EP1003902A1 - Method for racemic biochemical resolution of cis- and trans- pyrrolopiperidine - Google Patents
Method for racemic biochemical resolution of cis- and trans- pyrrolopiperidineInfo
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- EP1003902A1 EP1003902A1 EP98943821A EP98943821A EP1003902A1 EP 1003902 A1 EP1003902 A1 EP 1003902A1 EP 98943821 A EP98943821 A EP 98943821A EP 98943821 A EP98943821 A EP 98943821A EP 1003902 A1 EP1003902 A1 EP 1003902A1
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- Prior art keywords
- pyrrolopiperidine
- acyl
- mixture
- diacyl
- extraction
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- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
- C12P41/00—Processes using enzymes or microorganisms to separate optical isomers from a racemic mixture
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
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- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
- C12P17/00—Preparation of heterocyclic carbon compounds with only O, N, S, Se or Te as ring hetero atoms
- C12P17/18—Preparation of heterocyclic carbon compounds with only O, N, S, Se or Te as ring hetero atoms containing at least two hetero rings condensed among themselves or condensed with a common carbocyclic ring system, e.g. rifamycin
- C12P17/182—Heterocyclic compounds containing nitrogen atoms as the only ring heteroatoms in the condensed system
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- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
- C12P41/00—Processes using enzymes or microorganisms to separate optical isomers from a racemic mixture
- C12P41/006—Processes using enzymes or microorganisms to separate optical isomers from a racemic mixture by reactions involving C-N bonds, e.g. nitriles, amides, hydantoins, carbamates, lactames, transamination reactions, or keto group formation from racemic mixtures
- C12P41/007—Processes using enzymes or microorganisms to separate optical isomers from a racemic mixture by reactions involving C-N bonds, e.g. nitriles, amides, hydantoins, carbamates, lactames, transamination reactions, or keto group formation from racemic mixtures by reactions involving acyl derivatives of racemic amines
Definitions
- the present invention relates to a process for the resolution of racemates of both cis and trans-pyrrolopiperidine, in which a mixture of acyl derivatives of cis or trans-pyrrolopiperidine is prepared in the presence of enzymes and this mixture after treatment with acids and base and by extraction separates
- Enantiomerically pure pyrrolopiperidines are important intermediates for the production of quinolone and naphthyridine derivatives with antibacterial activity (see EP-A 550 903)
- This EP-A also describes a process for the production of enantiomerically pure cis-pyrrolopiperidines in which the racemate separation by crystallization on 6 -Benzyl derivatives of pyrrolopiperidine is made disadvantageous here is the complex crystallization of the enantiomers with enantiomeric auxiliary reagents, each of the two enantiomers being crystallized with an auxiliary reagent
- Heteroatom eg fluorine
- fluoroacetic acid and its esters are more difficult to access than unsubstituted ahphatic carboxylic acids and their esters
- a process has now been found for the resolution of racemates of cis and trans pyrrolopiperidine, which is characterized in that a mixture comprising (R, R) - and (S, S) -pyrrolopiperidine or (S, R) - and ( R, S) -Pyrrolop ⁇ peridin contains enzymatically monoacylated, so a mixture (I) receives that (R, R) - and (S, S) -6-acyl-pyrrolopiperidine or (S, R) - and (R, S) -6-acyl-pyrrolop ⁇ pe ⁇ d ⁇ n contains, this mixture (I) is further acylated enzymatically, thus obtaining a mixture (II) containing (S, S) -l, 6-d ⁇ acyl - and (R, R) -6-acyl-pyrrol ⁇ p ⁇ pe ⁇ d ⁇ n or (S, R) -1,6-d ⁇ acyl- and (R, S) -6-acyl-pyr
- the two acylation reactions will be carried out as a one-pot reaction and the mixture (I) will not be isolated.
- 1 to 35 moles of an acylating agent of the formula (I) can be used per mole of cis- or trans-pyrrolopiperidine. This amount is preferably 2 to 30 mol.
- Suitable reaction temperatures are, for example, those in the range from 10 to 90 ° C.
- reaction time for the preparation of the mixture (II) can be, for example, in the range from 200 to 450 hours. 250 to 350 hours are preferred.
- hydrolases such as proteases, esterases or lipases can be used.
- Lipases from Pseudomonas or Candida are preferred.
- the lipase from Candida antarctica is particularly preferred.
- the enzymes can be used in native or immobilized form.
- Immobilization can take place, for example, by microencapsulation or by combination with an organic or inorganic carrier material.
- Support materials include, for example, kieselguhr, ion exchangers, zeolites, polysaccharides, polyamides and polystyrene resins, in particular Celite ® and Lewatit ® .
- lipase from Candida antarctica in the form of the commercially available one is suitable
- the amount of the enzyme can be varied within wide limits. For example, 5 to 700% by weight of immobilized enzyme, based on the cis- or trans-pyrrolopiperidine used, or a corresponding amount of native enzyme can be used. This amount is preferably 10 to 600% by weight of immobilized enzyme or the corresponding amount of native enzyme.
- suitable acylating agents are those of the formula (I)
- R 1 and R 2 independently of one another represent hydrogen or -CC 2 alkyl.
- the alkyl groups can be straight-chain or branched.
- R 1 is preferably hydrogen or -C ⁇ alkyl and R 2 is C Cg-alkyl.
- Ethyl acetate is particularly preferably used
- This mixture is worked up according to the invention by first separating off the enzyme, for example by filtration.
- the separated and optionally washed enzyme can be used again in the acylation of cis- or trans-pyrrolopiperidine or for other purposes
- any diluent and any excess acylating agent which may be present can be carried out by evaporation, if appropriate under reduced pressure
- the reaction mixture remaining after the separation of the enzyme and, if appropriate, the diluent and excess acylating agent is then treated with aqueous acid.
