Chemistry: molecular biology and microbiology – Micro-organism – tissue cell culture or enzyme using process... – Preparing heterocyclic carbon compound having only o – n – s,...
Patent
2000-02-03
2000-11-28
Lilling, Herbert J.
Chemistry: molecular biology and microbiology
Micro-organism, tissue cell culture or enzyme using process...
Preparing heterocyclic carbon compound having only o, n, s,...
435195, 435227, C12P 4100, C12P 1718, C07D47104
Patent
active
061534145
DESCRIPTION:
BRIEF SUMMARY
BACKGROUND OF THE INVENTION
The present invention relates to a method for the racemate resolution of both cis- and trans-pyrrolopiperidine, in which a mixture of acyl derivatives of the cis- or trans-pyrrolopiperidine is prepared in the presence of enzymes, and this mixture, following treatment with acids and base, is separated off and by extraction.
Enantiomerically pure pyrrolopiperidines are important intermediates for the preparation of quinolone and naphthyridine derivatives having antibacterial effectiveness (see EP-A 550 903). This EP-A also describes a process for the preparation of enantiomerically pure cis-pyrrolopiperidines in which the racemate resolution is carried out by means of crystallization on 6-benzyl derivatives of the pyrrolopiperidine. A disadvantage in this connection is the complex crystallization of the enantiomers with enantiomeric auxiliary reagents, the two enantiomers each being crystallized using one ancillary reagent.
In a known process for the preparation of other enantiomerically pure secondary amines, hydrolases are used and the acylation must be carried on using esters in which, in the acid moiety, an electron-rich heteroatom (e.g. fluorine) is present in the vicinity of the carbonyl function (see DE-A 43 32 738). Fluoroacetic acid and its esters are more difficult to obtain than unsubstituted aliphatic carboxylic acids and esters thereof.
In a known process for the racemate resolution of primary arnines, the latter are treated with lipase from Candida antarctica and ethyl acetate, with selective acylation of the (R)-isomer (Chimia 48, 570 (1994)). However, this process is limited to the racemate resolution of primary amines.
We have now found a method for the racemate resolution of cis- and trans-pyrrolopiperidine, which is characterized in that a mixture, which comprises (R,R)- and (S,S)-pyrrolopiperidine or (S,R)- and (R,S)-pyrrolopiperidine, is enzymatically monoacylated to give a mixture (I) which comprises (R,R)- and (S,S)-6-acyl-pyrrolopiperidine or (S,R)- and (R,S)-6-acyl-pyrrolopiperidine, this mixture (I) is enzymatically further acylated to give a mixture (II) which comprises (S,S)-1,6-diacyl- and (R,R)-6-acyl-pyrrolipiperidine or (S,R)-1,6-diacyl- and (R,S)-6-acyl-pyrrolopiperidine, the enzyme and optionally solvent and excess acylating agent are separated off from the mixture (II), and the remainder is treated with aqueous acid, and (S,S)-1,6-diacyl-pyrrolopiperidine or (S,R)-1,6-diacyl-pyrrolopiperidine is separated off by extraction, and the extraction residue is rendered alkaline, and (R,R)-6-acyl-pyrrolopiperidine or (R,S)-6-acyl-pyrrolopiperidine is separated off by extraction.
DESCRIPTION OF THE INVENTION
The process according to the invention can be simplified by the following equation and illustrated using the racemate resolution of cis-pyrrolopiperidine as an example: ##STR1##
If, instead of cis-pyrrolopiperidine, trans-pyrrolopiperidine is used as starting material, then the method according to the invention proceeds analogously, giving, in the last stage, the (S,R)-diacyl compound and the (R,S)-monoacyl compound.
Generally, the two acylating reactions are carried out as a one-pot reaction and the mixture (I) is not isolated. For this procedure, it is possible to use, for example, from 1 to 35 mol of an acylating agent of the formula (I) per mole of cis- or trans-pyrrolopiperidine. This amount is preferably from 2 to 30 mol.
Suitable reaction temperatures are, for example, those in the range from 10 to 90.degree. C., preferably from 30 to 60.degree. C.
The reaction time for the preparation of the mixture (II) can, for example, be in the range from 200 to 450 hours, preferably from 250 to 350 hours.
Enzymes which can be used are, for example, hydrolases, such as proteases, esterases or lipases. Preference is given to lipases from Pseudomonas or Candida. Particular preference is given to the lipase from Candida antarctica.
The enzymes can be used in native or immobilized form. Immobilization can be carried out, for example, by microencapsulation
REFERENCES:
Chimia 48, pp. 570 1994, Reetz et al, Highly Efficient Lipase-Catalyzed Kinetic Resolution of Chiral Amines.
Houben-Weyl, Methoden der organischen Chemie, Methods in Organic Chemistry, 4th edition 1994, H. Henecka: Carbonsauren.
Advanced Organic Chemistry, 4th edition Reactions Mechanisms, and Structure Jerry March.
Bayer Aktiengesellschaft
Eyl Diderico van
Gil Joseph C.
Lilling Herbert J.
LandOfFree
Method for racemic biochemical resolution of CIS-and trans-pypro does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Method for racemic biochemical resolution of CIS-and trans-pypro, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Method for racemic biochemical resolution of CIS-and trans-pypro will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-1723916