Title of Invention	SEPARATION OF STEREOISOMERIC N,N-DIALKYLAMINO-2-ALKYL-3-PHENYL ALKANES
Abstract	Method for the isolation of a stereoisomer from a mixture comprising the two stereoisomers of the general formulae (I-A) and (I-A') and/or the two stereoisomers of the general formulae (I-B) and (I-B') in which R1, R2 and R3, identical or different, are selected from the group consisting of -H, -F, -CI, - C1-C6-alkyl, -S-C1-C6-alkyl, -OH, -O-C1-C6-alkyl, -O-C1-C6-alkylenephenyl, -OCO-C1-C6- alkyl, -OCO2-C1-C6-alkyl, -OCON(C1-C6-alkyl)2 and -O-SiR8R9R10 (in which R8, R9 and R10, identical or different, are -C1-C6-alkyl or -phenyl); R4 is -H or -C1-C6-alkyl; R5 is -C1-C6-alkyl; and R6 and R7, identical or different, are -H or -C1-C6-alkyl; wherein "C1-C6-alkyl" means a linear or branched, cyclic or open-chain saturated hydrocarbon residue with 1 to 6 carbon atoms, optionally substituted with 1 to 6 halogen atoms, identical or different, selected from F, CI and Br; and "C1-C6-alkylene" means a linear or branched, cyclic or open-chain saturated hydrocarbon residue with 1 to 6 carbon atoms, optionally substituted with 1 to 6 halogen atoms, identical or different, selected from F, CI and Br; or their salts with organic or inorganic acids; comprising the steps (a) manipulating the mixture ratio of the stereoisomers in the mixture so that at least one of the stereoisomers is present in an enantiomeric excess, and (b) adding phosphoric acid under conditions which bring about precipitation of the stereoisomer present in enantiomeric excess from a solution as phosphate, hydrogenphosphate or dihydrogenphosphate, (c) separating the precipitated salt obtained in step (b) from the supernatant solution.

Title of Invention

SEPARATION OF STEREOISOMERIC N,N-DIALKYLAMINO-2-ALKYL-3-PHENYL ALKANES

Abstract

Method for the isolation of a stereoisomer from a mixture comprising the two stereoisomers of the general formulae (I-A) and (I-A') and/or the two stereoisomers of the general formulae (I-B) and (I-B') in which R1, R2 and R3, identical or different, are selected from the group consisting of -H, -F, -CI, - C1-C6-alkyl, -S-C1-C6-alkyl, -OH, -O-C1-C6-alkyl, -O-C1-C6-alkylenephenyl, -OCO-C1-C6- alkyl, -OCO2-C1-C6-alkyl, -OCON(C1-C6-alkyl)2 and -O-SiR8R9R10 (in which R8, R9 and R10, identical or different, are -C1-C6-alkyl or -phenyl); R4 is -H or -C1-C6-alkyl; R5 is -C1-C6-alkyl; and R6 and R7, identical or different, are -H or -C1-C6-alkyl; wherein "C1-C6-alkyl" means a linear or branched, cyclic or open-chain saturated hydrocarbon residue with 1 to 6 carbon atoms, optionally substituted with 1 to 6 halogen atoms, identical or different, selected from F, CI and Br; and "C1-C6-alkylene" means a linear or branched, cyclic or open-chain saturated hydrocarbon residue with 1 to 6 carbon atoms, optionally substituted with 1 to 6 halogen atoms, identical or different, selected from F, CI and Br; or their salts with organic or inorganic acids; comprising the steps (a) manipulating the mixture ratio of the stereoisomers in the mixture so that at least one of the stereoisomers is present in an enantiomeric excess, and (b) adding phosphoric acid under conditions which bring about precipitation of the stereoisomer present in enantiomeric excess from a solution as phosphate, hydrogenphosphate or dihydrogenphosphate, (c) separating the precipitated salt obtained in step (b) from the supernatant solution.