- aqueous acid For example, 2 to 50% by weight aqueous sulfuric, hydrochloric, phosphoric or acetic acid can be used.
- the amount of the aqueous acid can be measured, for example, so that the pH after
- Acid addition is 4 or less, preferably 2 or less
- the treatment with aqueous acid can be carried out, for example, at temperatures from 0 to 90 ° C. Preference is given to 10 to 50 ° C.
- Inert organic solvents which are immiscible or only slightly miscible with water can be used to extract the mixture present after the treatment with the aqueous acid.
- Examples are chlorinated hydrocarbons, aromatic hydrocarbons and ethers
- Toluene, MTBE, diethyl ether, methylene chloride and chloroform are preferred.
- the extraction can be carried out, for example, at 10 to 50 ° C.
- the extract then contains the (S, S) -l, 6-diacyl-pyrrolopiperidine or (S, R) -l, 6-diacyl-pyrrolopiperidine prepared, for example by removing the extractant
- alkali hydroxides, alkali carbonates, alkali hydrogen carbonates, calcium hydroxide or ammonia can be used as such or in aqueous solution or suspension. 20 to 50% by weight aqueous sodium and potassium hydroxide are preferred.
- the amount of the agent for making alkaline for example, it can be dimensioned such that after its addition there is a pH of 7.5 or more, preferably 9 or more
- the alkaline mixture now present is also extracted.
- the organic solvents and temperatures described above come into question.
- the extract then contains the (R, R) -6-acyl-pyrrolopiperidione or (R, S) -6-acyl-pyrrolopiperidine. It can be isolated by removing the extractant, for example by evaporation, if appropriate under reduced pressure.
- 1,6-diacyl derivative and the (R, R) - or (R, S) -isomer in the form of the 6-acyl derivative can be obtained in free form from these acyl derivatives by splitting off the acyl group (s) by processes known per se (see, for example, Houben-Weyl, Methods of Organic Chemistry, 4th Edition, page 432).
- the optical antipodes are generally obtained in optical yields of at least 90% ee and in chemical yields of at least 25%.
- the optical yields are often over 95% ee and the chemical yields over 35%.
- the racemate separation according to the invention has the additional advantages that it delivers both enantiomers in one step and can be carried out using acylating agents which are inexpensive to obtain.
- the present invention further relates to mixtures which contain (R, R) - and (S, S) -6-acylpyrrolopiperidines (such mixtures have also been referred to as mixture (I) above).
- acyl groups may be, for example, those having a C j -C ⁇ alkyl. It is preferably a CC ⁇ alkyl radical, in particular a methyl radical.
- Preferred mixtures are those which contain (R, R) - and (S, S) -6-acetylpyrrolopiperidine.
- Mixtures (I) according to the invention can in principle be prepared as described above for the preparation of the mixtures (II), but with the difference that a shorter reaction time is observed for the acylation reaction.
- Mixtures (I) can be prepared, for example, from 10 minutes to 20 hours, preferably from 0.5 to 10 hours.
- the present invention also relates to (S, S) -l, 6-diacyl-pyrrolopiperidines as such.
- acyl groups may be, for example, those having a C j -C ⁇ alkyl. Preferably, this is a C j -C ⁇ alkyl, in particular a methyl radical.
- a preferred such diacyl-pyrrolopiperidine is (S, S) -l, 6-diacetyl-pyrrolopiperidine.
- the present invention also relates to (R, R) -6-acyl-pyrrolopiperidines and (R, R) - 1, 6-diacyl-pyrrolopiperidines.
- the enantiomeric excesses were determined by GC on cyclodextrin columns, the configuration by comparison with authentically synthesized pyrrolopiperidines.
- Enzyme was filtered off and the filter cake was washed with ethyl acetate. The combined organic solutions were spun in. The residue was dissolved in 100 ml
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Abstract
Cis- and trans-pyrrolopiperidines are advantageously separated into their optical isomers when monoacylating by enzymatic process a mixture containing (R,R)- and (S,S)-pyrrolopiperidine or (S,R)- and (R,S)-pyrrolopiperidine, thereby obtaining a mixture (I) containing (R,R)- and (S,S)-6-acyl-pyrrolopiperidine or (S,R)- and (R,S)-6-acyl-pyrrolopiperidine. Said mixture (I) is then again acylated by enzymatic process, thereby obtaining a mixture (II) containing (S,S)-1,6-diacyl- and (R,R)-6-acyl-pyrrolopiperidine or (S,R)-1,6-diacyl- and (R,S)-6-acyl-pyrrolopiperidine; the enzyme and optionally the solvent and the excess acylating agent are then separated from the mixture (II), and the rest is treated with an aqueous acid and the (S,S)-1,6-diacyl-pyrrolopiperidine or the (S,R)-1,6-diacyl-pyrrolopiperidine is separated by extraction and the extraction residue is alkalinized, and the (R,R)-6-acyl-pyrrolopiperidine or the (R,S)-6-acyl-pyrrolopiperidine is separated by extraction. From these acylated isomer-free derivatives, the free base can optionally be prepared according to the usual methods for separating acylated groups.
