EP1758878A1 - Process for the production of 4-(alpha-hydroxyalkyl)-1,3-dioxan-5-ones - Google Patents

Process for the production of 4-(alpha-hydroxyalkyl)-1,3-dioxan-5-ones

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Publication number
EP1758878A1
EP1758878A1 EP05753902A EP05753902A EP1758878A1 EP 1758878 A1 EP1758878 A1 EP 1758878A1 EP 05753902 A EP05753902 A EP 05753902A EP 05753902 A EP05753902 A EP 05753902A EP 1758878 A1 EP1758878 A1 EP 1758878A1
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EP
European Patent Office
Prior art keywords
aryl
substituted
compounds
independently
unsubstituted alkyl
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Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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EP05753902A
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German (de)
French (fr)
Inventor
Bernhard Westermann
Meinolf Lange
Nasir Hayat
Christiane Neuhaus
Fritz Link
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Girindus AG
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Girindus AG
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Priority to EP05753902A priority Critical patent/EP1758878A1/en
Publication of EP1758878A1 publication Critical patent/EP1758878A1/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D319/00—Heterocyclic compounds containing six-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D319/04—1,3-Dioxanes; Hydrogenated 1,3-dioxanes
    • C07D319/06—1,3-Dioxanes; Hydrogenated 1,3-dioxanes not condensed with other rings

Definitions

  • the present invention relates to a synthesis process and compounds obtainable thereby.
  • Aldol reactions are one of the essential carbon / carbon linking reactions both in nature and in the repertoire of the synthetic chemist. In nature, such reactions are catalyzed by enzymes that function either via an enamine mechanism (class 1 aldolases) or via a zinc cofactor (class 2 aldolases). Here a high stereoselectivity is achieved.
  • Marek Majewski et al. describe in J. Org. Chem. 65 (2000) 5152-5160 a process for the aldol reaction of enolates starting from 1,3-dioxan-5-ones by reaction with chiral lithium amides.
  • R substituted or unsubstituted alkyl, aryl, heterocycles containing one or more O, N, S, P or B;
  • Ri and R 2 independently of one another are H, substituted or unsubstituted alkyl, Aryl, heterocycles containing one or more O, N, S, P or B
  • R ' H, OH, OR or OSiX 3 where X are independently alkyl or aryl.
  • a cyclic starting compound namely derivatives of 1,3-dioxan-5-one, is used, which are reacted with aldehydes in the presence of proline or proline derivatives.
  • These starting compounds are dihydroxyacetone derivatives. High stereoselectivities are achieved.
  • proline or proline derivative forms an enamine intermediate, in which the carboxy group of the proline is involved in the orientation, so that the surprisingly high stereoselectivities are achieved.
  • Alkyl in the sense of this application are in particular straight-chain or branched alkyl, cycloalkyl, bicycloalkyl, tricycloalkyl, alkenyl, alkynyl, heterocycloalkyl compounds. Typical representatives are methyl, ethyl, N-propyl, isopropyl, butyl, cyclohexyl or substituted derivatives thereof.
  • Aryl in the sense of this application also includes, in particular, heteroaryl, arylalkyl or heteroarylalkyl groups. Typical representatives are phenyl, benzyl, pyrridine and substituted derivatives thereof.
  • the alkyl or aryl radicals can also be substituted by one or more hydroxy, alkoxy, aryloxy, alkanoyl, aroyl, carboxy, alkoxycarbonyl, amino, alkylamino, hydroxylamino, amido, carbamoyl , Ureido, amidino, guanidino, cyano, azido, mercapto, alkylthio, alkylsulfoxy, alkylsulfonyl, alkylsulfonyl, aminosulfonyl, fluorine, chlorine, bromine, iodine, alkyl or perfluoroalkyl radicals substituted derivatives.
  • R contains one or more nitrogen atoms.
  • nitrogen atoms are derivatives of compounds with, for example, azididine, pyrrolidine, pyrroline, piperidine, piperazine, homopiperazine, morpholine, thiomorpholine, pyridine, di- or tetra-hydropyridine, pyrimidine, Pyrazine, azepine, dihydroazepine, oxazepine, diazepine, imidazole, pyrazole, oxazole or Thiazole rings, which may have fused-on aliphatic, heteroaliphatic, aromatic or heteroaromatic rings and / or by one or more hydroxy, alkoxy, aryloxy, aklanoyl, aroyl, carboxy, alkoxycarbonyl, amino, alkylamino -, Hydroxylamino, amido, carbanoyl, ureido, amidino, guanidino, cyano, azido
  • the amounts of proline or proline derivative required for the reaction are typically 0.1 to 30 mol%, more preferably 1 to 10 mol%, even more preferably 1 to 5 mol%.
  • proline or proline derivative used only catalytically participates in the reaction and can therefore in principle be recovered.
  • reaction is carried out using L-proline.
  • D-proline is typically used to obtain the compounds 2, 4.
  • 4-hydroxyproline or a protected precursor thereof can also be used.
  • the ratio of the formation of anti (1, 2) or syn (2, ⁇ 4) compounds depends on the component of structural formula 6.
  • the reaction is carried out in an aqueous solvent.
  • the proportion of water is then preferably more than 50% and even more preferably more than 90%.
