EP0986538A1 - Method for producing chiral 3,4-dehydroprolines - Google Patents

Method for producing chiral 3,4-dehydroprolines

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Publication number
EP0986538A1
EP0986538A1 EP98933585A EP98933585A EP0986538A1 EP 0986538 A1 EP0986538 A1 EP 0986538A1 EP 98933585 A EP98933585 A EP 98933585A EP 98933585 A EP98933585 A EP 98933585A EP 0986538 A1 EP0986538 A1 EP 0986538A1
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Prior art keywords
chiral
formula
reaction
dehydroprolines
ammonia
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EP98933585A
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German (de)
French (fr)
Inventor
Bernd Schäfer
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Abbott GmbH and Co KG
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BASF SE
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D207/20—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms

Definitions

  • the present invention relates to a process for the preparation of chiral 3, 4-dehydroprolines.
  • Achiral syntheses usually start from pyrrolecarboxylic acid, which is reduced with phosphonium iodide / hydrogen iodide (J.W. Scott, Synth. Commun. 10 (1980) 529). The racemate is then separated by means of crystallization with chiral amines (S.S. Kerwar, J. Biol. Chem. 251 (1976) 503; US 4,066,658) or tartaric acid (A. Corbella, Chem. Ind. (1969) 583). The disadvantage of this synthesis is the handling of the highly toxic phosphine and a maximum yield of 50% in the resolution of racemates.
  • the invention relates to a process for the preparation of chiral 3, 4-dehydroprolines of the formula I.
  • R is a chiral auxiliary group
  • R ' is hydrogen or a Ci-e-alkyl, C 2 - 7 alkenyl, C 7 -g-arylalkyl or tri-C ⁇ _ -alkylsilylrest and
  • R '' mean a protective group, which consists in that a pyrrole carboxylic acid derivative of the formula II
  • Non-aromatic chiral secondary amines and non-aromatic chiral alcohols of the formula RH are particularly suitable as sources for the chiral auxiliary groups R. As such, be special
  • the compound D is particularly preferred.
  • R ' is preferably hydrogen, C 3 alkyl, allyl or benzyl.
  • the trimethylsilyl radical should be mentioned in particular as the tri-4-alkylsilyl radical.
  • Protective groups for R ′′ include Boc, C ⁇ _ 6 -acyl, mesyl, benzenesulfonyl and tosyl and preferably Boc.
  • Preferred leaving groups for X are Cl, Br, I, MesO, TosO or Trif lat.
  • Magnesium and in particular lithium, sodium and potassium are mentioned as alkali or alkaline earth metals for the reaction.
  • the reaction takes place in liquid or supercritical ammonia, to which an inert solvent can optionally be added.
  • Preferred solvents are THF and Ci- 6 alcohols.
  • the reaction is generally carried out in the temperature range from -100 to +100 ° C and a pressure range from 1 to 200 bar.
  • the boiling point temperature of the reaction mixture and 1 bar is preferred.
  • the reaction under self-pressure is very particularly preferred.
  • the reaction is complete when pyrrole derivatives can no longer be detected in the reaction mixture (for example by means of GC, HPLC, DC).
  • the processing of the process product is generally carried out using conventional processes, such as distillation, filtration, centrifugation or extraction.
  • the process according to the invention can be carried out batchwise, e.g. be carried out in a stirred reactor.
  • the simple feasibility offers the advantage that the reaction can also be carried out continuously, for example using a reaction tube or a stirred reactor cascade.
  • the raw products obtained can, if desired, be further purified, e.g. by crystallization, extraction or chromatography.
  • chiral 3, 4-dehydroprolines of the formula I which can be prepared in a simple manner by the process according to the invention are valuable intermediates for the synthesis of dyes, crop protection agents or medicaments, in particular thrombin inhibitors, such as e.g. described in PCT / WO 9625426.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pyrrole Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)

Abstract

The invention relates to a method for producing chiral 3,4-dehydroprolines of formula (I), in which R, R' and R'' have the meanings given in the description. The invention is characterized in that a pyrrolecarboxylic acid derivative of formula (II) is reacted first with an alkali or alkaline earth metal in ammonia and then with an aqueous salt solution or a compound having formula (III), in which X is a leaving group.

