AU2003224108A1 - OPTICALLY ACTIVE Beta-AMINOKETONES, OPTICALLY ACTIVE 1,3-AMINOALCOHOLS AND METHOD FOR THE PRODUCTION THEREOF - Google Patents

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IN THE MATTER OF an Australian Application corresponding to PCT Application PCT/EPO3/04127 RWS Group Ltd, of Europa House, Marsham Way, Gerrards Cross, Buckinghamshire, England, hereby solemnly and sincerely declares that, to the best of its knowledge and belief, the following document, prepared by one of its translators competent in the art and conversant with the English and German languages, is a true and correct translation of the PCT Application filed under No. PCT/EPO3/04127. Date: 29 June 2004 S. ANTHONY Director For and on behalf of RWS Group Ltd (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (43) International publication date (10) International publication number 13 November 2003 (13.11.2003) PCT WO 03/093259 Al 1) International patent classification 7 : CO7D 401/06 (81) Designated states (national): AE, AG, AL, AM, AT, AU, AZ, BA, BB, BG, BR, BY, BZ, CA, CH, CN, CO, CR, CU, CZ, DE, DK, DM, DZ, EC, EE, ES, FI, GB, GD, GE, 1) International application number: PCT/EP03/04127 GH, GM, HR, HU, ID, IL, IN, IS, JP, KE, KG, KP, KR, KZ, LC, LK, LR, LS, LT, LU, LV, MA, MD, MG, MK, 2) International filing date: 22 April 2003 (22.04.2003) MN, MW, MX, MZ, NO, NZ, OM, PH, PL, PT, RO, RU, . SC, SD, SE, SG, SK, SL, TJ, TM, TN, TR, TT, TZ, UA, 5) Language of filing: German UG, UZ, VC, VN, YU, ZA, ZM, ZW. 6) Language of publication: German (84) Designated states (regional): ARIPO Patent (GH, GM, KE, LS, MW, MZ, SD, SL, SZ, TZ, UG, ZM, ZW), 0) Data relating to the priority: Eurasian Patent (AM, AZ, BY, KG, KZ, MD, RU, TJ, 102 19987.6 3 May 2002 (03.05.2002) DE Euran Patent (A , B, , , , , , TM), European Patent (AT, BE, BG, CH, CY, CZ, DE, DK, EE, ES, FI, FR, GB, GR, HU, IE, IT, LU, MC, NL, i) Applicant: AVENTIS PHARMA DEUTSCHLAND GMBH P PT, RO, SE, SI, SK, TR), OAPI Patent (BF, B J, CF, CG, [DE/DE]; Brflningstrasse 50, 95929 Frankfurt (DE). CI, CM, GA, GN, GQ, GW, ML, MR, NE, SN, TD, TG). 2) Inventors: JENDRALLA, Heiner; Ciolfstrasse 11, 65931 Published: Frankfurt (DE). SCHWAB, Wilfried; Am Ruhwehr 22, 65207 With the International Search Report. Wiesbaden-Naurod (DE). STUEDEMANN, Thomas; Luisenstr. 5a, 65779 Kelkheim (DE). For an explanation of the two-letter codes and the other abbreviations, reference is made to the explanations ("Guidance Notes on Codes and Abbreviations") at the beginning ofeach regular edition ofthe PCT Gazette. As printed (54) Title: OPTICALLY ACTIVE P-AMINOKETONES, OPTICALLY ACTIVE 1,3-AMINOALCOHOLS AND METHOD FOR THE PRODUCTION THEREOF (54) Bezeichnung: OPTISCH AKT1VE D-AMINOKETONE, OPTISCH AKTIVE 13-AMINOALKOHOLE UND VERFAHREN ZU DEREN HERSTELLUNG F3H Y". I'lR2 R3\ IyR2 , H R N N R 0 R R s R ' 1 RR I H H F1OH (,N R5 C4 4 H F 5 F ~ l R' R4 R 4 H (57) Abstract: The invention relates to chiral Mannich bases of formula (1),chiral 1.3 aminoalcohols of formula (1I) derived there !f from and a method for the production of (I) and (II), beginning with Mannich salts of formula (III) containing a chiral anion Y*". S(57) Zusammenfassung: Die Erfindung betrifft chirale Mannich-Basen der Formel (I), davon abgeleitete chirale 1,3-Aminoalko " hole der Formel (II) und ein Verfahren zur Herstellung von (1) und (Tl) ausgehend von Mannich-Salzen der Formnel (1I) enthaltend ein chirales Anion Y*-.

WO 03/093259 PCT/EPO3/04127 Optically active -aminoketones, optically active 1,3-amino alcohols and method for the production thereof Aminoalkylations of CH-acidic compounds have been known for about 100 years. 5 They are referred to as Mannich reactions and are one of the most important C-C bond forming reactions of organic chemistry. O RKN ,R 2 + direct N + R"KH H Mannich RN _2 reaction W Rs Retro Mannich 4 where R 3 H where R 3 H R (N 4 ) reaction N + s indirect Mannich .base NBKNrR,,..R + . , indirect RCH o R preformed preformed preformed imine iminiumsalt enolateequivalent (e.g. enamine or silyl enol ether) 10 in its original and most well-known form, the Mannich reaction is carried out with three reactants in the form of a "three-component coupling": an enolizable ketone, a nonenolizable aldehyde (frequently formaldehyde or an arylaldehyde) and an amine component (ammonia or a primary or secondary amine) react with one another to form a P-aminoketone. In this "Mannich base" the active hydrogen of the enolizable 15 ketone has been replaced by an aminoalkyl substituent. This direct variant of the Mannich reaction is particularly industrially attractive, because the three reactants specified are usually readily available and inexpensive, and at least very easily obtainable. Also, these reactants are generally not sensitive (i.e. have good storability) and therefore allow simple handling. Finally, the direct three-component 20 coupling of commercially available reactants is a single-stage, i.e. the shortest conceivable, synthesis of 1-aminoketones.

2 In addition, there are less industrially attractive indirect variants of the Mannich reaction in which preformed enolate equivalents (usually enamines or silyl enol ethers) are used. These compounds are generally not commercially available or are 5 expensive. Their preceding preparation is an additional synthetic step. Also, the trimethylsilyl enol ethers in particular and, to a lesser extent, the enamines, are acid and hydrolysis-sensitive, poorly storable and difficult to handle. Although silyl enol ethers having certain other silyl groups are more stable, they are more expensive to prepare. The high nucleophilicity of the preformed enolate equivalents has 10 advantages and disadvantages. On the one hand, it allows frequently mild reaction conditions and thus occasionally makes possible Mannich reactions which in the direct variant are accompanied by too many secondary reactions. On the other hand, the aminomethylations of preformed enolate equivalents are frequently low temperature reactions and therefore costly and inconvenient on the industrial scale. 15 Further disadvantages of stereoselective variants using preformed enolate equivalents are the use of industrially problematic Lewis acid catalysts, poor solubilities of reaction components at the low temperature and, for this reason, the necessity of using large amounts of solvent (poor space/time yields) or the use of problematic or expensive solvents. Iminium salts in the Mannich reaction are 20 distinctly more reactive (more electrophilic) than imines. This brings advantages and disadvantages which are similar to those described above for preformed enol equivalents. Asymmetric Mannich reactions are described, for example, in M. Arend et al. (Angew. 25 Chem. Int. Ed. Engl. 1998, 37, 1044-1070), which states on page 1067: "Despite many studies, and some notable successes, penetration into enantiomerically pure Mannich bases is still only beginning. [...] When one thinks of the many in situ racemization-free routes to derivatization of the kinetic products (to, for example, amino alcohols, diamines, amines etc.), it becomes understandable that the 30 possibility of developing efficient and effective routes to products of controlled absolute configuration may indeed be realizable. Catalytic processes, which are established in many other areas of stereochemistry, are almost completely untouched".

3 The use of stoichiometric amounts of chiral auxiliaries in an asymmetric Mannich reaction is described, for example, by H. Ishitani et al. (J. Am. Chem. Soc. 2000, 122, 8180-8186). This method has no industrial relevance, since the chiral auxiliary is covalently bonded to the preformed imine (or more rarely to the preformed enolate 5 equivalent), in order to conduct the Mannich reaction as a diastereoselective addition. Synthesis, linking and, after completed Mannich reaction, removal of the chiral auxiliary require a plurality of additional synthetic steps. The Mannich additions were in addition frequently low temperature reactions, and the chiral auxiliaries were difficult to obtain or only available in an absolute configuration. 10 Catalytic asymmetric Mannich variants were summarized by S.E. Denmark & O.J.-C. Nicaise ("Catalytic Enantioselective Mannich-Type Reactions" in Comprehensive Asymmetric Catalysis, E.N. Jacobsen, A. Pfaltz, H. Yamamoto, Eds.; Springer Verlag: New York, 1999; Vol. 2, Chapter 26.2.9; pages 954-958). The catalytic 15 variants are for the most part indirect Mannich reactions which limits their industrial attractiveness. Also, complicated chiral transition metal catalysts have to be used. Direct asymmetric three-component Mannich reactions using unmodified ketones can be induced by heteropolymetallic chiral catalysts based on lanthanides, although, as 20 described in S. Yamasaki et al. (Tetrahedron Lett. 1999, 40, 307-310), result in only moderate chemical yields (~ 16%) and enantiomeric excesses (~ 64% ee). The first direct catalytic asymmetric three-component Mannich reaction which comes near to fulfilling the industrial demands was reported only recently (B. List, J. Am. 25 Chem. Soc. 2000, 122, 9336-9337; cf. H. Grbger & J. Wilken, Angew. Chem. Int. Ed. Engl. 2001, 40, 529 - 532 ). In this reaction, unmodified ketones are reacted with aryl- or alkylaldehydes and certain aniline derivatives with catalysis using 35 mol% of (L)-proline in dimethyl sulfoxide or chloroform at room temperature to give optically active Mannich bases. The chemical yields were moderate to good (35-90%), and 30 the optical purities average to very good (73-96% ee). Mannich bases and their derivatives have numerous industrial applications which are summarized in M. Arend et al. (Angew. Chem. 1998, 110, 1096-1122) on page 1045. The most important field of use, in particular of chiral Mannich bases, is the 4 preparation of active ingredients for drugs, for example the neuroleptic Moban. On this subject, it is stated in Arend et al. on page 1047: "The classical Mannich reaction is not suited to the enantioselective synthesis of P-amino ketones and amino aldehydes. Thus, the majority of pharmaceutical products, which are derived from the 5 Mannich reaction, are used in the form of racemates. The application of enantiomerically pure Mannich bases is only possible when these are available by separation of the racemate. This problem becomes more severe when one takes into consideration the increasing importance of stereochemically pure pharmaceuticals (the avoidance of "isomer ballast" and of undesirable side effects)." 10 Racemic 1-amino ketones which can be described by a mixture of a compound of the formula (I) and its enantiomer R I-,R 2 N 0 R H R rac-(I) R 1 " " H " R 5

R

4 15 in which the substituents R 1 = phenyl, R 2 = H, R 3 = phenyl, R 4 = methyl and

R

s = phenyl, are described in T. Akiyama et al., Synlett 1999, 1045-1048; in which R 1 = p-tolyl, R 2 = H, R 3 = p-methoxycarbonylphenyl, R 4 = methyl and

R

s = phenyl are described in N. Shida et al, Tetrahedron Lett. 1995, 36, 5023-5026; 20 in which R 1 = phenyl, R 2 = H, R 3 = p-chlorophenyl, R 4 = methyl and R s = phenyl are described in CA120: 257988; in which R 1 = tert-butyl or phenyl, R 2 = R 3 = R 4 = methyl and R s = phenyl are described in E.G. Nolen et al., Tetrahedron Lett. 1991, 32, 73-74. 25 Chiral 1,3-amino alcohols, like, for example, the analgesic tramadol, are important as active pharmaceutical ingredients, and also as chiral auxiliaries for asymmetric syntheses, documented, for example, in S. Cicchi et al. ("Synthesis of new enantiopure P-amino alcohols: their use as catalysts in the alkylation of benzaldehyde by diethylzinc", Tetrahedron: Asymmetry 1997, 8, 293-301). 30 5 The limited diastereoselective reduction of Mannich bases with LiAIH 4 was described as early as 1985 by J. Barluenga et al. ("Diastereoselective synthesis of P-amino alcohols with three chiral centers by reduction of P-amino ketones and derivatives" J. Org. Chem. 1985, 50, 4052-4056). 5 Chiral 1,3-amino alcohols of the formula (II), , NxR 2 H O3H R 1 '' H R 5 (II "' H

R

4 10 i.e. with (SR,RS,SR) configuration could hitherto not be prepared with industrially usable diastereoselectivities from Mannich bases of the formula (I). The assignment of (R) and (S) configuration is based on the priority rules of Cahn, Ingold and Prelog. This prioritization may be reversed when one or more of the 15 substituents is modified. The designation (SR,RS,SR) states that in this compound the middle stereocenter (which bears R 4 as a substituent) has (R) configuration when the two outer stereocenters have (S) configuration (this is the configuration drawn in formula II), or else that the middle stereocenter has (S) configuration when the two outer stereocenters have (R) configuration (this is the mirror image of the 20 configuration drawn in formula II). The configuration of the stereoisomers depends on the selection of the chiral anion Y*" vide infra. The above-specified configuration designation (SR,RS,SR) relates to the model product as specified in the examples, but may be reversed in the case of other compounds or substituents. The stereochemistry of the compound of the formula (11) is reported unambiguously by the 25 structural formula (11). A multistage enzymatic method for producing chiral 1,3-amino alcohols starting from racemic butane-1,4-diols is described in the US patent US 5,916,786. 30 The carbonyl reduction of a-chiral P-aminoketones using LiAIH 4 (lithium aluminum hydride) or with hydrogen in the presence of platinum catalysts results preferentially 6 in the 1,3-amino alcohol dia-(ll) whose hydroxyl configuration is diastereomeric to formula (II) when the amino substituent is tertiary R<Nx/R 2 N OH R %

H

s dia-(Il) R4 5 and an approximately equimolar mixture of the diastereomers (Il) and dia-(Il) results when the amino substituent is secondary (M.-J. Brienne et al., Bull. Soc. Chim. France 1969, 2395; A. Andrisano & L. Angiolini Tetrahedron 1970, 26, 5247). 10 The patent application EP 1117645 describes optically active 1,3-amino alcohols of the formula (11) where R 1 = o-aminophenyl, R 2 = H, R 3 = R 4 = 2-pyridyl and

R

5 = phenyl or 3,5-dimethylisoxazol-4-yl which had previously been prepared by a classical optical resolution. 15 The present invention provides a compound of the formula (1) or its enantiomer R N/-R 2 N0 R H R RI R (I) R4 where 20 R 1 is 1. hydrogen, 2. a tert-butyl group or 3. a carbocyclic or heterocyclic aryl radical R 6 , where the aryl radical R 6 is a carbocyclic aryl radical having 5-14 carbon atoms or a heterocyclic aryl radical 25 having 5-14 carbon atoms, where from 1 to 4 carbon atoms are replaced by N, 0 or S, 7 where R 6 is unsubstituted or bears from 1 to 5 substituents which are each independently (C-C7)alkyl, (Cs-C 7 )cycloalkyl, alkanoyl (-CO-(Ci-C7)alkyl), aroyl (-CO-(Cs-C14)aryl), fluoro, chloro, bromo, iodo, hydroxyl, (Cl-C7)alkoxy, (C3-C7)cycloalkoxy, (Cs-C 1 4)8aryloxy, (Cl-C7)alkanoyloxy, (C 5

-C

14 )aroyloxy, 5 -O-CO-NHR, -O-CO-NRR', -O-CO-OR, -O-CO-SR, -O-CS-NHR, -O-CS-NRR', -O-CS-OR, -O-CS-SR, -O-SO 2 -(Cl-C7)alkyl, -O-SO 2 -(Cs-C 14 )aryl, nitro, -NH-CO-R, -NR'-CO-R, -NH-CO-OR, -NR'-CO-OR, -NH-CO-NHR, -NR' CO-NHR, -NR'-CO-NRR", di(Cl-C 7 )alkylamino, di(Cs-C14)arylamino,

N-(C

1 -C7)alkyl-N-(C 5 -C1 4 )arylamino, (Cl-C7)alkylthio, (Cs-C14)arylthio, 10 (Ci-C 7 )alkylsulfonyl, (Cs-C14)arylsulfonyl, (Cs-C14)arylsulfoxidyl, or an unsubstituted aryl radical R 6 , where R, R' and R" are each independently (C,-C 7 )alkyl, (C 3 -C7)cycloalkyl or