  • reaction is carried out without a solvent.
  • Particularly suitable solvents are trifluoroethanol and formamide, both optionally mixed with water.
  • the water content is preferably below 20%.
  • Other suitable solvents are DMSO and DMF. Mixtures of these solvents can of course also be used.
  • radicals R are those in which R is -CH (OH) -CH 2 -N 3 (R or S) or 6
  • the invention further relates to the use of compound 5 as a reagent for an aldol reaction.
  • the invention further relates to compounds of the general formula
  • R substituted or unsubstituted alkyl, aryl, heterocycles containing one or more O, N, S, P or B;
  • Ri and R 2 are independently H, substituted or unsubstituted alkyl, aryl, heterocycles containing one or more O, N, S, P or B.
  • the substances according to the invention which can be obtained in high stereoselectivities on the new synthetic route, are particularly suitable as starting or intermediate products in the synthesis of carbohydrates and aza-carbohydrates. Therefore the use of the compound according to the invention as an intermediate in the synthesis of carbohydrates or Aza carbohydrates Subject of the invention.
  • the dihydroxyacetone backbone is recovered. If necessary, this can enter into ring closure reactions coupled with the rest coupled through the aldol reactions. In embodiments in which R contains an amine, this can be used to form aza sugars or amino sugars.
  • L-proline produced both the anti and the syn product. They could be separated chromatographically and showed the following NMR spectroscopy data.

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

Abstract

The invention relates to a method for the synthesis of compounds of general formula (1), (2), (3), (4). Said method consists of converting formulae (5) and (6) in the presence of formula (7), wherein R = substituted or unsubstituted alkyl, aryl, heterocycles containing one or more O, N, S, P or B; R1 and R2 represent, independently from each other, H, substituted or unsubstituted alkyl, aryl, heterocycles containing one or more O, N, S, P or B, R' = H, OH, OR or OSiX3, wherein X independently represents alkyl or aryl.

Description

Svntheseverfahren Svntheseverfahren
Die vorliegende Erfindung betrifft ein Syntheseverfahren und dadurch erhältliche Verbindungen.The present invention relates to a synthesis process and compounds obtainable thereby.
Aldolreaktionen sind eine der wesentlichen Kohlenstoff/Kohlenstoff verknüpfende Reaktionen sowohl in der Natur als auch im Repertoire des synthetischen Chemikers. In der Natur werden solche Reaktionen katalysiert von Enzymen, die entweder über einen Enamin-Mechanismus (Klasse 1 Aldolasen) oder über einen Zink-Kofaktor (Klasse 2 Aldolasen) funktionieren. Hierbei wird eine hohe Stereoselektivität erreicht.Aldol reactions are one of the essential carbon / carbon linking reactions both in nature and in the repertoire of the synthetic chemist. In nature, such reactions are catalyzed by enzymes that function either via an enamine mechanism (class 1 aldolases) or via a zinc cofactor (class 2 aldolases). Here a high stereoselectivity is achieved.
Trotz der bahnbrechenden Entwicklungen der stereoselektiven, metallkatalysierten Aldolreaktion in den vergangenen Jahren (siehe hierzu: "Comprehensive Asymmetrie Catalysis"; Kapitel 29, ed. Eric N. Jacobsen, Andreas Pflatz, Hisahi Yamamoto, Springer Verlag, Berlin, 2002) konnten Erfolge mittels organokataly- tischer Methoden mit einer großen Substratbreite erst in jüngerer Zeit vorgestellt werden.Despite the groundbreaking developments in the stereoselective, metal-catalyzed aldol reaction in recent years (see: "Comprehensive Asymmetry Catalysis"; Chapter 29, ed. Eric N. Jacobsen, Andreas Pflatz, Hisahi Yamamoto, Springer Verlag, Berlin, 2002), success was achieved using organokataly - tical methods with a wide range of substrates have only recently been introduced.
All diese Methoden ergeben aber schlechte Ausbeuten und Selektivitäten, wenn das natürliche, phosphorylierte Substrat der Aldolasen, Dihydroxyaceton (DHA), eingesetzt wird.However, all of these methods result in poor yields and selectivities when the natural, phosphorylated substrate of the aldolases, dihydroxyacetone (DHA), is used.
Kwan Soo Kim et al. beschreiben in Tetrahedron Letters 31 (2000) 5909-5913 ein Verfahren zur Herstellung von Dihydroxyaceton-Derivaten über Dihydroxy- acetonsilylenolether und anschließende Aldolreaktion. Die Reaktion umfasst eine metallorganische Umsetzung mit Lithiumdiisopropylamid bei -78°C.Kwan Soo Kim et al. describe in Tetrahedron Letters 31 (2000) 5909-5913 a process for the preparation of dihydroxyacetone derivatives via dihydroxyacetonesilylenol ether and subsequent aldol reaction. The reaction involves an organometallic reaction with lithium diisopropylamide at -78 ° C.
Marek Majewski et al. beschreiben in J. Org. Chem. 65 (2000) 5152-5160 ein Verfahren zur Aldolreaktion von Enolaten ausgehend von l,3-Dioxan-5-onen durch Umsetzung mit chiralen Lithiumamiden.Marek Majewski et al. describe in J. Org. Chem. 65 (2000) 5152-5160 a process for the aldol reaction of enolates starting from 1,3-dioxan-5-ones by reaction with chiral lithium amides.
