MXPA97008145A - Procedure for the separation of a deenantime mixture - Google Patents

Abstract

A diastereomeric complex comprising at least three compounds of which at least one is an resolving agent in an optically active form is described, and at least one compound is an enantiomer in an optically active form, and a process for preparing said complete

Description

PROCEDURE FOR THE SEPARATION OF A MIXTURE OF BINDERS DESCRIPTIVE MEMORY The invention relates to a process for the separation of a mixture of enantiomers. - Mixtures of enantiomers are obtained, for example, in reactions that do not proceed, or only to an extent rnuy small, stereoselectively and in reactions in which there is no investment or complete retention. The physical properties of the enantiomers, such as boiling point, melting point and the like, are the same, p > or so a mixture of enantiomers can not be separated using the usual separation techniques. In one of the methods for the separation of mixtures of enantiomers, for example racemic mixtures, an optically active resolving agent is used to convert both enantiomers into the corresponding diastereors. Since the physical properties of these diasterrs if they differ, the diasterrs can, in any regime in principle, subsequently be separated for example by crystallization or chromatography, both diastereors being obtained substantially chemically pure and optically enriched. The diastereors, in a third step, can again be separated into the corresponding optically enriched enantiomer and the optically active resolving agent. Some optically active resolution methods and agents for the separation of enantiomers are for example extensively described in "Stereochemistry of Organic Cornpounds" by E.L. Eliel and S.H. Uilwn (Uiley Interscience, 1994). However, it is commonly known that the finding of the correct resolving agent for the separation of mixtures of enantiomers by crystallization from a mixture of diastereors is in practice a laborious and time-consuming process; for a correct choice of resolution agent, it can not be done in advance, nor when advanced techniques are applied such as, for example, computer simulations or X-ray diffraction, and therefore must be found by trial and error for each mixture of new enantios. This implies that for the separation of enantiomers through diasterrs often many experiments have to be conducted, whereas individual experiments can take a long time considering a tedious crystallization. Also, not in all cases is an appropriate resolution agent. Therefore, it will be obvious that the search for a good resolving agent for the separation of mixtures of enantiomers from a compound and the conditions under which good results are obtained is a matter that requires time and the probability of success is unpredictable. Therefore, the present invention is designed to provide a method by which a separation of enantiomers can be effected rapidly and with high probability of success and that the desired enantiomer with a high enantiornérico excess be obtained. According to the invention, among other things, this is achieved by means of a process for the separation of mixtures of enantiomers in which more than one resolution agent is used, which at least one resolution agent is optically active, and that produces a diastereorne complex that contains at least two resolution agents in an optically active form. It has been found that with the method according to the invention more frequently than in resolutions with a single resolution agent, a crystalline product is obtained directly instead of an oil, so that the result of the experiment is immediately known. Subsequent experiments can be done consistently in a shorter period. In addition, the method according to the invention allows several resolving agents and / or mixtures of enantiomers to be tested in a single experiment, whereby the method according to the invention also allows a rapid selection of suitable resolving agents. further, it has been found that in many cases the enantiomeric excess (e.e.) of the desired resolved enantiomer is higher when more than one resolving agent is used than when a single resolving agent is used. Furthermore, it has been found that mixtures of enantiomers, which by themselves can not be resolved using a certain resolving agent, could be solved when applied in combination with mixtures of enantiomers of similar structure.