Description
Verfahren zur Racematspaltung von cis- und trans-PyrrolopiperidinProcess for the resolution of racemates of cis- and trans-pyrrolopiperidine
Die vorliegende Erfindung betrifft ein Verfahren zur Racematspaltung von sowohl cis- als auch trans-Pyrrolopiperidin, bei dem man in Gegenwart von Enzymen ein Gemisch von Acylderivaten des cis- oder trans-Pyrrolopiperidins herstellt und dieses Gemisch nach dem Behandeln mit Sauren und Base und durch Extraktion auftrenntThe present invention relates to a process for the resolution of racemates of both cis and trans-pyrrolopiperidine, in which a mixture of acyl derivatives of cis or trans-pyrrolopiperidine is prepared in the presence of enzymes and this mixture after treatment with acids and base and by extraction separates
Enantiomerenreine Pyrrolopiperidine sind wichtige Zwischenprodukte für die Herstellung von Chinolon- und Naphthyridinderivaten mit antibakterieller Wirksamkeit (siehe EP-A 550 903) In dieser EP-A ist auch ein Verfahren zur Herstellung von enantiomerenreinen cis-Pyrrolopiperidinen beschrieben, bei dem die Racemattrennung mittels Kristallisation an 6-Benzylderivaten des Pyrrolopiperidins vorgenommen wird Nachteilig hierbei ist die aufwendige Kristallisation der Enantionmeren mit enan- tiomeren Hilfsreagenzien, wobei beide Enantiomere jeweils mit einem Hilfsreagenz kristallisiert werdenEnantiomerically pure pyrrolopiperidines are important intermediates for the production of quinolone and naphthyridine derivatives with antibacterial activity (see EP-A 550 903) This EP-A also describes a process for the production of enantiomerically pure cis-pyrrolopiperidines in which the racemate separation by crystallization on 6 -Benzyl derivatives of pyrrolopiperidine is made disadvantageous here is the complex crystallization of the enantiomers with enantiomeric auxiliary reagents, each of the two enantiomers being crystallized with an auxiliary reagent
Bei einem bekannten Verfahren zur Herstellung von anderen enantiomerenreinen sekundären Aminen arbeitet man mit Hydrolasen und muß mit Estern acylieren, bei denen im Saureteil in Nachbarschaft zur Carbonylfunktion ein elektronenreichesIn a known process for the preparation of other enantiomerically pure secondary amines, one works with hydrolases and has to be acylated with esters, in which an electron-rich region in the acid part in the vicinity of the carbonyl function
Heteroatom (z B Fluor) vorhanden ist (siehe DE-A 43 32 738) Fluoressigsaure und deren Ester sind schwieriger zuganglich als unsubstituierte ahphatische Carbonsauren und deren EsterHeteroatom (eg fluorine) is present (see DE-A 43 32 738) fluoroacetic acid and its esters are more difficult to access than unsubstituted ahphatic carboxylic acids and their esters
Bei einem bekannten Verfahren zur Racemattrennung von primären Aminen werden diese mit Lipase aus Candida antarctica und Essigsaureethylester behandelt, wobei das (R)-Isomere selektiv acyliert wird (Chimia 48, 570 (1994)) Dieses Verfahren ist jedoch auf die Racemattrennung primärer Amine beschranktIn a known process for the resolution of primary amines, these are treated with lipase from Candida antarctica and ethyl acetate, the (R) isomer being selectively acylated (Chimia 48, 570 (1994)). However, this process is limited to the resolution of primary amines
Es wurde nun ein Verfahren zur Racematspaltung von cis- und trans-Pyrrolopiperidin gefunden, das dadurch gekennzeichnet ist, daß man ein Gemisch, das (R,R)- und (S,S)-Pyrrolopiperidin oder (S,R)- und (R,S)-Pyrrolopιperidin enthalt enzymatisch monoacyliert, so ein Gemisch (I) erhalt, das (R,R)- und (S,S)-6-Acyl-pyrrolopiperidin
oder (S,R)- und (R,S)-6-Acyl-pyrrolopιpeπdιn enthalt, dieses Gemisch (I) enzymatisch weiter acyliert, so ein Gemisch (II) erhalt, das (S,S)-l,6-Dιacyl- und (R,R)-6-Acyl-pyrrolιpιpeπdιn oder (S,R)-1,6-Dιacyl- und (R,S)-6-Acyl-pyrrolo- pφeπdin enthalt, aus dem Gemisch (II) das Enzym und gegebenenfalls Losungsmittel und überschüssiges Acylierungsmittel abtrennt, den Rest mit wäßriger Saure behandelt und durch Extraktion (S,S)-l,6-Dιacyl-pyrrolopιpeπdιn oder (S,R)-1,6- Diacyl-pyrrolopipeπdin abtrennt und den Ruckstand der Extraktion alkalisch stellt und durch Extraktion (R,R)-6-Acyl-pyrrolopιpeπdιn oder (R,S)-6-Acyl-pyrrolopιpeπdιn abtrenntA process has now been found for the resolution of racemates of cis and trans pyrrolopiperidine, which is characterized in that a mixture comprising (R, R) - and (S, S) -pyrrolopiperidine or (S, R) - and ( R, S) -Pyrrolopιperidin contains enzymatically monoacylated, so a mixture (I) receives that (R, R) - and (S, S) -6-acyl-pyrrolopiperidine or (S, R) - and (R, S) -6-acyl-pyrrolopιpeπdιn contains, this mixture (I) is further acylated enzymatically, thus obtaining a mixture (II) containing (S, S) -l, 6-dιacyl - and (R, R) -6-acyl-pyrrolιpιpeπdιn or (S, R) -1,6-dιacyl- and (R, S) -6-acyl-pyrrolo- pφeπdin contains, from the mixture (II) the enzyme and, if appropriate, solvent and excess acylating agent are separated off, the remainder is treated with aqueous acid and separated off by extraction (S, S) -l, 6-dιacyl-pyrrolopιpeπdιn or (S, R) -1,6-diacyl-pyrrolopipeπdin and the residue of the extraction makes alkaline and by extraction (R, R) -6-acyl-pyrrolopιpeπdιn or (R, S) -6-acyl-pyrrolopιpeπdιn separated
Das erfindungsgemaße Verfahren kann durch folgendes Formelschema vereinfacht und beispielhaft aufgezeigt an der Racemattrennung von cis-Pyrrolopipeπdm dargestellt werden
The process according to the invention can be simplified by the following formula and shown by the racemate separation of cis-pyrrolopipeπdm
Gemisch aus cis-(R,R)- und cis-(S,S)-PyrrolopiperidinMixture of cis- (R, R) - and cis- (S, S) -pyrrolopiperidine
Enzym (schnellere Reaktion)Enzyme (faster reaction)
Gemisch (I)Mixture (I)
R-R-
Enzym (langsamere Reaktion)Enzyme (slower reaction)
Gemisch (II)Mixture (II)
H©H ©
H20H 2 0
Extraktion OhP/ ExtraktionExtraction OhP / extraction
(S.S)-Diacylverbindung (R,R)-Monoacylverbindung
Geht man anstelle von cis- von trans-Pyrrolopiperidin aus, so verläuft das erfindungsgemäße Verfahren analog und man erhält in der letzten Stufe die (S,R)- Diacyl- und die (R,S)-Monoacylverbindung.(SS) diacyl compound (R, R) monoacyl compound If one starts from trans-pyrrolopiperidine instead of cis, the process according to the invention proceeds analogously, and the (S, R) -diacyl and (R, S) -monoacyl compound are obtained in the last stage.