Es sind entsprechende Aldolreaktionen mit zyklischen sekundären Aminen in organischen Lösungsmitteln und in wässrigen Medien bekannt; vgl. A. Cόrdova, W. Notz and C.F. Barbas III. in Chem. Commun. 2002, Seiten 3024 bis 3025. Die dort beobachteten Stereoselektivitäten sind überwiegend gering. Aufgabe der vorliegenden Erfindung war es, ein verbessertes Syntheseverfahren mit hoher Stereoselektivität auf Grundlage von Aldolreaktionen zu entwickeln.Corresponding aldol reactions with cyclic secondary amines in organic solvents and in aqueous media are known; see. A. Cordova, W. Notz and CF Barbas III. in Chem. Commun. 2002, pages 3024 to 3025. The stereoselectivities observed there are predominantly low. The object of the present invention was to develop an improved synthesis process with high stereoselectivity based on aldol reactions.
Gelöst wird die Aufgabe durch ein Verfahren zur Synthese von Verbindungen der allgemeinen FormelThe object is achieved by a process for the synthesis of compounds of the general formula
umfassend den Schritt der Umsetzung voncomprehensively the step of implementing
in Gegenwart vonin the presence of
wobei R = substituierte oder unsubstituierte Alkyl, Aryl, Heterozyklen enthaltend ein oder mehr O, N, S, P oder B; Ri und R2 unabhängig voneinander H, substituierte oder unsubstituierte Alkyl, Aryl, Heterozyklen enthaltend ein oder mehr O, N, S, P oder Bwhere R = substituted or unsubstituted alkyl, aryl, heterocycles containing one or more O, N, S, P or B; Ri and R 2 independently of one another are H, substituted or unsubstituted alkyl, Aryl, heterocycles containing one or more O, N, S, P or B
R' = H, OH, OR oder OSiX3 wobei X unabhängig voneinander Alkyl oder Aryl sind.R '= H, OH, OR or OSiX 3 where X are independently alkyl or aryl.
Erfindungsgemäß wird mit einer zyklischen Ausgangsverbindung, nämlich Deri- vaten des l,3-Dioxan-5-on gearbeitet, die in Gegenwart von Prolin oder Prolin- derivaten mit Aldehyden umgesetzt werden. Diese Ausgangsverbindungen sind Dihydroxyacetonderivate. Es werden hohe Stereoselektivitäten erreicht.According to the invention, a cyclic starting compound, namely derivatives of 1,3-dioxan-5-one, is used, which are reacted with aldehydes in the presence of proline or proline derivatives. These starting compounds are dihydroxyacetone derivatives. High stereoselectivities are achieved.
Es wird vermutet, dass durch das Prolin oder Prolinderivat eine Enamin- Zwischenstufe gebildet wird, bei der die Carboxy-Gruppe des Prolins an der Orientierung beteiligt ist, so dass hierdurch die überraschend hohen Stereoselektivitäten erreicht werden.It is believed that the proline or proline derivative forms an enamine intermediate, in which the carboxy group of the proline is involved in the orientation, so that the surprisingly high stereoselectivities are achieved.
"Alkyl" im Sinne dieser Anmeldung sind insbesondere gradkettige oder verzweigte Alkyl-, Cycloalkyl-, Bicycloalkyl-, Tricycloalkyl-, Alkenyl-, Alkinyl-, Heterocyc- loalkyl-Verbindungen. Typische Vertreter sind Methyl-, Ethyl-, N-Propyl-, Isopro- pyl-, Butyl-, Cyclohexyl- oder substituierte Derivate hiervon."Alkyl" in the sense of this application are in particular straight-chain or branched alkyl, cycloalkyl, bicycloalkyl, tricycloalkyl, alkenyl, alkynyl, heterocycloalkyl compounds. Typical representatives are methyl, ethyl, N-propyl, isopropyl, butyl, cyclohexyl or substituted derivatives thereof.
"Aryl" im Sinne dieser Anmeldung umfasst insbesondere auch Heteroaryl-, Aryl- alkyl- oder Heteroarylalkyl-Gruppen. Typische Vertreter sind Phenyl-, Benzyl-, Pyrridin-, sowie substituierte Derivate hiervon.“Aryl” in the sense of this application also includes, in particular, heteroaryl, arylalkyl or heteroarylalkyl groups. Typical representatives are phenyl, benzyl, pyrridine and substituted derivatives thereof.
Dabei können die Alkyl- oder Aryl-Reste auch durch ein oder mehrere Hydroxy-, Alkoxy, Aryloxy-, Alkanoyl-, Aroyl-, Carboxy-, Alkoxycarbonyl-, Amino-, Alkyla- mino-, Hydroxylamino-, Amido-, Carbamoyl-, Ureido-, Amidino-, Guanidino-, Cyano-, Azido-, Mercapto-, Alkylthio-, Alkylsulfoxy-, Alkylsulfonyl-, Alkylsulfe- nyl-, Aminosulfonyl-, Fluor-, Chlor-, Brom-, Jod-, Alkyl- oder Perfluoralkyl-Reste substituierte Derivate sein.The alkyl or aryl radicals can also be substituted by one or more hydroxy, alkoxy, aryloxy, alkanoyl, aroyl, carboxy, alkoxycarbonyl, amino, alkylamino, hydroxylamino, amido, carbamoyl , Ureido, amidino, guanidino, cyano, azido, mercapto, alkylthio, alkylsulfoxy, alkylsulfonyl, alkylsulfonyl, aminosulfonyl, fluorine, chlorine, bromine, iodine, alkyl or perfluoroalkyl radicals substituted derivatives.