According to the invention, it is also possible to separate a mixture of enantiomer mixtures, ie, a mixture of two or more different chemical compounds in which both enantiomers of each compound are present, in 5 substantially optically active enantiomers using one or more resolution agents, of which at least one resolution agent is optically active. This is elucidated with reference to the following example, in which only one resolution agent is used: a mixture of the enantiomers, For example, compounds A, B and C (the mixture therefore contains three mixtures of enantiomers: 3 pairs of two enantiomers each) is separated into a mixture containing optically enriched enantiomers of compounds F, B and C, being used only an optically active resolution agent. From After this second mixture, the compounds A, B and C are separated from the resolving agent. After this, the components A, B and C are separated by means of the usual separation techniques. Of course, it is also possible to use - - a combination of different resolution agents. This In a single experiment, many combinations can be tested quickly. The invention relates, inter alia, to a complex of diastereomers, for example a salt, comprising at least 3 compounds of which at least one The compound is a resolving agent in optically active form and at least one compound is an enantiomer in optically active form. A diastereonomer complex of one or more optically active and one or more enantiomeric resolving agents is understood to form complexes in which resolving agents and enantiomers are linked through one or more non-covalent bonds, for example, van der Uaals, go-go interactions, inclusion, ionogenic bonds, coordination links, hydrogen bonds and / or a combination of these links. A resolving agent can be made from any compound that is suitable for converting a mixture of enantiomers through presipitation into a diastereomeric salt containing a mixture of enantiomers with higher enantiormeric excess. The resolving agent may contain a metal, optionally with the associated ligands. Preferably, as an optically active resolving agent, a resolving agent with the highest possible enantiomeric excess, for example, an enantiornteric excess > 95%, in particular > 98%, especially in > 99% The term "enantiomer" in this context refers to the mixture of enantiomers that are to be enriched. As a mixture of enantiomers comprises in principle all chiral compounds, in practice compounds containing at least one asymmetric carbon atom can generally be used. The enantiomers, for example, may be compounds which contain at least one acid group, an amino group, a hydroxyl group and / or a thiol group. In principle, a chemical compound that can be used appropriately as a mixture of enantiomers that have to be separated with an appropriate resolving agent, also represents an appropriate resolving agent to be used in the separation of a mixture of enantiomers. Within the scope of this invention, the term "enantiomer mixture" means a mixture of the enantiomers of an optically active compound in any ratio. Naturally, within the framework of this invention, the same holds true with respect to the separation of a mixture of enantiomers which already has some enantiomeric excess than for racemic mixtures. In a particularly suitable embodiment, the mixtures of enantiomers are separated through salt formation. Examples of mixtures of enantiomers that can be suitably separated through salt formation are acids, and very particularly carboxylic acids, phosphoric acids, sulfonic acids, phosphinic acids, sulfinic acids, amines, acid alcohols, amino acids, to indole alcohols and acid thiols. Other examples of ways in which mixtures of enantiomers can be suitably separated according to the invention are separations through inclusion compounds, by which in principle any chiral compound that forms an inclusion compound, or separation can be used. through metal complexes, for example, as described in 3.A. Gladysz and B.J. Boone, Angew. Chern. Int. Ed. Engl. 36_, p. 576-577, 1997. As an example of a possible use of the method according to the invention, the invention will now be elucidated with reference to the separation of a racemic mixture from an amine using at least two optically active or using acids. at least one optically active acid and one non-optically active acid. A first interesting use of the method according to the invention is the selection of resolving agents. In practice, this is done through a laboratory scale, with several acids, for example 2-20, in particular 2-12, rnuy in particular 2-5, simultaneously being used as resolution agents. The combination of acids found in the precipitated complex generally offers the best prospects for a good result, it is probably possible in a number of cases not to use acids that are in the complex in small quantities. Deede later, it is also possible that only one resolution agent, in this case specific acid, is in the complex. In that case, the resolution agent preferably used will contain only one component. Acids that are subsequently selected on a laboratory scale can be used as an agent in the form of a mixture of at least two, for example 2-6, in particular 2-3 acids in the separation of a racemic mixture from the amine on an industrial scale. An optically active amine and a mixture of at least two acids are obtained from the resulting mixture of diastereorium salts. Preferably, the resolution agents are of the same type, for example resolution agents within a certain group. Examples of groups of resolving agents that can be suitably used in the process according to the invention are: substituted phosphoric acids, for example phosphoric acids of the formula SI: wherein Ri and R2 each independently represent H, an alkyl group or an aryl group; The optically active substituted tartaric acids, for example tartaric acids of formula S2: where Ri and 2 are as defined above; substituted a-hydroxycarboxylic acids, for example rnandélicos acids of the formula S3; where Ri and R2 are co or defined above; N-acylarnino acids, substituted or unsubstituted, for example N-acyl amino acids of the formula S4: C = 0 (S4) I R3 wherein R3 has a fixed meaning within a group, chosen from an alkyl group or an aryl group, and R4 represents an aryl group, for example a phenyl group Ri and R2 substituted with Ri and R2 as defined above, or an alkyl group, for example, an amino acid radical as it exists in natural amino acids, or wherein R4 has a fixed meaning within a group, chosen from an aryl group, for example a phenyl group Ri and R2 substituted with Ri and R2 co or as defined above, or an alkyl group, for example an amino acid radical of natural amino acids, and R3 represents an alkyl group or an aryl group. A special example is acylated protein hydrolyzate, or of the formula S5 (N-benzoyloxycarbonylamino acids). R «-CH-C02H where R4 is as defined above; N-carbamoylamino acids, whether or not substituted, for example, N-carbamoylamino acids of the formula S5: I (S6) C = 0 I NH2 where R4 is as defined above. A special example is carbamoylated protein hydrolyzate; The substituted phenylalkylarynins, for example phenylalkylamines of the formula S7: wherein R 1 and R 2 can vary within a group as defined above and R 5 has a fixed meaning, chosen from alkyl, or Ri and R 2 are fixed choices of the groups co or defined above and R 5 varies within the alkyl group; Amino acid amines, substituted or unsubstituted, for example amino acid amides of the formula S8: R4-CH-C-NH2 (S8) I Re? wherein R4 is as defined above and Re and 7 are independently chosen from each other of H and alkyl, - substituted N-glucosarnines, for example N-glucosarnins of the formula S9: wherein Rs is as defined above, - Aryloxypropionic acids, for example, aryloxypropionic acids of the formula SIO: where Ri and R2 are as defined above; Optically active ethers of tartaric acids, for example ethers of the formula Sil: R8-0 C02H \ / wherein Re is preferably methyl or benzyl; optically active acids of tartaric acids, for example acetals of the formula S12: R3 O-CH-CO2H C j (S12) R3 'O-CHCO2H wherein R3 is as defined above and R3' independently represents the other groups and is not equal to R3; optically active alkanoyl esters of tartaric acids, for example of the formula S13: Rs O CO2 H \ / \ / || CH 0 I (S13) CH / \ R5 0 CO2 H \ / o 11 wherein Rs is as defined above, -phenylalanopropanediols, for example of the formula S14: where Ri and R2 are co or defined before.

