi- schen Drenwerte zum Vergleich herangezogen:

  • [α]
    Figure imgb0004
     = -157,5° (Wasser, C = 3,2) (R. Roger, J. Chem. Soc. 1935, 1544).
  • [α]
    Figure imgb0005
     = -157,3° (Wasser, C = 1,4 ) (Schwab et al., Z-. physiol. Chem. 215, (1933) 121).
To calculate the optical purity of mandelic acid, the highest specific values used for comparison:
  • [α]
    Figure imgb0004
     = -157.5 ° (water, C = 3.2) (R. Roger, J. Chem. Soc. 1935, 1544).
  • [α]
    Figure imgb0005
     = -157.3 ° (water, C = 1.4) (Schwab et al., Z-. Physiol. Chem. 215, (1933) 121).

Für das noch nicht literaturbekannte Salz der D(-)-Mandelsäure mit D(-)-2-Aminobutanol-(1) wurden folgende Kennwerte ermittelt:

  • Fp = 130° - 131° C (Äthanol) [α]
    Figure imgb0006
     = -80,3° (C = 2, H2O)
  • 1H-NMR (D2O): δ(Na-TMS) 0,90 (t, 3); 1,55 (m, 2); 2,9 - 3,9 (m, 3); 4,83 (s, 5); 4,98 (s, 1); 745 (m, 5).
The following characteristic values were determined for the salt of D (-) - mandelic acid with D (-) - 2-aminobutanol- (1), which is not yet known from the literature:
  • Mp = 130 ° -131 ° C (ethanol) [α]
    Figure imgb0006
     = -80.3 ° (C = 2, H 2 O)
  • 1 H NMR (D 2 O): δ (Na-TMS) 0.90 (t, 3); 1.55 (m, 2); 2.9 - 3.9 (m, 3); 4.83 (s, 5); 4.98 (s, 1); 745 (m, 5).

Elementaranalyse für C12H19NO4 ber.: C 59,7 %; H 7,9 %; N 5,8 %; gef.: C 59,8 %; H 7,7 %; N 5,8 %.Elemental analysis for C 12 H 19 NO 4 calc .: C 59.7%; H 7.9%; N 5.8%; Found: C 59.8%; H 7.7%; N 5.8%.

Die Erfindung soll durch folgende Beispiele ohne Einschränkung der Allgemeingültigkeit erläutert werden:The following examples are intended to illustrate the invention without restricting its general validity:

Beispiel 1 :Example 1 :

Figure imgb0007
Figure imgb0007
Figure imgb0008
Figure imgb0008
Figure imgb0009
Figure imgb0009

In ähnlicher Weise wurden die folgenden Beispiele ausgeführt, bei denen das Molverhältnis Mandelsäure / Aminobutanol, bzw. die Menge und die Zusammensetzung des Lösungsmittels variiert wurden. Die Ansatzgrösse betrug jeweils 0,1 Mol. Die Fehlerbreite der spez. Drehungen ist mit ± 0,5° anzusetzen.

Figure imgb0010
Figure imgb0011
 The following examples were carried out in a similar manner, in which the molar ratio of mandelic acid / aminobutanol or the amount and the composition of the solvent were varied. The batch size was 0.1 mol. The range of error of the spec. Rotations should be set at ± 0.5 °.
Figure imgb0010
Figure imgb0011

Claims (2)

1. Verfahren zur chemischen Spaltung racemischer Mandelsäure und Herstellung insbesondere von D(-)-Mandelsäure dadurch gekennzeichnet, dass man DL-Mandelsäure in einem oder einer Mischung mehrerer Lösungsmittel aus der Gruppe Wasser, niedere aliphatische Alkohole und Ketone mit D (-) -2-Aminobutanol-(1) umsetzt, das auskristallisierende diastereomere Salz von der Mutterlauge abtrennt und anschliessend die in Kristallisat und Mutterlauge enthaltenen diastereomeren Salze mit Säuren oder Basen nach an sich bekannten Methoden je- weils in die: optisch aktiven Säuren und D (-)-2-Aminobutanol-(1) auftrennt.1. Process for the chemical cleavage of racemic mandelic acid and preparation of D (-) - mandelic acid in particular, characterized in that DL-mandelic acid in one or a mixture of several solvents from the group water, lower aliphatic alcohols and ketones with D (-) -2 -Aminobutanol- (1), separates the crystallizing diastereomeric salt from the mother liquor and then the diastereomeric salts contained in crystals and mother liquor with acids or bases according to methods known per se into the: optically active acids and D (-) - 2-Aminobutanol- (1) separates. 2. Salz der D(-)-Mandelsäure mit D(-)-2-Aminobutanol-(1).2. Salt of D (-) - mandelic acid with D (-) - 2-aminobutanol- (1).
EP78100393A 1977-07-23 1978-07-14 Process for the chemical resolution of racemic mandelic acid Expired EP0000518B1 (en)

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DE2733425 1977-07-23

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EP0025841A1 (en) * 1979-08-22 1981-04-01 BASF Aktiengesellschaft Diastereomeric salts of malic acid and 2-amino-1-butanol and process for the scission of racemic malic acid
EP0036265A1 (en) * 1980-03-05 1981-09-23 Hiroyuki Nohira Method of optical resolution of (+/-)-2-amino-1-butanol and/or (+/-) -mandelic acid
EP0202522A2 (en) * 1985-05-11 1986-11-26 BASF Aktiengesellschaft Process for the racemic resolution of D,L-2-aminobutan-1-ol
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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0025841A1 (en) * 1979-08-22 1981-04-01 BASF Aktiengesellschaft Diastereomeric salts of malic acid and 2-amino-1-butanol and process for the scission of racemic malic acid
EP0036265A1 (en) * 1980-03-05 1981-09-23 Hiroyuki Nohira Method of optical resolution of (+/-)-2-amino-1-butanol and/or (+/-) -mandelic acid
EP0202522A2 (en) * 1985-05-11 1986-11-26 BASF Aktiengesellschaft Process for the racemic resolution of D,L-2-aminobutan-1-ol
EP0202522A3 (en) * 1985-05-11 1988-03-23 Basf Aktiengesellschaft Process for the racemic resolution of d,l-2-aminobutan-1-ol
US6743944B1 (en) 1999-09-07 2004-06-01 Mitsubishi Rayon Co., Ltd. Process for producing optically active aminoalcohol

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JPS5843939A (en) 1983-03-14
EP0000518B1 (en) 1981-01-07
DE2733425A1 (en) 1979-01-25
JPS5424849A (en) 1979-02-24
DE2733425C2 (en) 1982-08-26
DE2860412D1 (en) 1981-02-26

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