In einer bevorzugten Ausführungsform enthält R ein oder mehr Stickstoffatome. Es handelt sich dann um Derivate von Verbindungen mit beispielsweise Azeti- din-, Pyrrolidin-, Pyrrolin-, Piperidin-, Piperazin-, Homopiperazin-, Morpholin-, Thiomorpholin-, Pyridin-, Di- oder Tetra-hydropyridin-, Pyrimidin-, Pyrazin-, Azepin-, Dihydroazepin-, Oxazepin-, Diazepin-, Imidazol-, Pyrazol-, Oxazol- oder Thiazol-Ringen, die gegebenenfalls ankondensierte aliphatische, heteroaliphati- sche, aromatische oder heteroaromatische Ringe aufweisen und/oder durch einen oder mehrere Hydroxy-, Alkoxy-, Aryloxy-, Aklanoyl-, Aroyl-, Carboxy-, Alkoxycarbonyl-, Amino-, Alkylamino-, Hydroxylamino-, Amido-, Carbanoyl-, Ureido-, Amidino-, Guanidino-, Cyano-, Azido-, Mercapto-, Alkylthio-, Alkylsulfo- xy-, Alkylsulfonyl-, Alkylsulfenyl-, Aminosulfonyl-, Fluor-, Chrom-, Brom-, Jod-, Alkyl- oder Perfluoralkyl-Reste substituiert sind.In a preferred embodiment, R contains one or more nitrogen atoms. These are derivatives of compounds with, for example, azididine, pyrrolidine, pyrroline, piperidine, piperazine, homopiperazine, morpholine, thiomorpholine, pyridine, di- or tetra-hydropyridine, pyrimidine, Pyrazine, azepine, dihydroazepine, oxazepine, diazepine, imidazole, pyrazole, oxazole or Thiazole rings, which may have fused-on aliphatic, heteroaliphatic, aromatic or heteroaromatic rings and / or by one or more hydroxy, alkoxy, aryloxy, aklanoyl, aroyl, carboxy, alkoxycarbonyl, amino, alkylamino -, Hydroxylamino, amido, carbanoyl, ureido, amidino, guanidino, cyano, azido, mercapto, alkylthio, alkylsulfoxy, alkylsulfonyl, alkylsulfenyl, aminosulfonyl, fluorine, chromium -, Bromine, iodine, alkyl or perfluoroalkyl radicals are substituted.
Die zur Umsetzung notwendigen Mengen an Prolin bzw. Prolinderivat betragen typischerweise 0,1 bis 30 Mol%, mehr bevorzugt 1 bis 10 Mol%, noch mehr bevorzugt 1 bis 5 Mol%.The amounts of proline or proline derivative required for the reaction are typically 0.1 to 30 mol%, more preferably 1 to 10 mol%, even more preferably 1 to 5 mol%.
Die eingesetzte Menge an Prolin bzw. Prolinderivat nimmt nur katalytisch an der Reaktion teil und kann daher grundsätzlich wiedergewonnen werden.The amount of proline or proline derivative used only catalytically participates in the reaction and can therefore in principle be recovered.
Um Verbindungen der Strukturformel 1, 3 zu erhalten, erfolgt die Umsetzung mit Hilfe von L-Prolin. Um die Verbindungen 2, 4 zu erhalten, wird typischerwei- se D-Prolin eingesetzt. Alternativ kann auch 4-Hydroxyprolin oder eine geschützte Vorstufe hiervon eingesetzt werden.In order to obtain compounds of structural formula 1, 3, the reaction is carried out using L-proline. D-proline is typically used to obtain the compounds 2, 4. Alternatively, 4-hydroxyproline or a protected precursor thereof can also be used.
Das Verhältnis der Bildung von anti (1, 2) bzw. syn (2, <4) -Verbindungen hängt von der Komponente der Strukturformel 6 ab.The ratio of the formation of anti (1, 2) or syn (2, <4) compounds depends on the component of structural formula 6.
In einer Ausführungsform wird die Reaktion in einem wässrigen Lösungsmittel durchgeführt. Vorzugsweise beträgt der Anteil an Wasser dann mehr als 50% und noch mehr bevorzugt mehr als 90%.In one embodiment, the reaction is carried out in an aqueous solvent. The proportion of water is then preferably more than 50% and even more preferably more than 90%.
In einer anderen Ausführungsform wird die Reaktion ohne ein Lösungsmittel durchgeführt.In another embodiment, the reaction is carried out without a solvent.