Substituents Ri with i = 1-8 preferably contain 1-30, particularly 1-20 carbon atoms and optionally can be substituted with an alkyl group, an alkoxy group, a carboxyl group, an alkoxycarbonyl group, an arnino group, a group nitro, a thio group, a thioalkyl group, a nitrile group, a hydroxyl group, an acyl group or halogen. Examples of suitable mixtures of enantiomers are: "-amino acids and their derivatives of the formula (El): wherein: R is as defined above Rβ and R7 are as defined above R9 represents OH, alkoxy, NH2 Rio represents H, alkyl and aryl and R4 is not the same as Rio a-aminonitriles, for example of the formula (E2 ) where R4, Re, R7 and Rio are as defined above; β-arnino acids (and derivatives) for example of the formula (E3) R4-CH-CH2-C-R9 I II (E3) NR6R7 wherein R4, Rs, R7 and 9 are as defined above, phenylalkylamines, for example from the formula E4: wherein Ri, R2, Rs, Re and R7 are co or defined above; piperazines, for example piperazines of the formula E5: wherein Rio is as defined above and Rn and R12 independently represent an alkyl group, aryl group or group COR9; piperidines, for example piperidines of the formula E6: Laughs (EB) where R o is as defined above and R 13 and R each independently represent R n, OH or an alkoxy group; pyrrolidines, for example pyrrolidines of the formula E7: I Rio (E7) where Rio, R13 and Ri4 are as defined above; rnorfolins, for example rnorfolines of the formula E8 I Rio where Rio, R11 and R12 are as defined above; diamines, for example diamines of the formula E9: R7 'Rs' N-ÍCH2) n ~ CH- (CH2) m-NRsR (E9) Rll where rn and n are each independently 0-5 and where Rll is as defined above and Rß 'and R7' independently of the same groups are presented as e and R7; ephedrines, for example, ephedrines of the formula E10: where Ri, R2, Rß V R? they are as defined before; arninoalcohols or arninoethers, for example of the formula Ella, Ellb or Elle: wherein n is 0-10, R? s = H or alkyl and wherein Rio, independently of the others, represents the same groups as Rio and R?, R7, Rio, R3 and 3 'are as defined above; 1- (2-naphthyl) alkyanolanes, for example l- (2-naphthyl) alkylamines of the formula E12: wherein Ri, R2, Rs, Rβ V R7 are as defined above; aliphatic amines, for example, aliphatic amines of the formula E13: Rio 'Rio - C - NR6R7 (E13) I "Rio" where Rβ, R? and Rio are as defined above, and Rio 'V Rio "are chosen from the same group as Rio and are not the same as others and Rio, phosphoric acids, for example phosphoric acids of the formula (E14) where Ri and R are co or defined before; carboxylic acids, for example carboxylic acids of the formula 5: R3-CH-COOH I (E15) R3 'wherein R3 and R3' are as defined above; substituted butanedicarboxylic acids for example of the formula (E16): R3 HO2C-CH-CH-CO2H (E16) I R4 wherein R3 and R4 are as defined above; aromatic or aliphatic hydroxycarboxylic acids or derivatives thereof, in particular substituted mandelic acids, for example α-hydroxycarboxylic acids of the formula E 17: where Rio, Rio 'and Ris are co-defined before and Rio and Rio' are different; sulphonic acids, in particular (substituted) camphorsulfonic acids or 1-phenylalkal-sonic acids (substituted) of the formula E18: where Ri, R2 and R3 are as defined above; 2-a ryloxyalkanoic acids, in particular 2-aryloxypropionic acids of the formula E19: wherein Ri and R2 are as defined above, biaryl bicarbides, in particular biarylbicarboxylic acids of the formula E20: wherein Ri and R2 are as defined above and Ri 'and R2' are independently of the same chosen from the same groups as R and R2; substituted bi (hetero) aryldiphosphinic oxides, particularly binaphthalene phosphinic oxides of the formula E21: wherein Ri and R2 are as defined above and are arbitrarily placed on the base structure of the naphthalene, and Ar represents a heteroaryl group. Substituents Ri with R2 i = 1-15 and Ar preferably contain 1-30, in particular 1-20 carbon atoms and may or may not be substituted with an alkyl group, alkoxy group, carboxyl group, alkoxycarbonyl group, amino group, group nitro, thio group, thioalkyl group, nitrile group, hydroxyl group, acyl group or halogen. As is known in the art, during crystallization, the inclusion of one or more solvent molecules can also take place. The diastereorne complex according to the invention can therefore also contain one or more molecules of a solvent. The ratio of resolving agents to one another can vary within a wide range, in the case of salt formation, with the sum of the acidic groups and the a of the basic groups in the complex having to be equal. Surprisingly it has been found that after one or two recrystallizations, the diastereomers according to the invention remain constant with respect to the ratio of the resolution agents in the diastereomer under subsequent recrystallizations. This proves that the wide range of resolution agents encountered is not the result of simple inclusion, for example, due to too rapid crystallization. The invention also relates to a mixture for separating a mixture of enantiomers, the agent comprising at least two resolving agents of which at least one is optically active. Preferably, the agent contains at least two resolution agents of the same type. The invention also relates to a process for separating a mixture of enantiomers. This process is characterized in that the mixture of enantiomers is contacted in a suitable solvent with at least two resolving agents, at least one of which is optically active, producing the diastereomeric complex as described above. The sequence in which this takes place is not critical. In the procedure, normal procedures and conditions are used which are generally known to the patient. separation of enantiomers through the formation of diastereomers. One skilled in the art can simply find that the principles and methods used for the optimization of classical resolution procedures can also be applied to the method according to the present invention. For example, one option is to replace a portion of the acids or resolution bases with acids or mineral bases to optimize the use of costly resolution agents. Also, the result of the resolution may depend strongly on the molar ratio of resolving agent to the recernate. Said relation, for example, can be varied between 0.5 and 2. Although this is not preferred, it is also possible to solve a mixture of enantiomers by first adding one or more resolution agents and, when the crystallization of a diastereomer does not take place, adding one or more additional resolution agents, etc. This can be done, for example, adding 2-21, preferably 2-13 and particularly 2-7 resolving agents. It will be obvious to a person skilled in the art that this process is more time consuming, which is why the resolution agents are preferably added simultaneously, certainly at the laboratory level. On an industrial scale, the addition of resolving agents will be chosen so that the crystallization is controllable and, for example, crystallization does not occur at undesirable sites in the installation and also the development of heat per unit of time remains controllable. To achieve this, the dosage over time of the combination of resolving agents can be adapted. Optionally, resolution agents are added one after the other. The optimal way to add the resolving agents can be - simply determined by one skilled in the art. The optically active resolving agents according to the invention preferably have an enantiormeric excess of greater than 95%, in particular greater than 98%, very particularly greater than 99%. Surprisingly it has also been found that when several optically active resolving agents are applied, they do not necessarily have the same absolute configuration. For example, it has been found that when using three resolution agents fi, B and C, a separation was possible when A and B had, for example, the configuration S and C the configuration R, and when A, B and C had all the configuration S. The complex formed in both cases contained A and B as well as C, in both cases C having a different configuration. This can be C useful in cases where only one enantiomer of the relevant resolution agent can be obtained. Preferably, substantially only the diastereomer complex according to the invention crystallizes with the highest possible enantiomeric excess of the separated compounds, after which it can be isolated using customary techniques. It may also involve chemical purification of the diastereorne complex. The methods according to the invention can therefore also be applied to effect chemical purification of the enantiomer mixture. The aforementioned diastereoronal complex conversion to the enantiomer present therein can be carried out in forms that are generally known to one skilled in the art, for example, by treatment with acid or base, followed by extraction, distillation or chromatography . From the practice it is known that the use of a mixture of two or more different solvents in crystallizations can sometimes give better results. If a solvent mixture is used, that mixture for example consists of 2-5 different solvents, and in particular 2-3. The process according to the present invention can also be carried out using a mixture of two or more different solvents. The invention will be elucidated based on examples.

Definitions and Synthesis Mixture P Phencyphos, Pl, 5,5-dirnethyl-4-fnyl-2-hydroxy-2-oxido of (1,3,2-dioxaphosforinan) Chlocyphos, P2, 5, 5-dirnethyl-4- (2 '-chlorophenyl) -2- hydroxy-2-oxide of (1,3,2-dioxa fos fo nano) Anicyphos, P3, 5,5-dimethyl-4- (2'-rhetoxy phenyl) -2-hydroxy- 2-oxido of (1,3,2-dioxa fos fori nano) were prepared and resolved according to Ten Hoeve and Uijnberg, US-fi-4, 814,477. Mixture U Wl, dibenzoyltartaric acid, U2, di-p-tolouyltartaric acid were obtained from Aldrich. U3, di-p-anisoltartaric acid was prepared and resolved following literature procedures.

Mixture A Al, rnandélico acid was obtained from Aldrich, A2, p-rnetilrnandélico acid A3, p-fluorornandélico acid were prepared and procedures of the literature were solved. Other analogs of rnandélico acid, p-rnetoximandélico acid, p-brornomandélico acid and p-chlorornandélico acid were prepared and were solved following procedures of the literature.