Description

Verfahren zur Herstellung von chiralen 3, 4-DehydroprolinenProcess for the preparation of chiral 3, 4-dehydroprolines
Beschreibungdescription
Die vorliegende Erfindung betrifft ein Verfahren zur Herstellung von chiralen 3, 4-Dehydroprolinen.The present invention relates to a process for the preparation of chiral 3, 4-dehydroprolines.
Chirale 3, 4-Dehydroproline stellt man ausgehend von 4-Hydroxy- prolin via Tschugaeff-Reaktion her (P. Grogg, Angew. Chem. 92 (1980) 761) . Neben den vergleichsweise schlechten Ausbeuten (64 %) erfordert diese Methode den Umgang mit hochtoxischen Verbindungen wie Schwefelkohlenstoff, Methyliodid und Methyl - mercaptan. Die pyrolytische Zersetzung bei 180 - 190 °C und 12 Torr erfordert einen hohen technischen Aufwand.Chiral 3,4-dehydroprolines are prepared starting from 4-hydroxyproline via the Tschugaeff reaction (P. Grogg, Angew. Chem. 92 (1980) 761). In addition to the comparatively poor yields (64%), this method requires the handling of highly toxic compounds such as carbon disulfide, methyl iodide and methyl mercaptan. The pyrolytic decomposition at 180 - 190 ° C and 12 Torr requires a high technical effort.
Durch Thermolyse kann man anstelle der Xanthogenate auch die entsprechenden Iodide, Sulfoxide oder Selenoxide umsetzen (J.-R. Dormoy, Synthesis (1982) 752) . Die grundlegenden Probleme hin- sichtlich Toxizität und technischem Aufwand werden hierdurch jedoch nicht gelöst.The corresponding iodides, sulfoxides or selenium oxides can also be converted by thermolysis instead of the xanthates (J.-R. Dormoy, Synthesis (1982) 752). However, this does not solve the fundamental problems with regard to toxicity and technical complexity.
Achirale Synthesen gehen üblicherweise von Pyrrolcarbonsäure aus, die mit Phosphoniumiodid / Iodwasserstoff reduziert wird (J.W. Scott, Synth. Commun. 10 (1980) 529). Anschließend trennt man das Racemat mittels Kristallisation mit chiralen Aminen (S.S. Kerwar, J. Biol . Chem. 251 (1976) 503; US 4.066.658) oder Weinsäure (A. Corbella, Chem. Ind. (1969) 583). Der Nachteil dieser Synthese ist der Umgang mit dem hochtoxischen Phosphan und eine maximale Ausbeute von 50 % bei der Racematspaltung.Achiral syntheses usually start from pyrrolecarboxylic acid, which is reduced with phosphonium iodide / hydrogen iodide (J.W. Scott, Synth. Commun. 10 (1980) 529). The racemate is then separated by means of crystallization with chiral amines (S.S. Kerwar, J. Biol. Chem. 251 (1976) 503; US 4,066,658) or tartaric acid (A. Corbella, Chem. Ind. (1969) 583). The disadvantage of this synthesis is the handling of the highly toxic phosphine and a maximum yield of 50% in the resolution of racemates.
In der nicht vorpublizierten deutschen Patentanmeldung 19630082.7, ist die Eliminierung von Sulfonsäureestern des Hydro- xyprolinesters und die anschließende enzymatische Racematspaltung beschrieben. Bei der Eliminierung racemisiert das Asymmetriezentrum des Prolins. Prinzipiell kann wie bei der klassischen auch bei der enzymatische Racematspaltung eine maximale Ausbeute von 50 % erreicht werden. Diese kann nur mit erheblichem Aufwand durch Rückführung des nicht gespaltenen Enantiomeren verbessert werden.The unpublished German patent application 19630082.7 describes the elimination of sulfonic acid esters of the hydroxyproline ester and the subsequent enzymatic resolution. The proline center of asymmetry racemizes upon elimination. In principle, a maximum yield of 50% can be achieved with the enzymatic resolution of racemates, as is the case with classic ones. This can only be improved with considerable effort by recycling the uncleaved enantiomer.