Als Lösungsmittel sind besonders geeignet Trifluorethanol und Formamid, beide gegebenenfalls im Gemisch mit Wasser. Bevorzugt liegt der Gehalt an Wasser jedoch unter 20%. Weitere geeignete Lösungsmittel sind DMSO und DMF. Natürlich können auch Gemische dieser Lösungsmittel eingesetzt werden.Particularly suitable solvents are trifluoroethanol and formamide, both optionally mixed with water. However, the water content is preferably below 20%. Other suitable solvents are DMSO and DMF. Mixtures of these solvents can of course also be used.
Bei Einsatz von Trifluorethanol werden typischerweise Enantiomerreinheiten >98% erreicht.When using trifluoroethanol typically enantiomeric purities > 98% reached.
Besonders bevorzugte Reste R sind solche, in denen R -CH(OH)-CH2-N3 (R oder S) oder 6Particularly preferred radicals R are those in which R is -CH (OH) -CH 2 -N 3 (R or S) or 6
Gegenstand der Erfindung ist weiterhin die Verwendung der Verbindung 5 als Reagenz einer Aldolreaktion.The invention further relates to the use of compound 5 as a reagent for an aldol reaction.
Ein weiterer Gegenstand der Erfindung sind Verbindungen der allgemeinen FormelThe invention further relates to compounds of the general formula
1 2 3 4 wobei 1 2 3 4 where
R = substituierte oder unsubstituierte Alkyl, Aryl, Heterozyklen enthaltend ein oder mehr O, N, S, P oder B;R = substituted or unsubstituted alkyl, aryl, heterocycles containing one or more O, N, S, P or B;
Ri und R2 unabhängig voneinander H, substituierte oder unsubstituierte Alkyl, Aryl, Heterozyklen enthaltend ein oder mehr O, N, S, P oder B sind.Ri and R 2 are independently H, substituted or unsubstituted alkyl, aryl, heterocycles containing one or more O, N, S, P or B.
Die erfindungsgemäßen Substanzen, die auf dem neuen Syntheseweg in hohen Stereoselektivitäten erhalten werden können, eignen sich insbesondere als Ausgangs- bzw. Zwischenprodukte in der Synthese von Kohlenhydraten und Aza- kohlenhydraten. Daher ist auch die Verwendung der erfindungsgemäßen Verbin- dung als Zwischenprodukt in der Synthese von Kohlenhydraten oder Azakohlenhydraten Gegenstand der Erfindung.The substances according to the invention, which can be obtained in high stereoselectivities on the new synthetic route, are particularly suitable as starting or intermediate products in the synthesis of carbohydrates and aza-carbohydrates. Therefore the use of the compound according to the invention as an intermediate in the synthesis of carbohydrates or Aza carbohydrates Subject of the invention.
Nach einer Abspaltung von C(RιR2), beispielsweise im sauren, bevorzugt durch Einsatz saurer Ionenaustauscher, wird das Dihydroxyaceton-Grundgerüst wiedergewonnen. Dieses kann gegebenenfalls mit dem durch die Aldolreaktionen angekoppelten Rest Ringschlussreaktionen eingehen. In Ausführungsformen, in denen R ein Amin enthält, kann dieses zur Bildung von Azazuckem oder Amino- zuckern genutzt werden.After cleavage of C (RιR 2 ), for example in acid, preferably by using acidic ion exchangers, the dihydroxyacetone backbone is recovered. If necessary, this can enter into ring closure reactions coupled with the rest coupled through the aldol reactions. In embodiments in which R contains an amine, this can be used to form aza sugars or amino sugars.
Die Erfindung wird durch die nachfolgenden weiteren Beispielen näher erläutert.The invention is explained in more detail by the following further examples.
BeispieleExamples
Allgemeine Arbeitsvorschrift:General working instructions:
Eine Suspension von .-Prolin (20-30 Mol %), 5-Oxo-l,3-dioxane 5 (1.0 mmol), und ein Aldehyd 6 (1.0 mmol) in DMSO (0-8 mL) wurden bei Raumtemperatur für 12 bis 48 Stunden gerührt. Nach kompletter Umwandlung des Ausgangsmaterials (dünnschichtchromatographisch geprüft) wurde das Reak- tionsgemisch durch Zugabe von gesättigter Ammoniumchloridlösung (3 mL), Extraktion mit Ethylacetat und Trocknung der organischen Phasen über Magnesiumsulfat aufgearbeit. Das Rohprodukt wurde durch Säulenchromatographie an Silicagel mit Heptan/Ethylacetat (3: 1) weitergereinigt.A suspension of. -Proline (20-30 mol%), 5-oxo-l, 3-dioxane 5 (1.0 mmol), and an aldehyde 6 (1.0 mmol) in DMSO (0-8 mL) were added at room temperature for 12 stirred up to 48 hours. After complete conversion of the starting material (checked by thin layer chromatography), the reaction mixture was worked up by adding saturated ammonium chloride solution (3 ml), extracting with ethyl acetate and drying the organic phases over magnesium sulfate. The crude product was further purified by column chromatography on silica gel with heptane / ethyl acetate (3: 1).
