HUP0500373A2 - Process for the production of nipecolic acid ethylester enantiomers - Google Patents

Abstract

Racemic nipecotic ethylester and (R,R)-tartaric acid are dissolved in ethyl alcohol. Concentrated hydrochloric acid aqueous solution is added, and diastereomeric salt is filtered. Salt is treated, phases are separated, and organic solvent is evaporated to obtain (R)-nipecotic acid ethylester. Filtrate of diastereomeric salt formation is evaporated, to obtain (S)-nipecotic acid ethylester. (S)-isomer is reacted with achiral acid to obtain salt. Salt of racemic composition is filtered, alkalized, extracted and evaporated, to obtain enantiomer mixture. One mole of racemic nipecotic ethylester and half mole (R,R)-tartaric acid are dissolved in ethyl alcohol. Concentrated aqueous solution of half mole hydrochloric acid is added, and the crystalline diastereomeric salt is filtered at 0[deg]C. The resulting salt is treated by aqueous sodium carbonate solution and ethyl acetate. The phases are separated, and organic solvent is evaporated to obtain (R)-nipecotic acid ethylester. The filtrate of diastereomeric salt formation is evaporated, and nipecotic acid ethylester rich in (S)-isomer is obtained from the residue by similar salt processing. The obtained (S)-isomer is reacted with achiral acid such as maleic acid to obtain salt. The crystallized ethyl-nipecotic maleic acid salt of racemic composition is filtered, and alkalized with an aqueous base followed by extraction and evaporation, to obtain enantiomer mixture having higher (S)-isomer content.

Description

Optical isomers of ethyl nipecotate, especially the (7?)-enantiomer, are widely used starting materials in pharmaceutical synthesis. For example, GABA (γ-aminobutyric acid) receptor blockers (K.E. Andersen, J.L. Sorensen et al.: J. Med. Chem. 44(13), 2152-2163 (2001)), antithrombotic agents (X. Zheng, C. Day et al.: Chirality 7(2), 90-95 (1995) and C.N. Hinko, A.M. Crider et al.: Neuropharmacology 27(5), 475-83 (1988)) would be produced from them. A chiral ligand has also been prepared from (7?)-ethyl nipecotate, which has been successfully used in the addition of diethylzinc to aldehydes (S.H. Lee, D.S. Im et al.: Heterocycles 51(8), 19131919 (1999)). Racemic ethyl nipecotate is prepared by catalytic hydrogenation of ethyl nicotinate. In some processes, the reduction is carried out in the presence of a chiral catalyst, and thus an enantiomeric excess of 24-27% has been achieved (M. Studer, C. Wedemeyer-Exl et al.: Monats. Chem. 131(12), 1335-1343 (2000), S.A. Reynor, J.M. Thomas et al.: Chem. Commun. (19), 1925-1926 (2000)). Due to the low selectivity of asymmetric hydrogenation processes, the optical isomers of ethyl nipecotate are most often separated by diastereomeric salt formation resolution. In several publications, ethyl nipecotate is resolved into its enantiomers with tartaric acid enantiomers (Akkerman et al.: Reel. Trav. Chim. Pays-Bas 70, 899-913 (1951), H. Ripperger, K. Schreiber: Chem. Bér. 102, 1864-1865 (1969), Bettoni et al.: Gazz Chim Ital. 102, 189-193 (1972), I. Vandersteene et al.: Bull Soc. Chim. Béig. 104(12), 721-726 (1995), S.H. Lee et al.: Heterocycles 51(8), 1913-1920 (1999), S. Abele et al.: Helv. Chim. Acta 82(10), 1539-1558 (1999), P. Magnus et al.: J. Org. Chem. 56, 1166-1170 (1991) and Y.J. Chung et al.: J. Am. Chem. Soc. 122, 3995-4004 (2000)). The common feature and disadvantage of the listed methods is that one mole of (7?,Δ)-tartaric acid is used as a resolving agent per mole of racemic ethyl nipecotate and the diastereomeric salt that forms from the solvent used, which is in most cases ethanol or an ethanol-acetone mixture, is purified by single or multiple recrystallizations until a salt with constant rotation is obtained and then the (Δ)-ethyl nipecotate is liberated from the diastereomeric salt, while (S)-ethyl nipecotate of low optical purity is obtained from the filtrate. It should be noted that during the recrystallizations, the yield calculated for half of the racemic starting material (the (7?)-isomer) is significantly reduced, which is between 18-25% based on the literature recipes. The use of molar amounts of resolvent and the multiple recrystallization of the diastereomeric salt and the movement of large masses of chemicals and solvents are also significant cost-intensive. The waste generated during possible regeneration or destruction can cause significant environmental pollution.