(C

5 -C14)aryl, 15 preferably an aryl radical having 6-10 carbon atoms, more preferably a carbocyclic aryl radical having 6-10 carbon atoms, more preferably a radical from the group of phenyl, naphthyl, anthracenyl, 20 phenanthrenyl, pyridyl, quinolinyl, isoquinolinyl, benzoquinolinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, tetrazinyl, benzopyridazinyl, benzopyrimidinyl, benzopyrazinyl (quinoxalinyl), benzotriazinyl, pyridopyridinyl, pyridoquinolinyl (phenanthrolinyl), benzoquinoxalinyl (phenazinyl), pyrrolyl, benzopyrrolyl (indolyl), benzoindolyl, pyrazolyl, benzopyrazolyl, imidazolyl, benzimidazolyl, triazolyl, 25 benzotriazolyl, tetrazolyl, imidazopyrimidinyl (9H-purinyl), furanyl, benzofuranyl, dibenzofuranyl, thiophene, benzothiophene, dibenzothiophene, isoxazolyl, benzisoxazolyl, oxazolyl, benzoxazolyl, oxadiazolyl, benzoxadiazolyl, thiazolyl, benzothiazolyl, isothiazolyl, benzisothiazolyl, thiadiazolyl or benzothiadiazolyl, 30 particularly preferably a radical R 7 where R 7 is defined as a radical from the group of phenyl, naphthyl, pyridyl, quinolinyl, isoquinolinyl or benzoquinolinyl, where R 7 is unsubstituted or is provided with up to 5 substituents which are each independently: (Cl-C7)alkyl, (C 3 -C7)cycloalkyl, fluoro, chloro, bromo, (CI-C 7 )alkoxy,

(C

3 -C7)cycloalkoxy, (C 5

-C

1 4)aryloxy, (C,-C 7 )alkanoyloxy, (Cs-C 14 )aroyloxy, -0- 8 CO-NHR, -O-CO-NRR', -O-CO-OR, nitro, phenyl, naphthyi, pyridyi, quinolinyl, isoquinolinyl, benzoquinolinyl, especially preferably a carbocyclic or heterocyclic aryl radical R 8 where R 8 is defined 5 as a radical from the group of phenyl, naphthyl, pyridyl or quinolinyl, and where R 8 is unsubstituted or provided with up to 5 substituents which are each independently: nitro, fluoro, chloro or bromo,

R

2 , R 3 and R 4 are each independently 10 1. hydrogen, 2. (Ci-C 7 )alkyl, where (C1-C 7 )alkyl is unsubstituted or substituted by an aryl radical R 6 , 3. (C 3

-C

7 )cycloalkyl or 4. an aryl radical R 6 , and 15 preferably each independently hydrogen or an aryl radical R 7 , more preferably each independently hydrogen or an aryl radical R 8 ,

R

5 is an aryl radical R 6 , preferably an aryl radical R 7 , 20 more preferably an aryl radical R 8 , excluding a compound of the formula (I) in which R 1 = o-aminophenyl or o nitrophenyl, R 2 = H, R 3 = 2-pyridyl, R 4 = 2-pyridyl and R 5 = phenyl or 3,5 dimethylisoxazol-4-yl. 25 Preference is given to a compound of the formula (1) as described above, excluding a compound of the formula (1) in which R 1 = o-aminophenyl or o-nitrophenyl, R 2 = H, R 3 = 2-pyridyl optionally substituted by methyl, fluorine or MeO, R 4 = 2-pyridyl optionally substituted by OH, CH 2 0H, MeO, CHO or NH 2 , and R- = phenyl or heteroaryl, where 30 phenyl and heteroaryl are optionally substituted by fluorine, chlorine, bromine, iodine, OH, NO 2 , (C 1

-C

7 )-alkyl, CHO, -(C=O)-(C 1 -Cs)-alkyl, (Cl-C 6 )-alkylthio or pyridyl. Alkyl and alkoxy radicals may be branched or unbranched.

9 Examples of (Cl-C7)alkyl radicals are methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl. Examples of (C 3 -C7)cycloalkyl are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 5 cycloheptyl, 2-methylcyclopentyl, 3-methylcyclohexyl. The invention also provides a compound of the formula (II) R N/-R 2 N H OH R I " '" H R 5

R

4 10 where the R 1 , R 2 , R 3 , R4 and R 5 radicals are each as defined in the compound of the formula (I), or its enantiomer or its salts, with the exception of a compound of the formula (II) where R' = o-aminophenyl or 0 15 nitrophenyl, R 2 = H, R 3 = 2-pyridyl, R 4 = 2-pyridyl and R 5 = phenyl or 3,5 dimethylisoxazol-4-yl. Preference is given to a compound of the formula (II) as described above, excluding a compound of the formula (11) in which R' = o-aminophenyl or o-nitrophenyl, R 2 = H, 20 R 3 = 2-pyridyl optionally substituted by methyl, fluorine or MeO, R 4 = 2-pyridyl optionally substituted by OH, CH20H, MeO, CHO or NH 2 , and R 5 = phenyl or heteroaryl, where phenyl and heteroaryl are optionally substituted by fluorine, chlorine, bromine, iodine, OH, NO 2 , (CI-C7)-alkyl, CHO, -(C=O)-(CI-C)-alkyl, (CI-Ce) alkylthio or pyridyl. 25 Over the entire application text, any stereochemical formula given refers either to the absolute configuration expressed by the stereochemical formula or its enantiomer, where the compounds are always present in an enantiomeric purity of greater than or equal to 90% ee, preferably greater than or equal to 95% ee, more preferably greater 30 than or equal to 98% ee. This applies in particular to the compounds of the formulae (1), (11) and (111).

10 Over the entire application text, a "classical optical resolution" is the separation of the image and mirror image of a racemic material by using a (substantially) enantiomerically pure auxiliary to form diastereomeric salts which, owing to differing 5 physical properties, for example different solubilities, are separated from one another without resulting in a (significant) conversion of the image to the mirror image under the conditions of the optical resolution. The maximum achievable yield of the enantiomerically pure material by means of a classical optical resolution is 50%. It differs fundamentally from the "dynamic optical cleavage" in which the image and 10 mirror image interconvert under the conditions of the optical resolution and thus enable yields of the enantiomerically pure material of up to 100% to be achieved. Dynamic optical resolutions may in principle be kinetically controlled or thermodynamically controlled. A group of reactions within the thermodynamically controlled dynamic optical resolutions are the crystallization-induced dynamic optical 15 resolutions. The examples described in the present invention belong to this group of reactions. It was found that, surprisingly, compounds of the formula (111) or their diastereomers (llI A), 20

Y

t - Y' H H R3 I.,R2 R3 I R2 N 0 N O R R 5 R R s

R

4 H

R

4 H (III) (111I A) salts of the P-aminoketones of the formula (I), whose cation has very high enantiomeric excesses and very high diastereomeric purity (syn/anti ratio), can be 25 prepared in high yield in a simple manner by direct four-component coupling based on a dynamic optical resolution. The cation of (Ill A) is the enantiomer of the cation (111). However, since the anion Y is homochiral, the compound (111 A) is a diastereomer to the compound (111).

11 The present invention therefore also provides a process for preparing a compound of the formula (Ill) or its diastereomer (111 A), Y H R> I R2 N 0

RR

5

R

4 H 5 (Ill) where the R 1 , R 2 , R 3 , R 4 and R s radicals are each as defined in the compound of the formula (I), and where the Y - anion is the conjugate base of an optically active, organic Bransted 10 acid (protic acid), preferably an optically active, naturally occurring or industrially prepared carboxylic acid, for example (R)-(-)-mandelic acid, (S)-(+)-mandelic acid, D-(-)-tartaric acid, L-(+)-tartaric acid, (+)-di-O,0'-pivaloyl-D-tartaric acid [(+)-DPTA], (-)-di-O,O'-pivaloyl 15 L-tartaric acid, [(-)-DPTA], (+)-O,O'-dibenzoyl-D-tartaric acid, (-)-O,O'-dibenzoyl-L tartaric acid, (-)-di-O,O'-benzoy-L-tartaric mono(dimethylamide), (+)-O,O'-dianisoyl D-tartaric acid [(+)-DATA], (-)-O,O'-dianisoyl-L-tartaric acid [(-)-DATA], (+)-di-O,O'-p tolyl-D-tartaric acid, (-)-di-O,O'-p-tolyl-L-tartaric acid, D-(+)-malic acid, L-(-)-malic acid, L-(+)-lactic acid, D-(-)-lactic acid, (S)-(-)-2-(phenylaminocarbonyloxy)propionic 20 acid, (R)-(+)-2-(phenylaminocarbonyloxy)propionic acid, D-(+)-gluconic acid, (-) 2,3,4,6-di-O-isopropylidene-2-keto-L-gulonic acid, (D)-(-)-quinic acid, (-)-3,4,5 trihydroxy-1 -cyclohexene-1 -carboxylic acid [shikimic acid], (S)-(+)-(2,2-dimethyl-5 oxodioxolan-4-yl)acetic acid, (+)-camphoric acid, (-)-camphoric acid, (1R)-(+) camphanic acid, (1S)-(-)-camphanic acid, (R)-(-)-O-acetylmandelic acid, (S)-(+)-O 25 acetylmandelic acid, (R)-2-phenoxypropionic acid, (S)-2-phenoxypropionic acid, (S) (+)-a-methoxyphenylacetic acid, (R)-(-)-a-methoxyphenylacetic acid, (R)-(+)-a methoxy-a-trifluoromethylphenylacetic acid, (S)-(-)-a-methoxy-a-trifluoromethyl phenylacetic acid, (S)-(+}-2-phenylpropionic acid, (R)-(-)-2-phenylpropionic acid, (R)- 12 (+)-2-chloropropionic acid, (S)-(-)-2-chloropropionic acid, (R)-(+)-N-(a-methylbenzyl) phthalic monoamide, (S)-(-)-N-(c-methylbenzyl)phthalic monoamide, (R)-(-)-5 oxotetrahydrofuran-2-carboxylic acid, (S)-(+)-5-oxotetrahydrofuran-2-carboxylic acid, D-(+)-3-phenyllactic acid, L-(-)-3-phenyllactic acid, L-(+)-a-hydroxyisovaleric acid, 5 D-(-)-a-hydroxyisovaleric acid, (+)-menthyloxyacetic acid, (-)-menthyloxyacetic acid, (+)-mono-(1S)-menthyl phthalate, (-)-mono-(1R)-menthyl phthalate, (+)-trans-5 norbornene-2,3-dicarboxylic acid, (-)-trans-5-norbornene-2,3-dicarboxylic acid, (R) (+)-methylsuccinic acid, (S)-(-)-methylsuccinic acid, (R)-(+)-6-hydroxy-2,5,7,8 tetramethyichroman-2-carboxylic acid [(R)-(+)-Trolox], (S)-(-)-6-hydroxy-2,5,7,8 10 tetramethylchroman-2-carboxylic acid [(S)-(-)-Trolox], (S)-(+)-2-(4-isobutylphenyl) propionic acid [(S)-ibuprofen], (R)-(-)-2-(4-isobutylphenyl)propionic acid [(R) ibuprofen], (+)-2-(6-methoxy-2-naphthyl)propionic acid [(+)-naproxen], (-)-2-(6 methoxy-2-naphthyl)propionic acid [(-)-naproxen], and also the available natural or unnatural a- or p-amino acids and their readily accessible derivatives, in particular N 15 acylated derivatives, or an optically active sulfonic acid, for example (1S)-(+)-camphor-10-sulfonic acid, (1 R)-(-)-camphor-10-sulfonic acid, (-)-3-bromocamphor-8-sulfonic acid or (+)-3 bromocamphor-10-sulfonic acid, 20 or an optically active phosphoric acid, phosphinic acid or phosphonic acid derivative, for example (R)-(-)-1,1'-binaphthalene-2,2'-diyl hydrogen phosphate, (S)-(+)-1 ,1' binaphthalene-2,2'-diyl hydrogenphosphate, (+)-phosphinothricin or (-) phosphinothricin, 25 or an optically active phenol, preferably (R)-(+)- or (S)-(-)-binaphthol, which comprises 30 converting the compounds of the formulae (IV), (V), (VI) and (VII) 13 O R< ~R 2 , l -N

R

s HY RI H H 4 (IV) (V) (VI) (VII) where the R', R 2 , R 3 , R 4 and R 5 radicals in the compounds of the formulae (IV), (V), (VI) and (VII) are defined as in the compound of the forumal (I), 5 in one or more suitable solvents or without solvent to the compound of the formula (Ill), by either reacting the compounds of the formulae (IV), (V), (VI) and (VII) at the same 10 time in a direct Mannich reaction, or initially reacting the compounds of the formulae (IV) and (V) to an imine of the formula (X) or to an aminal of the formula (Xl) which can optionally be isolated

,AR

2 H, N-"R2 R H RN H RA H N ' 15 (X) (XI) and then converting the compound of the formula (X) or (Xl) with the addition of the compounds of the formula (VI) and (VII) to a compound of the formula (Ill). 20 The above-described reaction to give a compound of the formula (111) is referred to hereinbelow as process step 1. In a preferred embodiment, the four components of the formulae (IV), (V), (VI) and (VII) and optionally a suitable solvent are introduced into a reactor and stirred. The 25 sequence of addition is uncritical. On a large scale, in particular when (IV) - (VII) are solids, it is most practicable to initially charge these reactants in the reactor and then 14 to feed in the solvent, if necessary with cooling. The reaction mixture is then heated to the desired reaction temperature. In the normal embodiment, a solution is initially present. However, in particular when one or more of the four components is sparingly soluble, the process step may also be carried out in such a way that the sparingly 5 soluble reactants only go into solution as the reaction advances. Owing to the crystallization of the salts (III) and (111 A) which sets in after a certain time, the latter case may result in a suspension being present over the entire course of the reaction. When the solution of the reactants (IV) - (VII) is initially clear and a sample is taken 10 from the reaction mixture immediately after the crystallization of the salts (111)/(Ill A), and this sample is filtered, the analysis shows that there is a small to moderate, but significant excess of the salt (111) over the diastereomeric salt (III A) in the precipitate. In contrast, the salts (111) and (III A) are present in the filtrate in a ratio of 1:1. In the further course of the reaction, the amount of precipitate increases continuously and 15 the ratio of (III) to (111 A) rises continuously, while it remains in the filtrate at 1:1. Finally, the reaction changes to a steady state in which neither the amount of precipitate nor the ratio of (Ill) to (Ill A) rises further. The amount of precipitate was generally 85-95% of theory and the enantiomeric excess of the Mannich base (I) in the (lll)/(Ill A) precipitate was 90-99% ee. 20 Owing to the retro-Mannich tendency of (111) and (111 A), it is generally not possible to determine the enantiomeric ratio by direct HPLC or DC analysis. Although determination by NMR is possible in principle, it is too inexact owing to signal overlapping. The best determination method is to derivatize the samples with 25 optically pure (+)- or (-)- camphanic chloride (VIII A) or achiral pivaloyl chloride (VIII B) by HPLC: 15 O (III) __ _ __ _ _ _N 0

R

5 (l)O R R

R'

1

NCIR

4 H R Cl R4(X) (VIII A): R = (-)-camphanyl O (VIII B): R = tert-Bu R3 R ( I I A ) R- - R H R4 (IX A) The N-acylated derivatives (IX) and (IX A) are stable and can no longer undergo a retro-Mannich reaction. The use of (-)-camphanic chloride has the advantage that the 5 derivatives (IX) and (IX A) are diastereomers and can therefore be separated on conventional HPLC columns having an achiral stationary phase. However, the method has the disadvantage that a (usually small) distortion of the stereoisomeric ratios (undesired kinetic optical resolution) may occur during the derivatization, since the reaction rates of (111) and (111 A) with this acid chloride are not identical. (111) and 10 (111 A) have to react with the achiral pivaloyl chloride (VIIll B) at the same rate, so that distortion of the stereoisomeric ratios can be ruled out in this case. However, the derivatization products (IX) and (IX A) in this case are enantiomers, so that an HPLC column having a chiral stationary phase is required for their separation. The analyses of a large number of samples show that the enantiomeric excesses determined using 15 (-)-camphanoyl chloride are distorted to give ee values which are worse by up to 4% compared to the more reliable determinations using pivaloyl chloride. As an example of the increase with time of the proportion of the product (111) at the expense of (Ill A) in the precipitate of a four-component coupling reaction, a reaction 20 was investigated in which R 1 = o-nitrophenyl, R 2 = 2-pyridyl, R 3 = H, R 4= 2-pyridyl,

R

5 = phenyl and HY = (+)-di-O,0'-pivaloyl-D-tartaric acid, and the solvent = ethanol, and the reaction temperature = 20-25*C.