Im allgemeinen wird man die beiden Acylierungsreaktionen als Eintopfreaktion durchfuhren und das Gemisch (I) nicht isolieren. Für diese Arbeitsweise kann man beispielsweise 1 bis 35 Mol eines Acylierungsmittels der Formel (I) pro Mol cis- oder trans-Pyrrolopiperidin einsetzen. Vorzugsweise liegt diese Menge bei 2 bis 30 Mol.In general, the two acylation reactions will be carried out as a one-pot reaction and the mixture (I) will not be isolated. For this procedure, for example, 1 to 35 moles of an acylating agent of the formula (I) can be used per mole of cis- or trans-pyrrolopiperidine. This amount is preferably 2 to 30 mol.
Geeignete Reaktionstemperaturen sind beispielsweise solche im Bereich 10 bis 90°C.Suitable reaction temperatures are, for example, those in the range from 10 to 90 ° C.
Bevorzugt sind 30 bis 60°C.30 to 60 ° C. are preferred.
Die Reaktionszeit für die Herstellung des Gemisches (II) kann beispielsweise im Bereich 200 bis 450 Stunden liegen. Bevorzugt sind 250 bis 350 Stunden.The reaction time for the preparation of the mixture (II) can be, for example, in the range from 200 to 450 hours. 250 to 350 hours are preferred.
Als Enzyme können z.B. Hydrolasen wie Proteasen, Esterasen oder Lipasen eingesetzt werden. Bevorzugt sind Lipasen aus Pseudomonas oder Candida. Besonders bevorzugt ist die Lipase aus Candida antarctica.As enzymes e.g. Hydrolases such as proteases, esterases or lipases can be used. Lipases from Pseudomonas or Candida are preferred. The lipase from Candida antarctica is particularly preferred.
Die Enzyme können in nativer oder immobilisierter Form eingesetzt werden. EineThe enzymes can be used in native or immobilized form. A
Immobilisierung kann z.B. durch Mikroverkapselung oder durch Kombination mit einem organischen oder anorganischen Trägermaterial erfolgen. Als Trägermaterialien kommen z.B. Kieselgur, Ionenaustauscher, Zeolithe, Polysaccharide, Polyamide und Polystyrolharze in Frage, insbesondere Celite® und Lewatit®. Geeignet ist beispielsweise Lipase aus Candida antarctica in Form des im Handel erhältlichenImmobilization can take place, for example, by microencapsulation or by combination with an organic or inorganic carrier material. Support materials include, for example, kieselguhr, ion exchangers, zeolites, polysaccharides, polyamides and polystyrene resins, in particular Celite ® and Lewatit ® . For example, lipase from Candida antarctica in the form of the commercially available one is suitable
Produkts Novozym® 435 (Hersteller: Fa. Novo Nordisk).Product Novozym ® 435 (manufacturer: Novo Nordisk).
Die Menge des Enzyms kann in weiten Grenzen variiert werden. Beispielsweise können 5 bis 700 Gew.-% immobilisiertes Enzym bezogen auf eingesetztes cis-oder trans-Pyrrolopiperidin oder eine entsprechende Menge natives Enzym eingesetzt werden. Vorzugsweise liegt diese Menge bei 10 bis 600 Gew.-% immobilisiertes Enzym oder bei der entsprechenden Menge natives Enzym.
