Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-12-14
2003-05-20
Rotman, Alan L. (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C546S112000
Reexamination Certificate
active
06566523
ABSTRACT:
The present invention relates to a process for the separation of enantiomers of cis-8-benzyl-7,9-dioxo-2,8-diazabicyclo[4.3.0]nonane (also called cis-6-benzyl-5,7-dioxooctahydropyrrolo[3,4-b]pyridine or dioxopyrrolopiperidine below). In a further aspect, the invention relates to a process for the preparation of (1S,6R)- and (
1
R,6S)-8-benzyl-7,9-dioxo-2,8-diazabicyclo[4.3.0]nonane using the aforementioned process. The invention furthermore relates to the (−)-2,3:4,6-di-O-isopropylidene-2-keto-L-gulonic acid salts of (1S,6R)- and (1R,6S)-8-benzyl-7,9-dioxo-2,8-diazabicyclo[4.3.0]nonane, and to a process for their preparation. The invention further relates to a process for the enrichment of enantiomers of (1S,6R)-8-benzyl-7,9-dioxo-2,8-diazabicyclo[4.3.0]nonane.
(1S,6R)-8-benzyl-7,9-dioxo-2,8-diazabicyclo[4.3.0]nonane of the formula (Ia)
is a valuable intermediate for the preparation of (S,S)-2,8-diazabicyclo[4.3.0]nonane:
to which it can be converted by reduction of the carbonyl groups and debenzylation in a manner known per se (EP-A-0350733). (S,S)-2,8-Diazabicyclo[4.3.0]nonane, for its part, is used for the preparation of the antibiotic moxifloxacin (INN):
1-Cyclopropyl-7-([S,S]-2,8-diazabicyclo[4.3.1]non-8-yl)-6-fluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolonecarboxylic acid (moxifloxacin) (EP-A-0350733).
The enantiomer
is also a valuable intermediate for the preparation of (R,R)-2,8-diazabicyclo-[4.3.0]nonane:
which, for its part, can be used for the preparation of very active antibacterial agents (e.g. Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC), 1996, Abstr. No. F-001).
There was therefore the desire for an inexpensive process for the preparation of (1S,6R)-8-benzyl-7,9-dioxo-2,8-diazabicyclo[4.3.0]nonane and of (1R,6S)-8-benzyl-7,9-dioxo-2,8-diazabicyclo[4.3.0]nonane from racemic cis-8-benzyl-7,9-dioxo-2,8-diazabicyclo[4.3.0]nonane, which is obtained by nuclear hydrogenation of pyridine-2,3-dicarboxylic acid N-benzylimide as described in EP-A-0 350 733 (Example K).
EP-A-0 550 903 discloses a process for the resolution of cis-8-benzyl-7,9-dioxo-2,8-diazabicyclo[4.3.0]nonane using tartaric acid (Example A, Method IV and Example B, Method IIa)). For the preparation, for example, of the (1S,6R) enantiomer, the processes described there necessitate the repeated recrystallization of the diestereomeric D-(−)-tartaric acid salts or reaction with L-(+)-tartaric acid and subsequent reaction of the released mother liquor with D-(−)-tartaric acid and recrystallization. The enantiomeric excesses obtained are inadequate at 93.8% ee for the (1R,6S) enantiomer and 96.6% ee for the (1S,6R) ehantiomer. The process suffers from the disadvantage that the provision of the desired enantiomer in adequate purity necessitates lengthy operations. The process is therefore unsuitable for the production of (1S,6R)-8-benzyl-7,9-dioxo-2,8-diazabicyclo[4.3.0]nonane on the industrial scale.
The object of the present invention therefore consisted in making available a process for the enrichment of enantiomers of cis-8-benzyl-7,9-dioxo-2,8-diazabicyclo[4.3.0]nonane, using which (1S,6R)-8-benzyl-7,9-dioxo-2,8-diaza-bicyclo[4.3.0]nonane or (1R,6S)-8-benzyl-7,9-dioxo-2,8-diazabicyclo[4.3.0]nonane can be made available inexpensively in large amounts and with the required purity.