16 IO -oo oo_ N N - - 2 - - 2 HO) N+ Ni H j * = (+)-dipivaloyl (Xll) (XII A) Table I: Progress against time of the formation of an exemplartratey compound of the N formula (III) as a ratio to its enantiomer 5 t [h]Content of (XII) Content of (XII A) [% ] [% ] 2 1 62.68 37.32 46 67.27 32.73 62.5 69.67 30.33 rNN 130 78.40 21.60 154.5 83.68 16.32 177Y 86.74 13.26 202 89.99 10.01 Ni -2 L kt-J2 (XII) (XII A) Table 1: Progress against time of the formation of an exemplary compound of the 225formula () as a ratio to its enantiomer5.11 5 t [h] Content of (XII) Content of (XII A) 1%] [%] 2971 62.68 3.0932 46322 97.67 2.33 62.5 69.67 30.33 130 78.40 21.60 154.5 83.68 16.32 177 86.74 13.26 202 89.99 10.01 225 94.89 5.11 297 96.91 3.09 322 97.67 2.33 17 In the precipitate (Xll)/(XII A) there are two cations for each (+)-DPTA anion. In this experiment, the reaction mixture was stirred using a Teflon-coated magnetic stirrer bar in a round-bottom flask. The first sample taken after 21 hours contained (111I) and (Ill A) in a ratio of 62.7:37.3. After 322 hours, the ratio was 97.7:2.3. This 5 corresponds to an enantiomeric excess of the underlying free base of 95.4% ee. The higher the reaction temperature, the more rapid the rise in the (XII)/(XII A) ratio in the precipitate of the four-component coupling, which also exhibits a distinct dependence upon solvents and upon the nature of the chiral Brensted acid (VII). 10 For optimum results, preference is given to carrying out the process step 1 according to the invention with the use of a stirrer which ensures particularly efficient mixing and comminution of solid particles in the reaction suspension. The process step 1 may be carried out in water, with or without the addition of 15 organic solvents and/or solubilizers, or, when one or more of the reactants (IV) - (VII) is liquid at the reaction temperature, may also be carried out in the absence of solvents ("neat"). A suitable solvent is water or an organic solvent, or a mixture of water with an 20 organic solvent, optionally containing a solubility-enhancing additive, for example a phase transfer catalyst, where organic solvents may be present in 100% purity or technical quality, for example a C 1

-C

8 -alcohol, branched or unbranched, preferably methanol, ethanol, n-propanol, isopropanol or n-butanol, or a ketonic solvent, preferably acetone or methyl ethyl ketone (MEK), or an ester, preferably ethyl acetate 25 or n-butyl acetate, or an ether, preferably tetrahydrofuran, methyl tert-butyl ether, diisopropyl ether, 1,2-dimethoxyethane or diethylene glycol dimethyl ether (diglyme), or a hydrocarbon, aliphatic or aromatic, preferably toluene, or a supercritical medium, preferably supercritical carbon dioxide or a halogenated hydrocarbon, preferably dichloromethane, or a polar, aprotic solvent, preferably DMF, DMSO or NMP, 30 and water present in the reaction is optionally removed, for example, by azeotropic distillation or by adding water-binding additives, for example magnesium sulfate or activated molecular sieves.

18 The reaction is carried out at from -15°C to +1400C, preferably at from +10*C to +100°C, more preferably at from +30*C to +70°C. The process step 1 may be carried out at atmospheric pressure, under reduced 5 pressure (vide supra, for example for the purpose of distilling off an azeotrope) or under pressure, the latter for the purpose of reaction acceleration, in an inert gas atmosphere or under air. The process step 1 according to the invention is carried out using 0.80-2.00 molar 10 equivalents of the reactants (lV) and (V), and also 0.80-4.00 molar equivalents of the chiral acid (VII), based in each case on reactant (VI). Preference is given to carrying out the process according to the invention using 0.95-1.30 molar equivalents of the reactants (IV) and (V), and also 1.00-2.00 molar equivalents of the chiral acid (VII), based in each case on 1.00 molar equivalents of the reactant (VI). Particular 15 preference is given to carrying out the process according to the invention using 1.00-1.25 molar equivalents of the reactants (IV) and (V), and also 1.05-1.50 molar equivalents of the chiral acid (VII), based in each case on 1.00 molar equivalents of the reactant (VI). 20 Table 2 shows the results of four-component couplings to give a compound of the formula (Ill) using (+)-dipivaloyl-D-tartaric acid [(+)-DPTA] as the chiral acid (VII) 19 O~ OO *D H3C'-H - HIC H \H O N HO O H3 +. o + + H 3C CH,

H

2 H 0 0 0

H

3 C OH 3 - 2 and using typical laboratory glass reaction vessels (up to 0.5 mol in multineck round bottom flasks, above 0.5 mol in cylindrical jacketed reactors rounded at the bottom) 5 equipped with motor-driven mechanical stirrers (up to 0.5 mol using a precision glass stirrer having Teflon paddles; above 0.5 mol using a steel turbine stirrer).

o ao 0)CD 0: C) 0) 00) ~ fu'Wi T ,0 ~ . OR4~ = r. 0 c G o ) rL~~~" a CO l) t'tt > >i -yr >N > > MCU ,AD ' 0 Cc ta No CU 0! 0o co) 5fN c z-~2>- ~~co co 0D co .C U' -z ) toc~ cc. _ Ecc C) C2 a) 0 zoE E) 0 0 0 'DC > (D m Cu) . (D r_ C c > Cl -. wr mr a_ _ _ __ _ _ _ O- 0(t let E 'z >0U .2 M CD :110E 00 SE 09q oP >. C)t) .t -2 CtD -e7 0 ( N E1 0 .o - L .-.- E C:t (6t Ctr ,-~ oNo..c Ct) Cj CL :3 tfl crcc, Ty E Nf cf) t ) M a.> 0) "Y 0 _ _ _ _ M CD0)0 a_ ~ N "DL) Mc -0) - -K .40) Lo oL r)nne 9 O "0) 0(D )c 00 n C'i co _ l -- c)(1 ) ( o* 0_ 0j L 0 rr ca -O0 Lo 0) 0 0)0 COL 004 'aD cu C)c C ) -5 -d C. co a)a)4 c C2 m )C Lo C 75 C%4 m a __ ; C N 0o EI o N> c6q Cc 00. ?t , N- CC4 It, N>w IflCA C N00g 00 ItOC C~ 0 iT 40 L a) E O E- _ _ _ _ _ _ 22 Four-component couplings corresponding to the above-described reactions were carried out to give compounds of the formula (llI) using S-(+)-mandelic acid. 0O 0N+'O 0 0 0. O OH H 0 _ N- NH 2 0 0, NO2 N2O HO 5 Table 3 shows the results of four-component couplings where R 1 = o-nitrophenyl,

R

2 = 2-pyridyl, R 3 = H, R 4 = 2-pyridyl, and R s = phenyl, and in which S-(+)-mandelic acid was used as a Bronsted acid (VII): 00 V 9' - N z, C) g;0rC sC 1 C)0) CD 0 D. C) _ _ _ _ _A c A C0) a) 0) 10) 0) a) > CV) r CD N! LO) cc r- r- LOin O rl I 0) 0) 0)D c 0) 0D 0) (n L6 CO CD l. LO CF)0 o0 o ) C CDc.. 0) 0) OO60 r-- ' t mL.. "C' P. CCrO u .. Ccu cu __ L__cc 0) .. ~0 .. C N V.. ?a) a aC)c5N4.I.O. E' CR C o0) ~ V CD m. 10 CO) 0- CN TDC 2 - S N tU"A 0 mc r- t c w ___ IT to 0 F i c, rcv) cv6 4 C6 6 z. 12 cu Oc 0 C% 0" to0 ca )01 0 0 0 0 0 0 0 0 ~ CD CO C> C) . C) C) (0 cc L cc co 0- 0D q0 ) 0) I) CD C""E L6 )g N CD D " C C) 0j g o6 o) 0 ~ 0 ) L6 C E m EE T- N LO~C 064. ) NO C%4 La Cr CD002Nr)Ul 0 C C.f I0 0 0N*C C 0C mC C 0 ~ E E Nr4c- ra4(D-r'.- C T- CNv-~- Lr T ___ :5r HZ - w Cn C) 0S CO N-) It 00 s CD It 0) 0) 0) 0) 0) A) zz: ) 10) a) 0) 0) A) 0 cc a.c 'V.0 m F )C N F c N C N c Nt tomCtN - It = 0 0) 6) a) N N I- N ( CL cc _o 0 om 0)m~ N- ),m 3 "" . . . o' . . c N - 0 TC N cn ( N - (D--MM t 0 -1 N 0- C- r CV -6 0 0 o 0 04~- Pa al - QUc- 0NQW U , QW QU 0~ QC) 0LUOg 9 N-. 0 . .IN + 05 N1 .- fo ,LO C) 60 0O0 C:O 00 0.C 0 tO r'~LO Lt')O CS) I E0 mNIEIL C) NCN- N 22 .)II0CD r- U)0 010.C DC 0n C0 C) E_ _ c gi qN (6 o CN C) - 0 OEw--' 6 N NV HZ 0) a) n- .,-~tU) ) 0 LO) 'tj C) i- M in__ __ A Im C c I C) Co ) C c) () C ) >D L IO C V) No m 0)0) 0) 0) C) 0) C 0) v j (C DV a)cE N m o~ Nq t I- N 14 =t LI0 CWN U- aON N C") La) N N __ _ __ ) Na )0) a) CF~ ) -0 r 0Nr N N co) CO 75 76 CD Na)) C6 0) CO 0)r C6 CO C -C 0 Cl) c c. CD C C N r_ F- - - - -o D to -c 1- (D LOo i5 ro C14Q 0 )0 oa=o a a a o o a M2 C2 0 0 0) 0 (woD 0 cc Cv50 N: 0 0 0( C0 LI) C) C) 5L). EtD COP V) rN- o CC)co ( ot 0 CP - N 9 r o NQ) r~ +N U) c0 N 0 0 0 CD 0 0) *I) CDLI) c0et ) - SE EN No Cq CDCOC'Q ) C14ItC C C a) 0 VO 0 0 0 V0 CIO C 00) E0 606 q0 0 LoC mC w C CE E w-rC% wnr rN -r U -N r -D C%4 LIC t ) CD Nl 19t C 0 N H 1 rO (D LO C r r- N,, NO N O -C t 0 C0 C) CF) A wJ> CL ca ~ O v O C))0 0 0 0 C 0C W00 > 0) a)y cv a..o 0) C UL Et Eo ____ cr crg LU 2C 0nGc :5 cc CfI 27 Four-component couplings using (+)-DPTA, (S)-(+)-mandelic acid or (-)-malic acid were carried out in the ten reactors operated in parallel of an Argonaut Surveyor Reaction Screening System in accordance with the reaction conditions summarized in Tables 4 and 5 and in different solvents. In these reactors, mixing is effected by 5 piston activated magnetic agitation. Mixing is distinctly more efficient than that of magnetic stirrer bars or of precision glass paddle stirrers and slightly more efficient than that of turbine stirrers. Table 4 shows the results of four-component couplings using (+)-DPTA, (S)-(+) 10 mandelic acid or (-)-malic acid: 0) 0 >- ~ CD-N N CN L6 Ni 6 N w N 0 C - to I n~U CN-4 r (1) "O CC ND o r r r r 16 N---N tooC toP' (rD0 (D OD~~~rC)" CCC 'LO0OD N D coI c qOD C Me ~ V CO ItOmCqr LODOL (0D Orr)t Cr. OjRRco P rIMcO 5cocto CD GoN-r < ccco e coo90cr, CDCc 04 o: 0 CC1 D0 V tCM (I 0 M N00lq l a)a 0, (Dc Zc )() oI LO 0 a)C )C or '' C) 0 V QoM 00 - C) fl ' N-C' 0 0 2 c '- C1 N r-_ CJ ( o D C N- C r 66 tT- 0 C., cu 2) a) C (D 0D C ECu ( 0) 0) 0) U) cmU)I C)c e ce) 0)Cm0Q Oc I OC4m0 J% (0 corc 0 pc q)) 0r) N4 02N r.. 20 ) 0 0C'0 o m 14 ce' ) N -U)LOLX) o S CO Nr C NN m )0 l-c 1 0D -i) C r:qCV )C 0C c 0 0 >4~ Ct OC N r3 0 00 0 U) 7 'ir) cci 2 orc 'o LLr fN02)00 V ) (D 0) cu CD)C)cuQ Q ) D( f 0 U 4-I 30 Table 5 shows four-component couplings using (S)-(+)-mandelic acid in various solvents in the surveyor screening system: Table 5 mol. eq. Mass Yield Solvent ee (HPLC) Ratio mandelic acid [g] % of theory [%] (I) / (VII) ['H NMR] 2.00 2.51 86.0 EtOH,MEK 95.2 1: 1 2.00 2.52 86.3 EtOH,toluene 94.4 1 : 1 2.00 2.39 81.8 EtOH, abs. 94.8 1 : 1 2.00 2.52 86.3 n-BuOH 96 1 : 1 2.00 2.75 94.2 i-PrOH 94 1: 1 2.00 2.24 76.7 MeOH 98.6 1: 1 2.00 1.49 51.0 MEK 97.4 1 : 1 2.00 1.92 65.8 Acetone 97.8 1 : 1 2.00 2.55 87.3 n-BuOAc 96.0 1 : 1 2.00 2.40 82.2 MeOH 98.6 1: 1 1.1 2.35 80.6 MeOH 95.0 1 : 1 1.2 2.44 83.5 MeOH 94.8 1 : 1 1.5 2.49 85.2 MeOH 95.2 1 : 1 2.0 2.57 88.0 MeOH 93.2 1 : 1 1.1 2.40 82.3 EtOH,MEK 91.2 1 1 1.2 2.48 85.0 EtOH,MEK 91.8 1 : 1 1.1 2.59 88.8 i-PrOH 92.0 1 1 1.2 2.69 92.2 i-PrOH 93.4 1 1 1.5 2.71 92.7 i-PrOH 93.0 1 1 2.0 2.40 82.2 i-PrOH 94.3 1 : 1 1.1 2.29 78.4 n-BuOAc 90.8 n.d. 1.2 2.53 86.6 n-BuOAc 94.0 n.d. 1.5 2.45 83.9 n-BuOAc 94.4 n.d. 2.0 2.57 88.0 n-BuOAc 96.0 n.d. 1.5 2.58 88.4 EtOH,MEK 93.6 n.d. 2.0 2.48 84.9 EtOH,MEK 93.0 n.d. 1.1 2.52 86.3 n-BuOH 92.4 n.d.