Als Acylierungsmittel kommen z B solche der Formel (I) in FrageThe amount of the enzyme can be varied within wide limits. For example, 5 to 700% by weight of immobilized enzyme, based on the cis- or trans-pyrrolopiperidine used, or a corresponding amount of native enzyme can be used. This amount is preferably 10 to 600% by weight of immobilized enzyme or the corresponding amount of native enzyme. Examples of suitable acylating agents are those of the formula (I)
R\^° R \ ^ °
O (I),O (I),
NR2 N R 2
bei derin the
R1 und R2 unabhängig voneinander für Wasserstoff oder Cι-Cι2-Alkyl stehen Die Alkylgruppen können geradkettig oder verzweigt sein. Bevorzugt stehen R1 für Wasserstoff oder -C^Alkyl und R2 für C Cg-Alkyl. Besonders bevorzugt wird Essigsaureethylester eingesetztR 1 and R 2 independently of one another represent hydrogen or -CC 2 alkyl. The alkyl groups can be straight-chain or branched. R 1 is preferably hydrogen or -C ^ alkyl and R 2 is C Cg-alkyl. Ethyl acetate is particularly preferably used
Als gegebenenfalls für die Acylierungsreaktion einzusetzende Verdünnungsmittel kommen die verschiedensten organischen Losungsmittel in Frage, beispielsweise Ether wie Diethylether oder Methyl-tert -butylether (= MTBE), Kohlenwasserstoffe wie Toluol und halogenierte Kohlenwasserstoffe wie Methylenchlorid Man kann auch ohne Zusatz eines besonderen Verdünnungsmittels arbeiten Dann ist es zweckmäßig, einen Überschuß des Acylierungsmittels der Formel (I) einzusetzenA wide variety of organic solvents can be used as diluents, if appropriate for the acylation reaction, for example ethers such as diethyl ether or methyl tert-butyl ether (= MTBE), hydrocarbons such as toluene and halogenated hydrocarbons such as methylene chloride. It is also possible to work without the addition of a special diluent expedient to use an excess of the acylating agent of the formula (I)
Man erhalt auf diese Weise ein Gemisch (II), das (S,S)-l,6-Diacyl- und (R,R)-6-Acyl- pyrrolopiperidin oder (S,R)-1,6-Diacyl- und (R,S)-6-Acyl-pyrrolopiperidin enthaltThis gives a mixture (II), the (S, S) -l, 6-diacyl- and (R, R) -6-acyl-pyrrolopiperidine or (S, R) -1,6-diacyl- and Contains (R, S) -6-acyl-pyrrolopiperidine
Dieses Gemisch wird erfindungsgemaß aufgearbeitet, indem man zunächst das Enzym abtrennt, beispielsweise durch Filtration Das abgetrennte und gegebenenfalls gewaschene Enzym kann man erneut in die Acylierung von cis- oder trans-Pyrrolopiperidin oder zu sonstigen Zwecken einsetzenThis mixture is worked up according to the invention by first separating off the enzyme, for example by filtration. The separated and optionally washed enzyme can be used again in the acylation of cis- or trans-pyrrolopiperidine or for other purposes
Die Abtrennung von gegebenenfalls vorhandenem Verdünnungsmittel und gegebenenfalls vorhandenem überschüssigem Acylierungsmittel kann man durch Verdampfen, gegebenenfalls unter vermindertem Druck, durchfuhren
Das nach der Abtrennung des Enzyms und gegebenenfalls des Verdünnungsmittels und überschüssigen Acylierungsmittels verbleibende Reaktionsgemisch wird nun mit wäßriger Saure behandelt Hierfür kommen beispielsweise 2 bis 50 gew -%ige wäßrige Schwefel-, Salz-, Phosphor- oder Essigsaure in Frage Die Menge der wäßrigen Saure kann beispielsweise so bemessen werden, daß der pH-Wert nach derThe separation of any diluent and any excess acylating agent which may be present can be carried out by evaporation, if appropriate under reduced pressure The reaction mixture remaining after the separation of the enzyme and, if appropriate, the diluent and excess acylating agent is then treated with aqueous acid. For example, 2 to 50% by weight aqueous sulfuric, hydrochloric, phosphoric or acetic acid can be used. The amount of the aqueous acid can be be measured, for example, so that the pH after
Saurezugabe bei 4 oder weniger, vorzugsweise bei 2 oder weniger liegtAcid addition is 4 or less, preferably 2 or less
Die Behandlung mit wäßriger Saure kann z B bei Temperaturen von 0 bis 90°C durchgeführt werden Bevorzugt sind 10 bis 50°CThe treatment with aqueous acid can be carried out, for example, at temperatures from 0 to 90 ° C. Preference is given to 10 to 50 ° C.
Zur Extraktion des nach der Behandlung mit der wäßrigen Saure vorliegenden Gemisches kann man inerte, mit Wasser nicht oder nur wenig mischbare organische Losungsmittel verwenden Beispiele sind chlorierte Kohlenwasserstoffe, aromatische Kohlenwasserstoffe und EtherInert organic solvents which are immiscible or only slightly miscible with water can be used to extract the mixture present after the treatment with the aqueous acid. Examples are chlorinated hydrocarbons, aromatic hydrocarbons and ethers
Bevorzugt sind Toluol, MTBE, Diethylether, Methylenchlorid und Chloroform Die Extraktion kann man beispielsweise bei 10 bis 50°C durchführenToluene, MTBE, diethyl ether, methylene chloride and chloroform are preferred. The extraction can be carried out, for example, at 10 to 50 ° C.
Das Extrakt enthält dann das hergestellte (S,S)-l,6-Diacyl-pyrrolopiperidιn oder (S,R)-l,6-Diacyl-pyrrolopiperidin Durch Entfernen des Extraktionsmittels, z B durchThe extract then contains the (S, S) -l, 6-diacyl-pyrrolopiperidine or (S, R) -l, 6-diacyl-pyrrolopiperidine prepared, for example by removing the extractant
Verdampfung, gegebenenfalls bei vermindertem Druck, kann man es isolierenEvaporation, if necessary at reduced pressure, can be isolated
Nunmehr wird der Ruckstand der Extraktion alkalisch gestellt Hierzu kann man z B Alka hydroxide, Alkalicarbonate, Alkalihydrogencarbonate, Calciumhydroxid oder Ammoniak als solche oder in wäßriger Losung bzw Suspension verwenden Bevorzugt sind 20 bis 50 gew -%ige wäßrige Natron- und Kalilauge Die Menge des Mittels zum Alkalischstellen kann z B so bemessen werden, daß nach dessen Zugabe ein pH-Wert von 7,5 oder mehr, vorzugsweise von 9 oder mehr, vorliegtNow the residue of the extraction is made alkaline. For example, alkali hydroxides, alkali carbonates, alkali hydrogen carbonates, calcium hydroxide or ammonia can be used as such or in aqueous solution or suspension. 20 to 50% by weight aqueous sodium and potassium hydroxide are preferred. The amount of the agent for making alkaline, for example, it can be dimensioned such that after its addition there is a pH of 7.5 or more, preferably 9 or more
Das nunmehr vorliegende alkalische Gemisch wird ebenfalls extrahiert Hierfür kommen die oben beschriebenen organischen Losungsmittel und Temperaturen in Frage Das Extrakt enthalt dann das hergestellte (R,R)-6-Acyl-pyrrolopiperidιn oder
(R,S)-6-Acyl-pyrrolopiperidin. Durch Entfernen des Extraktionsmittels, z.B. durch Verdampfung, gegebenenfalls bei vermindertem Druck, kann man es isolieren.The alkaline mixture now present is also extracted. The organic solvents and temperatures described above come into question. The extract then contains the (R, R) -6-acyl-pyrrolopiperidione or (R, S) -6-acyl-pyrrolopiperidine. It can be isolated by removing the extractant, for example by evaporation, if appropriate under reduced pressure.