PEA mixture I p-Br-PEA, p-Br-phenethylaminine was prepared according to 3. . C.S. 105, 157B-84 (1983) through synthesis of Leuc hart from commercially available p-Br-acetophenone (Aldrich). Resolution, see example 1.3; Table 1. p-Cl-PEA, p-Cl-phenethylamines was prepared as above from p-Cl-acetophenone (Aldrich). Resolution, see examples 1.6 and 1.7; box 1 P-CH3-PEA, p-CH3-phenethylamines was prepared as above from P-CH3 -acetophenone (Aldrich). Resolution, see example 1.4 and 1.5; Table 1. Resolution of PEA mixture rae I see E; example IX-XI.

Mixture of PEA II PEA, fenetilami (Aldrich), P-NQ-PEA, P-NO2 -f ene ti lami ay Q-NQ2-PEA, o-N02-feneti lamina P-NO2-PEA and 0-NO2-PEA prepared as a mixture of 1: 1 as described in the literature from optically pure PEA (Aldrich). The mixture is applied with a PEA ratio: P-MO2-PEA: 0-NO2-PEA = 1: 1: 1 PEA mixture HAS P-NO2-PEA and 0-NQ2-PEA as a 1: 1 mixture.

Mixture IIB PEA and P-NQ2-PEA as a mixture of 1: 1 pure P-NO2-PEA was obtained through crystallization of the HCl salt.

Mixture PEA III rn-MeQ-PEA, rn-CH3? -phenethylaniline rn-Cl-PEA, rn-Cl-phenethylaminine rn-Br-PE, rn-Bt-phenethylamine, were synthesized following the same procedure used for the synthesis of the analogues for. Resolution of mixture PEA III rae, see E; Example XII. Other analogs of PEA (of the series o-, rn-, and p-) were synthesized following the known procedure.

Blend BA I- a-Me-BA, a-rnetylbenzyllanine (Aldrich); α-Et-BA, o-ethylbenzylamine and α-iP-BA, α-isopropylbenzylamines were synthesized following the procedures of the literature. Resolution of the mixture BA I, see E; Example XIII.

A. Resolution of amines on a small scale with the mixture P, mixture U and mixture fl Example I General procedure: To a solution of the racemic amine (rae.) (1-10 rnmoles) to be solved in a solvent as indicated in table 1, one mole equivalent of the mixture P-, W- or A- was added. , each one as a 1: 1: 1 mixture of its components. The resulting mixture was heated to reflux (in some cases no clear solution was obtained) and the mixture was allowed to cool to room temperature (RT). The solid was collected by suction, dried and analyzed by means of iH-NMR (200 MHz, DflSO (dimethyl sulfoxide) -d6). The enantiomeric excess (e.e.) of the amines was determined by means of chiral HPLC after isolation of the free amine from the salt by treatment with 10% NaOH solution and extraction with organic solvent. The columns used are listed below along with their indication number in Table 1. Chiral HPLC columns: 1: Crownpak Cr 2: Chiralpak AD 3: Chiralcel OD 4: Chiralcel OB 5: Chiralcel 03 6: R, R Uhelk 7 : Ultron ES OVM The eal was recrystallized from the indicated solvent (s) and analyzed again. The number of recrystallizations is indicated in Table I together with the solvent. On a small scale, yields were not determined. The results of the small-scale resolutions are summarized in Table 1, where the indication of the solvent with A, B, C ... means: A: 2-butanone B: ethanol (EtOH) C: 2-propanol D: methanol (MeOH) E: ethyl acetate (EtOAc) F: toluene G: water The mixing ratio P1 / P2 / P3 refers to the molar ratio of the compound P1: P2: P3 present in the solid. * mixture of fil and A2 only • ** repeated at preparative scale • * • ** - HPLC analysis by benzoate • ** • * • * HPLC analysis by tosylate Examples of preparative resolutions Example II The experiment of Example 1.8 was repeated on a larger scale. fi a solution of o-Cl-PEfi rae. (57.5 g, 366 mmol) in 800 mL of EtOH, a mixture of (-) phencyphos (84 g) and (-) anicy? Hos (4 g) was added. The mixture was heated to reflux (no clear solution) and cooled to RT. The solid was collected and recrystallized from 1.5 1 EtOH. Yield 42 g (HPLC 90% e.e.). This salt was recrystallized from 650 nmol EtOH to yield 22.1 g (15%) of the salt with > 99% e.e.

Example III The experiment of Example 1.17 was repeated on a larger scale. 20.5 g (150 mmol) of racemic 3-rnethyl-phenylethylaminine were dissolved in 900 ml of 2- ro -olpanol and 13.35 g (50 πnnols) of (-) chlocy? Hos, 13.6 g (50 mrnol) of (-) were added. anicy? hos and 12.1 g (50 rnrnoles) of (-) phencyphos. It was heated to reflux and after the addition of 50 rnl of MeOH a clear solution was obtained. The heating was stopped and the solution was stirred for 18 hours. The salt was collected, rinsed with 2-propanol and wet salt (HPLC 78% e.e.), recrystallized from 500 rnl of 2-propanol and 120 rnl of ieOH, yielding 11.6 g (18%) of the salt with 96% e.e. (HPLC).

Example IV The experiment of Example 1.28 was repeated on a larger scale. fi a solution of 3-quinuclidinol benzoate (30 g, 126 rnmoles) in fleOH (1, 2 1), was added a mixture of di-p-anisoyl-L-tartaric acid (17 g, 34 rnrols), acid di-p-toluyl-L-tartaric (30.6 g, 76 mmol) and dibenzoyl-L-tartaric acid (4.4 g, 11 mrnols). The mixture was heated to reflux and cooled to RT. The resulting salt was heated to reflux in MeOH / water (8: 2) (11) for 10 minutes and cooled to Tfi. The salt was collected and treated with 10% NH-4OH / TBME. Quinuclidinol benzoate (12 g, 40%) was pure enantiomerically (> 98%) according to HPLC: Benzoate was converted to pure (+) (S) quinuclidinol enantiomerically by treatment with 10% HCl (reflux, 16 hours) .

Example V The experiment of Example 1.40 was repeated on a larger scale. 5 4.55 g (30 rnrols) of racemic 2-ethylrnorpholine were dissolved in 100 rnl EtOH (96%) and a solution of 3.76 g (10 rnmoles) of (-) dibenzoyltartaric acid, 4.0 g (10 mrnol) was added immediately. of (-) ditoluyltartaric acid and 4.36 g (10 rnrols) of (-) dianisoyltartaric acid in 100 l of EtOH (96%).

The crystallization started within 30 minutes and stirring was continued for another hour. The salt was collected, rinsed with EtOH (HPLC 70% e.e.) and recrystallized from 100 nmol of EtOH before contemplating drying. This produced 2.6 g (30%) of the salt with 88% e.e. Another recrystallization of EtOH produced 1.6 g (19%) of salt with 96% e.e.