NMR DatenNMR data
fl'S. 4S 4-fl'-HvdroxyVpropyl-2.2-dimethyl-ri.31dioxan-5-onfl'S. 4S 4-fl'-HvdroxyVpropyl-2,2-dimethyl-ri.31dioxan-5-one
Ausbeute: 56%Yield: 56%
*H NMR (250 MHz, CDCI3): δ = 0.97 (t, 3 H), 1.45, 1.49 (2s, 6 H), 1.51 - 1.81 (m, 2 H), 3.05 (br s, IH, OH), 3.80 - 3.88 (m, 1 H), 3.98 - 4.13 (m, 2 H), 4.20 - 4.34 (m, 1 H);- * H NMR (250 MHz, CDCI 3 ): δ = 0.97 (t, 3 H), 1.45, 1.49 (2s, 6 H), 1.51 - 1.81 (m, 2 H), 3.05 (br s, IH, OH) , 3.80 - 3.88 (m, 1 H), 3.98 - 4.13 (m, 2 H), 4.20 - 4.34 (m, 1 H); -
13C NMR (50 MHz, CDCI3): δ = 9.6, 23.8, 24.2, 25.6, 67.1, 72.1, 76.0, 101.3, 211.8.- 13 C NMR (50 MHz, CDCI 3 ): δ = 9.6, 23.8, 24.2, 25.6, 67.1, 72.1, 76.0, 101.3, 211.8.-
(l'S. 4SV4-f l,-Hvdroxy-3,-methvn-butyl-2.2-dimethyl-ri.31dioxan-5- on(l'S.4SV4-fl , -Hvdroxy-3 , -methvn-butyl-2.2-dimethyl-ri.31dioxan-5-one
Ausbeute: 72 %Yield: 72%
*H NMR (250 MHz, CDCI3): δ = 0.85 - 0.98 (m, 8 H), 1.40 ( s, 3 H), 1.43 ( s, 3 H), 1.72 - 1.94 (m, IH), 2.99 (s, lH,"bH)f 3.92 - 4.26 (m, 4 H);-* H NMR (250 MHz, CDCI 3 ): δ = 0.85 - 0.98 (m, 8 H), 1.40 (s, 3 H), 1.43 (s, 3 H), 1.72 - 1.94 (m, IH), 2.99 ( s, lH, " bH) f 3.92 - 4.26 (m, 4 H); -
13C NMR (50 MHz, CDCI3): δ = 21.8, 23.8, 24.1 24.2, 41.5, 67.1, 69.6, 77.1, 101.2, 211.1. 13 C NMR (50 MHz, CDCI 3 ): δ = 21.8, 23.8, 24.1 24.2, 41.5, 67.1, 69.6, 77.1, 101.2, 211.1.
fl'S. 4SV4-(l,-Hvdroxy-l,-cvclohexylVmethyl-2.2-dimethyl- ri,31dioxan-5-onfl'S. 4SV4- (l , -Hvdroxy-l , -cvclohexylVmethyl-2,2-dimethyl-ri, 31dioxan-5-one
Ausbeute: 70 %Yield: 70%
*H NMR (250 MHz, CDCI3): δ = 1.01 - 1.33 (m, 5 H), 1.44, 1.48 (2s, 6 H), 1.55 - 1.89 (m, 6 H), 3.11 - 3.24 (br s, 1 H), 3.59 - 3.72 (m, 1 H), 3.93 - 4.04 (m, 1 H), 4.10 - 3.19 (m, 1 H), 4.19 - 4.32 (m, 2 H);- * H NMR (250 MHz, CDCI 3 ): δ = 1.01 - 1.33 (m, 5 H), 1.44, 1.48 (2s, 6 H), 1.55 - 1.89 (m, 6 H), 3.11 - 3.24 (br s, 1 H), 3.59 - 3.72 (m, 1 H), 3.93 - 4.04 (m, 1 H), 4.10 - 3.19 (m, 1 H), 4.19 - 4.32 (m, 2 H); -
13C NMR (50 MHz, CDCI3): δ = 24.0, 24.2, 26.5, 26.6, 26.8, 29.9, 38.8, 67.0, 73.8, 74.6, 101.3, 212.5. 13 C NMR (50 MHz, CDCI 3 ): δ = 24.0, 24.2, 26.5, 26.6, 26.8, 29.9, 38.8, 67.0, 73.8, 74.6, 101.3, 212.5.
(l,S.4S -4-fl,-Hvdroxy-3,-phenyl -propyl-2.2-dimethyl-ri.31dioxan-5- on(l , S.4S -4-fl , -Hydroxy-3 , -phenyl-propyl-2,2-dimethyl-ri.31dioxan-5- one
Ausbeute: 80 %Yield: 80%
*H NMR (250 MHz, CDCI3): δ = 1.48 (s, 3 H), 1.51 (s, 3 H), 1.78 - 2.11 (m, 2 H), 2.56 - 2.83 (m, IH), 2.88 - 3.09 (m, 1 H), 3.18 (br s, 1 H, OH), 3.83 - 4.35 (m, 3 H), 7:13 - 7.45 (m, 5H);-* H NMR (250 MHz, CDCI 3 ): δ = 1.48 (s, 3 H), 1.51 (s, 3 H), 1.78 - 2.11 (m, 2 H), 2.56 - 2.83 (m, IH), 2.88 - 3.09 (m, 1 H), 3.18 (br s, 1 H, OH), 3.83 - 4.35 (m, 3 H), 7:13 - 7.45 (m, 5H); -
13C NMR (50 MHz, CDCI3): δ = 24.0, 24.2, 31.8, 34.6, 67.1, 70.3, 76.4, 101.5, 126.3, 128.8, 129.0, 142.4, 211.6. 13 C NMR (50 MHz, CDCI 3 ): δ = 24.0, 24.2, 31.8, 34.6, 67.1, 70.3, 76.4, 101.5, 126.3, 128.8, 129.0, 142.4, 211.6.