Alkylierende, asymmetrische Birch-Reduktionen sind von A.G. Schultz (J. Am. Chem. Soc. 110 (1988) 7828) an Benzoesäurederi - vaten und von T. Kinoshita (J. Heterocycl. Chem. 33 (1996) 1313) an Furancarbonsäurederivaten beschrieben. Die Birch-Reduktion von Pyrrol-Derivaten war bis vor kurzem unbekannt. T.J. Donohoe beschrieb in J. Org. Chem. 61 (1996) 7664 erstmals die achirale Birch-Reduktion von Pyrrol-2-carbonsäure- Derivaten. Diese konnten wie oben beschrieben bisher nur durch klassische oder enzymatische Racematspaltung in die Enantiomere getrennt werden.Alkylating, asymmetric Birch reductions are described by AG Schultz (J. Am. Chem. Soc. 110 (1988) 7828) on benzoic acid derivatives and by T. Kinoshita (J. Heterocycl. Chem. 33 (1996) 1313) on furan carboxylic acid derivatives . The Birch reduction of pyrrole derivatives was unknown until recently. TJ Donohoe first described the achiral Birch reduction of pyrrole-2-carboxylic acid derivatives in J. Org. Chem. 61 (1996) 7664. As previously described, these could only be separated into the enantiomers by classic or enzymatic resolution.
Es wurde nun gefunden, daß man chirale 3, 4-Dehydroproline mittels diastereoselektiver Birch - Reduktion erhalten kann.It has now been found that chiral 3, 4-dehydroprolines can be obtained by means of diastereoselective Birch reduction.
Gegenstand der Erfindung ist ein Verfahren zur Herstellung von chiralen 3, 4-Dehydroprolinen der Formel IThe invention relates to a process for the preparation of chiral 3, 4-dehydroprolines of the formula I.
worin R eine chirale Hilfsgruppe,where R is a chiral auxiliary group,
R' Wasserstoff oder einen Ci-e-Alkyl-, C2-7-Alkenyl- , C7-g-Aryl- alkyl- oder Tri-Cι_ -alkylsilylrest undR 'is hydrogen or a Ci-e-alkyl, C 2 - 7 alkenyl, C 7 -g-arylalkyl or tri-Cι_ -alkylsilylrest and
R' ' eine Schutzgruppe bedeuten, welches darin besteht, daß man ein Pyrrolcarbonsaurede- rivat der Formel IIR '' mean a protective group, which consists in that a pyrrole carboxylic acid derivative of the formula II
R"R "
in Ammoniak mit einem Alkali- oder Erdalkalimetall und anschließend mit einer wäßrigen Salzlösung oder einer Verbindung der Formel IIIin ammonia with an alkali or alkaline earth metal and then with an aqueous salt solution or a compound of formula III
R' X III,R 'X III,
worin X eine Abgangsgruppe bedeutet, umsetzt, Als Quellen für die chiralen Hilfsgruppen R eignen sich besonders nicht aromatische chirale sekundäre Amine und nicht aromatische chirale Alkohole der Formel RH. Als solche seien speziellin which X denotes a leaving group, Non-aromatic chiral secondary amines and non-aromatic chiral alcohols of the formula RH are particularly suitable as sources for the chiral auxiliary groups R. As such, be special
F GF G
00
HN -^0 (R' ' ' = Cι-4-Alkyl, vorzugsweiseHN - ^ 0 (R '' '= Cι-4-alkyl, preferably
R' / Methyl)R '/ methyl)
genannt. Unter diesen ist die Verbindung D besonders bevorzugt.called. Among them, the compound D is particularly preferred.