The separation of ethyl nipecotate enantiomers has also been solved with optically active 2-(4-hydroxyphenoxy)-propionic acid (Eur. Pat. Appl. EP 1146029 (2001)), but the molecular weight of the resolving agent used is significantly higher than that of tartaric acid, so when used, a larger mass of material must be moved, filtered, and regenerated, all of which increases costs. In addition, the resolving agent used is not a natural substance, and its residue, which may end up in natural rivers during use, is an environmental pollutant. The above-listed problems due to the high molecular weight of the resolving agent also exist in the process using the O,O’-dibenzoyl-(R,R)-tartaric acid resolving agent (PCT Int. Appl. WO 0268391 (2002)), furthermore, in this process, not the (R)-, but the (S)-ethyl nipecotate enantiomer is enriched in the crystalline diastereomeric salt, which limits the efficiency of producing the (R)-enantiomer, which is used in large quantities in the pharmaceutical industry, in high optical purity.

An enzymatic method for the resolution of ethyl nipecotate has also been described (E.J. Toone et al.: Can. J. Chem. 65(12), 2722-2726 (1987)). In this process, a pig liver esterase enzyme is used for the selective hydrolysis of one enantiomer of racemic ethyl nipecotate, thus obtaining optically active nipecotic acid and residual, optically active ethyl nipecotate. However, the enantiomeric purity of the latter substance is only 47% at best. However, the use in the pharmaceutical and chemical industries relies on the highly optically pure enantiomers, primarily (7?)-ethyl nipecotate, so its more efficient and environmentally friendly production is of great practical importance.

In the course of our work, we unexpectedly found that if racemic ethyl nipecotate is reacted with an amount of (R7?)-tartaric acid equivalent to half the racemic amount, while the other half of the base is neutralized with an achiral acid, such as hydrochloric acid, then practically optically pure (R)-ethyl nipecotate-(7?,A)-hemitartrate crystallizes from the solvent used, while the salt of (S)-ethyl nipecotate formed with an achiral acid remains in solution. It is therefore not necessary to recrystallize the crystalline diastereomeric salt, but it is possible to obtain (7?)-ethyl nipecotate of high optical purity from it by extraction and evaporation following the addition of an aqueous solution of base in a manner known per se.

We have also found that the production of the crystallizable diastereomeric salt is strongly dependent on the water content of the solvent used. Therefore, a convenient procedure is to dissolve racemic ethyl nipecotate and (R,7?)-tartaric acid in an anhydrous solvent or a solvent with a known water content, preferably ethyl alcohol, and then add an aqueous solution of the achiral acid of known concentration so that the water content of the resulting mixture is between 5-20%.

Our discovery also has the significant advantage that, compared to the previously known processes, only half a mole of natural (7?,R)-tartaric acid and half a mole of low molecular weight achiral acid are required for one mole of racemic ethyl nipecotate, and there is no need to recrystallize the diastereomeric salt. Therefore, we save a significant amount of solvent and resolving agent and greatly reduce the total amount of auxiliary materials used in the process, and thus the amount of environmentally hazardous waste.

We also observed, unexpectedly, that in order to recover the (Sj-isomer from the enantiomer mixture rich in (Sj-ethyl-nipecotate isomer remaining in the filtrate of the diastereomeric salt formation, it is not necessary to perform diastereomeric salt formation with the extremely expensive unnatural (S'S'j-tartaric acid, but rather to crystallize the salt of the enantiomer mixture with a suitable achiral carboxylic acid from a solvent. From samples of low or medium optical purity, the fraction with a nearly racemic composition crystallizes out, while the fraction that is optically purer than the starting one remains in solution, and thus a significant isomer enrichment can be achieved. For example, from the salt formed with an achiral carboxylic acid, such as maleic acid, of a 20% optically pure ethyl-nipecotate sample, a 5% optically pure crystalline salt was obtained, and a 64% optically pure salt was isolated from the filtrate. In the case of samples of high optical purity the optically pure fraction crystallizes. Of course, isomer enrichment can be carried out with the same efficiency not only starting from the enantiomeric mixture rich in the (Sj)-isomer, but also, if necessary, starting from the mixture rich in the (A)-isomer.