Full Text	Separation of stereo isomeric N,N-dialkylamino-2-alkyl-3-hydroxy-3- phenylalkanes The invention concerns a method for the separation of stereoisomeric N,N-dialkyl- amino-2-alkyl-3-hydroxy-3-phenylalkanes. Opioids have been used for many years as analgesics for the treatment of pain although they can induce a number of side effects, for example addiction and dependency, respiratory depression, gastro-intestinal inhibition and constipation. Over an extended period or at high doses they can only be administered with particular precautionary measures such as special prescribing requirements. It is known that certain N,N-dialkylamino-2-alkyl-3-hydroxy-3-phenylalkanes (especially 1-phenyl-3-dimethylaminopropane compounds) possess analgesic activity without causing the side effects typical of opioids. These compounds are characterised by a pronounced analgesic action that is significantly increased in comparison with, for example, the opioid tramadol. These analgesically active N,N-dialkylamino-2-alkyl-3-hydroxy-3-phenylalkanes are chiral. Since two chiral centres are usually present, the compounds exist in the form of 4 stereoisomers, i.e. two enantiomeric pairs that are diastereomeric with one another. The activity of an analgesic is frequently attributable to its interaction with a certain receptor of a human or animal cell. Since these receptors are constructed of chiral amino acids and optionally also chiral glycosides, their interaction with chiral pharmaceuticals is stereoselective. Therefore the pharmacological activity of chiral pharmaceuticals is frequently different for the individual stereoisomers. There is therefore a requirement for a method for the separation of the stereoisomers, i.e. the diastereoisomers and enantiomers, of N,N-dialkylamino-2- alkyl-3-hydroxy-3-phenylalkanes. The synthesis of (2RS,3RS)-1-dimethylamino-3-(3-methoxyphenyl)-2-methylpentan- 3-ol is known from of EP-A 693475.The separation of the diastereoisomers, that is the two enantiomeric pairs, is carried out by hydrochloride precipitation with trimethylchlorosilane/water in 2-butanone. The racemic mixture of the two enantiomers of (2R,3R) and (2S,3S) configuration is carried out by separation on a chiral HPLC column. However, the chromatographic separation of enantiomers on chiral stationary phases is usually unsuitable for relatively large quantities of active compounds and is instead used almost solely for analytical purposes. There is therefore a requirement for a method that is also suitable for the separation of the enantiomers of chiral N,N-dialkylamino-2-alkyl-3-hydroxy-3-phenylalkanes on a preparative scale. Thus the problem that forms the basis of the invention is to provide a method for the separation of the stereoisomers, preferably enantiomers, of chiral N,N-dialkylamino- 2-alkyl-3-hydroxy-3-phenylalkanes that can also be carried out on the gram and kilogram scale. The method must be cost-effective and guarantee a good yield and high enantiomeric purity. This object is achieved by the subject matter of the claims. It has surprisingly been found that the isolation of a stereoisomer from a mixture comprising the two stereoisomers of the general formulae (l-A) and (l-A') and/or the two stereoisomers of the general formulae (l-B) and (l-B'), in which R1, R2 and R3, identical or different, are selected from the group consisting -H, -F, -CI, C1-C6-alkyl, -S-C1-C6-alkyl, -OH, -O-C1-C6-alkyl, -O-C1-C6-alkylenephenyl, -OCO-C1-C6-alkyl, -OCON(C1-C6-alkyl)2 and -O-SiR8R9R10 (in which R8, R9 and R10, identical or different, are -C1-C6-alkyl or-phenyl); R4 is -H or -C1-C6-alkyI; R5 is -C1-C6-alkyl; and R6 and R7, identical or different, are -H or -C1-C6-alkyl; or their salts with organic or inorganic acids; is possible by a method comprising the step (a) manipulating the mixture ratio of the stereoisomers in the mixture so that at least one of the stereoisomers, preferably the stereoisomer to be isolated, is present in an enantiomeric excess. It has surprisingly been found that individual stereoisomers may be crystallised with high stereoselectivity from the mixture of stereoisomers when at least one of the stereoisomers is not present in racemic mixture, but instead in an enantiomeric excess. The compounds of the general formula (I) exhibit at least two chiral centres. The compounds can be synthesised in different ways. For example, it is possible firstly to prepare a Mannich base in a Mannich reaction by which means the first chiral centre is produced: If the Mannich reaction takes place without chiral induction, i.e. in the absence of chiral auxiliaries, chiral catalysts, chiral solvents, etc., the Mannich base is formed as a racemic mixture, since transition states leading to the two enantiomeric Mannich bases are enantiomorphic and thus energetically identical. The second chiral centre can be introduced, for example, by reaction of the Mannich base with a Grignard reagent at the carbonyl: In this way, the four stereoisomeric N,N-dialkylamino-2-alkyl-3-hydroxy-3-phenyl- alkanes of the general formulae (l-A), (l-A'), (l-B) and (l-B') are formed from the racemic Mannich base. Depending on the substitution pattern at the two chiral centres, the R- or S-configuration is in each case formed. In principal, it is also possible for further chiral centres also to be present in one of the side chains. In the case of three chiral centres, the number of stereoisomers increases to a total of eight, four enantiomeric pairs being present. The N,N-dialkyl- amino-2-alkyl-3-hydroxy-3-phenylalkanes preferably comprise only two chiral centres. Preferably, the stereoisomers (l-A) and (l-A') on the one hand and the stereoisomers (l-B) and (l-B') on the other are in each case enantiomeric to one another. In other respects the stereoisomers are diastereoisomeric among one another. Stereoisomer (l-A) is accordingly preferably enantiomeric to (l-A) and diastereoisomeric to (l-B) and (l-B'), stereoisomer (l-A') is enantiomeric to (l-A) and diastereoisomeric to (l-B) and (l-B'), stereoisomer (l-B) is diastereomeric to (l-A) and (l-A') and enantiomeric to (l-B'), and finally stereoisomer (l-B') is diastereoisomeric to (l-A) and (l-A') and enantiomeric to (l-B). If, for example, in step (a) of the method of the invention the mixture ratio of the stereoisomers in the mixture is manipulated in such a way that the stereoisomer of the general formula (l-A') is present in an enantiomeric excess, the excess relates to the relative amount of its enantiomer, i.e. preferably to the stereoisomer of the general formula (l-A). The mixture ratio of the optionally likewise present stereoisomers, for example of the general formulae (l-B) and (l-B') need not necessarily be manipulated, such that these may also (optionally still) be present, for example, in the racemic mixture. In a preferred embodiment of the method of the invention, this serves to isolate one stereoisomer from a mixture comprising the two stereoisomers of the general formulae (l-A) and (l-A'), but not, however, the two stereoisomers of the general formulae (l-B) and (l-B'). In another preferred embodiment of the method of the invention, this serves to isolate one stereoisomer, preferably of the general formula (l-A) or (l-A), from a mixture of all four stereoisomers, i.e. the stereoisomers of the general formulae (l-A), (l-A'), (l-B) and (l-B'). In a preferred embodiment of the method of the invention, the manipulation in step (a) is carried out by addition of the stereoisomer which is to be present in excess, or by enantioselective synthesis of the stereoisomers. The manipulation in step (a) has the consequence that at least one of the stereoisomers is present in an enantiomeric excess. This means preferably that it is relatively enriched in relation to its enantiomer. This enrichment can be achieved in different ways. On the one hand, it involves achieving an enantiomeric excess during the course of synthesis of the stereoisomers, on the other it also involves shifting the relative weight ratio of the two enantiomers of a mixture originally present as a racemate in respect of these two stereoisomers/enantiomers. The latter variant can be achieved, for example, by external addition or enantioselective derivatisation of one of the two enantiomers (e.g. kinetic racemate separation). If the manipulation in step (a) is carried out by addition of the stereoisomer which is to be present in enantiomeric excess, it can be isolated previously by separate isolation from a mixture of the stereoisomers. For example, it is possible to this end initially to separate the diastereoisomers by selective precipitation of the one enantiomeric pair as hydrochlorides. In this way, the two stereoisomers of the general formula (l-A) and (l-A') (enantiomeric pair 1) may be separated from the two stereoisomers of the general formula (l-B) and l-B') (enantiomeric pair 2). The separation of the two enantiomers, i.e. the separation of the racemic enantiomeric pairs 1 and 2, respectively, can then be carried out with the aid of chiral auxiliaries, for example, chiral acids. It has now surprisingly been found that the two enantiomers of the general formulae (l-A) and (l-A') may be selectively precipitated with the aid of (+)- and (-)-di-O,O'-p- toluyltartaric acid, the respective other enantiomer remaining in the mother liquor. One aspect of the invention thus concerns a method for racemate separation of the two enantiomers of the general formulae (l-A) and (l-A) comprising the addition of (+)- or (-)-di-O,O'-p-toluyltartaric acid. A suitable solvent is, for example, 2-butanone. The two enantiomers of the general formulae (l-A) and (l-A') are dissolved in the solvent. Depending upon the configuration of the tartaric acid derivative used, a stereoselective precipitation of the enantiomer of the general formula (l-A) or (l-A') as addition salt takes place after its addition Owing to the comparatively high cost of the enantiomerically pure tartaric acid derivative ((-)- or (+)-di-O,O'-p-toluyltartaric acid) as a chiral auxiliary, this method is only of limited use for enantiomeric separation on a preparative scale. This method is preferably merely used initially to obtain the respective enantiomerically pure stereoisomers of the general formula (l-A) and (l-A') and, through their addition to the reaction mixture, to manipulate the relative weight ratio in favour of one or the other stereoisomer for the purposes of step (a) of the method of the invention, i.e. to produce an enantiomeric excess. Alternatively, a small but sufficient amount of the enantiomerically pure compounds can be obtained by HPLC on a chiral stationary phase. In principle, it is also conceivable for the manipulation in step (a) of the method of the invention not to take place by the addition of one enantiomer, but instead by selective removal of the other enantiomer. Thus, for example, alternatively to enrichment of one of the two enantiomers, one of the two enantiomers may be selectively degraded. In this connection, it is for example conceivable to carry out selective enzymatic derivatisation of one stereoisomer, as a result of which its enantiomer is present in excess. The manipulation in step (a) of the method of the invention can also be carried out by enantioselective synthesis of the stereoisomers. In this case, enantioselectivity can be induced at different steps of the synthesis. Thus it is, for example, possible to induce an excess of one of the two resulting enantiomers by suitable measures even at the stage of the aforementioned Mannich reaction. Suitable measures are known to a person skilled in the art. Alternatively, it is also possible, for example, to induce an enantiomeric excess by enantioselective reaction control in the also previously described Grignard reaction (or an equivalent reaction with another organometallic reagent) subsequent to the Mannich reaction. Suitable methods are known to a person skilled in the art here too. Ojima, Catalytic Asymmetric Synthesis, 2nd ed., Wiley VCH; R.A. Aitken et al., Asymmetric Synthesis, 2nd ed., CRC Press; L.A. Paquette, Handbook of Reagents for Organic Synthesis: Chiral Reagents for Asymmetric Synthesis, John Wiley & Sons; H.B. Kagan, Asymmetric Synthesis, Thieme Medical Pub.; W. Carruthers, Modern Methods of Organic Synthesis, 4th ed., Cambridge University Press; and R.S. Atkinson, Stereoselective Synthesis, John Wiley & Sons. In a preferred embodiment, the enantiomeric excess after carrying out step (a) of the method of the invention is at least 1.0% ee, more preferably at least 2.5% ee, still more preferably at least 5.0% ee, most preferably at least 7.5% ee and in particular at least 10% ee. However, the enantiomeric excess is preferably at most 25% ee, more preferably at most 20% ee and in particular at most 15% ee. [(-)] denoting the concentration of the dextrorotatory and levorotatory enantiomer and a positive number always being obtained. Suitable methods for the determination of the enantiomeric excess are familiar to a person skilled in the art. HPLC on chiral stationary bases and NMR investigations with chiral shift reagents may be mentioned by way of example. The method of the invention is successful with N,N-dialkylamino-2-alkyl-3-hydroxy-3- phenylalkanes of different structure. In a preferred embodiment R1 and R3 are -H. Preferred substitution patterns of the phenyl ring (R1, R2 and R3) are summarised in the following table: R1 and R3 are particularly preferably in each case -H and R2 is -O-C1-C6-alkyl, preferably -OCH3, or -OH. R4 is preferably -C1-C6-alkyl, preferentially -CH3 or -CH2CH3. R5 is preferably -C1-C6-alkyl, preferentially -CH3. R6 and R7 are preferably in each case -C1-C6- alkyl, preferentially -CH3. R4 is particularly preferably -CH2CH3 and R5, R6 and R7 are in each case -CH3. "C1-C6-alkyl" for the purpose of the description means a linear or branched, cyclic or open-chain saturated hydrocarbon residue with 1 to 6 carbon atoms, optionally substituted with 1 to 6 halogen atoms (identical or different, selected from F, CI and Br). Examples are -CH3, -CF3, -CH2F, -CHF2, -CH2CH3, -CH(CH3)2, -CH2CH2CH3, -CH(CH3)CH2CH3, -CH2CH(CH3)CH3, -C(CH3)3, -CH2CH2CH2CH3, etc. "C1-C6-alkylene" for the purposes of the description means a linear or branched, cyclic or open-chain saturated hydrocarbon residue with 1 to 6 carbon atoms, optionally substituted with 1 to 6 halogen atoms (identical or different, selected from F, CI and Br). Examples are -CH2, -CH2CH2-, -CH(CH3)CH2-, -CH2CH2CH2-, -CH(CH3)CH2CH2-, - CH2CH(CH3)CH2-, -C(CH3)2CH2-, -CH(CH3)CH(CH3)-, - CH2CH2CH2CH2- etc. In one particularly preferred embodiment of the method of the invention R1 is -H, R2 - OCH3, R3-H, R4-CH2CH3, R5-CH3, R6-CH3 and R7-CH3, such that the stereoisomers of the general formula (I-A), (I-AO, (I-B) and (I-B7) are l-dimethyl-amino-3-(3-methoxyphenyl)- 2-methylpentan-3-ol. In this instance, the stereoisomer of the general formula (I-A) is (2S,3S)-l-dimethyl- amino-3-(3-methoxyphenyl)-2-methylpentan-3-ol, the stereoisomer of the general formula (I-A') is (2R, 3R)-l-dimethylamino-3-(3-methoxyphenyl)-2-methylpentan-3-ol, the stereoisomer of the general formula (I-B) is (2S, 3R)-l-dimethylamino-3-(3- methoxyphenyl)-2-methylpentan-3-ol, and the stereoisomer of the general formula (I-B') is (2R,3S)-1-dimethylamino-3-(3-methoxyphenyl)-2-methylpentan-3-ol, or their salts with organic or inorganic acids. In a preferred embodiment, the method of the invention comprises the step (bi) addition of a chiral compound of the general formula (II) or (IT) The chiral compound of the general formula (II) or (IT) is preferably added in optically pure form. Its enantiomeric excess is preferably at least 90% ee, more preferably at least 95%ee, most preferably 98% ee and in particular at least 99% ee. The chiral compounds of the general formula (II) or (II') are tartaric acid or its derivatives. The configuration of the two chiral centres is either R,R or S,S. Tartaric acid and many of its derivatives are available commercially in enantiomerically pure form. R11 is preferably -H or -CO-p-tolyl. In another preferred embodiment, the method of the invention comprises the step (b2) addition of phosphoric acid. The addition of phosphoric acid preferably serves to convert at least one of the stereoisomers into the phosphate, hydrogenphosphate or dihydrogenphosphate and consequently to induce selective crystallisation. By means of the stoichiometric ratio between the amount of phosphoric acid added and the stereoisomers of the general formulae (l-A), (l-A'), (l-B) and (l-B') it is possible to exert an influence upon whether salt formation takes place as phosphate (PO43-), hydrogenphosphate (HPO42) or dihydrogenphosphate (H2PO4"). Besides the addition of a suitable amount of phosphoric acid, the stereoisomers can be converted into the phosphate, hydrogenphosphate or dihydrogenphosphate in other ways. Such variants are known to a person skilled in the art, for example the addition of phosphate salts and subsequent acidification with mineral acids. Step (b1) or (b2) is preferably carried out under conditions that bring about the precipitation from a solution of the stereoisomer present in enantiomeric excess as salt of the chiral compound of the general formula (II) or (IT), or as phosphate, hydrogenphosphate or dihydrogenphosphate. If R11 is -H, the chiral compound of the general formula (II) or (IT) is tartaric acid. It has surprisingly been found that the stereoisomers of the general formulae (l-A) and (l-A') can in each case be precipitated selectively in step (b1) with one of the two tartaric acid enantiomers if care is first taken to ensure that the two enantiomers of the general formulae (l-A) and (l-A') are not present as a racemate, but instead one of the two enantiomers is present in excess. It has surprisingly been found that the enantiomeric purity of the precipitate is sometimes significantly greater than the enantiomeric excess before precipitation. The difference between the possibly somewhat low enantiomeric excess before precipitation and the enantiomeric purity of the precipitate can in some cases be quite considerable. Such crystallisation behaviour is unusual and represents a significant advantage of the method of the invention relative to conventional methods for racemate separation. By using the correct tartaric acid enantiomer it is possible to ensure that practically only the stereoisomer of the general formula (l-A) or (l-A') present in excess is