Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-11-09
2001-05-22
Dentz, Bernard (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
active
06235908
ABSTRACT:
The present invention relates to a process for preparing (S,S)-8-benzyl-2,8-diazabicyclo[4.3.0]nonane [(S,S)-benzylpyrrolopiperidine] of the formula
hereinbelow also referred to as (S,S)-benzylpyrrolopiperidine, by separation of the enantiomers of a mixture of (S,S)-8-benzyl-2,8-diazabicyclo[4.3.0]nonane and (R,R)-8-benzyl-2,8-diazabicyclo[4.3.0]nonane. (S,S)-8-Benzyl-2,8-diazabicyclo[4.3.0]-nonane is a useful intermediate for preparing (S,S)-2,8-diazabicyclo[4.3.0]nonane:
which for its part is used for preparing the antibiotic moxifloxacin (INN):
The preparation of racemic cis-(S,S/R,R)-8-benzyl-2,8-diazabicyclo[4.3.0]nonane is described in EP-A-0 350 733.
EP-A-0 550 903 describes various processes for the separation of the enantiomers of racemic cis-(S,S/R,R)-8-benzyl-2,8-diazabicyclo[4.3.0]nonane using D-(−)- or L-(+)-tartaric acid (Example A). These processes are carried out in dimethylformamide (DMF) as the solvent in which the racemate is dissolved. Thus, for example, according to method V (R,R)-benzylpyrrolopiperidine L-tartrate precipitates out after addition of a solution of 0.5 equivalents of L-(+)-tartaric acid in DMF to a solution of an equivalent of the cis-8-benzyl-2,8-diazabicyclo[4.3.0]nonane racemate in DMF. In a second step, the desired (S,S)-benzylpyrrolopiperidine L-(+)-tartrate is precipitated out by further addition of 0.5 equivalents of L-(+)-tartaric acid and is subsequently crystallized in pure form from ethanol/water. The tartrate is finally converted into the free amine using bases. However, this process has disadvantages with respect to the present object, since it requires prior removal of the undesired R,R enantiomer, i.e. an additional operation. Method I of Example A of EP-A-0 550 903 describes a process for the separation of the enantiomers of racemic cis-(S,S/R,R)-8-benzyl-2,8-diazabicyclo[4.3.0]nonane using D-(−)-tartaric acid in DMF. Here, the S,S-enantiomer is precipitated out first, but application of this process on an industrial scale can be ruled out owing to the high cost of the unnatural D-(−)-tartaric acid.
The solvent DMF used in the processes of EP-A-0 550 903 for the separation of the enantiomers, however, has various disadvantages. According to Römpp Lexikon Chemie Version 1.3, Stuttgart/New York: Georg Thieme Verlag 1997, entry “Dimethylformamid”, DMF is readily bioabsorbed through the skin, is highly irritant to skin and mucous membranes and may damage liver and kidneys. The MAK value (maximum workplace concentration) is therefore only 10 ppm, a fact which requires special protective measures which lead to increased production costs. It was therefore desirable to develop a process for preparing (S,S)-8-benzyl-2,8-diazabicyclo-[4.3.0]nonane in which the use of problematic solvents is avoided. Furthermore, such a process should afford very high yields to avoid loss of substance, and should have few steps.
Owing to intensive investigations, the inventor surprisingly succeeded in developing a novel process for preparing (S,S)-benzylpyrrolopiperidine which permits the separation of the enantiomers of a mixture of (S,S)-8-benzyl-2,8-diaza-bicyclo[4.3.0]nonane and (R,R)-8-benzyl-2,8-diazabicyclo[4.3.0]nonane in high yields in unobjectionable solvents.
The invention accordingly provides a process for preparing (S,S)-8-benzyl-2,8-diaza-bicyclo[4.3.0]nonane which encompasses the reaction of a mixture of (S,S)-8-benzyl-2,8-diazabicyclo[4.3 .0]nonane and (R,R)-8-benzyl-2,8-diazabicyclo[4.3.0]nonane with L-(+)-tartaric acid in an alcohol/water mixture:
The mixture of (S,S)-8-benzyl-2,8-diazabicyclo[4.3.0]nonane and (R,R)-8-benzyl-2,8-diazabicyclo[4.3.0]nonane used according to the invention encompasses any mixtures of the S,S and R,R enantiomer. The ratio of S,S to R,R isomer is preferably from 99:1 to 40:60, particularly preferably from 99:1 to 50:50 and very particularly preferably from 99:1 to 60:40 (based on the molar amounts).