According to our method, we therefore preferably proceed as follows: one mole of racemic ethyl nipecotate and half a mole of (R, R)-tartaric acid are dissolved in a solvent that dissolves the two substances separately well, preferably in ethyl alcohol, then half a mole of a concentrated aqueous solution of achiral acid, preferably hydrochloric acid, is added to the reaction mixture and the diastereomeric salt is crystallized at a temperature between -10 - +10 °C and filtered. The filtered salt is treated with an aqueous sodium carbonate solution and a water-immiscible organic solvent, preferably ethyl acetate, and the (R)-ethyl nipecotate is obtained by evaporating the organic solvent solution after separation of the phases. The filtrate of the diastereomeric salt formation is evaporated under reduced pressure and the ethyl nipecotate rich in the (S)-isomer is obtained from the residue in the same way as the salt processing. This latter enantiomeric mixture is optionally dissolved in a suitable solvent, for example ethyl acetate, and an achiral carboxylic acid, for example maleic acid, is added, then the crystallized ethyl nipecotate achiral carboxylic acid salt of nearly racemic composition is separated by filtration, and the enantiomeric mixture with a higher (S)-isomer content than the starting one is obtained from the filtrate by extraction and evaporation after alkalinization with an aqueous base.

Claims (5)

Our method is illustrated by the following example without limiting the scope of the invention to the example. Example: a) A mixture of racemic ethyl nipecotate (5 g, 31.8 mmol) and (7?,7?)-tartaric acid (2.4 g, 15.9 mmol) is dissolved in 15 ml of abs. ethanol and 32% aqueous hydrochloric acid (1.58 ml, 15.9 mmol) is added while stirring, then the mixture is stirred at a temperature between 0-+5 °C for 12 hours. The precipitated crystals are filtered cold, washed with 3x3 ml of cold ethanol, dried (1.9 g, 38%). The filtrate is combined with the washing alcohol and evaporated in a water vacuum. The crystalline diastereomeric salt is suspended in 20 ml of ethyl acetate and a solution of 1.2 g of sodium carbonate in 7 ml of water is added while cooling with external ice. The phases are separated, the aqueous phase is extracted with 3x10 ml of ethyl acetate, the combined organic solutions are dried over sodium sulfate and evaporated. The weight of the residual (A)-ethyl nipecotate: 0.90 g [a] _D : +4.2° (c:2, chloroform), OT:>95%. From the evaporation residue of the filtrate, (.S')-ethyl nipecotate is obtained in a manner analogous to the salt work-up, weighing 3.8 g [α] _D : -1.1° (c:2, chloroform). b) The 20% optically pure (Sj-ethyl-nipecotate (2.5 g, 15.9 mmol) is dissolved in ethyl acetate (12 ml) and maleic acid (1.9 g, 15.9 mmol) is added while stirring, then the mixture is cooled with ice water, the crystallized salt is filtered, the filter is washed with cold ethyl acetate. The filtrate is evaporated, then processed according to the method given for salt processing in point a) of the example. The mass of the (Sj-ethyl-nipecotate obtained: 1.3 g [a] _D : -1.5° (c:2, chloroform), OT:33%. The crystalline salt is also processed according to point a) of the example, thus obtaining nearly racemic ethyl-nipecotate, the mass of which is: 0.9 g [a] D : -0.3° (c:4, chloroform), OT.:7 %. Patent claims 1. Process for the preparation of ethyl nipecotate enantiomers starting from racemic ethyl nipecotate, characterized in that one mole of the racemic base is reacted with half a mole of optically active tartaric acid, preferably natural (7?,7?)-tartaric acid, in the presence of half a mole of an achiral acid, preferably hydrochloric acid, in a solvent or solvent mixture, and the resulting crystalline (7?)ethyl nipecotate-(7?,7?)-hemitartrate is isolated by filtration, then (7?)-ethyl nipecotate is liberated from the salt in a manner known per se, in the presence of water and a water-immiscible organic solvent with a base, which is recovered from the organic solvent solution by evaporation and, if desired, the isomer mixture rich in (7?)- and (Sj-ethyl nipecotate enantiomers is purified by selective crystallization of the salt formed with an achiral carboxylic acid. 2. The process according to claim 1, characterized in that hydrochloric acid is used as the achiral acid in the diastereomeric salt formation. 3. The method according to claims 1 and 2, characterized in that a mixture of ethyl alcohol and water is preferably used as the solvent for salt formation, such that the water content of the mixture is adjusted to a value between 5-20%. 4. The process according to claims 1-3, characterized in that ethyl acetate is used as a water-immiscible organic solvent during the decomposition of the diastereomeric salt. 5. The process according to claims 1-4, characterized in that the achiral carboxylic acid maleic acid is used for the enrichment of enantiomeric mixtures. Qap lcá Liί <?... .____________ . (I ¹ <......lcc H tJ.....Cet