precipitated, while the other enantiomer remains in the stock solution. The suitable enantiomer for the particular situation can be determined by simple preliminary investigations. Owing to the comparatively low costs of the two enantiomers of tartaric acid, this preferred embodiment of the method of the invention is also suitable for use on a preparative scale. Unlike with tartaric acid or its derivatives of the general formula (II) or (IT), in the case of addition of phosphoric acid in step (b2) no further chiral reagent is added. Instead, the separation of the stereoisomers is based preferentially on the different crystallisation behaviour of the phosphates, hydrogenphosphates or dihydrogenphosphates of the stereoisomers as such. It has surprisingly been found that one enantiomer can be selectively precipitated as phosphate, hydrogenphosphate or dihydrogenphosphate from a mixture of the two enantiomers of the general formulae (l-A) and (l-A') if care has been previously taken to ensure that it is present in a specific, but not necessarily particularly large, enantiomeric excess. This embodiment of the method of the invention is even suitable for the selective crystallization of one of the stereoisomers from the mixture of all four stereoisomers of the general formulae (l-A), (l-A'), (l-B) and (l-B'). It is accordingly not even necessary initially to carry out a diastereomeric separation, for example by precipitation of one enantiomeric pair as hydrochloride. Instead, selective precipitation is even successful from the immediate reaction product from the Grignard reaction. Ethanol, for example, is a suitable solvent for this purpose. The method of the invention has the advantage that in step (a) only a comparatively small enantiomeric excess of the stereoisomer need be brought about in order to achieve a high enantiomeric excess of the precipitate during the precipitation with a compound of the general formula (II) or (IT) or as phosphate, hydrogenphosphate or dihydrogenphosphate. If, for example, step (a) of the method of the invention is carried out with enantioselective reaction control, the enantioselectivity of the reaction accordingly need not lie in the region of 95% ee and above as is normally required. Instead, even significantly less pronounced enantioselectivities suffice in the synthesis in order ultimately to obtain a product with very high enantiomeric purity. The method of the invention preferably comprises the step (c) separation of the precipitated salt obtained in step (b1) or (b2) from the supernatant solution. This can be achieved, for example, by decantation, filtration, centrifugation, etc. In a preferred embodiment, the method of the invention comprises the step (d) conversion of the salt separated in step (c) into the hydrochloride. Conversion of the separated salt into the hydrochloride can be achieved in different ways. In a preferred embodiment, the separated salt is first converted into the free base of the stereoisomer. This can be carried out by the addition of strong bases, for example NaOH or KOH. The free base of the stereoisomer released in this way may then either be initially isolated or converted directly into the hydrochloride in situ. It has surprisingly been found that improved yields are obtained during hydrochloride precipitation if hydrogen chloride is used in gaseous form in place of trimethylchlorosilane/water (cf. EP-A 693 475). Suitable solvents are, for example, acetone or 2-butanone. A further aspect of the invention concerns an addition salt of a stereoisomer of the general formula (l-A), (l-A'), (l-B) or (l-B') as defined above and - a compound of the general formula (II) or (II') as defined above, or - phosphoric acid. The addition salt is preferably selected from the group consisting of (2R,3R)-1 -dimethylamino-3-(3-methoxyphenyl)-2-methylpentan-3-ol (+)-tartrate, (2R,3R)-1 -dimethylamino-3-(3-methoxyphenyl)-2-methylpentan-3-ol (-)-tartrate, (2R,3R)-1 -dimethylamino-3-(3-methoxyphenyl)-2-methylpentan-3-ol (+)-di-O,O'-p- toluyltartrate, (2R,3R)-1 -dimethylamino-3-(3-methoxyphenyl)-2-methylpentan-3-ol (-)-di-O,O'-p- toluyltartrate, - (2R,3R)-1 -dimethylamino-3-(3-methoxyphenyl)-2-methylpentan-3-ol phosphate, - (2R,3R)-1-dimethylamino-3-(3-methoxyphenyl)-2-methylpentan-3-ol hydrogenphosphate, (2R,3R)-1-dimethylamino-3-(3-methoxyphenyl)-2-methylpentan-3-ol dihydrogenphosphate, - (2S,3S)-1 -dimethylamino-3-(3-methoxyphenyl)-2-methylpentan-3-ol (+)-tartrate, - (2S,3S)-1 -dimethylamino-3-(3-methoxyphenyl)-2-methylpentan-3-ol (-)-tartrate, (2S,3S)-1-dimethylamino-3-(3-methoxyphenyl)-2-methylpentan-3-ol (+)-di-O,O'-p- toluyltartrate, (2S,3S)-1 -dimethylamino-3-(3-methoxyphenyl)-2-methylpentan-3-ol (-)-di-O,O'-p- toluyltartrate, (2S,3S)-1 -dimethylamino-3-(3-methoxyphenyl)-2-methylpentan-3-ol phosphate, (2S,3S)-1-dimethylamino-3-(3-methoxyphenyl)-2-methylpentan-3-ol hydrogenphosphate, (2S,3S)-1-dimethylamino-3-(3-methoxyphenyl)-2-methylpentan-3-ol dihydrogenphosphate, - (2R,3S)-1 -dimethylamino-3-(3-methoxyphenyl)-2-methylpentan-3-ol (+)-tartrate, - (2R,3S)-1 -dimethylamino-3-(3-methoxyphenyl)-2-methylpentan-3-ol (-)-tartrate, - (2R,3S)-1 -dimethylamino-3-(3-methoxyphenyl)-2-methylpentan-3-ol (+)-di-O,O'-p- toluyltartrate, - (2R,3S)-1 -dimethylamino-3-(3-methoxyphenyl)-2-methylpentan-3-ol (-)-di-O,O'-p- toluyltartrate, (2R,3S)-1 -dimethylamino-3-(3-methoxyphenyl)-2-methylpentan-3-ol phosphate, - (2R,3S)-1-dimethylamino-3-(3-methoxyphenyl)-2-methylpentan-3-ol hydrogenphosphate, (2R,3S)-1-dimethylamino-3-(3-methoxyphenyl)-2-methylpentan-3-ol dihydrogenphosphate, (2S,3R)-1-dimethylamino-3-(3-methoxyphenyl)-2-methylpentan-3-ol (+)-tartrate, (2S,3R)-1 -dimethylamino-3-(3-methoxyphenyl)-2-methylpentan-3-ol (-)-tartrate, (2S,3R)-1-dimethylamino-3-(3-methoxyphenyl)-2-methylpentan-3-ol (+)-di-O,O'-p- toluyltartrate, (2S,3R)-1-dimethylamino-3-(3-methoxyphenyl)-2-methylpentan-3-ol (-)-di-O,O'-p- toluyltartrate, - (2S,3R)-1 -dimethylamino-3-(3-methoxyphenyl)-2-methylpentan-3-ol phosphate, (2S,3R)-1 -dimethylamino-3-(3-methoxyphenyl)-2-methylpentan-3-ol hydrogenphosphate and (2S,3R)-1-dimethylamino-3-(3-methoxyphenyl)-2-methylpentan-3-ol dihydrogenphosphate. In a preferred embodiment, the addition salt is selected from the above list, "(3- methoxyphenyl)" in each case being replaced by "(3-hydroxyphenyl)". A further aspect of the invention concerns a method for the preparation of a stereoisomer of the general formulae (l-A), (l-A'), (l-B) and (l-B') as defined above (preparation method) comprising the method for the isolation of the stereoisomer described above (separation method). The production method preferably comprises a method for the preparation of a stereoisomer of the general formula (l-A), (l-A'), (l-B) or (l-B') in which R1, R2 and R3, identical or different, are selected from the group consisting of -H, -F, -CI, -C1-C6-alkyl, -S-C1-C6-alkyl and -OH, providing that at least one of the residues R1, R2 and R3 is -OH; R4 is -H or -C1-C6-alkyI; R5 is -C1-C6-alkyl; and R6 and R7, identical or different, are -H or -C1-C6-alkyl; or their salts with organic or inorganic acids; comprising the separation method described above for the isolation of a stereoisomer, wherein during the implementation of the separation method at least one of the residues R1, R2 and R3 is -O-C1-C6-alkyl, -O-C1-C6-alkylenephenyl, -OCO-C1-C6-alkyl, -OCO2-C1-C6-alkyl, -OCON(C1-C6-alkyl)2 or -O-SiR8R9R10. In a preferred embodiment, after isolation of the stereoisomers, i.e. after the implementation of the separation method of the invention, the preparation method of the invention comprises the step (e) conversion of at least one of the residues R1, R2 and R3 which is -O-C1-C6-alkyl, -O-C1-C6-alkylenephenyl, -OCO-C1-C6-alkyl, -OCO2-C1-C6-alkyl, -OCON(C1-C6- alkyl)2 or -O-SiR8R9R10 into an -OH group. Conversion into an -OH group can be carried out in a manner known to a person skilled in the art, for example with acid, base, fluoride, complex metal hydrides, etc., depending upon the nature of the substitution. The following examples serve to illustrate the invention but should not to be construed to limit the scope thereof. Example 1 Preparation of a mixture of the four stereoisomers of 1-dimethylamino-3-(3- methoxyphenyl)-2-methylpentan-3-ol: A mixture of the four stereoisomers of 1-dimethylamino-3-(3-methoxyphenyl)-2- methylpentan-3-ol was prepared by a Grignard reaction of rac.-1-dimethylamino-2- methylpentan-3-one with 3-methoxyphenylmagnesium bromide in THF in accordance with example 1 of EP 0 693 475 A1. The two enantiomers (2R,3R)- and (2S,3S)-1-dimethylamino-3-(3-methoxyphenyl)-2- methylpentan-3-ol and the two enantiomers (2R,3S)- and (2S,3R)-1-dimethylamino- 3-(3-methoxyphenyl)-2-methylpentan-3-ol were in each case present in equal amounts, i.e. as a racemate. The ratio of the diastereoisomers (2R,3R)/(2S,RS) to (2R,3S)/(2S,3R) was 70 wt.% to 30 wt.%. Example 2 Diastereoisomer separation [separation of the enantiomeric pair of (2R,3R)/(2S,3S) configuration from the enantiomeric pair of (2R,3S)/(2S,3R) configuration] a) HCI precipitation A 100 I double wall jacketed reaction vessel with electric impeller stirrer, gas transfer line, Pt100 temperature sensor and oil-based cooling and heating system was charged with 15 kg (59.7 mol) of a mixture of the enantiomeric pair (2R,3R)/(2S,3S)- 1-dimethylamino-3-(3-methoxyphenyl)-2-methylpentan-3-ol (70%) and the enantiomeric pair (2R,3S)/(2S,3R)-1 -dimethylamino-3-(3-methoxyphenyl)-2- methylpentan-3-ol (30%) in 70 I of acetone at 20°C and a stirrer speed of 100 rpm The solution was cooled to 5°C. Within 20 min, approx. 2.0 kg of gaseous hydrogen chloride were passed over the solution, the temperature in the vessel rising continuously to 28oC despite cooling. The hydrogen chloride was taken from a hydrogen chloride cylinder which was connected to the gas transfer line of the vessel through a pressure reduction valve and hose and was placed on a balance for weight measurement. Further gaseous hydrogen chloride was then passed over until a 5 ml sample of the solution diluted with 10 ml of water had a pH value of 1-3. The solution was stirred at 5°C for 2 h. The suspension was then centrifuged off in a centrifuge and washed once with 10 I of acetone. The product was dried in a drying cabinet at 40°C for 24 h under reduced pressure to a final pressure of 20 mbar. 11.16 kg (65% of theoretical) of the enantiomeric pair (2R,3R)/(2S,3S)-1-dimethylamino-3-(3- methoxyphenyl)-2-methylpentan-3-ol hydrochloride were obtained as a colourless product. The residual content of the undesired enantiomeric pair (2S,3R)/(2R,3S)-1- dimethylamino-3-(3-methoxyphenyl)-2-methylpentan-3-ol hydrochloride was 3%. b) Conversion of the hydrochloride into the free base A 100 I double wall jacketed reaction vessel with electric impeller stirrer, Pt100 temperature sensor and oil-based cooling and heating system was charged with 11.16 kg (38,78 mol) of the enantiomeric pair(2R,3R)/(2S,3S)-1-dimethylamino-3-(3- methoxyphenyl)-2-methylpentan-3-ol hydrochloride from step a), contaminated with 3% of the enantiomeric pair (2R,3S)/(2S,3R)-1-dimethylamino-3-(3-methoxyphenyl)- 2-methylpentan-3-ol hydrochloride in 21 I of water at 20°C. The solution was treated with 32 wt.% aqueous sodium hydroxide solution up to a pH value of 13 and then extracted with 21 I of ethyl acetate. After evaporation of the ethyl acetate at 60-65°C to a final vacuum of 20 mbar, the base remained as a colourless oil with a yield of 8.77 kg (90% of theoretical), contaminated with 3% of the enantiomeric pair (2S,3R)/(2R,3S)-1-dimethylamino-3-(3-methoxyphenyl)-2-methylpentan-3-ol. c) Recrystallisation as hydrochloride A 100 I double wall jacketed reaction vessel with electric impeller stirrer, gas transfer line, Pt100 temperature sensor and oil-based cooling and heating system was charged with 15 kg (59.7 mol) of a mixture of the enantiomeric pair (2R,3R)/(2S,3S)- 1-dimethylamino-3-(3-methoxyphenyl)-2-methylpentan-3-ol (97%) and the enantiomeric pair (2R,3S)/(2S,3R)-1 -dimethylamino-3-(3-methoxyphenyl)-2- methylpentan-3-ol (3%) in 70 I of acetone at 20°C at a stirrer speed of 100 rpm. The solution was cooled to 5°C. Within 20 min, approx. 2.0 kg of gaseous hydrogen chloride were passed over the solution, the temperature in the vessel rising continuously to 28°C despite cooling. The hydrogen chloride was taken from a hydrogen chloride cylinder which was connected to the gas transfer line of the vessel through a pressure reduction valve and hose and was placed on a balance for weight measurement. Further gaseous hydrogen chloride was then passed over until a 5 ml sample of the solution diluted with 10 ml of water had a pH value of 1-3. The solution was stirred at 5°C for 2 h. The suspension was then centrifuged off in a centrifuge and washed once with 10 I of acetone. The product was dried in a drying cabinet at 40°C for 24 h under reduced pressure to a final pressure of 20 mbar. 13.74 kg (80% of theoretical) of the colourless enantiomeric pair (2R,3R)/(2S,3S)-1-dimethylamino- 3-(3-methoxyphenyl)-2-methylpentan-3-ol hydrochloride with a diastereomeric purity of 100% were obtained. d) Conversion of the hydrochloride into the free base A 100 I double wall jacketed reaction vessel with electric impeller stirrer, Pt100 temperature sensor and oil-based cooling and heating system was charged with 13.74 kg (47.7 mol) of the enantiomeric pair (2R,3R)/(2S,3S)-1-dimethylamino-3-(3- methoxyphenyl)-2-methylpentan-3-ol hydrochloride in 26 I of water at 20°C. The solution was treated with 32 wt.% aqueous sodium hydroxide solution up to a pH value of 13 and then extracted with 26 I of ethyl acetate. After evaporation of the ethyl acetate at 60-65°C to a final vacuum of 20 mbar, the enantiomeric pair (2R,3R)/(2S,3S)-1-dimethylamino-3-(3-methoxyphenyl)-2-methylpentan-3-ol remained as colourless oil with a yield of 10.80 kg (90% of theoretical) and a diastereomeric purity of 100%. Example 3 Separation of the two enantiomers of (2R,3R) and (2S,3S) configuration with the aid of (+)-di-O,O'-p-toluyltartaric acid a) Precipitation of (2S,3S)-1-dimethylamino-3-(3-methoxyphenyl)-2-methylpentan-3- ol; (+)-di-O,O'-p-toluyltartrate A 2 I three-necked flask with thermometer, mechanical pneumatic stirrer, reflux condenser and oil bath heating was charged with 121 g (0.48 mol) of the enantiomeric pair (2R,3R)/(2S,3S)-1 -dimethylamino-3-(3-methoxyphenyl)-2- methylpentan-3-ol (with a diastereomeric purity of 100%) in 100 ml of 2-butanone and a solution of 185.6 g (0.48 mol) of (+)-di-O,O'-p-toluyltartaric acid dissolved in 1700 ml of 2-butanone was added with stirring. After 48 h at room temperature, the resulting crystal mass was filtered off through a vacuum filter under reduced pressure and washed twice with 150 ml of cooled (3-8°C) 2-butanone each time. The product was dried in a drying cabinet at 40°C for 24 h to a final vacuum of 20 mbar. 125 g (40% of theoretical) of (2S,3S)-1-dimethylamino-3-(3-methoxyphenyl)-2- methylpentan-3-ol (+)-di-O,O'-p-toluyltartrate were obtained which were used without further purification for release of the base. b) Conversion of the (+)-di-O,O'-p-toluyltartrate into the free base 125 g (0.2 mol) of (2S,3S)-1-dimethylamino-3-(3-methoxyphenyl)-2-methylpentan-3- ol (+)-di-O,O'-p-toluyltartrate were dissolved in 500 ml of water, treated with stirring with 18 ml of 37 wt.% hydrochloric acid and extracted twice with 150 ml of diethyl ether each time. The aqueous phase was then treated with 35 ml of 32 wt.% aqueous sodium hydroxide solution and then extracted with 2 x 250 ml of dichloromethane. After distilling off the solvent at 40°C to a final pressure of 20 mbar, 47 g (95% of theoretical) of a colourless oil were obtained which consisted of 83% (2S,3S)-1 -dimethylamino-3-(3-methoxyphenyl)-2-methylpentan-3-ol and 17% (2R,3R)-1-dimethylamino-3-(3-methoxyphenyl)-2-methylpentan-3-ol. c) Isolation of the other enantiomer from the mother liquor as hydrochloride and conversion into the free base The mother liquor from the precipitation in step a) was combined with both washings, treated with 820 ml of water and 30 ml of 37 wt.% hydrochloric acid were added with stirring. The aqueous phase was extracted twice with 250 ml of diethyl ether each time. To release the base, the aqueous phase was treated with 57 ml of 32 wt.% aqueous sodium hydroxide solution and then extracted with 2 x 250 ml of dichloromethane. After distilling off the solvent at 40°C to a final pressure of 20 mbar, 70 g (58% of theoretical) of a colourless oil were obtained which consisted of 70% (2R,3R)-1 -dimethylamino-3-(3-methoxyphenyl)-2-methylpentan-3-ol and 30% (2S,3S)-1-dimethylamino-3-(3-methoxyphenyl)-2-methylpentan-3-ol. Example 4 Separation of the two enantiomers of (2R,3R) and (2S,3S) configuration with the aid of (-)-di-O,O'-p-toluyltartaric acid a) Precipitation of (2R,3R)-1-dimethylamino-3-(3-methoxyphenyl)-2-methylpentan-3- ol (-)-di-O,O'-p-toluyltartrate 13.7 g (54.5 mmol) of the enantiomeric pair (2R,3R)/(2S,3S)-1-dimethylamino-3-(3- methoxyphenyl)-2-methylpentan-3-ol (with a diastereomeric purity of 100%) and 10 ml of 2-butanone were treated with stirring with a solution of 22 g (56.9 mmol) of (-)- di-O,O'-p-toluyltartaric acid in 220 ml of 2-butanone. After 24 h at room temperature, the resulting crystal mass was filtered through a vacuum filter under reduced pressure and washed twice with 15 ml of cooled (3-8°C) 2-butanone each time. The product was dried for 24 h in a drying cabinet at a temperature of 40°C and a final vacuum of 20 mbar. 8.7 g (25% of theoretical) of (2R,3R)-1-dimethylamino-3-(3- methoxyphenyl)-2-methylpentan-3-ol (-)-di-O,O'-p-toluyltartrate were obtained which were used without further purification for release of the base. b) Conversion of the (-)-di-O,O'-p-toluyltartrate into the free base 8.7 g (13.6 mmol) of (2R,3R)-1-dimethylamino-3-(3-methoxyphenyl)-2-methylpentan- 3-ol (-)-di-O,O'-p-toluyltartrate were dissolved in 30 ml of water in a 100 ml three- necked flask with thermometer, magnetic stirrer and reflux condenser, treated with stirring with 1.1 ml of 37 wt.% hydrochloric acid and extracted twice with 15 ml of diethyl ether each time. 2.2 ml of 32 wt.