The alcohol/water solvent mixture, in which the formation of (S,S)-8-benzyl-2,8-diazabicyclo[4.3.0]nonane L-(+)-tartrate is carried out and which is used in the process of the invention, is advantageously a solvent mixture which contains at least 40% by volume, preferably at least 50% by volume, of a mixture of at least one alcohol and water, based on the total volume of the solvent used.
The alcohol/water solvent mixture used in accordance with the invention may, in addition to alcohol and water, comprise other solvents in an amount of up to 60% by volume, preferably up to 50% by volume.
The ratio by volume of alcohol to water is advantageously in a range of from 4:1 to 20:1, preferably in a ratio by volume of about 5 (alcohol) to 1 (water).
The alcohols used according to the invention in the solvent mixture are preferably one or more aliphatic, straight-chain or branched, primary, secondary or tertiary (C
2
-C
8
)-alcohols. These are selected, for example, from the group consisting of ethanol, n-propanol, isopropanol, n-butanol, sec-butanol, isobutanol, isoamyl alcohol and octanol. Preference is given to using n-, sec- or iso-butanol and ethanol. Very particular preference is given to n-butanol, iso-butanol and ethanol.
Solvents which may be present as further solvents in addition to alcohol and water in the alcohol/water solvent mixture used in accordance with the invention in an amount of up to 60% by volume (based on the total amount of solvent), preferably of up to 50% by volume, are selected, for example, from the group consisting of toluene, xylene, cyclohexane, ethyl acetate, methyl tert-butyl ether, etc., and preference is given to toluene. With a view to one of the objects of the present invention described above, substantial amounts of ecologically objectionable solvents, such as, for example, DMF, should be excluded, and they are preferably not present.
If the ratio of S,S to R,R isomer in the mixture of (S,S)-8-benzyl-2,8-diazabicyclo-[4.3.0]nonane and (R,R)-8-benzyl-2,8-diazabicyclo[4.3.0]nonane used according to the invention is from 99:1 to 60:40 (based on the molar amounts), preference is given to using the alcohol ethanol. Particular preference is given to an alcohol/water solvent mixture which contains only ethanol and water, advantageously in a ratio by volume of from 75:25 to 95:5, preferably from 80:20 to 85:15.
If the ratio of S,S to R,R isomer in the mixture of (S,S)-8-benzyl-2,8-diazabicyclo-[4.3.0]nonane and (R,R)-8-benzyl-2,8-diazabicyclo[4.3.0]nonane used according to the invention is approximately 50:50 (based on the molar amounts), i.e. the virtually racemic mixture is used, preference is given to using the alcohol butanol. Particular preference is given to an alcohol/water solvent mixture comprising butanol (n-butanol, sec-butanol or iso-butanol) and water, advantageously in a ratio by volume of butanol:water of from 4:1 to 20:1, preferably in a ratio by volume of approximately 5:1, optionally with addition of up to 60% by volume of toluene. Very particular preference is given to an alcohol/water solvent mixture which comprises only butanol (n-butanol, sec-butanol or iso-butanol) and water, advantageously in a ratio by volume of butanol:water of from 4:1 to 20:1, preferably in a ratio by volume of approximately 5 to 1. In a further preferred embodiment of the invention, the mixture of (S,S)-8-benzyl-2,8-diazabicyclo[4.3.0]nonane and (R,R)-8-benzyl-2,8-diazabicyclo[4.3.0]nonane used according to the invention which has a ratio of S,S to R,R isomer of approximately 50:50 (based on the molar amounts) can be reacted in a solvent mixture comprising ethanol, toluene and water, the solvent mixture containing at least 40% by volume and at most 60% by volume of toluene.
For the preparation of tartrate, the solvent volumes are advantageously in the range of 2-8 litres of the alcohol/water solve
Bayer Aktiengesellschaft
Chiu Jerry L.
Dentz Bernard
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