Auf diese Weise gelingt es, cis- oder trans-Pyrrolopiperidin in seine optischen Antipoden zu trennen und das (S,S)- oder (S,R)-Isomere in Form desIn this way it is possible to separate cis or trans pyrrolopiperidine into its optical antipodes and to isolate the (S, S) or (S, R) isomer in the form of the
1,6-Diacylderivates und das (R,R)- oder (R,S)-Isomere in Form des 6-Acylderivates zu erhalten. Aus diesen Acylderivaten kann man gewünschtenfalls das jeweilige Pyrrolopiperidin in freier Form erhalten, wenn man die Acylgruppe(n) nach an sich bekannten Verfahren abspaltet (siehe z.B. Houben-Weyl, Methoden der organischen Chemie, 4. Auflage, Seite 432).To obtain 1,6-diacyl derivative and the (R, R) - or (R, S) -isomer in the form of the 6-acyl derivative. If desired, the respective pyrrolopiperidine can be obtained in free form from these acyl derivatives by splitting off the acyl group (s) by processes known per se (see, for example, Houben-Weyl, Methods of Organic Chemistry, 4th Edition, page 432).
Mit der erfindungsgemäßen Racematspaltung erhält man die optischen Antipoden im allgemeinen in optischen Ausbeuten von mindestens 90 % ee und in chemischen Ausbeuten von mindestens 25 %. Häufig liegen die optischen Ausbeuten über 95 % ee und die chemischen Ausbeuten über 35 %.With the racemate resolution according to the invention, the optical antipodes are generally obtained in optical yields of at least 90% ee and in chemical yields of at least 25%. The optical yields are often over 95% ee and the chemical yields over 35%.
Die erfindungsgemäße Racemattrennung hat die zusätzlichen Vorteile, daß es beide Enantiomere in einem Schritt liefert und mit kostengünstig zugänglichen Acylierungs- mitteln durchgeführt werden kann.The racemate separation according to the invention has the additional advantages that it delivers both enantiomers in one step and can be carried out using acylating agents which are inexpensive to obtain.
Die vorliegende Erfindung betrifft weiterhin Gemische, die (R,R)- und (S,S)-6-Acyl- pyrrolopiperidine enthalten (weiter oben sind solche Gemische auch als Gemisch (I) bezeichnet worden). Bei den Acylgruppen kann es sich z.B. um solche handeln, die einen Cj-C^-Alkylrest aufweisen. Vorzugsweise handelt es sich dabei um einen C C^Alkylrest, insbesondere um einen Methylrest. Bevorzugte Gemische sind solche, die (R,R)- und (S,S)-6-Acetylpyrrolopiperidin enthalten.The present invention further relates to mixtures which contain (R, R) - and (S, S) -6-acylpyrrolopiperidines (such mixtures have also been referred to as mixture (I) above). In the acyl groups may be, for example, those having a C j -C ^ alkyl. It is preferably a CC ^ alkyl radical, in particular a methyl radical. Preferred mixtures are those which contain (R, R) - and (S, S) -6-acetylpyrrolopiperidine.
Erfindungsgemäße Gemische (I) kann man im Prinzip so herstellen, wie oben bei der Herstellung der Gemische (II) beschrieben, jedoch mit dem Unterschied, daß man für die Acylierungsreaktion eine kürzere Reaktionszeit einhält. Die Reaktionszeit zurMixtures (I) according to the invention can in principle be prepared as described above for the preparation of the mixtures (II), but with the difference that a shorter reaction time is observed for the acylation reaction. The response time to
Herstellung von Gemischen (I) kann z.B. 10 Minuten bis 20 Stunden, vorzugsweise 0,5 bis 10 Stunden betragen.
Die vorliegende Erfindung betrifft auch (S,S)-l,6-Diacyl-pyrrolopiperidine als solche. Bei den Acylgruppen kann es sich z.B. um solche handeln, die einen Cj-C^-Alkylrest aufweisen. Vorzugsweise handelt es sich dabei um einen Cj-C^Alkylrest, insbesondere um einen Methylrest. Ein bevorzugtes derartiges Diacyl-pyrrolopiperidin ist (S,S)-l,6-Diacetyl-pyrrolopiperidin.Mixtures (I) can be prepared, for example, from 10 minutes to 20 hours, preferably from 0.5 to 10 hours. The present invention also relates to (S, S) -l, 6-diacyl-pyrrolopiperidines as such. In the acyl groups may be, for example, those having a C j -C ^ alkyl. Preferably, this is a C j -C ^ alkyl, in particular a methyl radical. A preferred such diacyl-pyrrolopiperidine is (S, S) -l, 6-diacetyl-pyrrolopiperidine.