EXAMPLE VI Resolution of DL-3-amino-3-phenylpropionic acid with P mixture » A mixture of 3-arnino acid was heated to reflux 3- phenylpropionic (990 rng, 6 rnrnoles) and mixture (-) P (2 millirnoles each) in 15 rnl of 2-butanone. The clear solution was allowed to cool to room temperature. After stirring for 1 hour at room temperature, the solid was collected by suction, was washed with 1 nrn of 2-butanone and dried, yielding 804 rng of salt. The solid was analyzed by means of 1 H-NMR, showing a mixture of phencyphos, chlocyphos and anicyphos in a rnolar ratio of 5: 4: 1. An enantiomeric excess of > 98%, by means of chiral HPLC (Cro npack CR (+)).

C. Small scale resolution of acids with PEA mixtures Example VII General procedure: a solution of racernic acid (1-10 rnmoles) in the solvent as indicated (see lists) was added one mole equivalent of the PEA mixture each as a 1: 1 (: 1) mixture of its components . Solvents: fl: 2-butanone B: ethanol (EtOH) C: 2-? Ropanol D: methanol (MeOH) E: ethyl acetate (EtOAc) F: toluene G: water The resulting mixture was heated to reflux (in some cases no clear solution was obtained) and the mixture was allowed to cool to room temperature (RT). The solid was collected by suction, dried and analyzed by means of iH-NMR (200 MHZ, DMSO-B). The enantiomeric excess (e.e.) of the amines was determined by means of chiral HPLC, after isolating the free acid from the salt by treatment with 10% HCl solution and extraction with organic solvent. The columns used are listed below: Chiral HPLC Columns: 1: Crownpak Cr 2: Chiralpak AD 3: Chiralcel OD 4: Chiralcel OB 5: Chiralcel OJ 6: R, R Uhelk 7: Ultron ES OVM The salt was recrystallized from ( the solvent (s) as indicated and analyzed again. Small-scale yields were not determined. The results of the small-scale resolutions are summarized in Table 2. The ratio of the mixture refers to the rnolar ratio of the mixture compounds present in the solid, in a sequence as given in the definition of the mixtures.

TABLE 2 * ((-) - lezcla) D. Resolution with a mixture of N-acyl-phenylglycine Example VIII Resolution of cis-l-aminoir-dan-2-ol with N-acyl-phenylglycine mixture 992 rng of cis-l-arninoindan-2-ol and a mixture of N-benzoyl-D-phenylglycine, N-toluoyl-D-phenylglycine and N-α-anisoyl-D-phenylglycine were heated to reflux (2 mmol each). ) in 20 rnl of toluene and 5 rnl of butanone, and allowed to cool to room temperature. The solid was isolated, washed with 1 mL of toluene and dried. In this way, 380 g of the salt were obtained. HPLC analysis showed N-benzoylphenylglycine, N-toluoylphenylglycine and N-anisoylphenylglycine with a molar ratio of 1: 1.6: 0.9. The e.e. of (-) cis-l-aminoindan-2-ol was 82% (chiral HPLC, Crownpack CR (-). Recrystallization of the salt from 5 ml of toluene and 2 rnl of 2-butanone gave 180 rng of the salt with N-benzoylphenylglycine, N-toluoylphenylglycine and N-anisoylphenyl-glycine in an olar ratio of 1: 1.8: 0.8 The ee of (-) cis-l-arninoindan-2-ol was 96%.

E. Resolution of racemic mixtures (rae) of enantiomers Example IX Resolution of mixture PEA-1 rae, with (R) -p-CH3 -mandelic acid (R)) - p-rie-Mñ) To a mixture of rae. p-Br-PEA, p-Cl-PEA and p-fe-PEA (100 rnrols each) in 600 rnl of EtOH (96%) was added (R) -p-fle-MA (300 rnrnoles, 50 g ). The mixture was refluxed and allowed to cool to room temperature (RT). The solid was collected and recrystallized from EtOH (500 mL). The solid was collected and dried. Makes 33 g (35%). The mixed salt contained (R) -p-Br-PEA, (R) -p-Cl-PEA and (R) -p-le-PEA, in a 1: 1: 1 ratio. The salt was treated with 10% NaOH / TBNE and the PEA I mixture was isolated as a slightly yellow oil. HPLC analysis (1) showed the three amines with e.e. > 98%.

EXAMPLE X Resolution of PEfí-I rae mixture, with (S) -p-Me-mandelic acid and (S) -p-B? - andélico acid To a mixture of rae. p-Br-PEA, p-Cl-PEA and p-ie-PEA (13 rnrols each) in 200 rnl of EtOH (96%) was added a mixture of (S) -p-Br-MA and (YES p-Me-MA (20 rnmoles each) The mixture was refluxed and allowed to cool to RT The solid was collected and recrystallized from EtOH (100 nmol) The solid was collected and dried. g (43%) The mixed salt contained (S) - p-Br-PEA, (S) -? - Cl-PEA and (S) -p-Me-PEñ, in relation 1: 1: 1 and (S) ) ~ p-Br-MA and (YES-p-Me-MA (1: 1) .The salt was treated with 10% NaOH / TBIE and the PEA I mixture was isolated as a slightly yellow oil. HPLC (1) showed the three amines with ee> 98%.

Example XI Resolution of p-MeQ-PEfl rae, in the presence of PEft-I rae mixture. with (R) -p-CH3-mandelic acid To a mixture of rae. p-MeO-PEA, p-Br-PEA, p-Cl-PEA and p-tle-PEA (10 rnmoles each) in 60 ml of EtOH (96%) was added (R) -p-le- riA (40 rnmoles, 6.5 g). The mixture was refluxed and allowed to cool to RT. The solid was collected and recrystallized from EtOH (50 ml). The solid was collected and dried. HPLC analysis (1) showed that the rnixta salt consisted of the four amines with a ratio of 3: 52: 30: 13, respectively. The e.e. of the four amines was > 98%. Note: p-MeO-PEA could not be resolved with mixture A but could be resolved in the presence of other PEA amines.

Example XII Resolution of mixture PEA III rae.

To a mixture of rn-MeO-PEA, rn-Cl-PEA and -Br-PEA (100 rnrols each) in EtOH (60Q rnl) (96%) was added (S) -p-lieMA (45 g, 300 rnmoles). The mixture was heated to reflux and allowed to cool to RT overnight. The solid was collected and dried, yielding 34 g (38%). The salt was treated with 10% NaOH / TBME and 16.8 g of the PEA III mixture were isolated. The HPLC analysis (1) showed a 2: 4: 4 ratio with e.e. > 98%.