(l,S.4S -4-f l,-Hvdroxy-l,-phenvO-methyl-2.2-dimethyl-π.31dioxan- 5-on (antn(l , p.4S -4-fl , -hydroxy-l , -phenvO-methyl-2,2-dimethyl-π.31dioxan- 5-one (antn
fl,R.4S 4-ri,-Hvdroxy-l,-phenvn-methyl-2.2-dimethyl-ri.31dioxan- 5-on (svnfl , R.4S 4-ri , -Hydroxy-l , -phenvn-methyl-2,2-dimethyl-ri.31dioxan- 5-one (svn
Ausbeute: 77 % (gemeinsame Ausbeute beider Diastereomere)Yield: 77% (joint yield of both diastereomers)
In diesem Falle entstanden mit L-Prolin sowohl das anti- als auch das syn- Produkt. Sie konnten chromatographisch getrennt werden und zeigten die nachfolgenden NMR-Spektroskopiedaten. In this case, L-proline produced both the anti and the syn product. They could be separated chromatographically and showed the following NMR spectroscopy data.
*H NMR (250 MHz, CDCI3): δ = 1.29, 1.39 (2s, 6 H), 3.63 (br s, 1 H, OH), 3.92 - 4.39 (m, 3 H), 4.82 - 4.95 (m, 1 H), 7.34 - 7.51 (m, 5 H);-* H NMR (250 MHz, CDCI 3 ): δ = 1.29, 1.39 (2s, 6 H), 3.63 (br s, 1 H, OH), 3.92 - 4.39 (m, 3 H), 4.82 - 4.95 (m, 1 H), 7.34 - 7.51 (m, 5 H); -
13C NMR (50 MHz, CDCI3): δ = 23.6, 24.0, 67.1, 73.1, 76.6, 101.6, 127.5, 128.4, 139.7, 211.3. 13 C NMR (50 MHz, CDCI 3 ): δ = 23.6, 24.0, 67.1, 73.1, 76.6, 101.6, 127.5, 128.4, 139.7, 211.3.
*H NMR (250 MHz, CDCI3): δ = 1.38, 1.50 (2s, 6 H), 3.99 - 4.49 (m, 3 H), 5.02-5.20 (br s, 1 H, OH), 5.26 (d, 1 H, J = 2.7 Hz), 7.22 - 7.64 (m, 5 H);-* H NMR (250 MHz, CDCI 3 ): δ = 1.38, 1.50 (2s, 6 H), 3.99 - 4.49 (m, 3 H), 5.02-5.20 (br s, 1 H, OH), 5.26 (d, 1 H, J = 2.7 Hz), 7.22 - 7.64 (m, 5 H); -
13C NMR (50 MHz, CDCI3): δ = 23.7, 24.7, 67.6, 71.7, 78.6, 101.4, 126.9, 128.7, 130.5, 140.7, 208.3. 13 C NMR (50 MHz, CDCI 3 ): δ = 23.7, 24.7, 67.6, 71.7, 78.6, 101.4, 126.9, 128.7, 130.5, 140.7, 208.3.

Claims

Patentansprüche claims
1. Verfahren zur Synthese von Verbindungen der allgemeinen Formel1. Process for the synthesis of compounds of the general formula
1 2 umfassend den Schritt der Umsetzung von 1 2 comprehensively the step of implementing
in Gegenwart von in the presence of
l o wobei R = substituierte oder unsubstituierte Alkyl, Aryl, Heterozyklen enthaltend ein oder mehr O, N, S, P oder B; Ri und R2 unabhängig voneinander H, substituierte oder unsubstituierte Alkyl, Aryl, Heterozyklen enthaltend ein oder mehr O, N, S, P oder B lo where R = substituted or unsubstituted alkyl, aryl, heterocycles containing one or more O, N, S, P or B; Ri and R 2 independently of one another H, substituted or unsubstituted alkyl, aryl, heterocycles containing one or more O, N, S, P or B.
15 R' = H, OH, OR oder OSiX3 wobei X unabhängig voneinander Alkyl oder A- ryl sind. 15 R '= H, OH, OR or OSiX 3 where X are independently alkyl or aryl.
2. Verfahren nach Anspruch 1, dadurch gekennzeichnet, dass die Menge an Prolin 0.1 bis 30 Mol%, bezogen auf l,3-Dioxan-5-onverbindung 5 beträgt.2. The method according to claim 1, characterized in that the amount of proline is 0.1 to 30 mol%, based on 1,3-dioxan-5-one compound 5.
3. Verfahren nach Anspruch 1 oder 2, dadurch gekennzeichnet, dass R ein oder mehr N enthält.3. The method according to claim 1 or 2, characterized in that R contains one or more N.
