Racemization of R,S-dioxo-benzylpyrrolopiperidine

Details Racemization of R,S-dioxo-benzylpyrrolopiperidine Racemization of R,S-dioxo-benzylpyrrolopiperidine

2000-06-30

2002-05-21

Rotman, Alan L. (Department: 1625)

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C546S112000, C540S505000

Reexamination Certificate

active

06392044

ABSTRACT:

BACKGROUND OF THE INVENTION
The present invention relates to a process for racemizing (1R,6S)-8-benzyl-7,9-dioxo-2,8-diazabicyclo[4.3.0]nonane, also referred to here as R-DOPP or R,S-dioxobenzylpyrrolopiperidine, by reaction with a base.
For preparing the quinolone derivative described in EP-A 350 733, enantiomerically pure (S,S)-2,8-diazabicyclo[4.3.0]nonane, hereinbelow also referred to as cis-S,S-pyrrolopiperidine, is required, and this compound can be obtained from enantiomerically pure (1S,6S)-8-benzyl-2,8-diazabicyclo[4.3.0]nonane, hereinbelow also referred to as S-BEPP or S-benzylpyrrolopiperidine, by debenzylation. It is known that S-BEPP can be obtained from racemic cis-benzylpyrrolopiperidine via racemate resolution using tartaric acid (EP-A 550 903). The resulting undesired enantiomer (R,R)-8-benzyl-2,8-diazabicyclo[4.3.0]nonane, hereinbelow also referred to as R-BEPP, cannot be used any further. This process has the disadvantages that the undesired enantiomer, which is useful per se, is lost and that its disposal involves costs.
According to the applicant's earlier proposal (DE-A 199 27 412), the racemate resolution can be carried out at an earlier stage of the synthesis of cis-S,S-pyrrolopiperidine. Here, the enantiomers are, at the stage of racemic DOPP, hereinbelow also referred to as rac-DOPP, separated by racemate resolution using (−)-2,3:4,6-di-O-isopropylidene-2-oxo-L-gulonic acid, as its salts. Liberation from the corresponding salts gives S-DOPP (which is (1S,6R)-8-benzyl-7,9-dioxo-2,8-diazabicyclo[4.3.0]nonane) and R-DOPP.
A number of routes for racemizing R-DOPP and possible recycling of the undesired enantiomer are conceivable. On the one hand, the two stereocenters can be eliminated by dehydrogenating the undesired enantiomer to give a mixture of the pyridine or tetrahydropyridine derivative, and the dehydrogenation mixture can then be rehydrogenated to give the racemate. It is already known that pyridines can be prepared from the corresponding piperidines.
Thus, GB Patent Specification 1 157 001 describes a process for preparing pyridines by reacting the corresponding piperidines with oxygen and ions of copper, iron or cobalt in liquid phase at from about 120 to about 150° C., using acetic acid as solvent.
According to EP-A 61 982, pyridines and substituted pyridines are obtained by reacting the corresponding piperidines in the gas phase at temperatures of from about 200 to about 500° C. on a Pd or Pt contact, possible substituents being alkyl and 1,5-diaminopentane groups.
U.S. Pat. No. 4,051,140 describes the dehydrogenation of piperidines in the presence of oxygen in the gas phase at a vanadium contact at from about 260 to about 540° C. Here, too, mainly alkyl-substituted piperidines are employed.
The gas-phase dehydrogenations described require high reaction temperatures, so that this reaction can only be used for compounds which are stable at these temperatures, which does not apply to R-DOPP. Owing to oxygen being used, the liquid process described requires increased safety precautions.
Before it is possible to recycle the racemate into the preparation process for the quinolone derivative, all dehydrogenations require the hydrogenation of the resulting compound as an additional reaction step.
Overall, racemization by dehydrogenation is either unsuitable in principle for industrial application in the present case, or, owing to the particular safety precautions and additional reaction steps, it is technically complex and inefficient.
On the other hand, it is possible to consider racemization as basic isomerization. Basic racemization would take place by abstraction of a proton from a chiral center and formation of a carbanion. The carbanion would have to be stabilized by one or more neighbouring keto, ester, nitrile and/or nitro groups. Subsequent protonation would then usually afford the racemate. Such racemizations are known in particular for amino acids and amino acid derivatives having