Example XIII Mixing resolution of Bfl I rae. 50 g (0.33 mol) of a-isopropylbenzyllanine rae, 45 g (0.33 rnoles) of a-ethylbenzylannine rae were dissolved. and 24.2 g (0.2 rnoles) of S (-) - a-rnetylbenzylamine in 1.5 1 of IPA and 208 g (0.86 rnoles) of (+) Phencyphos were added. The mixture was heated to reflux and 1.0 1 of EtOH was added to obtain a clear solution. The mixture was allowed to cool to room temperature under stirring for 18 hours, the salt was collected. A sample of the resolved amines mixture was freed from the salt and by HPLC showed 90% e.e. for the two resolved amines. The salt was recrystallized from 1.2 1 EtOH, yielding 60 g (26%) of salt with >98% e.e. for the 3 amines. The ratio of the amines was 4: 6: 1 (α-methyl; α-ethyl; α-isopropyl), as determined by means of TC (120 ° C). An experiment without S (~) - -methylbenzylamine added, produced a salt with the other two amines with 40% e.e. and a recrystallization gave an e.e. 70% Separate resolution experiments with a-isopropylbenzyllanine and a-ethylbenzyllanine with (+) - phencyphos gave e.e.'s below 5%.

Example XIV Resolution of anicyphos, chlocyphos and 2,4-dichlocyphos rae, with (-) - ephedrine To a mixture of anicyphos, chlocyphos and 2,4-dichlocyphos rae. (1, 3,2-dioxaphosphorin-5,5-dirnethyl-4 (2 ', 4'-dichlorophenyl) -2-hyy-2-oxide) (10 mrnol each) in 2-propanol (250 rnl) is added (-) ephedrine (30 mrnols), the mixture was heated to reflux and allowed to cool to RT. The solid was collected and recrystallized from 2-propanol. The mixed salt was treated with 10% HCl for 30 minutes and the solid was collected. HPLC analysis (6) showed (+) -anicyphos, (+) - chlocyphos and (+) - 2,4-dichlocyphos in a ratio of 55: 35: 5 with e.e.'s > 98%.

Example XV Resolution of anicyphos, chlocyphos and 2,4-dichlocyphos rae, with (-) - p-hyyphenylglycine To a mixture of anicyphos, chlocyphos and 2,4-dichlocyphos rae. (10 rnrols each) in EtOH / water (8: 2) was added (-) - p-hyyphenylglycine (30 mmoles). The mixture was heated to reflux and allowed to cool to RT. The solid was collected and treated with 10% HCl for 30 rnin. The acids were collected by suction. The HPLC analysis (6) showed anicyphos, chlocyphos and 2,4-dichlocyphos in a ratio of 1:35:65 with e.e.'s > 98%.

F) Resolution of a racemate with a mixture of resolution agents of which some are racemic and others enantiomerically pure. Example XVI Resolution of p-Br-PEfl rae, with p -Br- an elic acid and p-lle-Mfl a) Using (S) -p-Br-mandelic acid and (S) -? - f1e ~ riA. To a mixture of p-Br-PEA rae. (2 g) in MeOH was added a mixture of (S) -p-Br-rnandélico acid and (?) - p-e-lviA (1 g each), the salt was collected and analyzed by means of 1 H-NMR (MA 1: 1) and HPLC (1). The e.e. of the amine was 84%. b) Using rac-p-Br-rnandélico acid and (S) -? - ie - A A a mixture of p-Br-PEA rae. (2 g) in HeOH was added a mixture of p-Br-MA and (S) -p-fle-riA (1 g each). The salt was collected and analyzed by means of iH-MR (MA 3: 4) and HPLC (1 and 2). The e.e. of the amine was 90% and the e.e. of 95% p-Br-MA. c) Using (S) -p-Br-mandelic acid and p-Me-MA rae A a mixture of p-Br-PEA rae. (2 g) in MeOH was added a mixture of (S) -p-B? -mandelic acid and p-Me-MA (1 g each). The salt was collected and analyzed by means of 1H-N-1R (HA 4: 3) and HPLC (1) and (2). The e.e. of the amine was 99% and the e.e. from p-Me-MA > 95-% ..

Example XVII Resolution of p-Cl-PEfl with mixture P containing racemic phencyphos To a solution of p-Cl-PEA rae. in 2-butanone, a mixture of (-) anicyphos, (-) chlocyphos and phencyphos rae was added. (1 g each). The resulting salt was recrystallized from EtOH and analyzed by HPLC (1) and (6). The amine had an e.e. of 84% and the phencyphos an e.e. from 8D-85%.

Example XVIII Resolution of chlocyphos with (-) - ephedrine and (+) - phencyphos To a solution of (-) ephedrine (2.4 g) in 2-propanol (50 rnl) was added (+) -? Hencyphos (1.75 g) and chlocyphos rae. (1.85 g). The mixture was heated to reflux and allowed to cool to RT. The salt (3.31 g) was treated with 10% KOH / toluene. The organic layer was acidified and the solid was analyzed with HPLC (6). Both (+) -phencyphos and (+) -chlocy? Hos were enantiomerically pure (> 98%).

Example IXX Resolution of phencyphos with O) -efe rina and (-) - chlocyphos To a solution of (+) ephedrine (2.6 g) in 2-propanol (70 ml) was added phencyphos rae. (1.90 g) and (-) chlocyphos (2.04 g). The mixture was heated to reflux and allowed to cool to RT. The salt (2.78 g) was treated with 10% KOH / toluene. The organic layer was acidified and the solid was analyzed with HPLC (6). Both (-) -phencyphos and (-) - chlocy? Hos were enantiomerically pure (> 98%). Note: Phencyphos could not be resolved with ephedrine but it could be resolved with ephedrine in the presence of chlocyphos.

EXAMPLE XX Resolution of N-benzyl-3,4-bis- (p-methoxy enyl) -pyrrolidine rae, with 1 -) - N-benzyl-3,4-diphenylpyrrolidine and (-) - di- (p-anisoyl) acid -tartá ico To a mixture of N-benzyl-3,4-bis- (p-rethoxyphenyl) -pyrrolidine rae. (1 g) in 2-butanone (50 rnl) was added (-) - di- (p-anisoiD-tartaric acid (2.4 g) .The mixture was heated to reflux and cooled to RT.The resulting salt was recrystallized Two times of 2-butanone The HPLC analysis (2) showed N-benzyl-3,4-bis- (p-methoxyphenyl) -pyrrolidine and (-) - N-benzyl-3,4-diphenylpyrrolidine in a ratio 1:10 with an ee of 93% for N-benzyl-3, -bis- (p-methoxyphenyl) -pi rolidine.