31 Table 5 mol. eq. Mass Yield Solvent ee (HPLC) Ratio mandelic acid [g] % of theory [%] (I) / (VII) [H NMR] 1.2 2.52 86.3 n-BuOH 95.4 n.d. 1.5 2.63 90.1 n-BuOH 96.4 n.d. 2.0 2.40 82.2 n-BuOH 95.0 n.d. 1.5 13.08 89.5 MeOH 91.2 n.d. 1.5 9.67 66.2 Acetone 94.6 n.d. Unless otherwise stated in the tables, the product (111) was isolated by cooling the suspension to room temperature, followed by filtration and washing of the solid with a little cold solvent. 5 In methanol at 60'C, the combined four-component coupling/dynamic optical resolution proceeded very quickly. After only one hour, the underlying free Mannich base (I) of the precipitate (111)/(111 A) had achieved an enantiomeric excess of 92.6% ee (Table 3, line 2) and, after a maximum of 3 hours, the reaction was completed at 10 97.3% ee (Table 3, line 1). Owing to the more efficient mixing, up to 98.6% ee was obtained in the Surveyor Screening System (Table 5). Owing to the not inconsiderable solubility at room temperature of (Ill) in methanol, the yields were at least 10% below those in ethanol. Even at only 30 0 C, the reaction in 15 methanol was completed within 15 hours (Table 4). In ethanol, the reaction at 40'C required 44-53 hours (Table 3, lines 4 and 5). Yields (up to 95.3% of theory) and enantiomeric excesses (approx. 95% ee) were high. At 60'C, the reaction in ethanol was completed after only approx. 4 hours when two equivalents of mandelic acid were used. Yields (up to 92.6% of theory) and enantiomeric excesses (up to 97.5% 20 ee) remained high (Table 3, lines 6-8). When the reaction was carried out at very high concentration, the reaction rate fell somewhat, while yield and ee fell marginally (Table 3, line 9). Using 1.5 equiv. of mandelic acid, the reaction at 60"C in ethanol required approx. 7 hours and led to only slightly lower yields and ee values (Table 3, lines 10 and 11). Using 1.10 equiv. of mandelic acid (Table 3, lines 12 to 14) and 25 using only 1.05 equiv. of mandelic acid (Table 3, lines 15 to 16), the phenomenon was again observed that an ee obtained at 60*C in ethanol distinctly worsened on 32 cooling the suspension to RT (before filtering off the product with suction). Standing overnight may result in an ee reduction of 8% (line 16). However, when the cooling of the suspension and the filtering off with suction of (I1) were effected rapidly, an 88% yield and 95.4% ee were obtained even when only 1.05 equiv. of mandelic acid were 5 used (line 15). In the case of reactions using 2.0 equiv. of mandelic acid, such ee deteriorations on cooling did not occur. An aliquot of the reacted reaction suspension (60 0 C, ethanol) was withdrawn and stirred at room temperature for 72 hours. The enantiomeric excess and the syn/anti ratio afterwards were unchanged. The reaction may be carried out with similar success in relatively long-chain branched 10 or unbranched alcohols, for example isopropanol (Table 3, line 17, Table 5) or n butanol (Table 3, lines 18 and 19; Tables 4 and 5). It also succeeds in ketonic solvents, for example acetone (Table 3, lines 20 and 21; Table 5) or methyl ethyl ketone (MEK, Table 5), in esters, for example ethyl acetate or n-butyl acetate (Table 3, lines 22 and 23; Table 5) and in halogenated hydrocarbons, for example 15 dichioromethane. The reaction can in principle be carried out in ethers, for example tetrahydrofuran, methyl tert-butyl ether, diisopropyl ether, 1,2-dimethoxyethane, or diethylene glycol dimethyl ether (diglyme), in hydrocarbons, for example toluene, and also in 20 supercritical media, for example supercritical carbon dioxide. The use of solubility enhancing additives, for example phase transfer catalysts or cosolvents may be advantageous. The reaction can be carried out in polar, aprotic solvents, for example dimethylformamide (DMF), dimethylacetamide (DMA), dimethyl sulfoxide (DMSO) or N-methylpyrrolidinone (NMP). The yields isolated in these solvents are competitive 25 when the solubility of (111) in them is not too high. The reaction tolerates a content of moisture. Comparison of Table 3, line 4 with line 5 and of Table 5, lines 1-3 shows that absolute ethanol offers no advantages over technical, or MEK- or toluene-denatured ethanol. In some examples, the observation 30 was made that when solvents were used which form low-boiling azeotropes with water (for example ethanol), continuous azeotropic distilling off of the water of reaction formed in the Mannich reaction at atmospheric pressure or under a reduced pressure leads to significant to moderate reaction acceleration. This may be utilized 33 to optimize the space-time yield and, owing to the relatively short thermal stress, occasionally be used to improve the chemical purity and isolated yield of the product. Similar results can also be obtained by water-binding additives, for example dried 5 magnesium sulfate or activated molecular sieves. However, the exclusion of water and/or the removal of the water of reaction formed are necessary neither for the practical quantitative progress of the four-component Mannich coupling, nor for the progress of the dynamic optical resolution. Tables 1-5 confirm that when the necessary reaction times are accepted, the product (111) may also be obtained in very 10 high yield, chemical purity and with high enantiomeric excess when undried apparatus and undried solvents are used and the resulting water of reaction is not removed. In accordance with Tables 2-5, the relative molar amounts of the four reactants 15 (IV)-(VI) can be varied within considerable intervals without any resulting negative effects on yield, chemical purity or enantiomeric excess of the product (111). Using 1.00 equivalents of the CH-acidic components (VI) as the basis in each case, the amounts of the remaining reactants used in the specific examples (Tables 1-5) were varied within the following intervals: aldehyde (IV): 1.00-1.20 equivalents; amine (V): 20 1.05-1.25 equivalents, chiral acid (VII): 1.05-2.00 equivalents. The most important factor for the efficiency of the dynamic optical resolution in process step 1 is a good choice of the chiral acid HY* of the formula (VII). In all fields of stereochemistry, there is now a consensus that there is no optimum chiral auxiliary 25 per se or an optimum chiral ligand per se, nor can there be one. The extent of asymmetry of reactions rather depends upon the specific reactant/auxiliary and product/auxiliary interactions ("chiral recognition"). Which chiral acid (VII) delivers an optimum result within the process according to the invention thus depends on the specific nature of the substituents R 1 to R s and has to be determined, generally 30 experimentally, in each case independently for each combination of the reactants (IV) to (VI). This may be achieved in the following way: a) The racemic free Mannich base rac.-(1) is prepared. This may be effected particularly simply by one of the two following alternative routes: 34 al) The four-component Mannich coupling is carried out in a similar manner to process step 1, except that the reactants (IV), (V) and (VI) are used with only catalytic amounts of an achiral acid in a solvent in which the Mannich base rac.-(I) has only moderate solubility. In many cases, the use of approx. 1 mol% of 5 p-toluenesulfonic acid hydrate in the solvent ethanol has proven useful. The free Mannich base rac.-(I) then crystallizes out of the reaction mixture sometimes in very high yields and may be isolated by filtration. Example 3 describes a corresponding procedure. a2) The four-component Mannich coupling is carried out in a similar manner to 10 process step 1, except that the reactants (IV), (V) and (VI) are carried out using stoichiometric or greater than stoichiometric amounts of an achiral acid in one of the abovementioned solvents suitable for process step 1. In this case, a salt similar to the formula (I11) is obtained in which the cation is racemic and the anion Y- is achiral. This salt rac.-(lll) is the converted to the free racemic Mannich base 15 rac.-(I) in a similar manner to process step 2. b) A solvent is found in which rac.-(I) is averagely to moderately soluble (preferred solubility approx. 1-5% by weight) and in which its retro-Mannich reaction proceeds as slowly as possible. To select this solvent, various alternative physical or chemical methods are available: 20 bl) Rac.-(I) is dissolved in appropriate perdeuterated solvents and the retro-Mannich rates in each case are monitored by repeatedly analyzing the solutions by 'H or

"

3 C NMR at short time intervals; b2) Rac.-(I) is dissolved in solvents to obtain real time monitoring of the retro Mannich reaction with the aid of a ReactlR probe, or by analyzing the solution in a 25 cuvette in a conventional two-beam IR instrument at regular time intervals, using in each case an identical cuvette filled with the pure solvent in the reference beam. b3) Rac.-(I) is dissolved or suspended in aprotic solvents which are compatible with an amidation reaction using acid chlorides. Immediately after they are prepared, 30 the solutions or suspensions are reacted with pivaloyl chloride (VIII B) to give the racemic pivaloyl derivative (IX)/(IX A). The slower the retro-Mannich reaction in the particular solvent, the higher the yield and purity of the amide (IX)/(IX A) achieved. Example 4 describes a corresponding procedure.

35 In the examples investigated hitherto, it has been found that the retro-Mannich tendency of the salts of structurally analogous Mannich bases with Bronsted acids (formula Ill) under identical conditions (same solvent, same temperature, same Bronsted acid) is supported by electron-donating substituents in the aldehyde 5 component of the formula (IV). Electron-withdrawing substituents in the aldehyde component of the formula (IV) reduced the retro-Mannich tendency. The 1H NMR monitoring of the syn/anti-isomerization of a syn-Mannich salt of the formula (111) via retro-Mannich reaction at 300 K in DMSO-d6 solution can be seen in Example 28. As can be seen from Example 27, good choice of the reaction parameters in the four 10 component coupling results in Mannich salts in excellent yield with very high diastereomeric and enantiomeric purity of the underlying Mannich base even when the aldehyde component contains electron-donating substituents and the retro Mannich tendency is high. 15 In the above-described examples, it has been found that the retro-Mannich reaction of free Mannich bases rac.-(I) frequently proceeds very slowly in acetone. c) A screening of all available optically active Bronsted acids HY (VIl) with regard to efficiency of a classical optical resolution is carried out with the solution or suspension of rac.-(1) in the solvent obtained according to b). To this end, when 20 the substituents R' to R s contain no basic centers, the freshly prepared suspension of rac.-(l) is reacted with 1.0 molar equivalent of the acid (VII) when (VII) is a monobasic acid, or with 0.5 molar equivalent of the acid (VII) when (VII) is a dibasic acid. When the substituents R 1 to R s contain basic centers, more molar equivalents of the acid (VII) are correspondingly added. The mixture is 25 stirred for approx. 20 h at room temperature, the precipitated salt (I11) is isolated by filtration and the enantiomeric ratio present in the underlying free base (I) is determined by derivatizing to (IX)/(IX A), followed by HPLC analysis (vide supra). The chiral Bronsted acids (VII) selected are those which deliver the highest (IX):(IX A) ratios, preferably (IX):(IX A) _ 95:<: 5 in the screening. Example 6 30 describes a representative experimental procedure for such a screening. d) Further selection may be effected among the optically active Brensted acids (VII) selected according to c) in order to very substantially fulfill the following criteria for particularly preferred acids (VII): - Y - has a stable configuration under the reaction conditions; 36 - it leads to a maximum difference in solubility between its two diastereomeric salts (Ill) and (111 A) - it effects a very low solubility of the desired diastereomer of the formula (Ill) and a very high solubility of the undesired diastereomer of the formula (111 A) 5 - the racemate of the salt of the formula (III) (1:1 mixture of salt (111) and its mirror image) crystallizes as a conglomerate. A conglomerate consists of a mixture of two mirror image crystal structures of which one crystal structure corresponds to the crystal structure of the optically active salt (Ill). In the conglomerate, not only the enantiomeric molecules, but also the two crystal 10 structures as supramolecular constructions are mirror images of one another. The two crystal structures in the conglomerate differ not only in the chirality of the molecules. The crystal packings, i.e. the three-dimensional periodic arrangements/stackings of the molecules in the two crystal structures are also mirror images. 15 - it catalyzes the four-component Mannich reaction which leads to the formation of (111) and (111 A), - it catalyzes the retro-Mannich reaction of the more soluble diastereomeric salt (IllI A), i.e. the cleavage of the salt (III A) to the enolizable ketone (VI) and the iminium salt R'CH=N'R 2

R

3 Y*- or its dissociation products, the aldehyde (IV) 20 and the salt of the amine (V) with HY. When the free Mannich base of the formula (I) crystallizes as a conglomerate, the present invention also encompasses a special embodiment in which the three component coupling and the dynamic optical resolution may be carried out in the absence of a chiral auxiliary acid HY*. In this embodiment, the solution of the three 25 components (IV), (V) and (VI), optionally in the presence of catalytic amounts (approx. 1-10 mol%) of an achiral acid, for example p-toluenesulfonic acid, is seeded with crystals of optically pure free Mannich base. Owing to the conglomerate effect (preferential crystallization), only this antipode of the free Mannich base can crystallize out of the reaction solution and is continuously formed from the mirror 30 image remaining in the solution. When this continued formation is rapid compared to the crystallization rate of the desired antipode, the boundary concentration of the wrong antipode at which it would also start to crystallize is never reached in the course of the reaction. For this reason, the precipitate at the end of the reaction consists exclusively of the desired antipode and the chemical yield may approach 37 100%. This asymmetric transformation of the 2nd kind without the necessity of a chiral auxiliary is referred to by the term "total spontaneous resolution" (E.H. Eliel, S.H. Wilen "Stereochemistry of Organic Compounds", John Wiley, New York, 1994, page 316 ; Y. Okada et al, J. Chem. Soc., Chem. Commun. 1983, 784 - 785). 5 In a further variant of the process step 1 according to the invention, the imine (X) is initially formed from the reactants (IV) and (V), and only then is the CH-acidic ketone (VI) added, which leads in the presence of a suitable optically active acid (VII) to the formation of the Mannich salt (III) with dynamic optical resolution. It will be 10 appreciated that it is also possible to form the imine (X) from the aldehyde (IV) and the amine (V) in a known manner, catalyzed by an acid which may be achiral, for example approx. 1 mol% of p-toluenesulfonic acid hydrate, and to isolate the imine. Such a procedure is described in Example 9. The imine (X) may then be reacted afterwards with the ketone (VI) and the optically active acid (VII) to give the Mannich 15 salt (Il1). Some of the disadvantages of the indirect Mannich reaction are avoided when a solution of the imine (X) is initially formed by heating the aldehyde (IV) and an at least equimolar amount of the amine (V) in one of the abovementioned suitable solvents, 20 more preferably n-butyl acetate, and azeotropically distilling off the resulting water of reaction, preferably under reduced pressure. Particular preference is given to carrying out this reaction step in an apparatus/a reactor which has the function of a water separator, i.e. after condensation of the azeotropic vapor and subsequent phase separation, the organic solvent having a lower specific gravity flows 25 automatically back into the reactor, while the water is retained in the separator. Once the theoretical amount of water has separated, 0.80-2.00 equivalents of the CH acidic ketone (VI) and 0.80-4.00 equivalents of the chiral acid (VII) (based in each case on the aldehyde (IV)), preferably 0.95-1.30 equivalents of (VI) and 1.00-2.00 equivalents of (VII), more preferably 1.00-1.25 equivalents of (VI) and 1.05-1.25 30 equivalents of (VII), are added to the reaction solution, and it is optionally further heated until the enantiomeric purity in the precipitate (111)/(III A) which appears after a short time has reached its maximum owing to the proceeding dynamic optical resolution.

38 As can be seen from Table 3 (No. 22, 23), when R' = o-nitrophenyl, R 2 = 2-pyridyl, R 3 = H, R 4 = 2-pyridyl, R 5 = phenyl, HY* = (S)-(+)-mandelic acid and the solvent was n butyl acetate, the normal four-component coupling at 60*C resulted in the Mannich salt III in an isolated yield of 84.6% of theory and in 95.1% ee. In contrast, when the 5 n-butyl acetate solution of the imine (X) was initially formed in the manner described, the Mannich salt (Ill) was obtained in a yield of 93.1% of theory in 96.7% ee when heating to 60*C was effected immediately after adding (VI) and (VII). A particularly high yield of 93.4% of theory and 98% ee was achieved when heating was initially effected only to 40*C (commencing precipitation) after addition of (VI) and (VII), and 10 the temperature was raised to 60 0 C only after 4 h. In contrast, the normal four component coupling resulted in parallel formation and reaction of the imine (X). In the present example, an investigation in a Mettler reaction calorimeter RC1 with real time monitoring of the progress of the reaction by ReactlR probe showed that in no phase of the four-component coupling was there any accumulation of more than 40% of the 15 theoretical amount of the imine (X) in the reaction mixture. Furthermore, the duration of the thermal stress there on significant amounts of the imine (X) is substantially shorter. In a further procedure variant of the process step 1 according to the invention, the 20 aminal of the formula (XI) may also be initially formed (Example 10) and then, either after intermediate isolation or in the original reaction solution, be reacted with the ketone (VI) and the acid (VII), optionally with the addition of an additional equivalent of the aldehyde (IV), to give the Mannich salt (111). In this procedure variant also, (111) is isolated in optical yields which approach those of the four-component coupling 25 (Tables 2 to 5). In all of the procedure variants of the process step 1 according to the invention mentioned here, the high optical activity of the Mannich salt (Ill) is based on the occurrence of a dynamic optical resolution. The process step according to the 30 invention thus differs fundamentally from the four-component Mannich reaction described by B. List (J. Am. Chem. Soc. 2000, 122, 9336-9337). The latter concerns a catalytic asymmetric Mannich reaction, i.e. the addition step of an enamine resulting from the condensation reaction of the CH-acidic ketone (VI) with the catalyst (L)-proline, to the imine (X) which results from the condensation reaction of the 39 aldehyde (IV) with the amine (V) with direct formation of the free Mannich base (I) is asymmetric. For this reason, only approx. 35 mol% of (L)-proline are used in the List reaction. The reaction product present in solution is already optically active and, according to the present level of understanding, the optical purity of the product does 5 not fundamentally change during the progress of the reaction. In contrast, the process step 1 according to the invention is not cardried out with "catalytic" amounts of the chiral acid (VII): when less than 0.8 molar equivalent of a monobasic acid (VII) or less than 0.4 molar equivalent of a dibasic acid (VII) is used, the isolated yields of the Mannich salt (Ill) inevitably fall to less than 70% of theory and are then no longer 10 industrially acceptable. Since the addition of the ketone (VI) to the imine (X) of the chiral acids (VII) which is formed in situ in the reaction mixture is not significantly asymmetrically induced, the ratio of the Mannich salts (111):(Ill A) in the solution is about 1:1. The optical purity in the Mannich salt (111) which has crystallized out also rises continuously over the entire course of the reaction. 15 The chiral acids (VII) of the process step 1 according to the invention may be obtained virtually quantitatively in a simple manner and in unchanged optical purity, and be reused in the next batch. Multiple reuse of the chiral auxiliary (VII) on repeated batchwise performance of the process step 1 means that the Mannich salt 20 (11I) can be prepared with substantially less than 0.35 mol% of (VII) gross. B. List (J. Am. Chem. Soc. 2000, 122, 9336-9337) also reports that the reaction only succeeds with proline and fails with even very closely related analogs of proline. In contrast, owing to its different type of mechanism, the process step 1 according to 25 the invention succeeds with a very wide variety of sometimes very structurally different acids (VII). For example, Tables 2 to 5 show that the same Mannich base could be prepared in high optical purity using (S)-(+)-mandelic acid, (+) dipivaloyltartaric acid or (L)-(-)-malic acid. It is also of industrial interest that (S)-(+) mandelic acid and (L)-(-)-malic acid have a price comparable to that of (L)-proline, but 30 the enantiomeric compounds (R)-(-)-mandelic acid and (D)-(+)-malic acid are substantially cheaper than (D)-proline. Significant advantages of the present process step 1 over the List reaction are the very wide variety of usable solvents, the isolation of the optically active Mannich salt (Ill) without workup (by simple filtration), and the 40 high isolated chemical yields (85-95% of theory). These properties are all confirmed by the examples in Tables 2 to 5. IN O0 ++ HIN N NH 2 (XIII) (XIV) (XV) 2-nitrobenzaldehyde 2-aminopyridine O- H HO H O NH2 OzN H 0 L-proline 0 2 N 0 2 N N-" N (XVI) (XVIll) 5 An asymmetric Mannich reaction experiment to give a compound of the formula (Ill) where R 1 = o-nitrophenyl, R 2 = 2-pyridyl, R 3 = H, R 4 = 2-pyridyl and R s = phenyl, and where L-proline was used as the transferor of the chiral information, was carried out by weighing 493 mg (1.00 equiv.) of the ketone of the formula (XV), 294 mg 10 (1.25 equiv.) of 2-aminopyridine (XIV) and 453 mg (1.20 equiv.) of 2 nitrobenzaldehyde (XIII) into each of the 8 glass reactors of a Surveyor Reaction Screening System. Also, 101 mg (0.35 equiv.) of L-proline were weighed into each of reactors 1-5 and 7, and 576 mg (2.00 equiv.) of L-proline were each weighed into reactors 6 and 8. 10 ml of the solvent specified in the table were then added in each 15 case. Reactors 1-6 were stirred at room temperature (22 0 C), and reactors 7-8 at 40°C internal temperature. After the specified reaction times, withdrawn samples were derivatized with camphanoyl chloride (VIII A), and the resulting isomeric amides (XVII), (XVII A), the anti-isomer of (XVII), and the anti-isomer of (XVII A) were quantified by HPLC. 20 Table 6 shows the results of an attempted asymmetric Mannich reaction using L-proline.