% aqueous sodium hydroxide solution were then added to the aqueous phase which was then extracted with 2 x 20 ml of dichloromethane. After distilling off the solvent at 40°C to a final pressure of 20 mbar, 3.36 g (98% of theoretical) of a colourless oil were obtained which consisted of 65% (2R,3R)-1 -dimethylamino-3-(3-methoxyphenyl)-2-methylpentan-3-ol and 35% (2S,3S)-1-dimethylamino-3-(3-methoxyphenyl)-2-methylpentan-3-ol. Example 5 Separation of the two enantiomers of (2R,3R) and (2S,3S) configuration with the aid of D-(-)-tartaric acid after enrichment of the enantiomer of (2R,3R) configuration a) Precipitation of (2R,3R)-1-dimethylamino-3-(3-methoxyphenyl)-2-methylpentan-3- ol (-)-tartrate A 2 I three-necked flask with thermometer, mechanical pneumatic stirrer, reflux condenser and oil bath heating was charged with 30 g (0.12 mol) of the mixture of the two enantiomers obtained in Example 4b) with an enantiomeric excess of 30% ee (65 wt.% (2R,3R)-1-dimethylamino-3-(3-methoxyphenyl)-2-methylpentan-3-ol and 35 wt.% (2S,3S)-1-dimethylamino-3-(3-methoxyphenyl)-2-methylpentan-3-ol) in 50 ml of ethanol and a solution of 18.0 g (0.12 mol) of (-)-(2S,3S)-tartaric acid in 200 ml of ethanol was added with stirring. After 1 h at room temperature, 200 ml of diethyl ether were added and stirring was continued for 24 h. The resulting crystal mass was filtered through a vacuum filter under reduced pressure and washed twice with 200 ml of cooled (3-8°C) diethyl ether each time. The product was dried for 24 h in a drying cabinet at a temperature of 40°C and a final vacuum of 20 mbar. 26.4 g (55% of theoretical) of (2R,3R)-1-dimethylamino-3-(3-methoxyphenyl)-2-methylpentan-3-ol (-)-tartrate were obtained which were used without further purification for release of the base. b) Conversion of the (-)-tartrate into the free base 26.4 g (65.8 mmol) of (2R,3R)-1-dimethylamino-3-(3-methoxyphenyl)-2- methylpentan-3-ol (-)-tartrate were dissolved in 100 ml of water, treated with stirring with 7.4 ml of 32 wt.% aqueous sodium hydroxide solution and then extracted with 2 x 50 ml of dichloromethane. After distilling off the solvent at 40°C to a final pressure of 20 mbar, 16.2 g (98% of theoretical) of a colourless oil were obtained which consisted of 98% (2R,3R)-1-dimethylamino-3-(3-methoxyphenyl)-2-methylpentan-3- ol and 2% (2S,3S)-1-dimethylamino-3-(3-methoxyphenyl)-2-methylpentan-3-ol. Example 6 Separation of the two enantiomers of (2R,3R) and (2S,3S) configuration with the aid of L-(+)-tartaric acid after enrichment of the enantiomer of (2S,3S) configuration a) Precipitation of (2S,3S)-1-dimethylamino-3-(3-methoxyphenyl)-2-methylpentan-3- ol (+)-tartrate A 100 I double wall jacketed reaction vessel with electric impeller stirrer, Pt100 temperature sensor and oil-based cooling and heating system was charged with 6.93 kg (46.17 mol) of (+)-(2R,3R)-tartaric acid in 75 I of ethanol. Then, 10.55 kg (41.97 mol) of a racemic mixture of the enantiomeric pair (2R,3R)/(2S,3S)-1- dimethylamino-3-(3-methoxyphenyl)-2-methylpentan-3-ol in 3.5 I of ethanol were introduced. The racemic mixture was enriched in respect of the enantiomer with the (2S,3S) configuration by addition of 1.06 kg (4.21 mol) of the enantiomerically pure compound (2S,3S)-1 -dimethylamino-3-(3-methoxyphenyl)-2-methylpentan-3-ol. This mixture was added to the prepared tartaric acid at 10°C and stirred at a stirrer speed of 150 rpm for 20 hours. The crystals were centrifuged off and dried in a drying cabinet at 50°C under reduced pressure for 12 h. After 24 h drying in a drying cabinet at 40°C and a final pressure of 20 mbar, 8.34 kg (20.77 mol, 45% of theoretical) of (2S,3S)-1 -dimethylamino-3-(3-methoxyphenyl)-2-methylpentan-3-ol (+)-tartrate were isolated as colourless crystals which were used as dried or moist with ethanol for release of the base. The other enantiomer (2R,3R)-1-dimethylamino- 3-(3-methoxyphenyl)-2-methylpentan-3-ol could be isolated from the centrifugation mother liquor. b) Conversion of the (+)-tartrate into the free base 16.68 kg (41.55 mol) of ethanol-moist or dried (2S,3S)-1-dimethylamino-3-(3- methoxyphenyl)-2-methylpentan-3-ol (+)-tartrate from step a) were dissolved in 65 I of water in a 100 I double wall jacketed reaction vessel with electric impeller stirrer, Pt100 temperature sensor and oil-based cooling and heating system and treated with approx. 5.2 kg of 32 wt.% aqueous sodium hydroxide solution until a pH value of 12- 13 was reached. The temperature was kept below 35°C by cooling the reaction vessel. 30 I of ethyl acetate were added, and after 10 min stirring, the stirrer was switched off to allow phase separation. The lower aqueous phase was drained off and the upper organic phase was distilled at a maximum internal temperature of 50°C under reduced pressure to 10 mbar. The remaining pale yellow oily residue was(2S,3S)-1-dimethylamino-3-(3-methoxyphenyl)-2-methylpentan-3-ol hydrochloride. The yield was 9.92 kg (95% of theoretical) with an enantiomeric purity of 98.5%. c) Recrystallisation as hydrochloride A 100 I double wall jacketed reaction vessel with electric impeller stirrer, gas transfer line Pt 100 temperature sensor and oil-based cooling and heating system was charged with 15 kg (59.7 mol) of a mixture of (2S,3S)-1-dimethylamino-3-(3- methoxyphenyl)-2-methylpentan-3-ol (98%) and (2R,3R)-1-dimethylamino-3-(3- methoxyphenyl)-2-methylpentan-3-ol (2%) in 70 I of acetone at 20°C and a stirrer speed of 100 rpm. The solution was cooled to 5°C. Within 20 min, approx. 2.0 kg of gaseous hydrogen chloride were passed over the solution, the temperature in the vessel rising continuously to 28°C despite cooling. The hydrogen chloride was taken from a hydrogen chloride cylinder which was connected to the gas transfer line of the vessel through a pressure reduction valve and hose and was placed on a balance for weight measurement. Further gaseous hydrogen chloride was then passed over until a 5 ml sample of the solution diluted with 10 ml of water had a pH value of 1-3. The suspension was stirred 5°C for 2 h. The suspension was then centrifuged off in a centrifuge and washed once with 10 I of acetone. The product was dried in a drying cabinet at 40°C for 24 h under reduced pressure to a final pressure of 20 mbar. 13.74 kg (80% of theoretical) of colourless (2S,3S)-1-dimethylamino-3-(3- methoxyphenyl)-2-methylpentan-3-ol hydrochloride with an enantiomeric purity of 100% were obtained. d) Isolation of the other enantiomer from the mother liquor from step a) as free base. The ethanol of the mother liquor from the centrifugation of the precipitation of (2S,3S)-1 -dimethylamino-3-(3-methoxyphenyl)-2-methylpentan-3-ol (+)-tartrate was distilled off in a 100 I double wall jacketed reaction vessel with electric impeller stirrer, Pt100 temperature sensor and oil-based cooling and heating system at an internal temperature of 75°C and a final pressure of 22 I of water and treated with 32 wt.% aqueous sodium hydroxide solution until a pH value of 12-13 was reached. The internal temperature was kept below 25°C by cooling the reaction vessel. 22 I of ethyl acetate were added, stirred for 10 min and the stirrer was switched off to allow phase separation. The lower aqueous phase was drained off and extracted with a further 11 I of ethyl acetate. The two combined ethyl acetate phases were distilled off at a maximum internal temperature of 60°C under reduced pressure to a final pressure of 10 mbar. The yield of (2R,3R)-1- dimethylamino-3-(3-methoxyphenyl)-2-methylpentan-3-ol was 5.8 kg (50% of theoretical). Example 7 Isolation of the enriched enantiomer of (2S,3S) configuration from the mixture of all four diastereoisomers [product of the Grignard reaction in Example 1] with the aid of L-(+)-tartaric acid A 100 I double wall jacketed reaction vessel with electric impeller stirrer, Pt100 temperature sensor and oil-based cooling and heating system was charged with 6.93 kg (46.17 mol) of (+)-(2R,3R)-tartaric acid in 75 I of ethanol. Then a mixture of 10.55 kg (41.97 mol) of the enantiomeric pair (2R,3R)/(2S,3S)-1-dimethylamino-3-(3- methoxyphenyl)-2-methylpentan-3-ol (70%) and the enantiomeric pair (2R,3S)/(2S,3R)-1-dimethylamino-3-(3-methoxyphenyl)-2-methylpentan-3-ol (30%) in 3.5 I of ethanol was enriched in respect of the enantiomer with the (2S,3S) configuration by the addition of 1.06 kg (4.21 mol) of the enantiomerically pure (2S,3S)-1 -dimethylamino-3-(3-methoxyphenyl)-2-methylpentan-3-ol. This mixture was added to the prepared tartaric acid at 10°C and stirred at a stirrer speed of 150 rpm for 20 hours. The crystals were centrifuged off and dried in a drying cabinet at 50°C for 12 h under reduced pressure to a final pressure of 20 mbar. 5.93 kg (32% of theoretical) of colourless crystals of 1-dimethylamino-3-(3-methoxyphenyl)-2- methylpentan-3-ol (+)-tartrate with a composition of the stereoisomers of 98.2% (2S,3S)-1 -dimethylamino-3-(3-methoxyphenyl)-2-methylpentan-3-ol (+)-tartrate, 0.8% (2R,3R)-1 -dimethylamino-3-(3-methoxyphenyl)-2-methylpentan-3-ol (+)-tartrate and 1% of the enantiomeric pair (2R,3S)/(2S,3R)-1-dimethylamino-3-(3-methoxyphenyl)- 2-methylpentan-3-ol (+)-tartrate were obtained. Example 8 Separation of the two enantiomers of (2R,3R) and (2S,3S) configuration with the aid of phosphoric acid precipitation of the enantiomer of (2S,3S) configuration a) with seeding 10 g (0.04 mol) of the enantiomeric pair (2R,3R)/(2S,3S)-1-dimethylamino-3-(3- methoxyphenyl)-2-methylpentan-3-ol were dissolved in 40 ml of ethanol, treated with stirring with 3 g of 85 wt.% ortho-phosphoric acid and seeded with 1 g (2.86 mmol) of (2S,3S)-1 -dimethylamino-3-(3-methoxyphenyl)-2-methylpentan-3-ol phosphate. After 24 h, the crystals formed were filtered off under reduced pressure and dried for 24 h in a drying cabinet at 40°C to a final pressure of 10 mbar. 3.3 g (22% of theoretical) of (2S,3S)-1 -dimethylamino-3-(3-methoxyphenyl)-2-methylpentan-3-ol phosphate were obtained as colourless crystals with an enantiomeric purity of 99.1%. b) without seeding 10 g (0.04 mol) of the enantiomeric pair (2R,3R)/(2S,3S)-1-dimethylamino-3-(3- methoxyphenyl)-2-methylpentan-3-ol were dissolved in 40 ml of ethanol and treated with stirring with 3 g of 85 wt.% ortho-phosphoric acid. After 24 h, the crystals formed were filtered off under reduced pressure and dried for 24 h in a drying cabinet at 40°C to a final pressure of 10 mbar. 2.2 g (16% of theoretical) of (2S,3S)-1- dimethylamino-3-(3-methoxyphenyl)-2-methylpentan-3-ol phosphate were obtained as colourless crystals with an enantiomeric purity of 85%. Example 9 Separation of the two enantiomers of (2R,3R) and (2S,3S) configuration with the aid of phosphoric acid precipitation of the enantiomer of (2R,3R) configuration from the mother liquor of the (+)-tartaric acid precipitation of Example 6 a) 1st. phosphate precipitation and base release The 7 kg (27.84 mol) of (2R,3R)-1-dimethylamino-3-(3-methoxyphenyl)-2- methylpentan-3-ol from Example 6 d) were dissolved in 42 I of ethanol at a temperature of 25°C in a 100 I double wall jacketed reaction vessel with electric impeller stirrer, Pt100 temperature sensor and oil-based cooling and heating system. 2.16 kg of 85 wt.% ortho-phosphoric acid were added at a stirrer speed of 100 min-1 and the solution was cooled to 5°C. After 24 h, the crystals formed were centrifuged off and washed with 7 I of ethanol. The precipitate (phosphate salt) was dissolved in 42 I of water and treated with 32 wt.% aqueous sodium hydroxide solution until a pH of 12-13 was reached. The temperature was kept below 35°C by cooling the reaction vessel. 20 I of ethyl acetate were added and, after stirring for 10 min, the stirrer was switched off to allow phase separation. The lower aqueous phase was extracted again with 12 I of ethyl acetate, the organic phases were combined and distilled off at a maximum internal temperature of 50°C under reduced pressure to 10 mbar. 4.9 kg (70% of theoretical) of a colourless oil were obtained which was used as such in the second phosphate precipitation. b) 2nd phosphate precipitation and base release 4.9 kg (19.5 mol) of the (2R,3R)-1-dimethylamino-3-(3-methoxyphenyl)-2- methylpentan-3-ol from step a) were dissolved in 30 I of ethanol at a temperature of 25°C in a 100 I double wall jacketed reaction vessel with electric impeller stirrer, Pt100 temperature sensor and oil-based cooling and heating system. 1.51 kg of 85 wt.% ortho-phosphoric acid were added at a stirrer speed of 100 min-1 and the solution was cooled to 5°C. After 24 h, the crystals formed were centrifuged off and washed with 5 I of ethanol. The precipitate was dissolved in 30 I of water and treated with 32 wt.% aqueous sodium hydroxide solution until a pH value of 12-13 was reached. The temperature was kept below 35°C by cooling the reaction vessel. 14 I of ethyl acetate were added and, after stirring for 10 min, the stirrer was switched off to allow phase separation. The lower aqueous phase was extracted again with 9 I of ethyl acetate, the organic phases were combined and distilled off at a maximum internal temperature of 50°C under reduced pressure to 10 mbar. 2.5 kg (51% of theoretical) of a colourless oil with an enantiomeric purity of 97% were obtained. c) Recrystallisation as hydrochloride A 100 I double wall jacketed reaction vessel with electric impeller stirrer, gas transfer line, Pt100 temperature sensor and oil-based cooling and heating system was charged with the 10 kg (39.8 mol) of the mixture of (2R,3R)-1-dimethylamino-3-(3- methoxyphenyl)-2-methylpentan-3-ol (97%) and (2S,3S)-1-dimethylamino-3-(3- methoxyphenyl)-2-methylpentan-3-ol (3%) from step b) in 45 I of acetone at 20°C and a stirrer speed of 100 rpm. The solution was cooled to 5°C. Within 20 min, approx. 1.3 kg of gaseous hydrogen chloride were passed over the solution, the temperature in the vessel rising continuously to 28°C despite cooling. The hydrogen chloride was taken from a hydrogen chloride cylinder which was connected to the gas transfer line of the vessel through a pressure reduction valve and hose and was placed on a balance for weight measurement. Further gaseous hydrogen chloride was then passed over until a 5 ml sample of the solution diluted with 10 ml of water had a pH value of 1-3. The solution was stirred at 5°C for 2 h. The suspension was centrifuged off in a centrifuge and washed once with 7 I of acetone. The product was dried in a drying cabinet at 40°C for 24 h under reduced pressure to a final pressure of 20 mbar. 9.73 kg (85% of theoretical) of colourless (2R,3R)-1-dimethylamino-3-(3- methoxyphenyl)-2-methylpentan-3-ol hydrochloride with an enantiomeric purity of 100% were obtained. WE CLAIM 1. Method for the isolation of a stereoisomer from a mixture comprising the two stereoisomers of the general formulae (I-A) and (I-A') and/or the two stereoisomers of the general formulae (I-B) and (I-B') in which R1, R2 and R3, identical or different, are selected from the group consisting of -H, - F, -CI, -C1-C6-alkyl, -S-C1-C6-alkyl, -OH, -O-C1-C6-alkyl, -O-C1-C6-alkylenephenyl, - OCO-C1-C6-alkyl, -OCO2-C1-C6-alkyl, -OCON(C1-C6-alkyl)2 and -O-SiR8R9R10 (in which R8, R9 and R10, identical or different, are -C1-C6-alkyl or -phenyl); R4 is -H or -C1-C6-alkyl; R5 is -C1-C6-alkyl; and R6 and R7, identical or different, are -H or -C1-C6-alkyl; wherein "C1-C6-alkyl" means a linear or branched, cyclic or open-chain saturated hydrocarbon residue with 1 to 6 carbon atoms, optionally substituted with 1 to 6 halogen atoms, identical or different, selected from F, CI and Br; and "C1-C6-alkylene" means a linear or branched, cyclic or open-chain saturated hydrocarbon residue with 1 to 6 carbon atoms, optionally substituted with 1 to 6 halogen atoms, identical or different, selected from F, CI and Br; or their salts with organic or inorganic acids; comprising the steps (a) manipulating the mixture ratio of the stereoisomers in the mixture so that at least one of the stereoisomers is present in an enantiomeric excess, and (b) adding phosphoric acid under conditions which bring about precipitation of the stereoisomer present in enantiomeric excess from a solution as phosphate, hydrogenphosphate or dihydrogenphosphate, (c) separating the precipitated salt obtained in step (b) from the supernatant solution. 2. Method as claimed in claim 1, wherein that the manipulation in step (a) is carried out - by addition of the stereoisomer which is to be present in excess, or - by enantioselective synthesis of the stereoisomers. 3. Method as claimed in claim 1 or claim 2, wherein the enantiomeric excess is at least 1.0% ee. 4. Method as claimed in one of the previous claims, wherein R1 and R3 are in each case - H and R2 is -OCH3. 5. Method as claimed in one of the previous claims, wherein R4 is -CH2CH3 and R5, R6 and R7 are in each case -CH3. 6. Method as claimed in one of the previous claims, wherein it comprises the step (c) separation of the precipitated salt obtained in step (b) from the supernatant solution. 7. Method as claimed in claim 6, wherein it comprises the step (d) conversion of the salt separated in step (c) into the hydrochloride. ABSTRACT Title: Separation of stereoisomeric N,N-Dialkylamino-2-Alkyl-3-Phenyl Alkanes Method for the isolation of a stereoisomer from a mixture comprising the two stereoisomers of the general formulae (I-A) and (I-A') and/or the two stereoisomers of the general formulae (I-B) and (I-B') in which R1, R2 and R3, identical or different, are selected from the group consisting of -H, -F, -CI, - C1-C6-alkyl, -S-C1-C6-alkyl, -OH, -O-C1-C6-alkyl, -O-C1-C6-alkylenephenyl, -OCO-C1-C6- alkyl, -OCO2-C1-C6-alkyl, -OCON(C1-C6-alkyl)2 and -O-SiR8R9R10 (in which R8, R9 and R10, identical or different, are -C1-C6-alkyl or -phenyl); R4 is -H or -C1-C6-alkyl; R5 is -C1-C6-alkyl; and R6 and R7, identical or different, are -H or -C1-C6-alkyl; wherein "C1-C6-alkyl" means a linear or branched, cyclic or open-chain saturated hydrocarbon residue with 1 to 6 carbon atoms, optionally substituted with 1 to 6 halogen atoms, identical or different, selected from F, CI and Br; and "C1-C6-alkylene" means a linear or branched, cyclic or open-chain saturated hydrocarbon residue with 1 to 6 carbon atoms, optionally substituted with 1 to 6 halogen atoms, identical or different, selected from F, CI and Br; or their salts with organic or inorganic acids; comprising the steps (a) manipulating the mixture ratio of the stereoisomers in the mixture so that at least one of the stereoisomers is present in an enantiomeric excess, and (b) adding phosphoric acid under conditions which bring about precipitation of the stereoisomer present in enantiomeric excess from a solution as phosphate, hydrogenphosphate or dihydrogenphosphate, (c) separating the precipitated salt obtained in step (b) from the supernatant solution.