R' ist vorzugsweise Wasserstoff, Cι_3-Alkyl, Allyl oder Benzyl . Als Tri-Cι-4-alkylsilylrest ist besonders der Trimethylsilylrest zu nennen.R 'is preferably hydrogen, C 3 alkyl, allyl or benzyl. The trimethylsilyl radical should be mentioned in particular as the tri-4-alkylsilyl radical.
Als Schutzgruppen für R' ' sind Boc, Cι_6-Acyl, Mesyl, Benzolsulfonyl sowie Tosyl und vorzugsweise Boc zu nennen.Protective groups for R ″ include Boc, Cι_ 6 -acyl, mesyl, benzenesulfonyl and tosyl and preferably Boc.
Bevorzugte Abgangsgruppen für X sind Cl, Br, I, MesO, TosO oder Trif lat.Preferred leaving groups for X are Cl, Br, I, MesO, TosO or Trif lat.
Als Alkali- bzw. Erdalkalimetalle sind für die Umsetzung Magnesium und insbesondere Lithium, Natrium und Kalium zu nennen. Die Umsetzung erfolgt in flüssigem oder überkritischen Ammoniak, dem man wahlweise noch ein inertes Lösungsmittel zusetzen kann. Bevorzugte Lösungsmittel sind THF und Ci-6-Alkohole.Magnesium and in particular lithium, sodium and potassium are mentioned as alkali or alkaline earth metals for the reaction. The reaction takes place in liquid or supercritical ammonia, to which an inert solvent can optionally be added. Preferred solvents are THF and Ci- 6 alcohols.
Die Reaktion führt man im allgemeinen im Temperaturbereich von -100 bis +100 °C und einem Druckbereich von 1 bis 200 bar durch. Bevorzugt ist die Siedepunkttemperatur des Reaktionsgemischs und 1 bar. Ganz besonders bevorzugt ist die Reaktion unter Eigen - druck . Die Reaktion ist beendet, wenn keine Pyrrol-Derivate im Reaktionsgemisch mehr nachgewiesen werden können (z.B. mittels GC, HPLC, DC) .The reaction is generally carried out in the temperature range from -100 to +100 ° C and a pressure range from 1 to 200 bar. The boiling point temperature of the reaction mixture and 1 bar is preferred. The reaction under self-pressure is very particularly preferred. The reaction is complete when pyrrole derivatives can no longer be detected in the reaction mixture (for example by means of GC, HPLC, DC).
Die Aufarbeitung auf das Verfahrensprodukt hin erfolgt in der Regel nach herkömmlichen Verfahren, wie Destillation, Filtration, Zentrifugation oder Extraktion.The processing of the process product is generally carried out using conventional processes, such as distillation, filtration, centrifugation or extraction.
Das erfindungsgemäße Verfahren kann diskontinuierlich, z.B. in einem Rührreaktor durchgeführt werden. Die einfache Durchführbarkeit bietet jedoch den Vorteil, daß man die Reaktion auch kontinuierlich, beispielsweise unter Verwendung eines Reaktionsrohres oder einer Rührreaktorkaskade, durchführen kann.The process according to the invention can be carried out batchwise, e.g. be carried out in a stirred reactor. However, the simple feasibility offers the advantage that the reaction can also be carried out continuously, for example using a reaction tube or a stirred reactor cascade.
Die erhaltenen Rohprodukte können gewünschtenfalls weiter gereinigt werden, z.B. durch Kristallisation, Extraktion oder Chromatographie .The raw products obtained can, if desired, be further purified, e.g. by crystallization, extraction or chromatography.