Note: The present authors have not been able to resolve this amine by resolution with a single resolving agent, neither using the mixture P nor the mixture W in the absence of N-benzyl-3,4-diphenyl-irrolidine.

G. Resolution of racemic (a) amine) (s) with a mixture of enantiomerically pure mandelic acids and a non-chiral acid (phenylacetic acid) Example XXI 1.35 (10 mrnols) of racemic p-CH3-phenethylaminerin were dissolved in 25 ml of IPA and 500 rng (3.3 rnrnoles) of R (-) - rnandélic acid, 550 mg (3.3 mmoles) of R (-) - acid were added. p-CH3-rnandélico and 450 rng (3.3 rnrnoles) of phenylacetic acid. Under reflux a clear solution was obtained which was allowed to cool to room temperature and the salt was collected after one hour. The 1H RI N of the salt showed the three acids present and the HPLC of the three free amines showed 82% e.e. The same experiment with p-Cl-phenylethylamine produced a salt that also included all three acids (68% e.e). An experiment with 1.35 g (10 mrnoles) of P-CH3-phenethylamine to racemic, 830 rng (5 mmoles) of R (-) - p-CH3-rnandélico acid and 680 rng (5 rnrnoles) of phenylacetic acid in 25 ml of IPA produced a salt containing both acids and amine with 90% e.e. An experiment with 1.35 g (10 mmoles) of P-CH3-phenenylaminenic racenica and 1.66 g (10 rnmoles) -of acid R - (-) - p-CH3 -rnandélico in 50 l of IPA produced a salt with 57% e.e.

H. Resolution of amines rae, with mixtures containing resolution agents with opposite configuration. Example XXII Resolution of PEA I mixture (ratio: 1: 1: 1) with substituted mandelic acids of opposite configuration The results are summarized in table 3, TABLE 3 Exp. 1: Yield after recrystallization, 12% e.e. after recrystallization, 99% Exp. 2 Salt: p-CHs-MAcMA = 4: 1 Example XXIII Resolution of p-Me-PEA with substituted mandelic acids with opposite configuration The results are summarized in table 4, TABLE 4 Exp.l: Salt p-CH3 ~ MA: MA = 4: 1 Exp.2: Salt P-CH3-MA: MA = 6: 1 Example XXIV Resolutions of o-Cl-PEfl with phosphoric acids with opposite configuration The results are summarized in table 5, CHART 5 I. Resolution (via inclusion) of 1-phenylethanol using mixtures of TflPDQL derivatives Example XXV They were prepared according to the literature, (4R, 5R) ~ 2, 2-dimethyl-c-., A, of. ' , a '-tetraphenyl-1,3-dioxolan-4, 5-dirnetanol (TADDOL I), (4R, 5R) -2,2-dirnethyl-a, a, a ', a'-tetra (p-rnetoxy phenyl) -l, 3-dioxolan-4,5-dirnetanol (TADDOL II) and (4R, 5R) -2,2-dirnethyl-a, a, (x ', a'-tetra (p-rnenyl enyl) -1,3-dioxolan-4,5-dirnetanol (TADDOL III). A mixture of TADDOL 1 (1.0 g) and TADDOL II (1.1 g) in 20 ml of benzene was added racemic 1-phenylethanol (PE) and the mixture was evaporated.To the residue, 50 ml of hexane was added and the suspension was added. The mixture was stirred overnight, the precipitate was collected and the * H NMR showed the 3 components present in a 2: 2: 1 ratio (TADDOL I: TADDOL II: PE) The enriched alcohol was isolated by means of distillation of the precipitate ( 0.1 rnrnHg: 80 ° C.) HPLC (Chiralcel OD) showed 82% enantiornérico excess. 3. Comparative resolutions of ot-methylphenylalaninamide using P mixture and > and separate components. Example XXVI The resolutions were on a scale of 1 nm in 2-tanone, using the general procedure. The results are summarized in table 6. for HPLC see Example 1.25, K. Obtaining a constant composition by repetitive crystallization Example XXVII To a solution of (-) ephedrine (3.6 g) in 75 mL of i-propanol was added a mixture of (+) P (5.1 g). The mixture was heated to reflux and cooled to RT. After a recrystallization of i-propanol, a mixed salt with a constant composition (ephedrine / phencyphos / chlocyphos; 2: 2: 1) was obtained, which does not change by repeated recrystallization of i-propanol. A solution of 1.8 g (20 rnmoles) 2-arnino-l-butanol rae. In a mixture of 5 nl of IPA and 30 rnl of 2-butanone was added 3.2 g (20 mrnol) of mixture (-) A and after heating to reflux a clear solution was obtained, which was allowed to cool to room temperature with stirring and after 3 hours the mixed salt was collected. After a recrystallization of 2-β-tanone, the mixed salt had the same composition, (alcohol: M.A .:? -Me-M.A. = 5: 2: 3).

L. Quick selection of resolution agents An equirnolar mixture of 11 resolution acids (mixture of 11 acids) containing: (-) - Pl, (-) - P2, was used.

(-) - P3, (-) - Wl, (-) - I2, (-) - UI3, (-) - Al, (~) ~ A2, (-) - rnálico acid, acid (-) - phenyls? cyclic and (+) - phonic acid alkylphosphine, in Examples XXVIII to XXIX.

Example XXVII 2 were dissolved. 9 g (11 rnmoles) of mixture of 11 acids in 80 rnl of IPA (isopropyl nina) under reflux and 1.72 g (11 rnmoles) of 2-chloro-oc-phenethylamine rae were added. to the hot solution. The mixture was allowed to cool to room temperature under stirring and the salt was collected after 18 hours. The composition of the salt was determined by means of iH NMR. The main components were the amine and the acids il, U2 and I3. The e.e. of the amine was 40% (HPLC). Recrystallization from IPA / MeOH (2: 1) did not change the composition of the salt but the e.e. increased to 84% (HPLC).

Example XXIX 2.9 g (11 rnrols) of 11 acid mixture were dissolved in 50 rnl of IPA under reflux and 1.5 g (11 mmol) oc-ethylbenzylamine rae was added. Crystallization started within one minute and the mixture was allowed to cool to room temperature under stirring. The salt was collected after 2 hours and the * H NMR showed that the salt consisted of the amine and the acids W1, W2 and U3. The e.e. of the amine was 10% according to HPLC. The salt was recrystallized from 50 ml of IPA plus 100 rnl of MeOH and the composition does not change (* H NMR), but the e.e. of the amine increased to 22%. Examples 30-32 show rapid selections of resolution agents according to the invention, which result in only resolution agent.

