Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1999-09-20
2001-02-13
Trinh, Ba K. (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C540S491000
Reexamination Certificate
active
06187936
ABSTRACT:
The present invention relates to a process for the resolution of 3-phenylglycidates and, more particularly, it relates to a process for the enzymatic kinetic resolution of 3-phenylglycidates by transesterification with aminoalcohols.
The esters of 3-phenylglycidic acid are known compounds, described in the literature and widely used as synthetic intermediates.
For example esters of trans-3-phenylglycidic acid, appropriately resolved, are commonly used for the preparation of (2R,3S)-N-benzoyl-3-phenylisoserine, side chain of paclitaxel, a known anticancer drug of natural source (Merck Index, XII edition, n. 7117, page 1200).
Another significant use of 3-phenylglycidates, and in particular of (2R,3S)-3-(4-methoxyphenyl)glycidates, is for the synthesis of the compound (+)-(2S,3S)-3-acetoxy-5-(2-dimethylaminoethyl)-2,3-dihydro-2-(4-methoxyphenyl)-1,5-benzothiaze pin-4(5H)-one, a known drug with calcium-blocker activity named Diltiazem (Merck Index, XII edition, n. 3247, page 541).
The preparation of Diltiazem, starting from esters of 3-(4-methoxyphenyl)glycidic acid, can be performed according to several literature methods, for example according to the processes claimed in the British patents N
o
1236467 and 2167063 or in the European ones N
o
127882 and 158340, all in the name of Tanabe Seyaku Co. Ltd.
In order to prepare Diltiazem it is necessary to accomplish an optical resolution on one of the intermediates of the synthesis. Obviously the resolution performed at an initial step of the process is economically more convenient in that the economic value of the product subjected to resolution is lower and as a consequence the discharged isomer does not represent a relevant loss.
Therefore it is advantageous to have esters of 3-(4-methoxyphenyl)glycidic acid in enantiomeric pure form in that said compound is the first optically active intermediate of the synthesis.
Most procedures reported in the literature for the preparation of 3-phenylglycidates yields racemic mixtures. It is possible mainly to obtain one of the two possible couples of enantiomers for example the trans racemate (2R*,3S*) as in the case of the Darzens condensation between 4-methoxybenzaldehyde and methyl chloroacetate [J.Org.Chem.,(1986), 51,2759] by suitably choosing the synthetic route and optimising the experimental conditions.
Nevertheless even disposing of the single couple of trans enantiomers it results anyway necessary to isolate the desired enantiomer, with a 2R,3S absolute configuration in the specific case of 3-(4-methoxyphenyl)glycidates used for Diltiazem synthesis, or the 2R,3S or 2S,3R enantiomer depending on the synthetic route in the case of 3-phenylglycidates used for the preparation of the side chain of paclitaxel [J.Org.Chem.,(1993), 58, 1287], resorting to resolution techniques.
Apart the more conventional procedures of resolution, that consist of transforming the racemic mixture into a diasteroisomeric mixture by interaction with an enantiomerically pure resolving agent and subsequently by separating such a mixture by classical methodologies, such as for example chromatographic purifications or fractional crystallisations, the kinetic resolution techniques are really attractive.
On the contrary, such resolution techniques are based on the different reaction rate of each enantiomer with respect to optically active reagents or to achiral reagents but in the presence of chiral catalysts.
A particularly important group of chiral catalysts is constituted by enzymes, whose use as resolving agents has only recently been recognised and developed [A. Zaks et al. in Drug Discovery Today, (1997), 2, 513].
Many enzymatic processes for the resolution of carboxylic acids and related esters are described in the literature, see for example the Reviews published on Angew.Chem.,Int.Ed.Eng.(1985), 24, 617 and (1989), 28,695.
Within this domain the processes that make use of hydrolitic enzymes, such as lipases and proteases in non-aqueous media, for the kinetic resolution of esters by transesterification reaction [A. Klibanov in Acc. Chem. Res. (1990), 23, 114], for example according to the following scheme:
are particularly interesting.
In the best conditions it is possible preferentially to transesterify only one of the two enantiomers, thus differentiating it from the other, and then to resolve the racemic mixture with nearly quantitative yields.
In the above mentioned processes the choice of the alcohol R
b
OH is crucial, in that it must ensure to the new formed ester completely different chemical-physical properties in comparison with the starting compound, thus facilitating the separation procedures of the two esters, for example by chromatography, preferential crystallisation, distillation or salification.
Some resolution processes of racemic phenylglycidates by enzymatic transesterification techniques are reported in the literature.
A first example of resolution of racemic 3-(4-methoxyphenyl)glycidates by enzymatic transesterification is described in the patent application GB 2246351, in the name of the same applicant.
A similar approach is used by Da-Ming Gou et al in J.Org.Chem. (1993), 58, 1287 for the synthesis of the side chain of paclitaxel. The authors describe the resolution of trans methyl 3-phenylglycidate by transesterification reaction, catalysed by the lipase from
Mucor miehei
, with isobutyl alcohol.
The final isolation of the single enantiomers is performed by chromatography or by fractional distillation, that is by employing procedures commonly used for laboratory scale but not easily applied at industrial level.
A similar process of kinetic resolution of phenylglycidates catalysed by esterases, in which the alcohol used in the transesterification reaction is a C
2
-C
10
alkanohol, is reported by Tanabe in JP 06/078790. Even if it allows the obtainment of the desired product, that is the already mentioned (2R,3S)-3-(4-methoxyphenyl)glycidate precursor of Diltiazem, with a high degree of optical purity, the method is not easily applicable at industrial level in that it exploits chromatographic techniques for its isolation.
On the contrary, a different approach, described in the European patent application N
o
498706 (Synthelabo), that suggests an alternative route to overcome the above mentioned problems of isolation of the single enantiomers, is based on the stereoselective insolubilization of a single enantiomer by transesterification: the enzymatic transesterification reaction performed on the racemic trans methyl 3-(4-methoxyphenyl)glycidate in the presence of sodium 4-hydroxybutyrate leads to the formation of the insoluble carboxyester of the (2S,3R) enantiomer. The desired enantiomer (2R,3S) is recovered by filtration and evaporation of the filtrate.
Nevertheless by working under concentrated conditions, preferable from the industrial point of view, the toluene reaction mixture turns out to be particularly thick also for the presence out of phase of the insoluble (2S,3R) carboxyester and sodium hydroxybutyrate, in addition to the enzyme: the precipitation of these solids on the enzymatic surface unavoidably reduces its activity and make its recovery difficult. With the aim to improve the filterability properties of the suspension it is necessary to work under rather diluted conditions, for example using 3% w/v solutions, as described in example 1 of the above mentioned patent, all at detriment of the process productivity. For the above reported reasons the process claimed by Synthelabo is hardly applicable in industry.
In our knowledge, a process for the enzymatic kinetic resolution of 3-phenylglycidates by transesterification with aminoalcohols of simple industrial applicability and with remarkably simplified isolation procedures of the desired enantiomer has never been described in the literature.
We have now found a process for the enzymatic kinetic resolution of enantiomeric mixtures of 3-phenylglycidates particularly suitable for the industrial application, by transesterification with aminoalcohols, in non-aqueous conditions,
Restelli Angelo
Riva Sergio
Tentorio Dario
Villa Marco
Arent, Fox Plotkin & Kahn
Trinh Ba K.
Zambon Group S.p.A.
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