Die vorliegende Erfindung betrifft schließlich auch (R,R)-6-Acyl-pyrrolopiperidine und (R,R)- 1 ,6-Diacyl-pyrrolopiperidine.
Finally, the present invention also relates to (R, R) -6-acyl-pyrrolopiperidines and (R, R) - 1, 6-diacyl-pyrrolopiperidines.
BeispieleExamples
Die Enantiomerenüberschüsse wurden durch GC an Cyclodextrin-Säulen, die Konfiguration durch Vergleich mit authenthisch synthetisierten Pyrrolopiperidinen bestimmt.The enantiomeric excesses were determined by GC on cyclodextrin columns, the configuration by comparison with authentically synthesized pyrrolopiperidines.
Beispiel 1example 1
10 g racemisches cis-Pyrrolopiperidin wurden in 250 ml Ethylacetat gelöst und mit 60 g Novocym® 435 versetzt. Dann wurde 14 Tage bei 40°C langsam gerührt. Das10 g of racemic cis-pyrrolopiperidine were dissolved in 250 ml of ethyl acetate and 60 g of Novocym ® 435 were added. Then the mixture was slowly stirred at 40 ° C. for 14 days. The
Enzym wurde abfiltriert und der Filterkuchen mit Ethylacetat gewaschen. Die vereinigten organischen Lösungen wurden einrotiert. Der Rückstand wurde in 100 mlEnzyme was filtered off and the filter cake was washed with ethyl acetate. The combined organic solutions were spun in. The residue was dissolved in 100 ml
10 gew.-%iger wäßriger Salzsäure gelöst und 4 mal mit je 100 ml Chloroform extrahiert. Die organischen Phasen wurden vereinigt, getrocknet und einrotiert. Man erhielt 6,43 g (S,S)-l,6-Diacetyl-pyrrolopiperidin (38 % der Theorie, Reinheit über10 wt .-% aqueous hydrochloric acid dissolved and extracted 4 times with 100 ml of chloroform. The organic phases were combined, dried and evaporated. 6.43 g of (S, S) -1, 6-diacetyl-pyrrolopiperidine (38% of theory, purity above
95 %, Fp. 58 bis 60°C). Die wäßrige Phase wurde mit 45 gew.-%iger wäßriger95%, mp 58 to 60 ° C). The aqueous phase became 45 wt .-% aqueous
Natronlauge alkalisch gestellt (pH über 10) und 4 mal mit je 100 ml Chloroform extrahiert. Die vereinigten organischen Phasen wurden mit Natriumsulfat getrocknet und einrotiert. Man erhielt 8,2 g (R,R)-6-Acetylpyrrolopiperidin mit 96,5 Gew.-% Gehalt (= 62 % der Theorie, Fp. 83,6 bis 84,2°C).Sodium hydroxide solution made alkaline (pH above 10) and extracted 4 times with 100 ml of chloroform. The combined organic phases were dried with sodium sulfate and evaporated. 8.2 g (R, R) -6-acetylpyrrolopiperidine were obtained with a content of 96.5% by weight (= 62% of theory, mp. 83.6 to 84.2 ° C.).
Beispiel 2Example 2
1 g (S,S)-l,6-Diacetyl-pyrrolopiperidin wurde in 10 ml konzentrieter wäßriger Salz- säure gelöst und 24 Stunden unter Rückfluß gekocht. Dann wurde mit wäßriger1 g (S, S) -l, 6-diacetyl-pyrrolopiperidine was dissolved in 10 ml of concentrated aqueous hydrochloric acid and boiled under reflux for 24 hours. Then it became watery
Natronlauge alkalisch gestellt und 3 mal mit je 20 ml Chloroform extrahiert. Die vereinigten organischen Phasen wurden über Natriumsulfat getrocknet und einrotiert. Man erhielt 0,55 g (S,S)-Pyrrolopiperidin (= 95 % der Theorie). Eine Racemisierung wurde nicht beobachtet.
Beispiel 3Sodium hydroxide solution made alkaline and extracted 3 times with 20 ml of chloroform. The combined organic phases were dried over sodium sulfate and evaporated. 0.55 g of (S, S) -pyrrolopiperidine (= 95% of theory) was obtained. No racemization was observed. Example 3
1 g (R,R)-6-Acetyl-pyrrolopiperidin wurde in 10 ml konzentrierter wäßriger Salzsäure gelöst und 24 Stunden unter Rückfluß gekocht. Dann wurde mit wäßriger Natron- lauge alkalisch gestellt und 3 mal mit je 20 ml Chloroform extrahiert. Die vereinigten organischen Phasen wurden über Natriumsulfat getrocknet und einrotiert. Man erhielt 0,7 g (R,R)-Pyrrolopiperidin (= 93 % der Theorie). Eine Racemisierung wurde nicht beobachtet.
1 g of (R, R) -6-acetyl-pyrrolopiperidine was dissolved in 10 ml of concentrated aqueous hydrochloric acid and boiled under reflux for 24 hours. The mixture was then made alkaline with aqueous sodium hydroxide solution and extracted 3 times with 20 ml of chloroform each time. The combined organic phases were dried over sodium sulfate and evaporated. 0.7 g (R, R) -pyrrolopiperidine (= 93% of theory) was obtained. No racemization was observed.