Full Text

Separation of stereo isomeric N,N-dialkylamino-2-alkyl-3-hydroxy-3-
phenylalkanes
The invention concerns a method for the separation of stereoisomeric N,N-dialkyl-
amino-2-alkyl-3-hydroxy-3-phenylalkanes.
Opioids have been used for many years as analgesics for the treatment of pain
although they can induce a number of side effects, for example addiction and
dependency, respiratory depression, gastro-intestinal inhibition and constipation.
Over an extended period or at high doses they can only be administered with
particular precautionary measures such as special prescribing requirements.
It is known that certain N,N-dialkylamino-2-alkyl-3-hydroxy-3-phenylalkanes
(especially 1-phenyl-3-dimethylaminopropane compounds) possess analgesic
activity without causing the side effects typical of opioids. These compounds are
characterised by a pronounced analgesic action that is significantly increased in
comparison with, for example, the opioid tramadol.

These analgesically active N,N-dialkylamino-2-alkyl-3-hydroxy-3-phenylalkanes are
chiral. Since two chiral centres are usually present, the compounds exist in the form
of 4 stereoisomers, i.e. two enantiomeric pairs that are diastereomeric with one
another.
The activity of an analgesic is frequently attributable to its interaction with a certain
receptor of a human or animal cell. Since these receptors are constructed of chiral
amino acids and optionally also chiral glycosides, their interaction with chiral
pharmaceuticals is stereoselective. Therefore the pharmacological activity of chiral
pharmaceuticals is frequently different for the individual stereoisomers.
There is therefore a requirement for a method for the separation of the
stereoisomers, i.e. the diastereoisomers and enantiomers, of N,N-dialkylamino-2-
alkyl-3-hydroxy-3-phenylalkanes.
The synthesis of (2RS,3RS)-1-dimethylamino-3-(3-methoxyphenyl)-2-methylpentan-
3-ol is known from of EP-A 693475.The separation of the diastereoisomers, that is
the two enantiomeric pairs, is carried out by hydrochloride precipitation with
trimethylchlorosilane/water in 2-butanone. The racemic mixture of the two
enantiomers of (2R,3R) and (2S,3S) configuration is carried out by separation on a
chiral HPLC column.
However, the chromatographic separation of enantiomers on chiral stationary phases
is usually unsuitable for relatively large quantities of active compounds and is instead
used almost solely for analytical purposes. There is therefore a requirement for a
method that is also suitable for the separation of the enantiomers of chiral
N,N-dialkylamino-2-alkyl-3-hydroxy-3-phenylalkanes on a preparative scale.
Thus the problem that forms the basis of the invention is to provide a method for the
separation of the stereoisomers, preferably enantiomers, of chiral N,N-dialkylamino-
2-alkyl-3-hydroxy-3-phenylalkanes that can also be carried out on the gram and
kilogram scale. The method must be cost-effective and guarantee a good yield and
high enantiomeric purity.

This object is achieved by the subject matter of the claims. It has surprisingly been
found that the isolation of a stereoisomer from a mixture comprising the two
stereoisomers of the general formulae (l-A) and (l-A') and/or the two stereoisomers
of the general formulae (l-B) and (l-B'),

in which
R1, R2 and R3, identical or different, are selected from the group consisting -H,
-F, -CI, C1-C6-alkyl, -S-C1-C6-alkyl, -OH, -O-C1-C6-alkyl,
-O-C1-C6-alkylenephenyl, -OCO-C1-C6-alkyl, -OCON(C1-C6-alkyl)2 and
-O-SiR8R9R10 (in which R8, R9 and R10, identical or different, are -C1-C6-alkyl
or-phenyl);
R4 is -H or -C1-C6-alkyI;
R5 is -C1-C6-alkyl; and
R6 and R7, identical or different, are -H or -C1-C6-alkyl;
or their salts with organic or inorganic acids;
is possible by a method comprising the step
(a) manipulating the mixture ratio of the stereoisomers in the mixture so that at
least one of the stereoisomers, preferably the stereoisomer to be isolated, is
present in an enantiomeric excess.
It has surprisingly been found that individual stereoisomers may be crystallised with
high stereoselectivity from the mixture of stereoisomers when at least one of the
stereoisomers is not present in racemic mixture, but instead in an enantiomeric
excess.

The compounds of the general formula (I) exhibit at least two chiral centres. The
compounds can be synthesised in different ways. For example, it is possible firstly to
prepare a Mannich base in a Mannich reaction by which means the first chiral centre
is produced:

If the Mannich reaction takes place without chiral induction, i.e. in the absence of
chiral auxiliaries, chiral catalysts, chiral solvents, etc., the Mannich base is formed as
a racemic mixture, since transition states leading to the two enantiomeric Mannich
bases are enantiomorphic and thus energetically identical.
The second chiral centre can be introduced, for example, by reaction of the Mannich
base with a Grignard reagent at the carbonyl:

In this way, the four stereoisomeric N,N-dialkylamino-2-alkyl-3-hydroxy-3-phenyl-
alkanes of the general formulae (l-A), (l-A'), (l-B) and (l-B') are formed from the

racemic Mannich base. Depending on the substitution pattern at the two chiral
centres, the R- or S-configuration is in each case formed.
In principal, it is also possible for further chiral centres also to be present in one of
the side chains. In the case of three chiral centres, the number of stereoisomers
increases to a total of eight, four enantiomeric pairs being present. The N,N-dialkyl-
amino-2-alkyl-3-hydroxy-3-phenylalkanes preferably comprise only two chiral
centres.
Preferably, the stereoisomers (l-A) and (l-A') on the one hand and the stereoisomers
(l-B) and (l-B') on the other are in each case enantiomeric to one another. In other
respects the stereoisomers are diastereoisomeric among one another. Stereoisomer
(l-A) is accordingly preferably enantiomeric to (l-A) and diastereoisomeric to (l-B)
and (l-B'), stereoisomer (l-A') is enantiomeric to (l-A) and diastereoisomeric to (l-B)
and (l-B'), stereoisomer (l-B) is diastereomeric to (l-A) and (l-A') and enantiomeric to
(l-B'), and finally stereoisomer (l-B') is diastereoisomeric to (l-A) and (l-A') and
enantiomeric to (l-B).
If, for example, in step (a) of the method of the invention the mixture ratio of the
stereoisomers in the mixture is manipulated in such a way that the stereoisomer of
the general formula (l-A') is present in an enantiomeric excess, the excess relates to
the relative amount of its enantiomer, i.e. preferably to the stereoisomer of the
general formula (l-A). The mixture ratio of the optionally likewise present
stereoisomers, for example of the general formulae (l-B) and (l-B') need not
necessarily be manipulated, such that these may also (optionally still) be present, for
example, in the racemic mixture.
In a preferred embodiment of the method of the invention, this serves to isolate one
stereoisomer from a mixture comprising the two stereoisomers of the general
formulae (l-A) and (l-A'), but not, however, the two stereoisomers of the general
formulae (l-B) and (l-B'). In another preferred embodiment of the method of the
invention, this serves to isolate one stereoisomer, preferably of the general formula
(l-A) or (l-A), from a mixture of all four stereoisomers, i.e. the stereoisomers of the
general formulae (l-A), (l-A'), (l-B) and (l-B').

In a preferred embodiment of the method of the invention, the manipulation in step
(a) is carried out
by addition of the stereoisomer which is to be present in excess, or
by enantioselective synthesis of the stereoisomers.
The manipulation in step (a) has the consequence that at least one of the
stereoisomers is present in an enantiomeric excess. This means preferably that it is
relatively enriched in relation to its enantiomer. This enrichment can be achieved in
different ways. On the one hand, it involves achieving an enantiomeric excess during
the course of synthesis of the stereoisomers, on the other it also involves shifting the
relative weight ratio of the two enantiomers of a mixture originally present as a
racemate in respect of these two stereoisomers/enantiomers. The latter variant can
be achieved, for example, by external addition or enantioselective derivatisation of
one of the two enantiomers (e.g. kinetic racemate separation).
If the manipulation in step (a) is carried out by addition of the stereoisomer which is
to be present in enantiomeric excess, it can be isolated previously by separate
isolation from a mixture of the stereoisomers. For example, it is possible to this end
initially to separate the diastereoisomers by selective precipitation of the one
enantiomeric pair as hydrochlorides. In this way, the two stereoisomers of the
general formula (l-A) and (l-A') (enantiomeric pair 1) may be separated from the two
stereoisomers of the general formula (l-B) and l-B') (enantiomeric pair 2). The
separation of the two enantiomers, i.e. the separation of the racemic enantiomeric
pairs 1 and 2, respectively, can then be carried out with the aid of chiral auxiliaries,
for example, chiral acids.
It has now surprisingly been found that the two enantiomers of the general formulae
(l-A) and (l-A') may be selectively precipitated with the aid of (+)- and (-)-di-O,O'-p-
toluyltartaric acid, the respective other enantiomer remaining in the mother liquor.
One aspect of the invention thus concerns a method for racemate separation of the
two enantiomers of the general formulae (l-A) and (l-A) comprising the addition of
(+)- or (-)-di-O,O'-p-toluyltartaric acid. A suitable solvent is, for example, 2-butanone.

The two enantiomers of the general formulae (l-A) and (l-A') are dissolved in the
solvent. Depending upon the configuration of the tartaric acid derivative used, a
stereoselective precipitation of the enantiomer of the general formula (l-A) or (l-A') as
addition salt takes place after its addition
Owing to the comparatively high cost of the enantiomerically pure tartaric acid
derivative ((-)- or (+)-di-O,O'-p-toluyltartaric acid) as a chiral auxiliary, this method is
only of limited use for enantiomeric separation on a preparative scale. This method is
preferably merely used initially to obtain the respective enantiomerically pure
stereoisomers of the general formula (l-A) and (l-A') and, through their addition to the
reaction mixture, to manipulate the relative weight ratio in favour of one or the other
stereoisomer for the purposes of step (a) of the method of the invention, i.e. to
produce an enantiomeric excess.
Alternatively, a small but sufficient amount of the enantiomerically pure compounds
can be obtained by HPLC on a chiral stationary phase.
In principle, it is also conceivable for the manipulation in step (a) of the method of the
invention not to take place by the addition of one enantiomer, but instead by
selective removal of the other enantiomer. Thus, for example, alternatively to
enrichment of one of the two enantiomers, one of the two enantiomers may be
selectively degraded. In this connection, it is for example conceivable to carry out
selective enzymatic derivatisation of one stereoisomer, as a result of which its
enantiomer is present in excess.
The manipulation in step (a) of the method of the invention can also be carried out by
enantioselective synthesis of the stereoisomers. In this case, enantioselectivity can
be induced at different steps of the synthesis. Thus it is, for example, possible to
induce an excess of one of the two resulting enantiomers by suitable measures even
at the stage of the aforementioned Mannich reaction. Suitable measures are known
to a person skilled in the art. Alternatively, it is also possible, for example, to induce
an enantiomeric excess by enantioselective reaction control in the also previously
described Grignard reaction (or an equivalent reaction with another organometallic
reagent) subsequent to the Mannich reaction. Suitable methods are known to a

person skilled in the art here too. Ojima, Catalytic Asymmetric Synthesis, 2nd ed.,
Wiley VCH; R.A. Aitken et al., Asymmetric Synthesis, 2nd ed., CRC Press; L.A.
Paquette, Handbook of Reagents for Organic Synthesis: Chiral Reagents for
Asymmetric Synthesis, John Wiley & Sons; H.B. Kagan, Asymmetric Synthesis,
Thieme Medical Pub.; W. Carruthers, Modern Methods of Organic Synthesis, 4th
ed., Cambridge University Press; and R.S. Atkinson, Stereoselective Synthesis, John
Wiley & Sons.
In a preferred embodiment, the enantiomeric excess after carrying out step (a) of the
method of the invention is at least 1.0% ee, more preferably at least 2.5% ee, still
more preferably at least 5.0% ee, most preferably at least 7.5% ee and in particular
at least 10% ee. However, the enantiomeric excess is preferably at most 25% ee,
more preferably at most 20% ee and in particular at most 15% ee.

[(-)] denoting the concentration of the dextrorotatory and levorotatory enantiomer and
a positive number always being obtained.
Suitable methods for the determination of the enantiomeric excess are familiar to a
person skilled in the art. HPLC on chiral stationary bases and NMR investigations
with chiral shift reagents may be mentioned by way of example.
The method of the invention is successful with N,N-dialkylamino-2-alkyl-3-hydroxy-3-
phenylalkanes of different structure.
In a preferred embodiment R1 and R3 are -H. Preferred substitution patterns of the
phenyl ring (R1, R2 and R3) are summarised in the following table:

R1 and R3 are particularly preferably in each case -H and R2 is -O-C1-C6-alkyl, preferably
-OCH3, or -OH. R4 is preferably -C1-C6-alkyl, preferentially -CH3 or -CH2CH3. R5 is
preferably -C1-C6-alkyl, preferentially -CH3. R6 and R7 are preferably in each case -C1-C6-
alkyl, preferentially -CH3. R4 is particularly preferably -CH2CH3 and R5, R6 and R7 are in
each case -CH3.
"C1-C6-alkyl" for the purpose of the description means a linear or branched, cyclic or
open-chain saturated hydrocarbon residue with 1 to 6 carbon atoms, optionally
substituted with 1 to 6 halogen atoms (identical or different, selected from F, CI and Br).
Examples are -CH3, -CF3, -CH2F, -CHF2, -CH2CH3,
-CH(CH3)2, -CH2CH2CH3, -CH(CH3)CH2CH3, -CH2CH(CH3)CH3, -C(CH3)3, -CH2CH2CH2CH3,
etc.
"C1-C6-alkylene" for the purposes of the description means a linear or branched, cyclic or
open-chain saturated hydrocarbon residue with 1 to 6 carbon atoms, optionally
substituted with 1 to 6 halogen atoms (identical or different, selected from F, CI and Br).
Examples are -CH2, -CH2CH2-, -CH(CH3)CH2-, -CH2CH2CH2-, -CH(CH3)CH2CH2-, -
CH2CH(CH3)CH2-, -C(CH3)2CH2-, -CH(CH3)CH(CH3)-, - CH2CH2CH2CH2- etc.
In one particularly preferred embodiment of the method of the invention R1 is -H, R2 -
OCH3, R3-H, R4-CH2CH3, R5-CH3, R6-CH3 and R7-CH3, such that the stereoisomers of the
general formula (I-A), (I-AO, (I-B) and (I-B7) are l-dimethyl-amino-3-(3-methoxyphenyl)-
2-methylpentan-3-ol.
In this instance, the stereoisomer of the general formula (I-A) is (2S,3S)-l-dimethyl-
amino-3-(3-methoxyphenyl)-2-methylpentan-3-ol, the stereoisomer of the general
formula (I-A') is (2R, 3R)-l-dimethylamino-3-(3-methoxyphenyl)-2-methylpentan-3-ol,
the stereoisomer of the general formula (I-B) is (2S, 3R)-l-dimethylamino-3-(3-
methoxyphenyl)-2-methylpentan-3-ol, and the stereoisomer of the general formula

(I-B') is (2R,3S)-1-dimethylamino-3-(3-methoxyphenyl)-2-methylpentan-3-ol, or their
salts with organic or inorganic acids.
In a preferred embodiment, the method of the invention comprises the step
(bi) addition of a chiral compound of the general formula (II) or (IT)