41 Table 6 Ratio [%, HPLC] ent- Molar equiv. ent- trans- t- t [h] T [*C] No. Solvent Molar equiv. (XVII) trans- of L-proline (XVII) (XVII) (XVI) - - - - 19 22 - - - - 40.5 - .5 1 Aceton 0.35 - - - 53 - - - - 131 49.7 47.8 1.2 1.2 19 22 51.1 47.6 0.6 0.7 40.5 2 Methanol 0.35 2 Methanol 0.35 51.9 47.4 0.3 0.5 53 56.0 43.7 0.1 0.2 155 - - - - 19 22 - - 40.5 3 DMSO 0.35 - - - 53 - - - - 131 - - - - 19 22 19.1 19.1 24.3 37.6 40.5 Dichloro- - 0.35 ..... 4 0.35 23.3 21.6 24.1 31.0 53 methane 24.9 22.6 23.1 29.4 131 50.5 49.5 - - 19 22 48.9 47.1 1.7 2.3 40.5 Ethanol 0.35 5 Ethanol 0.35 49.5 47.9 1.1 1.6 53 55.3 43.8 0.4 0.5 155 48.9 45.9 2.4 3.4 19 22 48.4 47.4 1.6 2.5 40.5 6 Ethanol 2.00 6 Ethanol 2.00 49.5 46.7 1.6 2.2 53 54.1 45.4 0.3 0.1 155 50.4 48.0 0.7 0.8 18 40 54.9 45.1 - - 131 7 Ethanol 0.35 49.8 48.7 0.6 0.8 18 40 52.6 44.7 2.4 0.3 131 8 Ethanol 2.00 5 Under the conditions explicitly described in J. Am. Chem. Soc. 2000, 122, 9336-9337 and under closely related variants of these conditions, no preparatively usable results are achieved. Under the preferred conditions (35 mol% of (L)-proline in acetone or DMSO solvent at room temperature), neither the Mannich base nor its enantiomer had been formed in significant amounts after reaction times of from 19 hours to 131 10 hours (Table 6, No. 1 and 3). In the methanol and ethanol solvents not specified by 42 List, the use of 35 mol% of (L)-proline at room temperature leads to the formation of the virtually racemic Mannich base within 19 hours (Table 6, No. 2 and 5). Only on continued stirring of the reaction mixture over 155 hours does the Mannich base formed attain a low, but significant enantiomeric excess (approx. 12% ee) with the 5 simultaneous disappearance of the small amounts of the trans-isomer originally present (Table 6, No. 2 and 5). An increase in the reaction temperature (ethanol, 40°C) does not increase the enantiomeric excess of the Mannich base achieved after 131 hours (Table 6, No. 7). Even using 200 mol% of (L)-proline in ethanol both at room temperature and at 400C results in only a small optical purity of the Mannich 10 base obtained (8-9% ee, Table 6, No. 6 and 8). When 35 mol% of (L)-proline are used in a dichioromethane solvent at room temperature, there is approximately twice as much trans-isomer as the desired cis-isomer of the Mannich base up to a reaction time of 40 hours. Only after 131 h have the amounts of trans- and cis-isomer become equal. No significant enantiomeric excesses are achieved by either diastereomer 15 over the entire period (Table 6, No. 4). Conditions have also been found under which a P-aminoketone of the formula (1) can be obtained from the compound of the formula (111) without significant loss of the stereochemical purity. 20 The invention further provides a process for preparing an optically active 13 aminoketone (Mannich base) of the formula (I) or its mirror image RK xR 2 N R 0 RI R s R4 H (I) 25 where the R', R 2 , R 3 , R 4 and R 5 radicals are each as defined above, which comprises 43 converting a compound of the formula (ill) in a suitable solvent by adding a suitable base. Suitable bases are organic amines, preferably (C 1

-C

10 )trialkylamines, preferably 5 (C 1

-C

3 )trialkylamines, for example triethylamine or diisopropylethylamine, and also alkali metal or alkaline earth metal hydrogencarbonates, carbonates or hydroxides. Suitable solvents are water or organic solvents, or a mixture of water with an organic solvent, optionally a solubility-enhancing additive, for example comprising a phase 10 transfer catalyst, where organic solvents may be present in 100% purity or in technical quality, and may be, for example, a Ci-Cr-alcohol, branched or unbranched, for example methanol, ethanol, n-propanol, isopropanol or n-butanol, or a ketonic solvent, for example acetone or methyl ethyl ketone (MEK), or an ester, for example ethyl acetate or n-butyl acetate, or an ether, for example tetrahydrofuran, methyl tert 15 butyl ether, diisopropyl ether, 1,2-dimethoxyethane or diethylene glycol dimethyl ether (diglyme), or a hydrocarbon, aliphatic or aromatic, for example toluene, or a supercritical medium, for example supercritical carbon dioxide or a halogenated hydrocarbon, for example dichloromethane, or a polar, aprotic solvent, for example DMF, DMSO or NMP. 20 (I) may be liberated from (11l) within the temperature range from the melting point to the boiling point of the solvent (or solvent mixture), for example from -30 to 100C, preferably from 0 to 400C, more preferably from 0 to 250C. 25 The liberation of the Mannich base (I) from the optically active Mannich salt (111) under complete retention of configuration is a nontrivial process step, since it has to be carried out under conditions under which 1. there is no deprotonation of the C-H acidic a-position to the keto function in (111) or (I), since this would lead to the formation of the undesired anti-diastereomer of (111) 30 or (I), and 2. there is no retro-Mannich cleavage of (Ill) or (I), since this would lead to yield loss, the formation of chemical impurities, the formation of the undesired anti diastereomer and also partial loss of the optical purity of the Mannich base (I).

44 The liberation may in principle be carried out in those organic solvents, preferably in acetone, in which the retro-Mannich cleavage proceeds very slowly (vide supra), with the use of bases, preferably triethylamine, diisopropylethylamine, alkali metal or alkaline earth metal hydrogencarbonates or carbonates which can deprotonate the N 5 H acidic ammonium group, but not the C-H acidic a-position of (111I) or (I). The liberation may further be carried out in an aqueous medium, and using as bases, for example, alkali metal or alkaline earth metal hydrogencarbonates, carbonates or hydroxides, preferably under pH-stat conditions at a pH of approx. 8-9. Preference is 10 given to sodium hydrogencarbonate or sodium hydroxide under pH-stat conditions at a pH of approx. 8-9, and particular preference is given to sodium hydroxide. Since the solubility both of the Mannich salts (111) and of the free Mannich bases (I) is usually very low in weakly basic water, the liberation reaction leads to conversion of a 15 suspension of the salt (111) to a suspension of free Mannich base (I). After the end of the reaction, the product (I) may therefore be isolated by simple centrifugation or filtration. Owing to the low solubility, only a very small proportion of the reactant (111) is ever present in solution, and only for a short time, since the free base (I) formed precipitates out again immediately. For this reason, the retro-Mannich reaction plays 20 virtually no role in aqueous media. The isolated yield of free base (I) in the cases investigated was 95-100% of theory, the content of the anti-diastereomer under the optimized conditions at 0.7-1.5% was unchanged within the margin of error compared to that of the Mannich salt (Ill) used, and the enantiomeric excess of (I) in the optimized procedure fell by less than or equal to 2%, preferably 1%, ee compared to 25 the salt (Ill) (Table 7). In the case of salts of the formula (11) which are insufficiently soluble in pure water to be deprotonated by bases such as NaOH or NaHCO 3 or Na 2

CO

3 at a usable rate to give (I), one or more organic, water-miscible solvents may be added in amounts of 30 < 25% by volume, preferably 1-10% by volume, more preferably 5-10% by volume (for example methanol, ethanol, isopropanol, n-propanol, acetone, tetrahydrofuran). Preference is given to adding 1-10% by volume of the cosolvent to the solvent in which the preceding four-component coupling (process step 1) has been carried out, as long as this solvent is water-miscible. Particular preference is given to using 45 methanol, ethanol, n-propanol or isopropanol both as the solvent for the four component coupling and as the cosolvent for the liberation of (I) in the aqueous medium. Very particular preference is given to using the Mannich salt (11l) dampened with alcohol, as obtained in the centrifugation, without preceding drying, for the 5 liberation in the aqueous medium. Whether, and to what extent an organic cosolvent has to be added to the aqueous suspension of (111) depends upon the solubility and aqueous wettability of (111), and also upon the nature of its substituents R 1 to R 5 and its anion Y*-. Preference is given to minimizing the cosolvent addition to such an extent as can be reconciled with an acceptable liberation rate under pH-stat 10 conditions. An unnecessarily high cosolvent addition to the aqueous medium may reduce the isolated yields of free Mannich base (I) or make a more complicated isolation of (I) necessary (distilling the cosolvent out of the reaction suspension before centrifuging off the solid for the purposes of complete precipitation of (I) in the suspension). Also, an unnecessarily high cosolvent addition may promote the retro 15 Mannich reaction during the liberation under pH-stat conditions and.thus worsen yields, chemical purity, diastereomeric purity and enantiomeric purity of the product (i). NO2HO M. I (XVIl) (XVii) 20 The liberation of a Mannich base of the formula (I) is illustrated hereinbelow using the example of a reaction of a compound of the formula (I) where R 1 = o-nitrophenyl,

R

2 = 2-pyridyl, R 3 = H, R 4 = 2-pyridyl and R s = phenyl (compound of the formula (XVII)), in which (XVII) has been liberated from the corresponding mandelate salt of 25 the formula (XVIII) under various conditions. aI 46 Table 7 shows the results of the conversion of the compound (XVIll) to compound

(XVII):

0 a) CC 2 0 C OCL CO in oz- C 0 04 0 X (1 a. a) 'a) ta E (0 oi 2) n )mr o3 a) 'D LOca I 0 C 0) 0anC. =S w CD rm0 : Eo 2=1 >) C1 > M - w-a0 c L -D ' w ~ 9 ) a~0 ' w) U) v W =D L AI -Cj V) - 0) -0 0 -o-1) D4)a )q 0 -0 - r0 -= C/) a aU aDC4C3 Du z z: z Wq- nC F or mE'0Z2 CUO CLUc LU O u0) 0)i U) o 2 Z O-o E000 n )C CC cN(' CD 0_ _ _ 0__CD__0 .4D kb a c6rl o- 0 a ' z 2 LX [L. 3 -. Pcr..L- (NJ 0o C . 0 Z " =!c 2- CD 0 co - be 0D ru 0 a) Cc o 0) to0): o~ (D CD o CDC>C CDC' 0 - 0 .E, )00= 0__ _ _ 0_ _ _ _ 0 C4 =___ -9 -a Va-I CD Mo 16 . Vo m C4C 4 a = o 03 a)( D.a ( n 0 - (D a) ciw X , 0V r 0 w) to (10 =V ( aum r3 CU1 0: 0 D V 0 0 CU D L C V aa a) a X) U)___ _ _ __ __ __ __ __ _ __ a)0 0 E ejC NoID' Z z Z EN STO 0in0 mcc Om O&'u~ z z z co~ RD0 aL a ~aCla 0 E E 0 L) > >Q (62 (00 x 0 a C aC cZ (D__ __ W_ _ _ _ qr__ _ Q 0 0 LO rci 8-EgP 0) w) - ' C - .c6 CU a6~ =3 = .- . (1) 01 .0 C Z- -> 2 xo'~z'oor &4 oL > ca~ Z~, om co CDC 0 CIS C" CLlOk V go E c- E i C -~I ~ 4C t wn nD Z0 o o 0 (D OLD Ott Z DiV) 0 xz o z Z z3 LL Lo u,0.cz 0 Vi W ' o aEo ~ r ) C U ra(1 -) 0 .If 3 4 4o ir Cc 4) CCa E (D CDa CL0 N ) cc ( o F 0 >Z 2_ __ _ E_ _ _ 0_ _0__0 0N 6 U) . C)JU E--c4JWNcm v52 o c6 Cci 2x > X 075 C) 0) EL > -0>7 CD= 0V -' 00 cE Co :3 -0- Uc!0c v- cu 0 6Dm i 2 0 - ,E F aA & A Lr) m -U) LL X.Z 2 g FTv V.)C> vO0 0 6 m e:3 0-a , r- 0 21) C) W z C I __ 0400 0 0)a)c c Cff C4 bC ) C Co CL ar rCu CU 0a Pa :rX P L ( n -1 :6 (D C CD 0 M 0 0 C/ cC%4 04C HZz z__ _ _ _ _ _ _ M- L) E LL (DU > _0 I0 0 > EE P E 20000 LA 05U0 2 c >5 E E~ E c ca ) C) 2Es 0 0 0 0) 0)0 CO 0Z 'J~ E0 0U CL= a: 0 c o04 s0T 0N 0u r) > 0 CD . ' E- g.E'O R=3X D MU Z) V

)

o_ U) z60)h 0 3t TU0Ct.in0 ::z w 0r3 0O 0D7 0. ot 0) ''0L0 -0 0 ( d ) c N D C )0W( In (na) ( C) 4) 0_ _ __ _ _ (D 0 3 (1 >. C4 C >

-

Oj) t __ __ __ z- z w : . E ) -a) a0) LO a > 26E 0 CO 0 a)D 0Y 0. 0f Hz '- c4- W 0n Q) -. C14 m .c .2 >c 0 - Q) Q U- 0 54 0 0C ~> E' .

L6 ( Z) 00 0).L - aC6 d) Cl c a. m) 0 - e0 EE 0rC)~ 0 d -D 6CF A C (U 6- - L)~U w 0 03CL= r-CL co 0 w E .jO 0~ =~ (UD Or CL)1 U)- C 4 Cfl- D ca. 0~ C ) .~ >.. c' a Cc' . 0 &V&O 0 0 V 0 V >) EV)64 n rq m c; c; 1- 0 C 6-6 o 1- ( -2 X, 00)D a> N) (3) >) E ) r (L CD V> uo 0 c6 0 00)T (D to C) 0 0 c0 o..ckA 6-0 m .0 - ±N -Z-:cu 5;C) LCU> Z2R C(.O> ) 0 :Eli. (a c0 .. vL.n ( U '§ =- 0 r- a 0aW m 23 C Ec Lo 0 E Lo - ' E. 0 16 C W U)W~ o~U cociX:C U) U) _ _ _ _ _ ;-- M5 m*5m5m cw ULE 00)3 (U W CU Cc 00 0 "V 2) aw 0 2U a -) 0 0 0-) a; a N t 0) 0 m c C3O 0)- 0 ' 0' 10(V E (D 12 .!n 0Z -3 0) N c> - -02 -6 a)~ EL > -5I > E 0 6 2 CY) a. ) 0 0) 0X Lo n x/ r N ,v .2 L)L.V -rC C I.- COC -- C a.) 5OwO CQ VCR E0V -r-V t Ca 00 A ~C N'Z 0 0) 00*-- 0 C 0-a - r.L.