4. Verfahren nach mindestens einem der Ansprüche 1 bis 3, dadurch gekennzeichnet, dass R -CH(OH)-CH2-N3 (Λ oder S) ist oder 64. The method according to at least one of claims 1 to 3, characterized in that R is -CH (OH) -CH 2 -N 3 (Λ or S) or 6
5. Verfahren nach mindestens einem der Ansprüche 1 bis 4, dadurch gekennzeichnet, dass die Reaktion in einem wässrigen Lösungsmittel durchgeführt wird.5. The method according to at least one of claims 1 to 4, characterized in that the reaction is carried out in an aqueous solvent.
6. Verfahren nach mindestens einem der Ansprüche 1 bis 6, dadurch gekenn- zeichnet, dass die Reaktion ohne Lösungsmittel durchgeführt wird.6. The method according to at least one of claims 1 to 6, characterized in that the reaction is carried out without a solvent.
7. Verfahren nach mindestens einem der Ansprüche 1 bis 6, dadurch gekennzeichnet, dass die Verbindungen 1, 3 durch Umsetzung mit L-Prolin und die Verbindungen 2, 4 durch Umsetzung mit D-Prolin erhalten wird.7. The method according to at least one of claims 1 to 6, characterized in that the compounds 1, 3 are obtained by reaction with L-proline and the compounds 2, 4 by reaction with D-proline.
8. Verwendung von wobei Ri und R2 unabhängig voneinander H, substituierte oder unsubstituierte Alkyl, Aryl, Heterozyklen enthaltend ein oder mehr O, N, S, P oder B R' = H, OH, OR oder OSiX3 wobei X unabhängig voneinander Alkyl oder A- ryl sind als Reagenz in einer Aldolreaktion mit dem Katalysator8. Use of in which Ri and R 2 independently of one another H, substituted or unsubstituted alkyl, aryl, heterocycles containing one or more O, N, S, P or BR '= H, OH, OR or OSiX 3 where X are independently of one another alkyl or aryl as Reagent in an aldol reaction with the catalyst
9. Verwendung von Trifluorethanol oder Formamid als Lösungsmittel für Aldolreaktionen von Verbindungen der allgemeinen Formel9. Use of trifluoroethanol or formamide as a solvent for aldol reactions of compounds of the general formula
wobei R = substituierte oder unsubstituierte Alkyl, Aryl, Heterozyklen enthaltend ein oder mehr O, N, S, P oder B; Ri und R2 unabhängig voneinander H, substituierte oder unsubstituierte Alkyl, Aryl, Heterozyklen enthaltend ein oder mehr O, N, S, P oder B R' = H, OH, OR oder OSiX3 wobei X unabhängig voneinander Alkyl oder A- ryl sind. where R = substituted or unsubstituted alkyl, aryl, heterocycles containing one or more O, N, S, P or B; Ri and R 2 independently of one another H, substituted or unsubstituted alkyl, aryl, heterocycles containing one or more O, N, S, P or BR '= H, OH, OR or OSiX 3 where X are independently of one another alkyl or aryl.
10. Verbindungen der allgemeinen Formel 1 2 3 4 wobei R = substituierte oder unsubstituierte Alkyl, Aryl, Heterozyklen enthaltend ein oder mehr O, N, S, P oder B; Ri und R2 unabhängig voneinander H, substituierte oder unsubstituierte Alkyl, Aryl, Heterozyklen enthaltend ein oder mehr O, N, S, P oder B, ausgenommen Verbindungen mit Rι=R2=CH3.10. Compounds of the general formula 1 2 3 4 where R = substituted or unsubstituted alkyl, aryl, heterocycles containing one or more O, N, S, P or B; Ri and R 2 independently of one another are H, substituted or unsubstituted alkyl, aryl, heterocycles containing one or more O, N, S, P or B, with the exception of compounds where R 1 = R 2 = CH 3 .
11. Verbindung nach Anspruch 10, dadurch gekennzeichnet, dass R ein oder mehr N enthält.11. A compound according to claim 10, characterized in that R contains one or more N.
12. Verwendung einer Verbindung nach Anspruch 10 oder 11 als Zwischenprodukt in der Synthese von Kohlenhydraten und Aza-Kohlenhydraten. 12. Use of a compound according to claim 10 or 11 as an intermediate in the synthesis of carbohydrates and aza carbohydrates.
EP05753902A 2004-06-15 2005-06-15 Process for the production of 4-(alpha-hydroxyalkyl)-1,3-dioxan-5-ones Withdrawn EP1758878A1 (en)

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EP04102730A EP1609787A1 (en) 2004-06-15 2004-06-15 Process for the production of 4-(alpha-hydroxyalkyl)-1,3-dioxan-5-ones
EP05753902A EP1758878A1 (en) 2004-06-15 2005-06-15 Process for the production of 4-(alpha-hydroxyalkyl)-1,3-dioxan-5-ones
PCT/EP2005/052757 WO2005123712A1 (en) 2004-06-15 2005-06-15 Method for the production of a-(alpha-hydroxyalkyl)-1,3 dioxan-5-ones

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WO2018124149A1 (en) 2016-12-27 2018-07-05 花王株式会社 Method for producing glyceric acid ester
US10870643B2 (en) 2016-12-27 2020-12-22 Kao Corporation Method for manufacturing 1,3-dioxane-5-one

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