The chiral compound of the general formula (II) or (IT) is preferably added in optically
pure form. Its enantiomeric excess is preferably at least 90% ee, more preferably at
least 95%ee, most preferably 98% ee and in particular at least 99% ee.
The chiral compounds of the general formula (II) or (II') are tartaric acid or its
derivatives. The configuration of the two chiral centres is either R,R or S,S. Tartaric
acid and many of its derivatives are available commercially in enantiomerically pure
form.
R11 is preferably -H or -CO-p-tolyl.
In another preferred embodiment, the method of the invention comprises the step
(b2) addition of phosphoric acid.
The addition of phosphoric acid preferably serves to convert at least one of the
stereoisomers into the phosphate, hydrogenphosphate or dihydrogenphosphate and
consequently to induce selective crystallisation. By means of the stoichiometric ratio
between the amount of phosphoric acid added and the stereoisomers of the general
formulae (l-A), (l-A'), (l-B) and (l-B') it is possible to exert an influence upon whether

salt formation takes place as phosphate (PO43-), hydrogenphosphate (HPO42) or
dihydrogenphosphate (H2PO4").
Besides the addition of a suitable amount of phosphoric acid, the stereoisomers can
be converted into the phosphate, hydrogenphosphate or dihydrogenphosphate in
other ways. Such variants are known to a person skilled in the art, for example the
addition of phosphate salts and subsequent acidification with mineral acids.
Step (b1) or (b2) is preferably carried out under conditions that bring about the
precipitation from a solution of the stereoisomer present in enantiomeric excess
as salt of the chiral compound of the general formula (II) or (IT), or
as phosphate, hydrogenphosphate or dihydrogenphosphate.
If R11 is -H, the chiral compound of the general formula (II) or (IT) is tartaric acid. It
has surprisingly been found that the stereoisomers of the general formulae (l-A) and
(l-A') can in each case be precipitated selectively in step (b1) with one of the two
tartaric acid enantiomers if care is first taken to ensure that the two enantiomers of
the general formulae (l-A) and (l-A') are not present as a racemate, but instead one
of the two enantiomers is present in excess.
It has surprisingly been found that the enantiomeric purity of the precipitate is
sometimes significantly greater than the enantiomeric excess before precipitation.
The difference between the possibly somewhat low enantiomeric excess before
precipitation and the enantiomeric purity of the precipitate can in some cases be
quite considerable. Such crystallisation behaviour is unusual and represents a
significant advantage of the method of the invention relative to conventional methods
for racemate separation.
By using the correct tartaric acid enantiomer it is possible to ensure that practically
only the stereoisomer of the general formula (l-A) or (l-A') present in excess is
precipitated, while the other enantiomer remains in the stock solution. The suitable
enantiomer for the particular situation can be determined by simple preliminary
investigations. Owing to the comparatively low costs of the two enantiomers of

tartaric acid, this preferred embodiment of the method of the invention is also
suitable for use on a preparative scale.
Unlike with tartaric acid or its derivatives of the general formula (II) or (IT), in the case
of addition of phosphoric acid in step (b2) no further chiral reagent is added. Instead,
the separation of the stereoisomers is based preferentially on the different
crystallisation behaviour of the phosphates, hydrogenphosphates or
dihydrogenphosphates of the stereoisomers as such. It has surprisingly been found
that one enantiomer can be selectively precipitated as phosphate,
hydrogenphosphate or dihydrogenphosphate from a mixture of the two enantiomers
of the general formulae (l-A) and (l-A') if care has been previously taken to ensure
that it is present in a specific, but not necessarily particularly large, enantiomeric
excess.
This embodiment of the method of the invention is even suitable for the selective
crystallization of one of the stereoisomers from the mixture of all four stereoisomers
of the general formulae (l-A), (l-A'), (l-B) and (l-B'). It is accordingly not even
necessary initially to carry out a diastereomeric separation, for example by
precipitation of one enantiomeric pair as hydrochloride. Instead, selective
precipitation is even successful from the immediate reaction product from the
Grignard reaction. Ethanol, for example, is a suitable solvent for this purpose.
The method of the invention has the advantage that in step (a) only a comparatively
small enantiomeric excess of the stereoisomer need be brought about in order to
achieve a high enantiomeric excess of the precipitate during the precipitation with a
compound of the general formula (II) or (IT) or as phosphate, hydrogenphosphate or
dihydrogenphosphate. If, for example, step (a) of the method of the invention is
carried out with enantioselective reaction control, the enantioselectivity of the
reaction accordingly need not lie in the region of 95% ee and above as is normally
required. Instead, even significantly less pronounced enantioselectivities suffice in
the synthesis in order ultimately to obtain a product with very high enantiomeric
purity.

The method of the invention preferably comprises the step
(c) separation of the precipitated salt obtained in step (b1) or (b2) from the
supernatant solution.
This can be achieved, for example, by decantation, filtration, centrifugation, etc.
In a preferred embodiment, the method of the invention comprises the step
(d) conversion of the salt separated in step (c) into the hydrochloride.
Conversion of the separated salt into the hydrochloride can be achieved in different
ways. In a preferred embodiment, the separated salt is first converted into the free
base of the stereoisomer. This can be carried out by the addition of strong bases, for
example NaOH or KOH.
The free base of the stereoisomer released in this way may then either be initially
isolated or converted directly into the hydrochloride in situ. It has surprisingly been
found that improved yields are obtained during hydrochloride precipitation if
hydrogen chloride is used in gaseous form in place of trimethylchlorosilane/water (cf.
EP-A 693 475). Suitable solvents are, for example, acetone or 2-butanone.
A further aspect of the invention concerns an addition salt of a stereoisomer of the
general formula (l-A), (l-A'), (l-B) or (l-B') as defined above and
- a compound of the general formula (II) or (II') as defined above, or
- phosphoric acid.
The addition salt is preferably selected from the group consisting of
(2R,3R)-1 -dimethylamino-3-(3-methoxyphenyl)-2-methylpentan-3-ol (+)-tartrate,
(2R,3R)-1 -dimethylamino-3-(3-methoxyphenyl)-2-methylpentan-3-ol (-)-tartrate,
(2R,3R)-1 -dimethylamino-3-(3-methoxyphenyl)-2-methylpentan-3-ol (+)-di-O,O'-p-
toluyltartrate,
(2R,3R)-1 -dimethylamino-3-(3-methoxyphenyl)-2-methylpentan-3-ol (-)-di-O,O'-p-
toluyltartrate,
- (2R,3R)-1 -dimethylamino-3-(3-methoxyphenyl)-2-methylpentan-3-ol phosphate,

- (2R,3R)-1-dimethylamino-3-(3-methoxyphenyl)-2-methylpentan-3-ol
hydrogenphosphate,
(2R,3R)-1-dimethylamino-3-(3-methoxyphenyl)-2-methylpentan-3-ol
dihydrogenphosphate,
- (2S,3S)-1 -dimethylamino-3-(3-methoxyphenyl)-2-methylpentan-3-ol (+)-tartrate,
- (2S,3S)-1 -dimethylamino-3-(3-methoxyphenyl)-2-methylpentan-3-ol (-)-tartrate,
(2S,3S)-1-dimethylamino-3-(3-methoxyphenyl)-2-methylpentan-3-ol (+)-di-O,O'-p-
toluyltartrate,
(2S,3S)-1 -dimethylamino-3-(3-methoxyphenyl)-2-methylpentan-3-ol (-)-di-O,O'-p-
toluyltartrate,
(2S,3S)-1 -dimethylamino-3-(3-methoxyphenyl)-2-methylpentan-3-ol phosphate,
(2S,3S)-1-dimethylamino-3-(3-methoxyphenyl)-2-methylpentan-3-ol
hydrogenphosphate,
(2S,3S)-1-dimethylamino-3-(3-methoxyphenyl)-2-methylpentan-3-ol
dihydrogenphosphate,
- (2R,3S)-1 -dimethylamino-3-(3-methoxyphenyl)-2-methylpentan-3-ol (+)-tartrate,
- (2R,3S)-1 -dimethylamino-3-(3-methoxyphenyl)-2-methylpentan-3-ol (-)-tartrate,
- (2R,3S)-1 -dimethylamino-3-(3-methoxyphenyl)-2-methylpentan-3-ol (+)-di-O,O'-p-
toluyltartrate,
- (2R,3S)-1 -dimethylamino-3-(3-methoxyphenyl)-2-methylpentan-3-ol (-)-di-O,O'-p-
toluyltartrate,
(2R,3S)-1 -dimethylamino-3-(3-methoxyphenyl)-2-methylpentan-3-ol phosphate,
- (2R,3S)-1-dimethylamino-3-(3-methoxyphenyl)-2-methylpentan-3-ol
hydrogenphosphate,
(2R,3S)-1-dimethylamino-3-(3-methoxyphenyl)-2-methylpentan-3-ol
dihydrogenphosphate,
(2S,3R)-1-dimethylamino-3-(3-methoxyphenyl)-2-methylpentan-3-ol (+)-tartrate,
(2S,3R)-1 -dimethylamino-3-(3-methoxyphenyl)-2-methylpentan-3-ol (-)-tartrate,
(2S,3R)-1-dimethylamino-3-(3-methoxyphenyl)-2-methylpentan-3-ol (+)-di-O,O'-p-
toluyltartrate,
(2S,3R)-1-dimethylamino-3-(3-methoxyphenyl)-2-methylpentan-3-ol (-)-di-O,O'-p-
toluyltartrate,
- (2S,3R)-1 -dimethylamino-3-(3-methoxyphenyl)-2-methylpentan-3-ol phosphate,

(2S,3R)-1 -dimethylamino-3-(3-methoxyphenyl)-2-methylpentan-3-ol
hydrogenphosphate and
(2S,3R)-1-dimethylamino-3-(3-methoxyphenyl)-2-methylpentan-3-ol
dihydrogenphosphate.
In a preferred embodiment, the addition salt is selected from the above list, "(3-
methoxyphenyl)" in each case being replaced by "(3-hydroxyphenyl)".
A further aspect of the invention concerns a method for the preparation of a
stereoisomer of the general formulae (l-A), (l-A'), (l-B) and (l-B') as defined above
(preparation method) comprising the method for the isolation of the stereoisomer
described above (separation method). The production method preferably comprises
a method for the preparation of a stereoisomer of the general formula (l-A), (l-A'),
(l-B) or (l-B')

in which
R1, R2 and R3, identical or different, are selected from the group consisting of
-H, -F, -CI, -C1-C6-alkyl, -S-C1-C6-alkyl and -OH, providing that at least one of
the residues R1, R2 and R3 is -OH;
R4 is -H or -C1-C6-alkyI;
R5 is -C1-C6-alkyl; and
R6 and R7, identical or different, are -H or -C1-C6-alkyl;
or their salts with organic or inorganic acids;
comprising the separation method described above for the isolation of a
stereoisomer, wherein during the implementation of the separation method at least
one of the residues R1, R2 and R3 is -O-C1-C6-alkyl, -O-C1-C6-alkylenephenyl,
-OCO-C1-C6-alkyl, -OCO2-C1-C6-alkyl, -OCON(C1-C6-alkyl)2 or -O-SiR8R9R10.

In a preferred embodiment, after isolation of the stereoisomers, i.e. after the
implementation of the separation method of the invention, the preparation method of
the invention comprises the step
(e) conversion of at least one of the residues R1, R2 and R3 which is -O-C1-C6-alkyl,
-O-C1-C6-alkylenephenyl, -OCO-C1-C6-alkyl, -OCO2-C1-C6-alkyl, -OCON(C1-C6-
alkyl)2 or -O-SiR8R9R10 into an -OH group.
Conversion into an -OH group can be carried out in a manner known to a person
skilled in the art, for example with acid, base, fluoride, complex metal hydrides, etc.,
depending upon the nature of the substitution.
The following examples serve to illustrate the invention but should not to be
construed to limit the scope thereof.
Example 1
Preparation of a mixture of the four stereoisomers of 1-dimethylamino-3-(3-
methoxyphenyl)-2-methylpentan-3-ol:
A mixture of the four stereoisomers of 1-dimethylamino-3-(3-methoxyphenyl)-2-
methylpentan-3-ol was prepared by a Grignard reaction of rac.-1-dimethylamino-2-
methylpentan-3-one with 3-methoxyphenylmagnesium bromide in THF in accordance
with example 1 of EP 0 693 475 A1.
The two enantiomers (2R,3R)- and (2S,3S)-1-dimethylamino-3-(3-methoxyphenyl)-2-
methylpentan-3-ol and the two enantiomers (2R,3S)- and (2S,3R)-1-dimethylamino-
3-(3-methoxyphenyl)-2-methylpentan-3-ol were in each case present in equal
amounts, i.e. as a racemate. The ratio of the diastereoisomers (2R,3R)/(2S,RS) to
(2R,3S)/(2S,3R) was 70 wt.% to 30 wt.%.
Example 2
Diastereoisomer separation [separation of the enantiomeric pair of (2R,3R)/(2S,3S)
configuration from the enantiomeric pair of (2R,3S)/(2S,3R) configuration]

a) HCI precipitation
A 100 I double wall jacketed reaction vessel with electric impeller stirrer, gas transfer
line, Pt100 temperature sensor and oil-based cooling and heating system was
charged with 15 kg (59.7 mol) of a mixture of the enantiomeric pair (2R,3R)/(2S,3S)-
1-dimethylamino-3-(3-methoxyphenyl)-2-methylpentan-3-ol (70%) and the
enantiomeric pair (2R,3S)/(2S,3R)-1 -dimethylamino-3-(3-methoxyphenyl)-2-
methylpentan-3-ol (30%) in 70 I of acetone at 20°C and a stirrer speed of 100 rpm
The solution was cooled to 5°C. Within 20 min, approx. 2.0 kg of gaseous hydrogen
chloride were passed over the solution, the temperature in the vessel rising
continuously to 28oC despite cooling. The hydrogen chloride was taken from a
hydrogen chloride cylinder which was connected to the gas transfer line of the vessel
through a pressure reduction valve and hose and was placed on a balance for weight
measurement. Further gaseous hydrogen chloride was then passed over until a 5 ml
sample of the solution diluted with 10 ml of water had a pH value of 1-3. The solution
was stirred at 5°C for 2 h. The suspension was then centrifuged off in a centrifuge
and washed once with 10 I of acetone. The product was dried in a drying cabinet at
40°C for 24 h under reduced pressure to a final pressure of 20 mbar. 11.16 kg (65%
of theoretical) of the enantiomeric pair (2R,3R)/(2S,3S)-1-dimethylamino-3-(3-
methoxyphenyl)-2-methylpentan-3-ol hydrochloride were obtained as a colourless
product. The residual content of the undesired enantiomeric pair (2S,3R)/(2R,3S)-1-
dimethylamino-3-(3-methoxyphenyl)-2-methylpentan-3-ol hydrochloride was 3%.
b) Conversion of the hydrochloride into the free base
A 100 I double wall jacketed reaction vessel with electric impeller stirrer, Pt100
temperature sensor and oil-based cooling and heating system was charged with
11.16 kg (38,78 mol) of the enantiomeric pair(2R,3R)/(2S,3S)-1-dimethylamino-3-(3-
methoxyphenyl)-2-methylpentan-3-ol hydrochloride from step a), contaminated with
3% of the enantiomeric pair (2R,3S)/(2S,3R)-1-dimethylamino-3-(3-methoxyphenyl)-
2-methylpentan-3-ol hydrochloride in 21 I of water at 20°C. The solution was treated
with 32 wt.% aqueous sodium hydroxide solution up to a pH value of 13 and then
extracted with 21 I of ethyl acetate. After evaporation of the ethyl acetate at 60-65°C
to a final vacuum of 20 mbar, the base remained as a colourless oil with a yield of
8.77 kg (90% of theoretical), contaminated with 3% of the enantiomeric pair
(2S,3R)/(2R,3S)-1-dimethylamino-3-(3-methoxyphenyl)-2-methylpentan-3-ol.

c) Recrystallisation as hydrochloride
A 100 I double wall jacketed reaction vessel with electric impeller stirrer, gas transfer
line, Pt100 temperature sensor and oil-based cooling and heating system was
charged with 15 kg (59.7 mol) of a mixture of the enantiomeric pair (2R,3R)/(2S,3S)-
1-dimethylamino-3-(3-methoxyphenyl)-2-methylpentan-3-ol (97%) and the
enantiomeric pair (2R,3S)/(2S,3R)-1 -dimethylamino-3-(3-methoxyphenyl)-2-
methylpentan-3-ol (3%) in 70 I of acetone at 20°C at a stirrer speed of 100 rpm. The
solution was cooled to 5°C. Within 20 min, approx. 2.0 kg of gaseous hydrogen
chloride were passed over the solution, the temperature in the vessel rising
continuously to 28°C despite cooling. The hydrogen chloride was taken from a
hydrogen chloride cylinder which was connected to the gas transfer line of the vessel
through a pressure reduction valve and hose and was placed on a balance for weight
measurement. Further gaseous hydrogen chloride was then passed over until a 5 ml
sample of the solution diluted with 10 ml of water had a pH value of 1-3. The solution
was stirred at 5°C for 2 h. The suspension was then centrifuged off in a centrifuge
and washed once with 10 I of acetone. The product was dried in a drying cabinet at
40°C for 24 h under reduced pressure to a final pressure of 20 mbar. 13.74 kg (80%
of theoretical) of the colourless enantiomeric pair (2R,3R)/(2S,3S)-1-dimethylamino-
3-(3-methoxyphenyl)-2-methylpentan-3-ol hydrochloride with a diastereomeric purity
of 100% were obtained.
d) Conversion of the hydrochloride into the free base
A 100 I double wall jacketed reaction vessel with electric impeller stirrer, Pt100
temperature sensor and oil-based cooling and heating system was charged with
13.74 kg (47.7 mol) of the enantiomeric pair (2R,3R)/(2S,3S)-1-dimethylamino-3-(3-
methoxyphenyl)-2-methylpentan-3-ol hydrochloride in 26 I of water at 20°C. The
solution was treated with 32 wt.% aqueous sodium hydroxide solution up to a pH
value of 13 and then extracted with 26 I of ethyl acetate. After evaporation of the
ethyl acetate at 60-65°C to a final vacuum of 20 mbar, the enantiomeric pair
(2R,3R)/(2S,3S)-1-dimethylamino-3-(3-methoxyphenyl)-2-methylpentan-3-ol
remained as colourless oil with a yield of 10.80 kg (90% of theoretical) and a
diastereomeric purity of 100%.