V;L ~ca -0- 5; Cr0) ' r 0 WQ) 5C1r: 0) ) 0L)-M 0 fi) wU) TIW. U)) V m )oa a. CoC 0) L Vo 0) c 1 0 o (1 c) 0 C C, LO) U) 0 . 5 0 0 9 a) 0 0 O N O (A 0o U )- U) 10 U) 7- o a <) 0 0< a)) 0 o aD o0V)0C N 0 L >~ E X E _ __o__ n H Z _ _ _ _ _ _ _ _ _ __M 4- Lo C 10 a4- w.E4 t5~ -0 > 0, 2>u X 0 S ) 0 n C w2 =m( 0 _ ) M V .- cC 0 0D Q.4-'0 CDj) zCU J m ~ . mL mU( -r- go2r_ FD - .c oc a) 0I W 0 0 r o, CL: caCODt U Z . U)U) W UJA C L 00>0

-

cc .. O C 0- -FD --D (D 0 0pC 10 0'L gn u

I-.I

4--6 r ) U- 0 c >_ _ _ _ -o 0 01 o~~ C. E 0 to10 o HZU_ __ _ _ __ _ _ _ 56 In the reactions described in Table 7, 0.95-1.10 equiv. of 2N sodium hydroxide solution were added all at once at 0 0 C or room temperature to a suspension of (XVIII) in pure water, which resulted in the quantitative liberation of (XVII), which was, however, accompanied by the formation of from 5 to 10% of the anti-diastereomer of 5 (XVII) (No. 1-5 and 8-11). Depending on the specific reaction conditions, the reduction in the enantiomeric excess of (XVII) was either only minimal (No. 1), slight (No. 2, 4, 5, 9-11) or distinct (No. 3 and 8). Immediately after the entire amount of sodium hydroxide solution had been added in one portion, the hydroxide ion concentration was therefore so high that not only did the desired deprotonation of the 10 ammonium function of the Mannich salt (XVIII) occur, but the undesired deprotonation of its C-H-acidic a-position to the carbonyl group also occurred to a considerable extent. Since the resulting enolate ion of (XVII) is not reprotonated stereospecifically, but to a 15 similar extent on both sides of the enolate plane, both (XVII) and its-anti-isomer are formed. When the stirring time after the sodium hydroxide solution addition was limited to 1 hour at room temperature, only 1.3-3.7% of the anti-isomer was formed (No. 6 and 7), but the degree of liberation in this time was only approx. 20%, and in one of the experiments, the enantiomeric excess of the salt (XVIlI) (96.2% ee) also 20 fell by 7% to only 89.0% in the free base (XVII) (No. 6). When 2 equivalents of sodium hydrogencarbonate were added at 0 0 C instead of sodium hydroxide solution to the aqueous suspension of the mandelate (XVIII), only 2.4% of liberation occurred within 14 hours (No. 12), but the product filtered off with 25 the suction as the (XVIII)/(XVII) mixture contained no increased amount of anti isomer. Equally, only 11-13% of liberation occurred when 1 equivalent of 2N sodium hydroxide solution was metered very slowly into the purely aqueous suspension of (XVIIlI) over 5 hours at 0 0 C (No. 13 and 15). 30 However, the addition of 5 or 10% by volume of acetone to the liberation using 2 equivalents of NaHCO 3 effected quantitative formation of the free base (XVII) with complete retention of the enantiomeric purity and without significant increase of the anti-isomer, not only at 0 0 C (No. 14, 16, 17, 22), but also at 10OC (No. 23), at room temperature (No. 18), and at 40'C (No. 24). Marginally even better results were 57 achieved using sodium hydrogencarbonate in water/ethanol (10:1) at room temperature (No. 19). Equally good results were achieved when 0.95-1.00 equivalent of 2N sodium 5 hydroxide solution was metered at pH 8.5 (using an autoburette under pH-stat conditions) into the suspension of (XVIII) in water/ethanol (10:1) (No. 20, 21, 25, 26). Retention of the enantiomeric and diastereomeric purity appeared to be slightly better at room temperature (No. 20 and 21)than at 4 0 *C (No. 25 and 26). 10 The process step 2 according to the invention offers the possibility of substantially recovering in unchanged enantiomeric purity the optically active acid HY of the formula (VII) used during the four-component coupling from the weakly basic, aqueous mother liquor of the liberation reaction. The preferred method for this purpose depends upon the solubility, and also on the chemical and optical stability of 15 the chiral acid in aqueous acidic media. In the case of acids (VII) which are very insoluble in water at approx. pH 3, it is generally sufficient to acidify the mother liquor and centrifuge off or filter off the precipitated solid (VII). When an a-amino acid has been used as the chiral acid (VII), it is generally sufficient to acidify the aqueous mother liquor of the liberation step to the isoelectric point of the a-amino acid and 20 then to centrifuge off or filter off the solid. When the chiral acid (VII) has a not inconsiderable water solubility, as in the case, for example, of tartaric acid, malic acid or mandelic acid, or there is a risk of partial racemization under too strongly acidic conditions, the preferred recovery method is frequently extraction from the weakly acidified aqueous mother liquor. For example, the recovery of (S)-(+)-mandelic acid 25 by ethyl acetate extraction succeeds in 88% yield, > 99.5% chemical purity and 100% ee. In the event of very high water solubility, mineral acid sensitivity or a high cost of the chiral auxiliary, other recovery methods, for example freeze drying of the neutralized 30 aqueous mother liquor of the liberation reaction, also come into consideration. Furthermore, a simple reduction method has been found by which p-aminoketones of the formula (I) or their salts of the formula (Ill) can be reduced with very high diastereoselectivity to 1,3-amino alcohols without losing the stereochemical purity 58 already present in the compounds of the formula (I) or (Ill) or having to use any chiral auxiliaries. The present invention therefore also provides a process for preparing an optically 5 active 1,3-amino alcohol of the formula (II) or its mirror image R< IR 2 N H OH R R5 R4 H (II) where the R 1 , R 2 , R 3 , R 4 and R s radicals are each as defined above, 10 which comprises reducing a compound of the formula (I) or a compound of the formula (Ill) with a suitable reducing agent. The compound of the formula (II) may then be worked up by methods known per se. 15 The conversion of a compound of the formula (I) to a compound of the formula (II) is referred to hereinbelow as process step 3. The conversion of a compound of the formula (III) to a compound of the formula (II) is 20 referred to hereinbelow as process step 4. Suitable reducing agents are borane or borohydride reagents, optionally in the presence of a chiral catalyst. 25 The process step 3 according to the invention achieves a distinct diastereoselection in the reduction of the keto group of optically active a.-aminoketones (1) in favor of 1,3-amino alcohols of the formula (II) when using borane or borohydride reagents. The diastereoselective reduction of (I) to (I) may be achieved using achiral reducing 30 agents (principle of simple diastereoselection) or in the presence of optically active 59 catalysts, and in the latter case, the enantioselectivity of the catalytically active reagent overlaps the simple diastereoselection and usually dominates. In the case of reduction in the presence of optically active catalysts, high diastereomeric excesses are achieved when the enantioselectivity of the chiral catalyst coincides with the 5 simple diastereoselectivity of the reduction (matched case). Lower diastereomeric excesses are obtained when the catalyst has the opposite absolute configuration and its enantioselectivity therefore counteracts the simple diastereoselectivity (mismatched case). 10 Examples of achiral reducing agents (principle of simple diastereoselection) include: 1. a borane-sulfide complex, for example borane-dimethyl sulfide or borane-1,4 thioxane complex; 2. a borane etherate, for example boron-tetrahydrofuran complex; 3. catecholborane; 15 4. a borane-sulfide complex or a borane etherate or catecholborane in the presence of a Lewis acid, for example titanium chloride triisopropoxide (iPrO)3TiCI; 5. a borane-amine complex, for example borane-ammonia, borane-tert-butylamine, borane-N,N-diethylaniline, borane-N-ethyldiisopropylamine, borane-N 20 ethylmorpholine, borane-N-methylmorpholine, borane-morpholine, borane piperidine, borane-pyridine, borane-triethylamine or borane-trimethylamine complexes; 6. a borane-amine complex in the presence of a Lewis acid, for example titanium chloride triisopropoxide (iPrO) 3 TiCI; 25 7. a borane-phosphine complex, for example borane-tributylphosphine or borane triphenylphosphine complexes; 8. a combination of a borohydride, preferably sodium borohydride or tetraalkylammonium borohydride, with a reagent which leads to in situ generation of borane. Examples of such combinations include sodium 30 borohydride/iodine, sodium borohydride/boron trifluoride diethyletherate, sodium borohydride/chlorotrimethylsilane; tetraalkylammonium borohydride/alkyl halide (for example methyl iodide) in dichloromethane or the biphasic mixture of an alkyl bromide (for example n-butyl bromide) and a saturated aqueous solution of sodium borohydride and catalytic amounts (approx. 10 mol%) of a quaternary 60 onium salt as a phase transfer catalyst (B. Jiang, Y. Feng, J. Zheng Tetrahedron Lett. 2000,41, 10281); 9. a borohydride of a mono- or bivalent metal cation, for example sodium borohydride, lithium borohydride or zinc borohydride, or a tetraalkylammonium 5 borohydride, in the presence or absence of a cerium(ill) salt, for example CeCI 3 , as an additive; 10. diborane (B2H6). The following reductions, for example, may be used in the presence of one or more 10 optically active catalysts: 1. a borohydride of a mono- or bivalent metal cation, preferably sodium borohydride, in the presence of catalytic amounts of an optically active aldiminato cobalt(II) complex, for example (1S,2S)-N,N'-bis[3-oxo-2-(2,4,6 trimethylbenzoyl)butylidene]-1,2-diphenylethylenediaminato cobalt(II) (S)-MPAC, 15 in the presence or absence of tetrahydrofurfurylalcohol as a coligand. This reagent combination was described by T. Makaiyama et al., Synlett 1996, 1076. It leads to a catalytic enantioselective borohydride reduction of carbonyl groups. In the case of the present novel application for reducing Mannich bases (I), the natural diastereoselectivity of sodium borohydride may be enhanced by the 20 coinciding enantioselectivity of the reagent. 2. a borohydride of a mono- or bivalent metal cation, preferably sodium borohydride, catalyzed by a rhodium complex which results from the coordination of two molecules of optically pure 1,3-amino alcohol (II) per molecule of [(p)-pentamethylcyclopentadienyl]rhodium dichloride dimer. It is 25 possible and advantageous in this case to choose the substituents R' to R s in the chiral ligand (11) in such a way that they are identical with those of the resulting reduction product (II), so that the sodium borohydride reduction proceeds autocatalytically. Such catalysts are similar to the CATHy T M catalysts from AVECIA (WO 98142643), but differ in the following points: 30 - CATHyTM catalysts are prepared from the cyclopentadienylrhodium chloride dimer and chiral 1,2-amino alcohols, for example cis-1-amino-2-indanol. In the present application, chiral 1,3-amino alcohols are used. - CATHy T M catalysts were used for enantioselective transfer hydrogenations in which secondary alcohols, preferably isopropanol, or triethylamine/formic acid 61 mixtures functioned as hydrogen donors. In contrast, a borohydride, preferably sodium borohydride, functions as the reducing agent in the present application. - CATHy T M catalysts were used for enantioselective transfer hydrogenations of different prochiral ketones, but not for the redution of the keto group in racemic 5 or optically active Mannich bases (for example (1)) or their salts (for example (III)). Preferred reducing agents are a borane-sulfide complex, a borane etherate, sodium borohydride or a sodium borohydride complex comprising an in situ catalyst which is 10 obtained by the coordination of the [(/.)-pentamethylcyclopentadienyl]rhodium dichloride dimer to the optically active 1,3-amino alcohol (II). Particularly preferred reducing agents are a borane-dimethyl sulfide complex or borane-tetrahydrofuran complex. 15 Owing to its titer stability on storage at room temperature and also to its industrial availability in high concentration (94-95% liquid), very particular preference is given to the borane-dimethyl sulfide complex. 20 The reaction is carried out using 0.3-10.0 molar equivalents of one of the reducing agents specified, preferably using 0.5-4.0 molar equivalents, more preferably using 1.0-2.5 molar equivalents. Process steps 3 and 4 may be effected, for example, in an aromatic hydrocarbon (for 25 example toluene, cumene, xylene, tetralin, pyridine), a saturated hydrocarbon (for example cyclohexane, heptane, pentane), an ether (for example anisole, tetrahydrofuran, tert-butyl methyl ether, diisopropyl ether, 1,2-dimethoxyethane, 1,4 dioxane), a chlorinated hydrocarbon (for example dichloromethane, chloroform, chlorobenzene), an amide (for example N-methylpyrrolidone, N,N 30 dimethylacetamide), an ester (for example isobutyl acetate, butyl acetate, isopropyl acetate, propyl acetate, ethyl acetate) or a sulfoxide or sulfone (for example dimethyl sulfoxide or sulfolane) as the solvent. The last three classes of solvent are not inert toward the borane. Preference is given to carrying out the reaction in toluene, 62 cumene, tetrahydrofuran or anisole. Particular preference is given to toluene, cumene, or THF. The reduction reaction is carried out in the temperature range from -70°C to the boiling point of the solvent used, preferably 1200C, preferably at from -10°C to +40 0 C, 5 more preferably at from 0 0 C to +25"C. There exist the options of a) adding the solution of the borane complex to the suspension or solution of the Mannich base (I) (normal addition), or 10 b) adding the suspension or solution of the Mannich base (I) to the initially charged solution of the borane complex (inverse addition). The duration of the reduction reaction depends upon the specific reactant (nature of the substituents R 1 to R 5 ), upon the reaction temperature selected and the solubility 15 of the reactant in the solvent. It is from approx. 30 minutes to 3 days, preferably from 1 to 5 hours, more preferably 1-2 hours. When the particularly preferred reducing agents, borane-dimethyl sulfide or borane THF complex are used, the primary product of the reaction is a diastereomer mixture 20 of oxazaborinanes which, if desired, can be easily isolated. The formula (C) is attributed to its strongly dominating component on the basis of its HPLC behavior, its molar mass determined by HPLC/MS (M+H: m/z = 437.3) and its smooth conversion to the 1,3-amino alcohol (II) under the action of methanol/methanesulfonic acid. 25 63 R 2 2 H H H H Ra / R \/\/ N, 0 B 3 RKIABH N3 NJ/ BH N 0 N RN' RHR R 5

-R

2 H R R s

FR

4 H

R

4 H (I) - (A) (B) H i R3 ,B solvolytic workup Ra . N Q z.B. MeSO 3 H / MeOH NH O ,H H R HFR 5

H

2 , B(OCH 3

)

3 R HR 5

R

4 * (C) (II) Table 8 summarizes the results of an exemplary reaction of the aminoketone (XVII) (compound of the formula (I) where R 1 = o-nitrophenyl, R 2 = 2-pyridyl, R 3 = H, 5 R 4 = 2-pyridyl and R 5 = phenyl) to the 1,3-amino alcohol (XIX) or its diastereomer dia-(XIX): N2 HN 1) Reduction 2) Workup (XVII) NO2 HN OH NO2 HN OH NN (XIX) dia-(XIX) a 2 oDccc a 0 0 o> 0 t*- Ic- i c >- a ___ _ __ 0 o> 0 0 0t ai EE2 .P By pa0 rg P S 0c6 Or 0. Ot Co o C r 26 C )4 0 . - CD 0E a a 0 - .c c . c a co o: I-c E LtEO E E .- 0 Co o 0 >CZDe cy 5 n > =3 -Z z >~8S -5 __c 03 0 2 0 1)Ca 09C o C) > ( 0i Qo 0) LO atL __ __r z __ __ H coc CV) C% c cm 0 ~ E 0 Cm 04 + 0 , 0 80 U-2: cnr cc j -C4 N c4P TxS