Es ist überraschend, daß sich Pyrrol-2-carbonsäureester und - amide trotz der sterisch anspruchsvollen und elektronisch unterschiedlichen chiralen Hilfsgruppen zu den entsprechenden Dehydro- prolinen mit z.T. sehr hohen Selektivitäten umsetzen lassen. Besonders überraschend hierbei ist, daß dies nicht nur für die Alkylierung sondern auch für die Protolyse des Reaktionsinter- mediats gilt.It is surprising that pyrrole-2-carboxylic acid esters and amides, despite the sterically demanding and electronically different chiral auxiliary groups, sometimes form the corresponding dehydrolines with have very high selectivities implemented. It is particularly surprising here that this applies not only to the alkylation but also to the protolysis of the reaction intermediate.
Die nach dem erfindungsgemäßen Verfahren auf einfache Weise herzustellende chiralen 3 , 4-Dehydroproline der Formel I sind wertvolle Zwischenprodukte zur Synthese von Farbstoffen, Pflanzenschutzmitteln oder Arzneimitteln, insbesondere Thrombin- inhibitoren, wie z.B. in der Druckschrift PCT/WO 9625426 beschrieben.The chiral 3, 4-dehydroprolines of the formula I which can be prepared in a simple manner by the process according to the invention are valuable intermediates for the synthesis of dyes, crop protection agents or medicaments, in particular thrombin inhibitors, such as e.g. described in PCT / WO 9625426.
Beispiel 1: Synthese von N-Boc-3 , 4-Dehydroprolin- ( (S) -2-methoxy- methylpyrrolidinid)Example 1: Synthesis of N-Boc-3,4-dehydroproline- ((S) -2-methoxy-methylpyrrolidinide)
150 ml Ammoniak und 50 ml THF wurden bei -30 °C vorgelegt. Anschließend wurden 0,42 g (0,06 mol) Lithium zugegeben. Zu dieser Mischung tropfte man 6,17 g (0,02 mol) N-Boc-Pyrrol-2-carbon- säure- ( (S) -2-methoxymethylpyrrolidinid) gelöst in 20 ml THF innerhalb von 5 min zu. Nach einer Nachrührzeit von 1 h gab man 10 ml gesättigte Ammoniumchlorid-Lösung und 150 ml gesättigte Natriumchlorid-Lösung zu, trennte die Phasen und extrahierte die wäßrige Phase dreimal mit je 50 ml Dichlormethan. Die organischen Phasen wurden vereinigt und eingeengt. 4,8 g (0,015 mol, 77 %) des Produkts wurden in Form eines gelbroten Öls erhalten. 1H - NMR (δ, ppm, d6-DMS0, T = 373K) : 1,38 (ls, Integral: 95 : 5, t-Butyl) .150 ml of ammonia and 50 ml of THF were placed at -30 ° C. Then 0.42 g (0.06 mol) of lithium was added. 6.17 g (0.02 mol) of N-Boc-pyrrole-2-carboxylic acid ((S) -2-methoxymethylpyrrolidinide) dissolved in 20 ml of THF were added dropwise to this mixture in the course of 5 minutes. After stirring for 1 h, 10 ml of saturated ammonium chloride solution and 150 ml of saturated sodium chloride solution were added, the phases were separated and the aqueous phase was extracted three times with 50 ml of dichloromethane each time. The organic phases were combined and concentrated. 4.8 g (0.015 mol, 77%) of the product were obtained in the form of a yellow-red oil. 1 H NMR (δ, ppm, d6-DMS0, T = 373K): 1.38 (ls, integral: 95: 5, t-butyl).
Beispiel 2: Synthese von N-Boc-3 , 4-Dehydroprolin- ( (IS) -endo-bor- nyl) -esterExample 2: Synthesis of N-Boc-3, 4-dehydroproline ((IS) -endo-boronyl) ester
150 ml Ammoniak und 50 ml THF wurden bei -30 °C vorgelegt. Anschließend wurden 0,24 g (0,034 mol) Lithium zugegeben. Zu dieser Mischung tropfte man 4 g (0,0115 mol) N-Boc-Pyrrol-2-carbon- säure- ( (IS) -endo-bornyl) -ester gelöst in 10 ml THF innerhalb von 5 min zu. Nach einer Nachrührzeit von 1 h gab man 2 ml gesättigte Ammoniumchlorid-Lösung und 150 ml gesättigte Natriumchlorid-Lösung zu, trennte die Phasen und extrahierte die wäßrige Phase dreimal mit je 100 ml Dichlormethan. Die organischen Phasen wur- den vereinigt, über Natriumsulfat getrocknet und eingeengt. Ausbeute: 3,2 g (0,009 mol, 61 %) . E - NMR (δ, ppm, d6-DMSO, T = 358K) : 1,4 (2s, Integral: 57 : 96, t-Butyl) .150 ml of ammonia and 50 ml of THF were placed at -30 ° C. Then 0.24 g (0.034 mol) of lithium was added. 