Example 3
Separation of the two enantiomers of (2R,3R) and (2S,3S) configuration with the aid
of (+)-di-O,O'-p-toluyltartaric acid
a) Precipitation of (2S,3S)-1-dimethylamino-3-(3-methoxyphenyl)-2-methylpentan-3-
ol; (+)-di-O,O'-p-toluyltartrate
A 2 I three-necked flask with thermometer, mechanical pneumatic stirrer, reflux
condenser and oil bath heating was charged with 121 g (0.48 mol) of the
enantiomeric pair (2R,3R)/(2S,3S)-1 -dimethylamino-3-(3-methoxyphenyl)-2-
methylpentan-3-ol (with a diastereomeric purity of 100%) in 100 ml of 2-butanone
and a solution of 185.6 g (0.48 mol) of (+)-di-O,O'-p-toluyltartaric acid dissolved in
1700 ml of 2-butanone was added with stirring. After 48 h at room temperature, the
resulting crystal mass was filtered off through a vacuum filter under reduced
pressure and washed twice with 150 ml of cooled (3-8°C) 2-butanone each time. The
product was dried in a drying cabinet at 40°C for 24 h to a final vacuum of 20 mbar.
125 g (40% of theoretical) of (2S,3S)-1-dimethylamino-3-(3-methoxyphenyl)-2-
methylpentan-3-ol (+)-di-O,O'-p-toluyltartrate were obtained which were used without
further purification for release of the base.
b) Conversion of the (+)-di-O,O'-p-toluyltartrate into the free base
125 g (0.2 mol) of (2S,3S)-1-dimethylamino-3-(3-methoxyphenyl)-2-methylpentan-3-
ol (+)-di-O,O'-p-toluyltartrate were dissolved in 500 ml of water, treated with stirring
with 18 ml of 37 wt.% hydrochloric acid and extracted twice with 150 ml of diethyl
ether each time. The aqueous phase was then treated with 35 ml of 32 wt.%
aqueous sodium hydroxide solution and then extracted with 2 x 250 ml of
dichloromethane. After distilling off the solvent at 40°C to a final pressure of 20 mbar,
47 g (95% of theoretical) of a colourless oil were obtained which consisted of 83%
(2S,3S)-1 -dimethylamino-3-(3-methoxyphenyl)-2-methylpentan-3-ol and 17%
(2R,3R)-1-dimethylamino-3-(3-methoxyphenyl)-2-methylpentan-3-ol.
c) Isolation of the other enantiomer from the mother liquor as hydrochloride and
conversion into the free base
The mother liquor from the precipitation in step a) was combined with both washings,
treated with 820 ml of water and 30 ml of 37 wt.% hydrochloric acid were added with

stirring. The aqueous phase was extracted twice with 250 ml of diethyl ether each
time. To release the base, the aqueous phase was treated with 57 ml of 32 wt.%
aqueous sodium hydroxide solution and then extracted with 2 x 250 ml of
dichloromethane. After distilling off the solvent at 40°C to a final pressure of 20 mbar,
70 g (58% of theoretical) of a colourless oil were obtained which consisted of 70%
(2R,3R)-1 -dimethylamino-3-(3-methoxyphenyl)-2-methylpentan-3-ol and 30%
(2S,3S)-1-dimethylamino-3-(3-methoxyphenyl)-2-methylpentan-3-ol.
Example 4
Separation of the two enantiomers of (2R,3R) and (2S,3S) configuration with the aid
of (-)-di-O,O'-p-toluyltartaric acid
a) Precipitation of (2R,3R)-1-dimethylamino-3-(3-methoxyphenyl)-2-methylpentan-3-
ol (-)-di-O,O'-p-toluyltartrate
13.7 g (54.5 mmol) of the enantiomeric pair (2R,3R)/(2S,3S)-1-dimethylamino-3-(3-
methoxyphenyl)-2-methylpentan-3-ol (with a diastereomeric purity of 100%) and 10
ml of 2-butanone were treated with stirring with a solution of 22 g (56.9 mmol) of (-)-
di-O,O'-p-toluyltartaric acid in 220 ml of 2-butanone. After 24 h at room temperature,
the resulting crystal mass was filtered through a vacuum filter under reduced
pressure and washed twice with 15 ml of cooled (3-8°C) 2-butanone each time. The
product was dried for 24 h in a drying cabinet at a temperature of 40°C and a final
vacuum of 20 mbar. 8.7 g (25% of theoretical) of (2R,3R)-1-dimethylamino-3-(3-
methoxyphenyl)-2-methylpentan-3-ol (-)-di-O,O'-p-toluyltartrate were obtained which
were used without further purification for release of the base.
b) Conversion of the (-)-di-O,O'-p-toluyltartrate into the free base
8.7 g (13.6 mmol) of (2R,3R)-1-dimethylamino-3-(3-methoxyphenyl)-2-methylpentan-
3-ol (-)-di-O,O'-p-toluyltartrate were dissolved in 30 ml of water in a 100 ml three-
necked flask with thermometer, magnetic stirrer and reflux condenser, treated with
stirring with 1.1 ml of 37 wt.% hydrochloric acid and extracted twice with 15 ml of
diethyl ether each time. 2.2 ml of 32 wt.% aqueous sodium hydroxide solution were
then added to the aqueous phase which was then extracted with 2 x 20 ml of
dichloromethane. After distilling off the solvent at 40°C to a final pressure of 20 mbar,
3.36 g (98% of theoretical) of a colourless oil were obtained which consisted of 65%

(2R,3R)-1 -dimethylamino-3-(3-methoxyphenyl)-2-methylpentan-3-ol and 35%
(2S,3S)-1-dimethylamino-3-(3-methoxyphenyl)-2-methylpentan-3-ol.
Example 5
Separation of the two enantiomers of (2R,3R) and (2S,3S) configuration with the aid
of D-(-)-tartaric acid after enrichment of the enantiomer of (2R,3R) configuration
a) Precipitation of (2R,3R)-1-dimethylamino-3-(3-methoxyphenyl)-2-methylpentan-3-
ol (-)-tartrate
A 2 I three-necked flask with thermometer, mechanical pneumatic stirrer, reflux
condenser and oil bath heating was charged with 30 g (0.12 mol) of the mixture of
the two enantiomers obtained in Example 4b) with an enantiomeric excess of 30%
ee (65 wt.% (2R,3R)-1-dimethylamino-3-(3-methoxyphenyl)-2-methylpentan-3-ol and
35 wt.% (2S,3S)-1-dimethylamino-3-(3-methoxyphenyl)-2-methylpentan-3-ol) in 50
ml of ethanol and a solution of 18.0 g (0.12 mol) of (-)-(2S,3S)-tartaric acid in 200 ml
of ethanol was added with stirring. After 1 h at room temperature, 200 ml of diethyl
ether were added and stirring was continued for 24 h. The resulting crystal mass was
filtered through a vacuum filter under reduced pressure and washed twice with 200
ml of cooled (3-8°C) diethyl ether each time. The product was dried for 24 h in a
drying cabinet at a temperature of 40°C and a final vacuum of 20 mbar. 26.4 g (55%
of theoretical) of (2R,3R)-1-dimethylamino-3-(3-methoxyphenyl)-2-methylpentan-3-ol
(-)-tartrate were obtained which were used without further purification for release of
the base.
b) Conversion of the (-)-tartrate into the free base
26.4 g (65.8 mmol) of (2R,3R)-1-dimethylamino-3-(3-methoxyphenyl)-2-
methylpentan-3-ol (-)-tartrate were dissolved in 100 ml of water, treated with stirring
with 7.4 ml of 32 wt.% aqueous sodium hydroxide solution and then extracted with 2
x 50 ml of dichloromethane. After distilling off the solvent at 40°C to a final pressure
of 20 mbar, 16.2 g (98% of theoretical) of a colourless oil were obtained which
consisted of 98% (2R,3R)-1-dimethylamino-3-(3-methoxyphenyl)-2-methylpentan-3-
ol and 2% (2S,3S)-1-dimethylamino-3-(3-methoxyphenyl)-2-methylpentan-3-ol.

Example 6
Separation of the two enantiomers of (2R,3R) and (2S,3S) configuration with the aid
of L-(+)-tartaric acid after enrichment of the enantiomer of (2S,3S) configuration
a) Precipitation of (2S,3S)-1-dimethylamino-3-(3-methoxyphenyl)-2-methylpentan-3-
ol (+)-tartrate
A 100 I double wall jacketed reaction vessel with electric impeller stirrer, Pt100
temperature sensor and oil-based cooling and heating system was charged with
6.93 kg (46.17 mol) of (+)-(2R,3R)-tartaric acid in 75 I of ethanol. Then, 10.55 kg
(41.97 mol) of a racemic mixture of the enantiomeric pair (2R,3R)/(2S,3S)-1-
dimethylamino-3-(3-methoxyphenyl)-2-methylpentan-3-ol in 3.5 I of ethanol were
introduced. The racemic mixture was enriched in respect of the enantiomer with the
(2S,3S) configuration by addition of 1.06 kg (4.21 mol) of the enantiomerically pure
compound (2S,3S)-1 -dimethylamino-3-(3-methoxyphenyl)-2-methylpentan-3-ol. This
mixture was added to the prepared tartaric acid at 10°C and stirred at a stirrer speed
of 150 rpm for 20 hours. The crystals were centrifuged off and dried in a drying
cabinet at 50°C under reduced pressure for 12 h. After 24 h drying in a drying
cabinet at 40°C and a final pressure of 20 mbar, 8.34 kg (20.77 mol, 45% of
theoretical) of (2S,3S)-1 -dimethylamino-3-(3-methoxyphenyl)-2-methylpentan-3-ol
(+)-tartrate were isolated as colourless crystals which were used as dried or moist
with ethanol for release of the base. The other enantiomer (2R,3R)-1-dimethylamino-
3-(3-methoxyphenyl)-2-methylpentan-3-ol could be isolated from the centrifugation
mother liquor.
b) Conversion of the (+)-tartrate into the free base
16.68 kg (41.55 mol) of ethanol-moist or dried (2S,3S)-1-dimethylamino-3-(3-
methoxyphenyl)-2-methylpentan-3-ol (+)-tartrate from step a) were dissolved in 65 I
of water in a 100 I double wall jacketed reaction vessel with electric impeller stirrer,
Pt100 temperature sensor and oil-based cooling and heating system and treated with
approx. 5.2 kg of 32 wt.% aqueous sodium hydroxide solution until a pH value of 12-
13 was reached. The temperature was kept below 35°C by cooling the reaction
vessel. 30 I of ethyl acetate were added, and after 10 min stirring, the stirrer was
switched off to allow phase separation. The lower aqueous phase was drained off
and the upper organic phase was distilled at a maximum internal temperature of

50°C under reduced pressure to 10 mbar. The remaining pale yellow oily residue
was(2S,3S)-1-dimethylamino-3-(3-methoxyphenyl)-2-methylpentan-3-ol
hydrochloride. The yield was 9.92 kg (95% of theoretical) with an enantiomeric purity
of 98.5%.
c) Recrystallisation as hydrochloride
A 100 I double wall jacketed reaction vessel with electric impeller stirrer, gas transfer
line Pt 100 temperature sensor and oil-based cooling and heating system was
charged with 15 kg (59.7 mol) of a mixture of (2S,3S)-1-dimethylamino-3-(3-
methoxyphenyl)-2-methylpentan-3-ol (98%) and (2R,3R)-1-dimethylamino-3-(3-
methoxyphenyl)-2-methylpentan-3-ol (2%) in 70 I of acetone at 20°C and a stirrer
speed of 100 rpm. The solution was cooled to 5°C. Within 20 min, approx. 2.0 kg of
gaseous hydrogen chloride were passed over the solution, the temperature in the
vessel rising continuously to 28°C despite cooling. The hydrogen chloride was taken
from a hydrogen chloride cylinder which was connected to the gas transfer line of the
vessel through a pressure reduction valve and hose and was placed on a balance for
weight measurement. Further gaseous hydrogen chloride was then passed over until
a 5 ml sample of the solution diluted with 10 ml of water had a pH value of 1-3. The
suspension was stirred 5°C for 2 h. The suspension was then centrifuged off in a
centrifuge and washed once with 10 I of acetone. The product was dried in a drying
cabinet at 40°C for 24 h under reduced pressure to a final pressure of 20 mbar.
13.74 kg (80% of theoretical) of colourless (2S,3S)-1-dimethylamino-3-(3-
methoxyphenyl)-2-methylpentan-3-ol hydrochloride with an enantiomeric purity of
100% were obtained.
d) Isolation of the other enantiomer from the mother liquor from step a) as free base.
The ethanol of the mother liquor from the centrifugation of the precipitation of
(2S,3S)-1 -dimethylamino-3-(3-methoxyphenyl)-2-methylpentan-3-ol (+)-tartrate was
distilled off in a 100 I double wall jacketed reaction vessel with electric impeller stirrer,
Pt100 temperature sensor and oil-based cooling and heating system at an internal
temperature of 75°C and a final pressure of 22 I of water and treated with 32 wt.% aqueous sodium hydroxide solution until a pH
value of 12-13 was reached. The internal temperature was kept below 25°C by
cooling the reaction vessel. 22 I of ethyl acetate were added, stirred for 10 min and

the stirrer was switched off to allow phase separation. The lower aqueous phase was
drained off and extracted with a further 11 I of ethyl acetate. The two combined ethyl
acetate phases were distilled off at a maximum internal temperature of 60°C under
reduced pressure to a final pressure of 10 mbar. The yield of (2R,3R)-1-
dimethylamino-3-(3-methoxyphenyl)-2-methylpentan-3-ol was 5.8 kg (50% of
theoretical).
Example 7
Isolation of the enriched enantiomer of (2S,3S) configuration from the mixture of all
four diastereoisomers [product of the Grignard reaction in Example 1] with the aid of
L-(+)-tartaric acid
A 100 I double wall jacketed reaction vessel with electric impeller stirrer, Pt100
temperature sensor and oil-based cooling and heating system was charged with
6.93 kg (46.17 mol) of (+)-(2R,3R)-tartaric acid in 75 I of ethanol. Then a mixture of
10.55 kg (41.97 mol) of the enantiomeric pair (2R,3R)/(2S,3S)-1-dimethylamino-3-(3-
methoxyphenyl)-2-methylpentan-3-ol (70%) and the enantiomeric pair
(2R,3S)/(2S,3R)-1-dimethylamino-3-(3-methoxyphenyl)-2-methylpentan-3-ol (30%) in
3.5 I of ethanol was enriched in respect of the enantiomer with the (2S,3S)
configuration by the addition of 1.06 kg (4.21 mol) of the enantiomerically pure
(2S,3S)-1 -dimethylamino-3-(3-methoxyphenyl)-2-methylpentan-3-ol. This mixture
was added to the prepared tartaric acid at 10°C and stirred at a stirrer speed of 150
rpm for 20 hours. The crystals were centrifuged off and dried in a drying cabinet at
50°C for 12 h under reduced pressure to a final pressure of 20 mbar. 5.93 kg (32%
of theoretical) of colourless crystals of 1-dimethylamino-3-(3-methoxyphenyl)-2-
methylpentan-3-ol (+)-tartrate with a composition of the stereoisomers of 98.2%
(2S,3S)-1 -dimethylamino-3-(3-methoxyphenyl)-2-methylpentan-3-ol (+)-tartrate, 0.8%
(2R,3R)-1 -dimethylamino-3-(3-methoxyphenyl)-2-methylpentan-3-ol (+)-tartrate and
1% of the enantiomeric pair (2R,3S)/(2S,3R)-1-dimethylamino-3-(3-methoxyphenyl)-
2-methylpentan-3-ol (+)-tartrate were obtained.
Example 8
Separation of the two enantiomers of (2R,3R) and (2S,3S) configuration with the aid
of phosphoric acid precipitation of the enantiomer of (2S,3S) configuration