Claims
1. Verfahren zur Racematspaltung von cis- und trans-Pyrrolopiperidin, dadurch gekennzeichnet, daß man ein Gemisch, das (R,R)- und (S,S)-Pyrrolopiperidin oder (S,R)- und (R,S)-Pyrrolopiperidin enthält, enzymatisch monoacyliert, so ein Gemisch (I) erhält, das (R,R)- und (S,S)-6-Acyl-pyrrolopiperidin oder (S,R)- und (R,S)-6-Acyl-pyrrolopiperidin enthält, dieses Gemisch (I) enzymatisch weiter acyliert, so ein Gemisch (II) erhält, das (S,S)-l,6-Diacyl- und (R,R)-6-Acyl-pyrrolipiperidin oder (S,R)-1,6-Diacyl- und (R,S)-6-Acyl- pyrrolopiperidin enthält, aus dem Gemisch (II) das Enzym und gegebenenfalls1. A process for the resolution of racemic cis and trans pyrrolopiperidine, characterized in that a mixture comprising (R, R) - and (S, S) -pyrrolopiperidine or (S, R) - and (R, S) - Pyrrolopiperidine contains, enzymatically monoacylated, thus obtaining a mixture (I) which contains (R, R) - and (S, S) -6-acyl-pyrrolopiperidine or (S, R) - and (R, S) -6-acyl -pyrrolopiperidine, this mixture (I) is further acylated enzymatically, thus obtaining a mixture (II) which contains (S, S) -l, 6-diacyl- and (R, R) -6-acyl-pyrrolipiperidine or (S, R) -1,6-diacyl- and (R, S) -6-acyl-pyrrolopiperidine contains, from the mixture (II) the enzyme and optionally
Lösungsmittel und überschüssiges Acylieerungsmittel abtrennt, den Rest mit wäßriger Säure behandelt und durch ExtraktionSeparates solvent and excess acylating agent, the rest treated with aqueous acid and by extraction
(S,S)-l,6-Diacyl-pyrrolopiperidin oder (S,R)-l,6-Diacyl-pyrrolopiperidin abtrennt und den Rückstand der Extraktion alkalisch stellt und durch Extraktion (R,R)-6-Acyl-pyrrolopiperidin oder (R,S)-6-Acyl-pyrrolopiperidin abtrennt.(S, S) -l, 6-diacyl-pyrrolopiperidine or (S, R) -l, 6-diacyl-pyrrolopiperidine is separated off and the residue of the extraction is made alkaline and by extraction (R, R) -6-acyl-pyrrolopiperidine or (R, S) -6-acyl-pyrrolopiperidine is separated off.
2. Verfahren nach Anspruch 1, dadurch gekennzeichnet, daß man als Acylierungsmittel solche der Formel (I) einsetzt2. The method according to claim 1, characterized in that the acylating agent used is that of the formula (I)
bei derin the
R1 und R2 unabhängig voneinander für Wasserstoff oder Cι-C12-Alkyl stehenR 1 and R 2 are independently hydrogen or -CC 12 alkyl
und die beiden Acylierungsreaktionen als Eintopfreaktion bei 10 bis 90°C durchführt.
Verfahren nach Ansprüchen 1 und 2, dadurch gekennzeichnet, daß man als Enzym eine Hydrolase in nativer oder immobilisierter Form einsetztand performs the two acylation reactions as a one-pot reaction at 10 to 90 ° C. Process according to Claims 1 and 2, characterized in that a hydrolase in native or immobilized form is used as the enzyme
Verfahren nach Ansprüchen 1 bis 3, dadurch gekennzeichnet, daß man als wäßrige Saure 2 bis 50 gew -%ιge Schwefel-, Salz-, Phosphor- oder Essigsaure in einer Menge einsetzt, daß der pH-Wert nach der Saurezugabe bei 4 oder weniger liegtProcess according to Claims 1 to 3, characterized in that 2 to 50% by weight of sulfuric, hydrochloric, phosphoric or acetic acid is used as the aqueous acid in an amount such that the pH after the acid addition is 4 or less
Verfahren nach Ansprüchen 1 bis 4, dadurch gekennzeichnet, daß man den Ruckstand nach der Extraktion mit Alkalihydroxid, Alkalicarbonat,Process according to Claims 1 to 4, characterized in that the residue after extraction with alkali hydroxide, alkali carbonate,
Alkalihydrogencarbonat, Calciumhydroxid oder Ammoniak bis zu einem pH- Wert von 7,5 oder hoher alkalisch stelltAlkali hydrogen carbonate, calcium hydroxide or ammonia up to a pH of 7.5 or higher alkaline
Gemische, die (R,R)- und (S,S)-6-Acyl-pyrrolopιpeπdιne enthaltenMixtures containing (R, R) - and (S, S) -6-acyl-pyrrolopιpeπdιne
(S, S)- 1 ,6-Diacyl-pyrrolopiperidine(S, S) - 1,6-diacyl-pyrrolopiperidine
(R,R)-6-Acyl-pyrrolopiperidine(R, R) -6-acyl-pyrrolopiperidine
(R,R)-l,6-Diacyl-pyrrolopipeπdine
(R, R) -l, 6-diacyl-pyrrolopipeπdine
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DE19735198A DE19735198A1 (en) | 1997-08-14 | 1997-08-14 | Optical resolution of cis- or trans-pyrrolo:piperidine derivatives |
DE19735198 | 1997-08-14 | ||
PCT/EP1998/004820 WO1999009200A1 (en) | 1997-08-14 | 1998-08-01 | Method for racemic biochemical resolution of cis- and trans- pyrrolopiperidine |
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CN103044418B (en) * | 2011-10-14 | 2015-02-04 | 上海朴颐化学科技有限公司 | Asymmetric synthesis method, relevant raw materials and preparation method of (S,S)-2,8-diazabicyclo[4,3,0] nonane |
CN104672234B (en) * | 2015-02-14 | 2016-01-27 | 佛山市赛维斯医药科技有限公司 | One class is containing FXa inhibitor, the preparation method and its usage of biamide structure |
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