4 g (0.0115 mol) of N-Boc-pyrrole-2-carboxylic acid ((IS) -endo-bornyl) ester dissolved in 10 ml of THF were added dropwise to this mixture in the course of 5 minutes. After stirring for 1 h, 2 ml of saturated ammonium chloride solution and 150 ml of saturated sodium chloride solution were added, the phases were separated and the aqueous phase was extracted three times with 100 ml of dichloromethane each time. The organic phases were combined, dried over sodium sulfate and concentrated. Yield: 3.2 g (0.009 mol, 61%). E - NMR (δ, ppm, d6-DMSO, T = 358K): 1.4 (2s, integral: 57: 96, t-butyl).
Beispiel 3: Synthese von N-Boc-3 , 4 -Dehydroprolin- ( (1R, 2S, 5R) - menthyl) -esterExample 3: Synthesis of N-Boc-3, 4-dehydroproline- ((1R, 2S, 5R) - menthyl) ester
100 ml Ammoniak und 23 ml THF wurden bei -30°C vorgelegt und 0,58 g (0,084 mol) Lithium zugegeben. Zu dieser Mischung tropfte man 10 g (0,028 mol) N-Boc-Pyrrol -2 -carbonsäure- ( (1R, 2S, 5R) - menthyl) -ester gelöst in 20 ml THF. Nach einer Nachrührzeit von 1 h gab man 5 g Ammoniumchlorid, 100 ml THF und 7,5 g Celite® zu und ließ den Ammoniak abdampfen. Die Suspension wurde abfiltriert und das Filtrat eingeengt. Ausbeute: 8,4 g (0,024 mol, 85 %) . iH-NMR (δ, ppm, CDC13) : 1,325 - 1,425 (je 2s, Integral: 67 : 92, t-Butyl) .100 ml of ammonia and 23 ml of THF were placed at -30 ° C and 0.58 g (0.084 mol) of lithium was added. 10 g (0.028 mol) of N-Boc-pyrrole -2-carboxylic acid ((1R, 2S, 5R) - menthyl) ester dissolved in 20 ml of THF were added dropwise to this mixture. After stirring for 1 h, 5 g of ammonium chloride, 100 ml of THF and 7.5 g of Celite® were added and the ammonia was allowed to evaporate. The suspension was filtered off and the filtrate was concentrated. Yield: 8.4 g (0.024 mol, 85%). i H-NMR (δ, ppm, CDC1 3 ): 1.325-1.425 (2s each, integral: 67:92, t-butyl).
Beispiel 4: Synthese von N-Boc-3 , 4 -Dehydroprolin- ( (IS) -2 , 10-cam- phersulfamidExample 4: Synthesis of N-Boc-3, 4-dehydroproline- ((IS) -2, 10-camphorsulfamide
100 ml Ammoniak und 50 ml THF wurden bei -70°C vorgelegt und100 ml of ammonia and 50 ml of THF were placed at -70 ° C and
0,15 g (0,023 mol) Lithium zugegeben. Zu dieser Mischung tropfte man 3,2 g (0,0078 mol) N-Boc-Pyrrol -2 -carbonsäure- (IS) -2 , 10-cam- phersulfamid gelöst in 20 ml THF zu. Nach einer Nachrührzeit von 1 h gab man 4 g Ammoniumchlorid, 25 ml THF und 3 g Celite® zu und ließ den Ammoniak abdampfen. Die Suspension wurde abfiltriert und das Filtrat eingeengt. Ausbeute: 4 g (enthält noch LiCl) . ^-H-NMR (δ, ppm, CDC13) : 1,37 - 1,46 (je 2s, Integral: 69 : 30, t-Butyl). 0.15 g (0.023 mol) of lithium was added. 3.2 g (0.0078 mol) of N-Boc-pyrrole -2-carboxylic acid (IS) -2, 10-camphorsulfamide dissolved in 20 ml of THF were added dropwise to this mixture. After stirring for 1 h, 4 g of ammonium chloride, 25 ml of THF and 3 g of Celite® were added and the ammonia was allowed to evaporate. The suspension was filtered off and the filtrate was concentrated. Yield: 4 g (still contains LiCl). ^ H NMR (δ, ppm, CDC1 3 ): 1.37 - 1.46 (2s each, integral: 69:30, t-butyl).