Example XXX Resolution of racemic ct-methylbenzylamine with N-acetyl-L-amino acid mixture a) To a solution of 1.25 g (10 rnrnoles) of racemic α-rnethylbenzylamine in 10 ml of toluene, 3 ml of isopropanol and one drop of water was added to a mixture of 6 N-acetyl-L-arnino acids ( 1.6 mrnoles each). The mixture was prepared from the following L-arnino acids: L-Phe, L-Tyr, L-Try, L-phenylglycine, L (+) - p-hydroxyphenylglycine and S-indoline-2-carboxylic acid. The mixture was heated to reflux and the clear solution was cooled to room temperature. After stirring for 2 hours at room temperature, the resulting solid was isolated, washed with 1 ml of toluene and dried, yielding 131 mg of the salt. HPLC analysis showed salt formation with only N-acetyl-L-p-hydroxyphenylglycine. Chiral HPLC (Crownpack CR (-)) gave an e.e. = 62%. b) Subsequently, a mixture of 720 rngs (6 rnrnoles) of racemic α-rnetylbenzylamine and 1 was heated to reflux. 26 g of N-acetyl-L-p-hydroxy-phenylglycine (6 rnmoles) in 20 ml of toluene, 20 ml of isopropanol and 3 ml of water, and the clear solution was cooled to room temperature. After stirring for 1 hour at room temperature, the solid was isolated, washed with 2 ml of toluene and dried. We obtained 537 rng (32%) of the salt, with an e. e. = 94% HPLC qui ral, Crownpack: CR (-).

Example XXXI Resolution of cis-l-amino-tan-2-ol with mixture of N-acetyl-L- to n-acid a) 990 rng of racemic cis-1-arninoindan-2-ol and the same mixture of N-acetyl-L-arnino acid used in Example 30 (1.6 rnmoles each) in 12 rnl of 2-butanone were heated to reflux. 3 ml of isopropanol, and cooled to room temperature. After stirring for 4 hours, the resulting solid was isolated, washed with 1 mL of 2-β-tanone and dried, yielding 180 mg of the salt. HPLC analysis of the salt showed the presence only of N-acetyl-S-indolinecarboxylic acid and an e.e. of 36% (Crownpack CR (-)). b) Subsequently 500 rng of racemic cis-1-arninoindan-1-ol and 648 rng of N-acetyl-S-indolinecarboxylic acid in 30 rnl of 2-butanone and 5 drops of refluxing water were heated and the clear solution was cooled at room temperature. After stirring for 4 hours at room temperature, the solid was isolated, washed with 1 ml of 2-butanone and dried. 326 rng of the salt were obtained (yield 29%). The (-) - cis-l-aminoindan-2-ol had e.e. = 98% (chiral HPLC, Crownpack CR (-)).

Example XXXII Resolution of dl-andelic acid with L-amino acid amide mixture 910 rng (6 mrnol) of dl-rnandélico acid, 160 mg of NaOH-50% and a mixture of L-tyrosinarni a, L-phenylalaninamide-HCl and L-phenylglycinamide (2 mrnol each) in 10 nl were heated to reflux. of 96% ethanol. The clear solution was allowed to cool to ambient temperature. After stirring for 1.5 hours, the solid was isolated, washed with 2 rnl of 96% ethanol and dried. The yield was 310 g. HPLC and * H NMR analysis showed a salt with only L-phenylglycinanide. The rnandélico acid was isolated by means of treatment with hydrochloric acid and extraction with toluene. After evaporation, the residue was resolved in 6 rnl of water and the concentration of rnandélico acid was measured with HPLC. The optical rotation of this solution was measured: [CÜD = -146 (25 ° C, c = 0.47) "For this value an e.e. of 95%.

This provides a rapid selection method for resolving agents that can generally be considered as: Add a mixture of resolving agents (eg acids or amines) to the scavenger and determine the composition of the salt and the e.e. of the resolved enantiomer. If the e.e., even after recrystallization of a suitable solvent, is good enough, then observe which resolution agents are responsible for the resolution and use these in subsequent resolution experiments. If the e.e. it is not acceptable, even after recrystallization of a suitable solvent, then start a new experiment without the resolving agents present in the first salt. Repeating this sequence co or rule can be financed with an e.e. acceptable salt composition that reflects the resolution agent that can be used in later resolutions, and can serve as a starting point for further optimization.

Claims (17)

NOVELTY OF THE INVENTION CLAIMS

1. A diastereomeric complex comprising at least three compounds of which at least one is an optically active resolving agent and at least one enantiomeric compound in optically active form.

2. The diastereomeric complex according to claim 1, characterized in that the complex is salt.

3. The diastereomeric complex according to claim 1 or 2, further characterized in that it contains at least two resolving agents in optically active form and at least one enantiomer in optically active form.

4. The diastereomeric complex according to claim 1 or 2, further characterized in that it contains at least two enantiomers in optically active form and at least one resolving agent in optically active form.

5. The diastereomeric complex according to any of claims 1-4, further characterized in that it comprises at least three resolving agents in an optically active form.

6. The diastereomeric complex according to any of claims 1 or 5, further characterized in that it contains at least three enantiomers in optically active form.

7. - The diastereomeric complex according to any of claims 1-6, further characterized in that the enantiomer in optically active form is a carboxylic acid, an amine, an alcohol, an amino acid, an aminoalcohol or an n-thiol.

8. The diastereomeric complex according to any of claims 1-7, further characterized in that at least one enantiomer is present in an enantiormeric excess of greater than 95%.

9. The diastereomeric complex according to any of claims 1-8, further characterized in that the mixture (s) of enantiomers are chosen from one of the groups having the formula El up to and including E21.

10. The diastereomeric complex according to any of claims 1-9, further characterized in that the resolving agents are chosen from one of the groups having the formula Sl up to S14, inclusive.

11. Process for the preparation of a diastereomeric complex according to any of claims 1-10, in which one or more mixtures of enantiomers in a solvent are contacted, with one or more resolution agents, producing the diastereomeric complex.

12. The method according to claim 11, characterized in that more than one of the resolution agents is added.

13. The process according to claim 11, further characterized in that individual agents are added, one after another, without intermediate recovery of any solid formed.

14. The method according to claim 12, further characterized in that the resolution agents are added simultaneously.

15. The process according to any of claims 11-14, further characterized in that (a mixture of) the enantiomer (s) present in the diastematorium is subsequently isolated in an optically active form from the diastereomeric complex. .

16. An agent for the separation of a mixture of enantiomers comprising at least two resolving agents, of which at least one resolving agent is an optically active form.

17. An agent according to claim 16, characterized in that the agent comprises at least three resolution agents, of which at least two resolution agents are in optically active form.