a) with seeding
10 g (0.04 mol) of the enantiomeric pair (2R,3R)/(2S,3S)-1-dimethylamino-3-(3-
methoxyphenyl)-2-methylpentan-3-ol were dissolved in 40 ml of ethanol, treated with
stirring with 3 g of 85 wt.% ortho-phosphoric acid and seeded with 1 g (2.86 mmol) of
(2S,3S)-1 -dimethylamino-3-(3-methoxyphenyl)-2-methylpentan-3-ol phosphate. After
24 h, the crystals formed were filtered off under reduced pressure and dried for 24 h
in a drying cabinet at 40°C to a final pressure of 10 mbar. 3.3 g (22% of theoretical)
of (2S,3S)-1 -dimethylamino-3-(3-methoxyphenyl)-2-methylpentan-3-ol phosphate
were obtained as colourless crystals with an enantiomeric purity of 99.1%.
b) without seeding
10 g (0.04 mol) of the enantiomeric pair (2R,3R)/(2S,3S)-1-dimethylamino-3-(3-
methoxyphenyl)-2-methylpentan-3-ol were dissolved in 40 ml of ethanol and treated
with stirring with 3 g of 85 wt.% ortho-phosphoric acid. After 24 h, the crystals formed
were filtered off under reduced pressure and dried for 24 h in a drying cabinet at
40°C to a final pressure of 10 mbar. 2.2 g (16% of theoretical) of (2S,3S)-1-
dimethylamino-3-(3-methoxyphenyl)-2-methylpentan-3-ol phosphate were obtained
as colourless crystals with an enantiomeric purity of 85%.
Example 9
Separation of the two enantiomers of (2R,3R) and (2S,3S) configuration with the aid
of phosphoric acid precipitation of the enantiomer of (2R,3R) configuration from the
mother liquor of the (+)-tartaric acid precipitation of Example 6
a) 1st. phosphate precipitation and base release
The 7 kg (27.84 mol) of (2R,3R)-1-dimethylamino-3-(3-methoxyphenyl)-2-
methylpentan-3-ol from Example 6 d) were dissolved in 42 I of ethanol at a
temperature of 25°C in a 100 I double wall jacketed reaction vessel with electric
impeller stirrer, Pt100 temperature sensor and oil-based cooling and heating system.
2.16 kg of 85 wt.% ortho-phosphoric acid were added at a stirrer speed of 100 min-1
and the solution was cooled to 5°C. After 24 h, the crystals formed were centrifuged
off and washed with 7 I of ethanol. The precipitate (phosphate salt) was dissolved in
42 I of water and treated with 32 wt.% aqueous sodium hydroxide solution until a pH

of 12-13 was reached. The temperature was kept below 35°C by cooling the
reaction vessel. 20 I of ethyl acetate were added and, after stirring for 10 min, the
stirrer was switched off to allow phase separation. The lower aqueous phase was
extracted again with 12 I of ethyl acetate, the organic phases were combined and
distilled off at a maximum internal temperature of 50°C under reduced pressure to 10
mbar. 4.9 kg (70% of theoretical) of a colourless oil were obtained which was used
as such in the second phosphate precipitation.
b) 2nd phosphate precipitation and base release
4.9 kg (19.5 mol) of the (2R,3R)-1-dimethylamino-3-(3-methoxyphenyl)-2-
methylpentan-3-ol from step a) were dissolved in 30 I of ethanol at a temperature of
25°C in a 100 I double wall jacketed reaction vessel with electric impeller stirrer,
Pt100 temperature sensor and oil-based cooling and heating system. 1.51 kg of
85 wt.% ortho-phosphoric acid were added at a stirrer speed of 100 min-1 and the
solution was cooled to 5°C. After 24 h, the crystals formed were centrifuged off and
washed with 5 I of ethanol. The precipitate was dissolved in 30 I of water and treated
with 32 wt.% aqueous sodium hydroxide solution until a pH value of 12-13 was
reached. The temperature was kept below 35°C by cooling the reaction vessel. 14 I
of ethyl acetate were added and, after stirring for 10 min, the stirrer was switched off
to allow phase separation. The lower aqueous phase was extracted again with 9 I of
ethyl acetate, the organic phases were combined and distilled off at a maximum
internal temperature of 50°C under reduced pressure to 10 mbar. 2.5 kg (51% of
theoretical) of a colourless oil with an enantiomeric purity of 97% were obtained.
c) Recrystallisation as hydrochloride
A 100 I double wall jacketed reaction vessel with electric impeller stirrer, gas transfer
line, Pt100 temperature sensor and oil-based cooling and heating system was
charged with the 10 kg (39.8 mol) of the mixture of (2R,3R)-1-dimethylamino-3-(3-
methoxyphenyl)-2-methylpentan-3-ol (97%) and (2S,3S)-1-dimethylamino-3-(3-
methoxyphenyl)-2-methylpentan-3-ol (3%) from step b) in 45 I of acetone at 20°C
and a stirrer speed of 100 rpm. The solution was cooled to 5°C. Within 20 min,
approx. 1.3 kg of gaseous hydrogen chloride were passed over the solution, the
temperature in the vessel rising continuously to 28°C despite cooling. The hydrogen
chloride was taken from a hydrogen chloride cylinder which was connected to the

gas transfer line of the vessel through a pressure reduction valve and hose and was
placed on a balance for weight measurement. Further gaseous hydrogen chloride
was then passed over until a 5 ml sample of the solution diluted with 10 ml of water
had a pH value of 1-3. The solution was stirred at 5°C for 2 h. The suspension was
centrifuged off in a centrifuge and washed once with 7 I of acetone. The product was
dried in a drying cabinet at 40°C for 24 h under reduced pressure to a final pressure
of 20 mbar. 9.73 kg (85% of theoretical) of colourless (2R,3R)-1-dimethylamino-3-(3-
methoxyphenyl)-2-methylpentan-3-ol hydrochloride with an enantiomeric purity of
100% were obtained.

WE CLAIM
1. Method for the isolation of a stereoisomer from a mixture comprising the two
stereoisomers of the general formulae (I-A) and (I-A') and/or the two stereoisomers
of the general formulae (I-B) and (I-B')

in which
R1, R2 and R3, identical or different, are selected from the group consisting of -H, -
F, -CI, -C1-C6-alkyl, -S-C1-C6-alkyl, -OH, -O-C1-C6-alkyl, -O-C1-C6-alkylenephenyl, -
OCO-C1-C6-alkyl, -OCO2-C1-C6-alkyl, -OCON(C1-C6-alkyl)2 and -O-SiR8R9R10 (in
which R8, R9 and R10, identical or different, are -C1-C6-alkyl or -phenyl);
R4 is -H or -C1-C6-alkyl;
R5 is -C1-C6-alkyl; and
R6 and R7, identical or different, are -H or -C1-C6-alkyl;
wherein "C1-C6-alkyl" means a linear or branched, cyclic or open-chain saturated
hydrocarbon residue with 1 to 6 carbon atoms, optionally substituted with 1 to 6
halogen atoms, identical or different, selected from F, CI and Br; and
"C1-C6-alkylene" means a linear or branched, cyclic or open-chain saturated
hydrocarbon residue with 1 to 6 carbon atoms, optionally substituted with 1 to 6
halogen atoms, identical or different, selected from F, CI and Br;
or their salts with organic or inorganic acids;
comprising the steps
(a) manipulating the mixture ratio of the stereoisomers in the mixture so that at least
one of the stereoisomers is present in an enantiomeric excess, and

(b) adding phosphoric acid under conditions which bring about precipitation of the
stereoisomer present in enantiomeric excess from a solution as phosphate,
hydrogenphosphate or dihydrogenphosphate,
(c) separating the precipitated salt obtained in step (b) from the supernatant solution.
2. Method as claimed in claim 1, wherein that the manipulation in step (a) is carried out
- by addition of the stereoisomer which is to be present in excess, or
- by enantioselective synthesis of the stereoisomers.
3. Method as claimed in claim 1 or claim 2, wherein the enantiomeric excess is at least
1.0% ee.
4. Method as claimed in one of the previous claims, wherein R1 and R3 are in each case -
H and R2 is -OCH3.
5. Method as claimed in one of the previous claims, wherein R4 is -CH2CH3 and R5, R6 and
R7 are in each case -CH3.
6. Method as claimed in one of the previous claims, wherein it comprises the step
(c) separation of the precipitated salt obtained in step (b) from the supernatant
solution.
7. Method as claimed in claim 6, wherein it comprises the step
(d) conversion of the salt separated in step (c) into the hydrochloride.

ABSTRACT

Title: Separation of stereoisomeric N,N-Dialkylamino-2-Alkyl-3-Phenyl Alkanes
Method for the isolation of a stereoisomer from a mixture comprising the two
stereoisomers of the general formulae (I-A) and (I-A') and/or the two stereoisomers of
the general formulae (I-B) and (I-B')

in which
R1, R2 and R3, identical or different, are selected from the group consisting of -H, -F, -CI, -
C1-C6-alkyl, -S-C1-C6-alkyl, -OH, -O-C1-C6-alkyl, -O-C1-C6-alkylenephenyl, -OCO-C1-C6-
alkyl, -OCO2-C1-C6-alkyl, -OCON(C1-C6-alkyl)2 and -O-SiR8R9R10 (in which R8, R9 and
R10, identical or different, are -C1-C6-alkyl or -phenyl);
R4 is -H or -C1-C6-alkyl;
R5 is -C1-C6-alkyl; and
R6 and R7, identical or different, are -H or -C1-C6-alkyl;
wherein "C1-C6-alkyl" means a linear or branched, cyclic or open-chain saturated
hydrocarbon residue with 1 to 6 carbon atoms, optionally substituted with 1 to 6 halogen
atoms, identical or different, selected from F, CI and Br; and
"C1-C6-alkylene" means a linear or branched, cyclic or open-chain saturated hydrocarbon
residue with 1 to 6 carbon atoms, optionally substituted with 1 to 6 halogen atoms,
identical or different, selected from F, CI and Br;
or their salts with organic or inorganic acids;
comprising the steps
(a) manipulating the mixture ratio of the stereoisomers in the mixture so that at least
one of the stereoisomers is present in an enantiomeric excess, and
(b) adding phosphoric acid under conditions which bring about precipitation of the
stereoisomer present in enantiomeric excess from a solution as phosphate,
hydrogenphosphate or dihydrogenphosphate,
(c) separating the precipitated salt obtained in step (b) from the supernatant solution.

Documents:

04635-kolnp-2007-abstract.pdf

04635-kolnp-2007-claims.pdf

04635-kolnp-2007-correspondence others.pdf

04635-kolnp-2007-description complete.pdf

04635-kolnp-2007-form 1.pdf

04635-kolnp-2007-form 2.pdf

04635-kolnp-2007-form 3.pdf

04635-kolnp-2007-form 5.pdf

04635-kolnp-2007-international exm report.pdf

04635-kolnp-2007-international publication.pdf

04635-kolnp-2007-international search report.pdf

04635-kolnp-2007-pct request form.pdf

04635-kolnp-2007-translated copy of priority document.pdf

4635-KOLNP-2007-(23-07-2012)-ABSTRACT.pdf

4635-KOLNP-2007-(23-07-2012)-AMANDED CLAIMS.pdf

4635-KOLNP-2007-(23-07-2012)-ANNEXURE TO FORM 3.pdf

4635-KOLNP-2007-(23-07-2012)-DESCRIPTION (COMPLETE).pdf

4635-KOLNP-2007-(23-07-2012)-EXAMINATION REPORT REPLY RECEIVED.pdf

4635-KOLNP-2007-(23-07-2012)-FORM-1.pdf

4635-KOLNP-2007-(23-07-2012)-FORM-2.pdf

4635-KOLNP-2007-(23-07-2012)-OTHERS.pdf

4635-KOLNP-2007-(23-07-2012)-PETITION UNDER RULE 137.pdf

4635-KOLNP-2007-(26-07-2013)-CLAIMS.pdf

4635-KOLNP-2007-(26-07-2013)-CORRESPONDENCE.pdf

4635-KOLNP-2007-CANCELLED PAGES.pdf

4635-KOLNP-2007-CORRESPONDENCE OTHERS 1.1.pdf

4635-KOLNP-2007-CORRESPONDENCE OTHERS 1.2.pdf

4635-KOLNP-2007-CORRESPONDENCE.pdf

4635-KOLNP-2007-EXAMINATION REPORT.pdf

4635-KOLNP-2007-FORM 18.pdf

4635-KOLNP-2007-FORM 26.pdf

4635-KOLNP-2007-GRANTED-ABSTRACT.pdf

4635-KOLNP-2007-GRANTED-CLAIMS.pdf

4635-KOLNP-2007-GRANTED-DESCRIPTION (COMPLETE).pdf

4635-KOLNP-2007-GRANTED-FORM 1.pdf

4635-KOLNP-2007-GRANTED-FORM 2.pdf

4635-KOLNP-2007-GRANTED-FORM 3.pdf

4635-KOLNP-2007-GRANTED-FORM 5.pdf

4635-KOLNP-2007-GRANTED-SPECIFICATION-COMPLETE.pdf

4635-KOLNP-2007-INTERNATIONAL PUBLICATION.pdf

4635-KOLNP-2007-INTERNATIONAL SEARCH REPORT & OTHERS.pdf

4635-KOLNP-2007-OTHERS.pdf

4635-KOLNP-2007-PA.pdf

4635-KOLNP-2007-PETITION UNDER RULE 137.pdf

4635-KOLNP-2007-REPLY TO EXAMINATION REPORT.pdf

4635-KOLNP-2007-TRANSLATED COPY OF PRIORITY DOCUMENT.pdf

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Patent Number

257758

Indian Patent Application Number

4635/KOLNP/2007

PG Journal Number

44/2013

Publication Date

01-Nov-2013

Grant Date

31-Oct-2013

Date of Filing

29-Nov-2007

Name of Patentee

GRUNENTHAL GMBH

Applicant Address

ZIEGLERSTRASSE 6, 52078 AACHEN

Inventors:

#	Inventor's Name	Inventor's Address
1	HELL, WOLFGANG	MARSHALLSTRASSE 10, 52066 AACHEN
2	BUSCHMANN, HELMUT, HEINRICH	CL. DELS AVELLANERS, 11, E-08960 SANT JUST DESVERN

PCT International Classification Number

C07C 217/72

PCT International Application Number

PCT/EP2006/005101

PCT International Filing date

2006-05-29

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1	10 2005 024 824.1	2005-05-27	Germany
2	10 2005 033 732.5	2005-07-15	Germany