one
chiral center (see Tetrahedron 53, 9417 (1997)).
However, in the case of R-DOPP, the reaction would have to involve
two
chiral centers, since in the case of only partial racemization it may be that the corresponding trans compound is formed. Thus, basic racemization cannot be readily applied to the racemization of R-DOPP.
SUMMARY OF THE INVENTION
We have now found a process for racemizing R-DOPP which is characterized in that R-DOPP is treated with a substoichiometric amount of base. These and other features, aspects, and advantages of the present invention will become better understood with reference to the following description and appended claims.
DETAILED DESCRIPTION OF THE INVENTION
For the racemization according to the invention, it is possible to use pure R-DOPP or mixtures comprising predominantly R-DOPP, for example mixtures comprising more than 75% by weight, preferably more than 80% by weight, of R-DOPP. The remainder to 100% by weight of these mixtures can be S-DOPP.
Suitable bases for the racemization according to the invention are, for example, alkoxides, and these can correspond to the formula (I)
MOR  (I),
in which
M represents lithium, sodium or potassium and
R represents a straight-chain or a branched C
1
-C
6
-alkyl group.
In the formula (I), M preferably represents sodium or potassium and R preferably represents methyl or tert-butyl. Preferred individual compounds of the formula (I) include sodium methoxide, sodium tert-butoxide and potassium tert-butoxide. Particular preference is given to potassium tert-butoxide.
The alkoxides can be added in solid form or dissolved in a solvent. Suitable solvents include solvents such as alcohols and aprotic solvents. Examples of suitable alcohols include the alcohol which corresponds to the respective alkoxide used and straight-chain, branched and cyclic ethers, and also aromatic hydrocarbons. Specific examples of aprotic solvents are: methyl tert-butyl ether, tetrahydrofuran, dioxane, toluene and xylene. Preferred alkoxide solutions are: potassium tert-butoxide in tert-butanol and in tetrahydrofuran and sodium methoxide in methanol.
The use of alkoxides in solid form or of a small amount of a concentrated alkoxide solution may result in the formation of reaction mixtures which cannot be stirred or are poorly stirrable. In such cases, it is necessary to make the reaction mixture readily stirrable by adding one or more solvents, for example alcohols and/or ethers of the type described above.
For carrying out the racemization according to the invention, it is not necessary for the R-DOPP used and the base used to be present completely dissolved. However, the amount of alcohol and/or aprotic solvent present should be such that a reaction mixture is obtained which is readily stirrable.
Depending on the choice of solvent, it is possible to carry out the racemization in relatively highly concentrated reaction mixtures. Thus, if the solvent used is, for example, tetrahydrofuran, the concentration of R-DOPP in the solvent can be up to about 50% by weight.
The base can be used, for example, in an amount from about 1 to about 20 mol %, based on the R-DOPP used. This amount is preferably from about 2 to about 15 mol %, in particular from about 3 to about 10 mol %.
To minimize undesirable side reactions, it is advantageous to carry out the racemization according to the invention under substantial exclusion of oxygen. To this end, it is possible, for example, to flush the reaction vessel with an inert gas prior to charging the reactants, and to carry out the racemization under an atmosphere of inert gas. Suitable inert gases are, for example, nitrogen and noble gases, such as argon.
The racemization according to the invention can be carried out, for example, at temperatures below about 40° C. For low temperatures, care has to be taken not to choose a temperature where the reaction mixture is no longer readily stirrable. At which temperature the stirrability is no longer sufficient depends essentially on the type and the amount of solvents

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