-C

0- ccc E C)~ HZ Z .0) te M %4M C%4 CN ) 0 0 ) 6C u CO co ( - -O 0 o - - -S M% C ) CN (%Ji (6a)) C LI M C- m It S ~ Cf V 0'4 N '- 57 n 57 0 cc 6 - 6 6 O)w cv) M' ' C) 0X 'li r d) 0 N-6 r 0 0) p(0 LO 0 O ~ t-V0 0 aN~ a~ ) CJ b) QCi o CC C 0 4 +C c C c= r cC E E cE E E EE =E M no no Do no n -5 0 iU') -o o5 i-b U 5Z 5V tfl2 >$ IF- H- H H-Z 0 =0 o . 0.0 _ . 0. CiD .) A2 .9 C.d > Ua C1 % E 0 E E ~E EXC <( c > 3E wDE wDE E 2 D - E E M I C0 o 0 vo a a- n SoU-) 'Q oL CI0 CN V c HZ z - (3 0 0 0 aD . 0 S034J awN C) 0 30 N O r ) 9 0 2L A -- Ar OD r-4 0 (0 , 0) 00 '- 10 :OC0 .5! CiCuC O X S~~ L) 1: (003 a co md 4. co 00 0) 00 00 0 0) c, 0 0 t C0 or 0~ 0 4- 2 ao m +4.~ ~ ~ ON ON O 0 ON O 0= ~ 0= 0C E c E CE C E C E C: CE CE 0) a) 0 W E > 0 c -SI -S ES 5 cr ~ OLU -o0u10E0 LOLO 10101 toNIOOoI! j L U)U ClU) W e41m V a) mWCN,4~ ei2 a60 ei2a6 c JS6 eCi 2 C)i? £o o~ o £Q: - o) 0Q 0 o CDI~ w 75 (b 5>a)= w6X r) EX-~ Om 75 *) B - wmI _ Et% E e E> E oNE -R E , E 6g U, LO 0, 0 0r HZI Tr I T f-L2 IN N- 0L 0 (Da -2 0 0 0 0 L0 0 0 Q~ 7 - - aq cS C) C C6 C N I- Co cXX SO C--ITt Cf) -X0 C)0 a 11710 1751 1710 o~ + Co 2+0 n WHo a) . 0.- 0.-0 00 >9 Q N no nO nO 0 0) E0)wC a) 0) CD 0. . L.w Ec ca ccc .(D .922 (D Q 4D '; -- C 0-~c tr% E~~ LO E'gr LO EKr Eo axo&a T-~ 00 0 >N Q C14 > (1 I 4CC 7)> o C HZ N) MN Z N Dmc D= aX L. c;_,: 1 .= 00-: -D C= 0 0) V l - LCC LC V C ~ o C) to c 0) S 0 X N m mC I-') cr, 0)C C ~L InL)I ~ ) c) O 0) 0 0) cr00 Cf) Er 0: 0 0D 0 0 00d 0 rM C _ C , C-4' CI 030 a) (D c 0 '-4-' 0:- i >D Zo nn oo 5Cu o~ - EZ >-~- HZ F- I2. 7: ~ ~ 0r- C - qL q O L ' o L t 0 _E .2E -SEE 0 I - -) -a-' =~ > (D N =O " . =- -- >0<D)> o'Ow& >-00 W . D > cn-C Q) -COW4 E >O' -N > o 0~ - 0) a0 D= E ' HE N E N N z E C.) 'D " 0 0 0)a 2 : C0 LQ Cfl) 0) (D'W S&L' S Qh 04s CLaW 0)ODiCC 2 6oi OD aC,) 00oo '4 a)V0 S Co co _ E c6:3 ctt6?5 E *b a)cc) (0 Xt U) CF ) (n 0 00 - . 4' e . 2 0 r >c0 >cr 1 r 0) 0 - E L C)~ 0 z -' 0m C)' CD' (N0)25 0) m3 > j5 m2 -0 L) C ,0 . >* = ~ E ff, a--- U 050 05 > o -4- L' 0 . AU G) N -C4AC A0 ) AC)C Ha_ _ _ _ _ _ _ _ _ _ _ u c N CL Mg a, 00 'a 0 2 0 .2 C' a4LW N 0 0 ,a, 0 a 2 u CD 0 x 0 Eaa D wo 00 o 0 :3 CL U') > E 0 0) 0)c -= CD 00 m4 X0 .- = 0 -r: a) w Uw. =00 -/ , cu o, E a) c o E a L in C 0 r_ co- d o cgo ~ co -o (D La, CL Eu -5 ,E oE (a 'n C4M -2 r-. n. '- =a . < o 0 33 E o 00 a r c ~~ ~ ' E r-EEr-=- 0 a,( 4 b- -E' 0a ' -D co N U E CC) CECZ =50 o 4- 1.. >z :U w 0 a Q 0) 0Eo &. :~~ a, - >0 D ' -a0 -a 0 0) -. r Lc 2 a 8 0- 000 0 L C a 0 -Y E.0i 0 O . 0 E >E6w0 Z Z CU ~ ~ ~ ~ ~ ~ a 0) 'q0) N Vr U Co 1-0 70 00 ~ >. CC)0 [h-z co co o0 a - ass CO 0 . . L-F z~ t5 CD d) ' 020 -o C) U) C/ 3 *5 .0 C) a) -a oo -z =~ r0 N- v6(A CU CU 0I 10 (D C~ E 0 ) C: CUU 0)) x xi CU CU .2 L 0 0 0 0 -E r

'CMU

72 The results show that this method allows the carbonyl group to be reduced with high stereoselectivity (up to >97:<3; see No. 9 and 11) and the retro-Mannich reaction of the reactant (1) is very substantially suppressed under the reaction conditions, so that the stereochemical information already present in the reactant is virtually entirely 5 retained. An example of a workup method known per se for reductions with borane or borohydride reagents is the solvolytic cleavage and/or a crystallization. 10 The solvolytic cleavage of the oxazaborinane (C) initially formed in the reduction of (I) to the 1,3-amino alcohol (11), and its isolation from the reaction mixture leads to the greatest possible extent of removal of stereoisomers: the enantiomer ent-(ll), RK 'R 3 HO H N R5

R

I H

R

4 ent-(ll) 15 the diastereomer dia-(ll) R3 R 2 N HO H R1 R5 R4 H dia-(ll) 20 and the enantiomer of the diastereomer ent-dia-(ll) 73

R

2 N

R

3 HO H N R5 s R' H R 4 ent-dia-(II) Optionally, within the workup of the reaction solution of the product of the formula (Il), a crystallization proceeding in high yields may be carried out which completely 5 removes the small amounts of stereoisomers of (II) contained in the crude reaction solution. In this way, it was possible to prepare 1,3-amino alcohols of the formula (II) in very high purity (> 99.5% chemical purity, -100% de, > 99% ee) in 2-3 stages from usually commercially obtainable starting materials while achieving high overall yields, sometimes above 70% of theory. 10 The solvolytic cleavage may be achieved by a variety of different procedures: a) Preference is given to carrying out the cleavage using 1-4 equivalents of a strong acid, more preferably methanesulfonic acid or sulfuric acid, in an excess of a low molecular weight alcohol, more preferably methanol, at 0-60°C, more preferably 15 15-40'C (Table 8, No. 6-36). Under these conditions, the boron from (C) is converted to a volatile trialkyl borate ester, in the particularly preferred case to the volatile trimethyl borate B(OCH3) 3 with forms an MeOH-B(OMe) 3 azeotrope with methanol of boiling point 59 0 C which contains approx. 70% of B(OMe) 3 in the azeotropic mixture (M. Couturier et al., Tetrahedron Lett. 2001, 42, 2285). 20 Particularly when the borane reduction has been carried out in the particularly preferred solvents such as toluene or cumene, the boric ester solvate and excess methanol can be easily distilled off quantitatively after completed solvolysis by applying a vacuum. The 1,3-amino alcohol of the general formula (II) is present in protonated form and therefore generally has good water solubility. Therefore, 25 when water is added to the toluenic or cumenic distillation residue, the salt of (II) is in most cases virtually quantitatively extracted into the aqueous phase. The toluenic or cumenic phase then removes most reaction by-products, for example retro-Mannich products and their reduction products. When the product containing, aqueous acidic solution is then rendered strongly basic, for example 30 with aqueous sodium hydroxide solution, the free 1,3-amino alcohol (II) 74 precipitates out and can easily be isolated. However, particular preference is given to isolating (II) by crystallizing one its salts while the small amounts of stereoisomers contained in the crude product remain in the mother liquor. The optimum anion and solvent for such crystallization depend upon the nature of the 5 substituents R 1 to R s in (II) and therefore have to be determined independently for each 1,3-amino alcohol of the formula (II). When R 1 = o-nitrophenyl, R 2 = 2 pyridyl, R 3 = H, R 4 = 2-pyridyl, R s = phenyl, for example, the optimum crystallization of the dihydrochloride of (11) proved to be from 1-butanol. The dihydrochloride was obtained in 99.3-100% ee and a chemical purity of 10 99.1-99.9% in a yield of 74-84% of theory, based on the Mannich base (I) used (Table 7, No. 19-29, 31-35). This crystallization can even compensate for an untypically low enantiomeric purity of the Mannich base (1) used. In the experiment of Tab. 7, No. 32, (1) of only 90.5% ee was used. Despite this, (II) dihydrochloride was isolated in 76.8% yield with 99.4% ee and 99.7% chemical 15 purity. b) Alternatively, the solvolysis of (C) may be carried out using an excess of a strong aqueous acid, preferably 2-normal to concentrated hydrochloric acid or aqueous methanesulfonic acid, at 0-1000C, preferably 0-40*C, after distilling off the organic solvent of the borane reduction beforehand. This workup was applied in Table 9 20 (No. 4-7, 9-14 and 16-18) and in Table 10 (No. 5-8). Under these conditions, the boron from (C) is converted to boric acid B(OH) 3 which is only sparingly soluble in aqueous acidic reaction mixtures, in particular when cooled to 0-10OC, and very substantially crystallizes out and can therefore be easily removed. In contrast, the 1,3-amino alcohol is present in protonated form and therefore generally has good 25 water solubility. When the product-containing, aqueous acidic solution is rendered strongly basic, for example with aqueous sodium hydroxide solution, after removing the boric acid, the free 1,3-amino alcohol (11) precipitates out and can be easily removed. Appropriate typical procedures are described in Examples 23 (corresponding to Tab. 9, No. 18) and 24 (corresponding to Tab. 10, No. 5). 30 However, preference is given, as is the case in a), to isolating (11) by crystallizing one of its salts. This is achieved by rendering the aqueous acidic product containing solution basic in the presence of a suitable organic water-immiscible solvent, for example n-butanol. The free 1,3-amino alcohol (11) is virtually quantitatively extracted into this organic phase which is then heated and, by 75 adding a suitable aqueous acid, for example concentrated hydrochloric acid, a salt of (11) is formed which crystallizes out on gradual cooling of the butanolic solution. c) A further alternative solvolysis method for (C) is the addition of an excess of the 5 solution of an alkali metal hydroxide or alkaline earth metal hydroxide, followed by heating to 30-100 0 C, preferably to 50-70C. The free 1,3-amino alcohol (11) may then be extracted with an inert organic solvent, while the alkali metal borate or alkaline earth metal borate formed remains in the aqueous phase. An appropriate typical procedure is described in Example 25 (corresponding to Table 10, No. 3). 10 d) A further alternative solvolysis method for (C) is the addition of an organic complexing agent (for example diethylenetriamine) which forms a strong chelate complex with the boron. Preference is given to applying this method in the following form: Methanol is initially charged in the solvolysis reactor at 20-60 0 C, preferably at 15 40-50*C, under an inert gas atmosphere. The preferably toluenic reduction mixture (comprising substantially (C) and excess borane) at 20-60'C, preferably 40-50 0 C, is gradually metered into the initially charged methanol. On completion of metered addition, the complexing agent, for example diethylenetriamine, is metered in and the solvolysis mixture is stirred until the solvolysis of (C) to form 20 (11) is quantitative. Water is then fed to the reaction mixture, preferably at 60-70 0 C. The organic (toluenic) phase is then separated from the aqueous phase, and washed with water, preferably at 60-70'C. The boron-amine chelate and excess methanol are removed with the aqueous phase. The amino alcohol of the formula (1I1) can be isolated from the toluenic phase by known processes. Depending on 25 the specific nature of the substituents R' to R s , direct crystallization by gradual cooling of the warm, concentrated toluene solution may also be advantageous. However, it may also be advantageous to transfer (ll), as described under a), into another more polar solvent, for example n-butanol, followed by the crystallization of a suitable salt of (II), for example a hydrochloride. 30 e) A further alternative cleavage method for (C) to form the 1,3-amino alcohol (ll) is the solvolytic cleavage by adding hydrogen peroxide solution. This method is only advantageous for those products (II) which are not easily oxidized by hydrogen peroxide. Also, since the reaction of boranes and some oxazaborinanes of the 76 formula (11) with hydrogen peroxide may be extremely exothermic, the workup methods a) and d) are frequently preferred over e). Process step 4 is carried out with the same reducing agents and under the same 5 reaction conditions (molar equivalents of reducing agents, solvents which can be used, reaction temperature and duration, method of adding) and workup methods as have already been described for process step 3. The following special features apply to process step 4: 10 - Mannich salts of the formula (Ill) are generally distinctly more polar than the free Mannich bases of the formula (I). The solubility of the Mannich salts (111) in nonpolar solvents (toluene or less polar) is in most cases no longer sufficient for a viable reaction rate with the reducing agent. Preferred solvents for the reduction of the Mannich salts (11l) are therefore relatively polar solvents in 15 which (111) has better solubility, and particular preference is given to tetrahydrofuran. - Particularly preferred counterions Y*" in the Mannich salts (111) are chiral carboxylates or dicarboxylates. These counterions Y* are generally not completely inert toward boranes, borane complexes or activated borohydrides 20 and are themselves gradually reduced by the reducing agents used. This consumption has to be taken into account by an appropriate increase in the equivalents of reducing agents. As is described for process step 3, an oxazaborinane (C) is formed as the primary 25 reaction product and is then converted by one of the above-described solvolysis/workup procedures to the desired 1,3-amino alcohol of the formula (II). In Table 9, the results of diastereoselective carbonyl reductions of the (S)-(+) mandelate salt (XVIII) (compound of the formula (111) where R 1 = o-nitrophenyl, 30 R 2 = 2-pyridyl, R 3 = H, R 4 = 2-pyridyl and R s = Ph) to the 1,3-amino alcohol (XIX) are compiled by way of example: 77 0 0 "O _ OH 1) BH 3 -Me 2 S, NO2+NH2 THF 2) HCI am I I (XVIII1) N02 NH OH NH OH (Nxx) diNa-(XX) (XIX) dia-(XIX) oc 2 U) o a _ X)0 a0 a )( o I 0 0 0 _ m 3 m z z N - o- a° ° - a 0A A A "Dm ca a ( .o ,oo < tsC r "E - o= cc c -, I.Ro m + +l 0 OL C% O U") OE . '- o o o o 0 a o o . Eco I- 80 o as U) A -. L-12 x "a e-5 E o e E* Eo0E60gE E S E ES ES E. :; o - J ' 0o ° E .Vo O to t. o °-o o:k 0 i3 L6 r (6 06C U) U)) ..- "- A V- ami.-O ' a 0M U) r: 0N CN (DC 0l Z ND ZNDZa iC C CD p) ) C: rto c Cl a)l Uo a) .U O C) _ N C 0N 0)NC 0 (D a) 0) 0) 0') @t Z. 5 . 0 . Zu 0-. OL ' . ~ U L ZL. O 0 on O W E to o~ S "So0U 0D ) c, Ni C)> 0C O F= U-E - U ELLE A-E - E *cL E - E L

DC

4 4 O 4 ccCCC a) UEUEUEIa ~~'5~ EEg~~ o E C)U- * .LaU. 9o 0 o~u o P Vr- .- L r C r O V) CR- Clo mt VO w OM L O C C:-6 0 ) 36 0 E 0 E Q ) E (D E a E 0 E 0 0E E~ E SEE ES ES ES ES ES0)L T, EEE~~v ~ ooo (N L6 0 WN~) t NLOU;jinL6 uS'0 CD C6C to e6 ( t aA- (D 0) ) ) a) ,0) n 4 0') 0 CUD If (No 0)D I. U) C NC HZ ____ I_ _ _ _ _ _ __ _ _ I "e -o S0 0 - A-AA E• o- a 0 L) 4 CD c-a ro - O C O) .E m E V7 . .7 .! .- . -- L.o 4- I- (L 0 O U mvi a) 00 x -0 0 0o ) 1- o - 4c E C •-- ,- .C9c o- ,o- , 9 9o . OL 0) = , 0) D 4- E 0 w E S'-- 0 - 0 0 - 253 C:E t:EMEE E0EE 0.- . .- - E E E E E E Er EDQ) m ome a Ea) m o "- -O .

a o z5 X X W WEf of5 nr (D. a)~5; O~ ) ac 0 C E i) 0) 0 0 -o a) E ) C> c, ~U Cu . LLE E L u u-ca o 0~- 0-0 - to-0 coOCO V)C o c ) U)U~C I- 4- 4- 4 ONcOc (DC*C~ 2EY12U C O E -, E H 0 E -E - E 0) 4-' 0 M0 0Z000 Qo P a) Efr'~ Q)-f * (r- fl a) 0 C) ) 0) ) 0. -L 04 C) 0 ) L) 1 ' 11) If E * 80 Quantitative conversions of the Mannich base to components of the salt (XVIII) were achieved down to 3.0 equivalents of reducing agent (Table 9, No. 8-11, 16 and 18). While hardly any conversion to (XIX) was achieved in toluene (Table 9, No. 1), there was substantial to complete conversion in THF (Tab. 9, No. 2-18). In the case of the 5 carbonyl reduction, diastereoselectivities (ratio of (XIX)/dia-(XIX)) of up to 96.8:3.2 were achieved (Table 9, No. 4 and 18). The isolated yields of (XIX) were 78-83% of theory, and these products also contained 3-4% of the diastereomer dia-(XIX) and almost 2% of the enantiomer of (XIX) (Table 9, No. 9 and 18), since there was in this case no crystallization step of the dihydrochloride of (XIX) similar to process step 3, 10 section a). Including the crystallization of the dihydrochloride, the enantiomerically and diastereomerically pure amino alcohol (XIX) (> 99% ee, > 99% de, > 99% chemical purity) was obtained in a yield of 70-75% of theory, based on the mandelate (XVIII) used. 15 In Table 10, the results of diastereoselective carbonyl reductions of (+)-dipivaloyl tartaric acid salt (XII) (compound of the formula (111) where R' = o-nitrophenyl,

R

2 = 2-pyridyl, R 3 = H, R 4 = 2-pyridyl, R s = Ph and HY* = (+)-dipivaloyltartaric acid) to the 1,3-amino alcohol (XIX) are summarized by way of example: 81

H

3 C CH 3

H

3 C 0 NNH +0 NO2 '0. O 0 0 0 0O /N O 'O CH3

H

3 C

CH

3 -2 (XII) NH NH OH H N2 N02 NN (XIX) dia-(XIX) 0 00 o oD -C m 0 _jWm)c oC - on oE m9o c 0 X c - c - ( 0 o C >85 on MEc t or-6 a~ 0 2-0 Lo2oC'4 . X0emya q go 0 0 C6 4O...4 .0 a 0 o O--C Eoo 0 22 -0Oc 2 oC..E> 0 N0$# N 0 a e5 - ooL o E o 2 E C LCF 0 L)( O c C) ta 0a 0 a) CD 0 0 > ) m) 0co[ CUDO HZ0_ _ _ N_ _ _ _ o -D ) 0 0" am a, 0-le a ' r- .