The inventor therefore undertook intensive investigations to solve the problems of resolution using cis-8-benzyl-7,9-dioxo-2,8-diazabicyclo[4.3.0]nonane. In the course of this, various chiral acids known in the prior art were investigated for their suitability in solving the objects described above. It was shown here that numerous chiral acids mentioned in the prior art for the resolution of amines were unsuitable for achieving the objective. Finally, in a completely surprising manner, an economical process for the enrichment of enantiomers of cis-8-benzyl-7,9-dioxo-2,8-diazabicyclo[4.3.0]nonane was found, which uses (−)-2,3:4,6-di-O-isopropylidene-2-keto-L-gulonic acid or (1S)-(+)-camphor-10-sulfonic acid or (1R)-(−)-camphor-10-sulfonic acid as a chiral acid. (−)-2,3:4,6-Di-O-isopropylidene-2-keto-L-gulonic acid is known per se for the resolution of amines (US-A-3,682,925). However, it has surprisingly been shown that when using these specific chiral acids (1S,6R)-8-benzyl-7,9-dioxo-2,8-diazabicyclo[4.3.0]nonane and (1R,6S)-8-benzyl-7,9-dioxo-2,8-diazabicyclo[4.3.0]nonane can be obtained inexpensively in a few steps with high purity in a particularly simple manner.
The invention thus relates in one embodiment of the invention to a process for the enrichment of enantiomers of cis-8-benzyl-7,9-dioxo-2,8-diazabioclo[4.3.0]nonane, that comprises the reaction of mixtures of enantiomers of cis-8-benzyl-7,9-dioxo-2,8-diazabicyclo[4.3.0]nonane of the formula (I)
with (−)-2,3:4,6-di-O-isopropylidene-2-keto-L-gulonic acid or its hydrates of the formula (II):
Enrichment of enantiomers here means that the molar ratio of one enantiomer to the other is increased as far as complete separation of enantiomers. The mixture of enantiomers of cis-8-benzyl-7,9-dioxo-2,8-diazabicyclo[4.3.0]nonane includes any desired mixtures of the enantiomers and is not restricted to the racemate (1:1 mixture). Thus mixtures of (1S,6R)- and (1R,6S)-8-benzyl-7,9-dioxo-2,8-diazabicyclo[4.3.0]nonane in the molar ratio of, for example, 80:20 to 20:80 can be employed.
The reaction of the mixture of enantiomers with (−)-2,3:4,6-di-O-isopropylidene-2-keto-L-gulonic acid is carried out in solution or suspension. As solvents, organic solvents or mixtures thereof with up to 20% by weight of water can be employed. These organic solvents are preferably selected from the group which consists of alcohols (e.g. methanol, ethanol, n-propanol, isopropanol, isobutaiol, n-butanol and sec-butanol), ketones (e.g. acetone, methyl ethyl ketone, methyl isobutyl ketone) and ethers (such as, for example, tetrahydrofuran, dimethoxyethane), acetonitrile, ethyl acetate, toluene, dimethylformamide. Mixtures of the organic solvents can also be used. Ketones are preferred, particularly preferably methyl ethyl ketone.
The mixture of enantiomers and the (−)-2,3:4,6-di-O-isopropylidene-2-keto-L-gulonic acid can be mixed together in any desired manner. Expediently, they can be mixed together, however, by adding, for example, the acid dissolved or suspended in the respective solvent to a solution or suspension of the mixture of enantiomers. The addition is carried out at room temperature (20° C.) or elevated temperature of up to approximately 110° C. The mixture of enantiomers and the (−)-2,3:4,6-di-O-isopropylidene-2-keto-L-gulonic acid are preferably reacted at elevated temperature from 60 to 110° C., preferably at the boiling temperature of the respective solvent. The reaction can optionally also be carried out under pressure. The reaction of the amines with the acids takes place spontaneously per se. However, it can be expedient to carry out the reaction for a longer period of time of approximately 10 minutes up to a number of hours (e.g. at most 20 hours, preferably approximately up to 2 hours), since as a result of redissolution processes of the two diestereomeric salts an enrichment of one of the two diestereomeric salts can take place under the given conditions (temperature, solvent).
The molar ratio of the racemic amine and the acid is expediently 1:0.4 to 1:1. The molar ratio of the racemic amine and of the acid is preferably 1:0.4 to 1:0.6 and the molar ratio is particularly preferably approximately 1:0.5. The reason why the reaction is preferably carried out with a molar deficit of the acid consists in the fact that the (1R,6S)-8-benzyl-7,9-dioxo-2,8-di azabicyclo[4.3.0]nonane-(−)-2,3:4,6-di-O-isopropylidene-2
Bayer Aktiengesellschaft
Chiu Jerrie
Desai Rita
Rotman Alan L.
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