Claims

Patentansprüche claims
1. Verfahren zur Herstellung von chiralen 3, 4-Dehydroprolinen der Formel I1. Process for the preparation of chiral 3, 4-dehydroprolines of the formula I.
worinwherein
R: eine chirale Hilfsgruppe,R: a chiral auxiliary group,
R' : Wasserstoff oder einen Cι-C6-Alkyl-, C .7-Alkenyl- , C7.9-Arylalkyl oder Tri-Cι-4-alkylsilylrest und R' ' : eine Schutzgruppe bedeuten, dadurch gekennzeichnet, daß man ein Pyrrolcarbonsaurederivat der Formel IIR ': hydrogen or a -CC 6 alkyl, C. 7 alkenyl, C 7 . 9- arylalkyl or tri-Cι- 4 alkylsilyl radical and R '': a protective group, characterized in that a pyrrolecarboxylic acid derivative of the formula II
in Ammoniak mit einem Alkali- oder Erdalkalimetall und anschließend mit einer wäßrigen Salzlösung oder einer Verbindung der Formel IIIin ammonia with an alkali or alkaline earth metal and then with an aqueous salt solution or a compound of formula III
R' X III,R 'X III,
worin X eine Abgangsgruppe bedeutet, umsetzt.where X represents a leaving group.
2. Verfahren nach Anspruch 1, dadurch gekennzeichnet, daß R für den Rest eines chiralen Amins oder eines chiralen Alkohols steht.2. The method according to claim 1, characterized in that R represents the rest of a chiral amine or a chiral alcohol.
3. Verfahren nach Anspruch 2, dadurch gekennzeichnet, daß RH für alle enantio eren bzw. diastereomeren Formen folgender Verbindungen steht:3. The method according to claim 2, characterized in that RH stands for all enantio eren or diastereomeric forms of the following compounds:
E F GE F G
00
HN ■^^0HN ■ ^^ 0
, | (R'" = Cι-4-Alkyl), | (R '"= Cι- 4 alkyl)
R'R '
4. Verfahren nach Anspruch 1, dadurch gekennzeichnet, daß man die Reaktion in Gegenwart eines inerten Lösungsmittels durchführt.4. The method according to claim 1, characterized in that one carries out the reaction in the presence of an inert solvent.
5. Verfahren nach Anspruch 1, dadurch gekennzeichnet, daß man die Reaktion im Druckbereich von 1 bis 200 bar und einer Reaktionstemperatur zwischen -100 und +100 °C durchführt. 5. The method according to claim 1, characterized in that one carries out the reaction in the pressure range from 1 to 200 bar and a reaction temperature between -100 and +100 ° C.
EP98933585A 1997-06-04 1998-06-02 Method for producing chiral 3,4-dehydroprolines Withdrawn EP0986538A1 (en)

Applications Claiming Priority (3)

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DE19723473A DE19723473A1 (en) 1997-06-04 1997-06-04 Process for the preparation of chiral 3,4-didehydroprolines
DE19723473 1997-06-04
PCT/EP1998/003284 WO1998055456A1 (en) 1997-06-04 1998-06-02 Method for producing chiral 3,4-dehydroprolines

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JP (1) JP2002506430A (en)
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CN (1) CN1259122A (en)
AU (1) AU8335298A (en)
BR (1) BR9809726A (en)
CA (1) CA2291787A1 (en)
DE (1) DE19723473A1 (en)
HU (1) HUP0002772A3 (en)
IL (1) IL132988A0 (en)
NO (1) NO995939D0 (en)
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MX9910984A (en) 2000-04-01
NO995939L (en) 1999-12-03
KR20010013342A (en) 2001-02-26
HUP0002772A3 (en) 2001-02-28
DE19723473A1 (en) 1998-12-10
CA2291787A1 (en) 1998-12-10
CN1259122A (en) 2000-07-05
BR9809726A (en) 2000-07-11
US6166222A (en) 2000-12-26
NO995939D0 (en) 1999-12-03
IL132988A0 (en) 2001-03-19
HUP0002772A2 (en) 2000-12-28

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