" C a I.. c -i c io.. ) -0 (A 0 o 28 r- e xo a- -oe -i y co cy -X -w-- o E - --- E . 0 ( 0 0 0 >s b 0-- -- O -- " - =o 13 X LCo MO o O - E.z CD r -@ z . E . 0 0o x . 1'1o a mm 0._e a 4 EE- E'%-0'-E2E E2 EE o z LI -0Z a8 0 00 8 C ~C 0 - DmC NU % 0 a) E E E z c m4Er o 3' E u) 4 0U "oC E) 3 .A2 a LO c 0 1 C) -< o co . L m E ) 0 -- o -- a. c E .E 2l o )P C-H CO DO CO DO < 6w < o 0 o , aC<v < o w cy W LL U.. -i H- H 0 0 0 a co 0 Ua) =3 c U) U 0)' 5 a aNa CD CT 0N CN CN rZ C0o- 0 > a) > on5 -0- 2 5 0 g a 0a (Dn mn mZ "D -Z 3 a)0 E t 0 2 5 oo 0. -=N H-Z V w C w 0 -a U)8 GO 0 Scc " aS .,l ._a r o > --2-C c 0 t t o o'- -. , ao ,.

.

_ c on- Cc -oO L.aX Xoa, 4 ,= a c) 0t o or 80 a I I ) ._ S#si _ 0 .0..,co- --m,--- Z " ,-i: 0.00 c . O C. 8-O -- (_ C X' cco I I VI o~~- xj C)~~Nc 'ocE - 02 0 E 0 -0- C N O C o OD ~ ~ lVo~ 0f 5zzu 0r Z Sir Z -a~ = 04 c5Mo -r< -D > ee Sb EE~ ~~ .0 0 cm E E .0 $. SRe R E A2 m- A 2 gO m a -Oi5 m c .0r moL z- I E E 5 U D c0 ng o 1 ) T, : ( .5 -l P 22 a,> Z0 m a) 0 -0,C r?( 00 -LOC r n r a 0 0 ED > s (D Cr.. (D CU SCUD aC ~ W~ E a)O r -N D0 tO~f HZ~ Z - m o0 ' 0) 0) 0 > .-- m -) CY~ _j 00 ( -c 2n ?5O (D a.0) &D§--Qcto ) .c Lnl0 CD 0) 0O D & 0 -. ;qCO - CDC =v .. r CL 'a - 04.. a b 0.) 0 LAD 0" N (IO r3CjMX 0 & : 3: :3 n - Q ~1, r~~. CM M M. CO C0) ~jZ .c ~ L c." E0 n 0w~F HZ 00 86 The use of sodium borohydride in butanol/water resulted in only a little of the desired product (XIX) (Table 10, No. 1). Although the conversion was better using sodium borohydride in ethanol in the presence of catalytic amounts of a quaternary ammonium salt, the diastereoselectivity was only very low (Table 10, No. 2). When 5 the borane-dimethyl sulfide complex was used as the reducing agent, excellent conversions and diastereoselectivities were achieved in THF (Tab. 9, No. 5-9), while there was no reaction in methyl tert-butyl ether (Tab. 9, No. 4). The ratio of (XIX) to dia-(XIX) (diastereoselectivity of the carbonyl reduction) in the crude reaction mixture after solvolysis of the intermediate (C) was up to 98:2 (Table 10, No. 9). In the 10 isolated products (XIX) (yield 84-89% of theory, based on the salt (XII) used), the diastereomeric ratio was up to 99.2:0.8 and the enantiomeric purity 95.2% ee, although the charge of Mannich salt (XII) used had an optical purity of only 93.2% ee which was moderate for the four-component coupling, and although the workup procedure included no crystallization step of the dihydrochloride of (XIX) from butanol 15 (Table 10, No. 9). With regard to the chemical purity, no UV-active impurities apart from dia-(XIX) could be detected by HPLC, and the (XIX) content of the isolated product according to an HPLC assay (based on a purified reference standard of (XIX)) was 97.9%. 20 The present invention allows compounds of the formulae (I), (11) and (111) to be prepared in high yields with high stereoselectivity starting from achiral, commercially obtainable reactants (IV), (V) and (VI) which are inexpensive or very easy to prepare by a short route using inexpensive, readily available auxiliaries (VII) and mild reaction conditions which are easy to realize from a technical point of view. The process 25 described in the present invention is therefore particularly suitable for the industrial production of optically active compounds of the formulae (I) and (11). The following scheme provides an overview of the process according to the invention: 87 H y* O Process RI ., R 2 RN

R

2 R5+ HY step 1 R O + .N / + + HY* RI H H

R

4 H (IV) (V) (VI) (VII) )

RKN./R

2 0 N 0 Process step 2 (I) R' I." RS Process

R

4 H step 4 (I) R< /R 2 N H OH Process step 3 N H (I) R R

R

4 H (II) The abovementioned tables and exemplary reactions contain a total of 162 examples which illustrate the wide variety of possible variations of reaction parameters within 5 the process according to the invention. Of these 162 examples recorded in the tables, the particularly representative procedures have been described in detail. These procedures are preferred embodiments of the process according to the invention. However, they do not in any way limit the subject matter of the invention. 10 In the examples which follow, methods, ways of working and procedures are described which it is necessary to know in order to be able to reproduce or verify the subject matter of the invention without problems and are intended to illustrate the process steps according to the invention without limiting the subject matter of the invention. 15 Example 1: Determination of the enantiomeric excess of Mannich bases of the general formula (I) or of Mannich salts of the general formula (111) where R 1 = o-nitrophenyl, 88

R

2 = 2-pyridyl, R 3 = H, R 4 = 2-pyridyl, R s = phenyl and HY* = (S)-(+)-mandelic acid, by derivatizing with (-)-camphanoyl chloride. 10 mg of the Mannich base (1) specified in the title or its salt (111) are weighed into a 5 10 ml volumetric flask and admixed with 200 mg of (-)-camphanoyl chloride. 1 ml of triethylamine is added and the mixture is made up to exactly 10 ml using approx. 9 ml of acetonitrile (HPLC grade). The mixture is dissolved within 30 seconds in an ultrasound bath. 1 ml of the initially light yellow solution is transferred to an HPLC vial and, after a 10 min delay time, 8.0 pl thereof are injected to a Machery-Nagel CC 10 250 mm x 4 mm Nucleosil 100-5 C18/5 pm HD HPLC column. The elution is effected at a flow rate of 1.00 ml/min with a linear gradient composed of the two following eluents: Eluent 1: Water/acetonitrile/trifluoroacetic acid = 900/100/1.00 15 Eluent 2: Water/acetonitrile/trifluoroacetic acid = 100/900/0.75 at the following gradient variation: Time (in min) 0 2 22 26 27 Eluent 1 (in % by volume) 75 75 35 35 75 Eluent 2 (in % by volume) 25 25 65 65 25 The detection is effected at 254 nm. The derivatization products are eluted at the 20 following retention times: Corresponding amide of the general formula (IX A) (resulting from the undesired enantiomer of (1)): 19.59 min. Amide of the formula (IX) (resulting from the desired enantiomer of (I)): 20.50 min. 25 Amide resulting from the anti-diastereomer of (I): 23.12 min. Amide resulting from the anti-diastereomer of (I)-enantiomer: 24.09 min. A peak at retention time 20.01 min. is also visible which results from a derivatization component. 30 The enantiomeric excess (I) is determined with the aid of the chromatogram as follows: the sum of peak areas of (IX) and (IX A) is set to 100%. The proportions of 89 (IX) and (IX A) are calculated (for example (IX) = 97.0%, (IX A) = 3.0%). The proportion of (IX A) is deducted from the proportion of (IX). In the example specified, the free Mannich base (I), or the underlying Mannich base 5 (I) of the Mannich salt (111) had an enantiomeric purity of 94.0% ee. Example 2: Determination of the enantiomeric excess of Mannich bases of the general formula (1) or of Mannich salts of the general formula (111) where R' = o-nitrophenyl, 10 R 2 = 2-pyridyl, R 3 = H, R 4 = 2-pyridyl, R 5 = phenyl and HY = (S)-(+)-mandelic acid, by derivatizing with pivaloyl chloride. In a 2 ml HPLC vial, 1 mg of the Mannich base (I) specified in the title or its salt (111) is dissolved in 20 pl of pivaloyl chloride, 100 pl of triethylamine and 500 pl of acetonitrile 15 (HPLC grade). After exactly 5 minutes, the reaction is stopped by adding 500 pl of water. The vial is immediately sealed with the septum cap, placed in the autosampler of the HPLC instrument and, after a 10 min delay time, 5 pl thereof are injected onto a Merck Darmstadt 250 mm x 4 mm 5 pm CHIRADEX column (f3-Cyclodextrin) (Order No. 1.51333.0001, Cartridge No. 971324). The elution is effected isocratically 20 at a flow rate of 1.00 ml/min using the following eluent mixture: Eluent 1: 1% of triethylamine in acetic acid (pH 4.1) Eluent 2: 100% of acetonitrile Eluent 1 : Eluent 2 = 82.5:17.5. 25 Detection is effected at 254 nm. Figure 1 shows a typical chromatogram starting from the Mannich base of the general formula (I) with the substituents specified in the title and an enantiomeric purity of 95.3% ee. 30 Figure 2 shows a chromatogram of a corresponding racemic Mannich base of the general formula (I) with the substituents specified in the title.

90 Example 3: Preparation of the free racemic Mannich base rac.-(l) [R 1 = o-nitrophenyl,

R

2 = 2-pyridyl, R 3 = H, R 4 = 2-pyridyl, R 5 = phenyl] by catalysis of the three component coupling with 1 mol% of p-toluenesulfonic acid 5 70 ml of abs. ethanol, 5.91 g (30 mmol) of 1-phenyl-2-(pyridin-2-yl)ethanone, 3.53 g (37.5 mmol) of 2-aminopyridine, 5.44 g (36.0 mmol) of 2-nitrobenzaldehyde and 57 mg (0.30 mmol) of 4-toluenesulfonic acid monohydrate are introduced in succession under nitrogen into a 250 ml four-neck flask equipped with a precision 10 glass stirrer. The solution is stirred at 25*C under nitrogen. After approx. 18 hours, the crystallization of the product rac.-(I) commences. At this juncture, TLC (n-Heptane/EtOAc) shows a conversion of approx. 40%. After a total of 96 hours, a thin layer chromatogram (TLC) shows virtually quantitative conversion. The precipitate is filtered off with suction, washed with mother liquor and then with 10 ml 15 of ethanol, and dried at 30*C under reduced pressure. 11.9 g (28.0 nmol; 93.2% of theory) of yellow crystals are obtained. The integral of the 'H NMR spectrum (CDCl 3 , measured immediately after dissolution) shows a ratio of the desired compound to the anti-diastereomer of 97:3. 20 Example 4: Reaction of rac.-(I) with pivaloyl chloride in acetone to give the amide rac.-(IX)

[R

1 = o-nitrophenyl, R 2 = 2-pyridyl, R 3 = H, R 4 = 2-pyridyl, R 5 = phenyl, R = tert-Bu] I in a 500 ml four-neck flask, 15.02 g (35.4 mmol) of the racemic Mannich base rac.-(I) 25 from Example 3 are initially charged at 0OC under nitrogen. 90 ml of acetone are then fed in with cooling to O'C internal temperature, and then 6.44 g (53.3 mmol) of pivaloyl chloride and 13.82 g (106.9 mmol) of diisopropylethylamine are metered in in parallel from two dropping funnels. After stirring at 00C for three hours, HPLC analysis shows 95.9% of the desired rac.-(iX), 1.1% of the corresponding trans 30 diastereomer and 1.9% of unconverted rac.-(I). 40 ml of acetone are distilled off under reduced pressure (bath temperature < 350C). 200 ml of water are fed in to the residue and then stirred at 0°C internal temperature for a further 2 hours. The precipitate is filtered off with suction, washed on the filter with 20 ml of ice-cold ethyl acetate and then dried at 40"C under reduced pressure. 16.4 g (32.2 mmol, 91% of 91 theory) of a light yellow crystalline solid is obtained, m.p. 162 0 C. The HPLC purity is 99.4%. Example 5: 5 Classical optical resolution of rac.-(l) [R' = o-nitrophenyl, R 2 = 2-pyridyl, R 3 = H,

R

4 = 2-pyridyl, R s = phenyl] using (S)-(+)-mandelic acid in acetone 6 ml of acetone were added to 503.9 mg (1.19 mmol) of rac.-(I) from Example 3 and 359.0 mg (2.36 mmol, 1.98 equiv.) of (S)-(+)-mandelic acid. The reaction mixture was 10 magnetically stirred in a tightly seated flask at 25*C for 20 hours, and the precipitate was filtered off with suction and dried under reduced pressure. 446 mg (0.773 mmol) of the corresponding mandelate salt (Ill) were obtained which, according to 1H NMR, consisted of Mannich base (I) and mandelic acid in a ratio of 1:1.00. Derivatization of a sample with (-)-camphanoyl chloride and subsequent HPLC analysis according to 15 Example 1 delivered a ratio of the amide (IX A) to the amide (IX) of 5.0 to 95.0. The enantiomeric excess of the Mannich base (I) in the mandelate salt (Ill) was therefore 90% ee. Example 6: 20 Classical optical resolution of rac.-(I) [R 1 = o-nitrophenyl, R 2 = 2-pyridyl, R 3 = H,

R

4 = 2-pyridyl, R s = phenyl] using L-(-)-malic acid in acetone 6 ml of acetone were added to 504.2 mg (1.19 mmol) of rac.-(I) from Example 3 and 161.5 mg (1.20 mmol, 1.01 equiv.) of L-(-)-malic acid. The reaction mixture was 25 magnetically stirred in a tightly sealed flask at 25°C for 20 hours, and the precipitate was filtered off with suction and dried under reduced pressure. 400 mg (0.716 mmol) of the corresponding malate salt (111) were obtained which, according to 1H NMR, consisted of Mannich base (I) and malic acid in a ratio of 1:1.04. Derivatization of a sample with (-)-camphanoyl chloride and subsequent HPLC analysis according to 30 Example 1 delivered a ratio of the amide (IX A) to the amide (IX) of 2.4 to 97.6. The enantiomeric excess of the Mannich base (I) in the malate salt (Ill) was therefore 95.2% ee.

92 Example 7: Classical optical resolution of rac.-(I) [R 1 = 0-nitrophenyl, R 2 = 2-pyridyl, R 3 = H,

R

4 = 2-pyridyl, R 5 = phenyl] using (-)-di,O,O'-pivaloyl-D-tartaric acid [(-)-DPTA] in acetone 5 6 ml of acetone were added to 506.2 mg (1.19 mmol) of rac.-(I) from Example 3 and 379.2 mg (1.19 mmol, 1.00 equiv.) of (-)-DPTA. The reaction mixture was magnetically stirred in a tightly sealed flask at 25°C for 20 hours, and the precipitate was filtered off with suction and dried under reduced pressure. 557 mg of the 10 corresponding DPTA salt (111) were obtained which, according to 1 H NMR, consisted of Mannich base (I) and DPTA in a ratio of 1:0.57. Derivatization of a sample with (-) camphanoyl chloride and subsequent HPLC analysis according to Example 1 delivered a ratio of the amide (IX A) to the amide (IX) of 97.6 to 2.4. The enantiomeric excess of the corresponding Mannich base (1) in the DPTA salt (111) was therefore 15 95.2% ee. Example 8: Attempted classical optical resolution of rac.-(I) [R 1 = o-nitrophenyl, R 2 = 2-pyridyl,

R

3 = H, R 4 = 2-pyridyl, R 5 = phenyl] using (S)-(+)-mandelic acid in ethanol 20 6 ml of ethanol were added to 500 mg (1.18 mmol) of rac.-(I) from Example 3 and 358.5 mg (2.36 mmol, 2.00 equiv.) of (S)-(+)-mandelic acid. The reaction mixture was magnetically stirred in a tightly sealed flask at 20-25 0 C for 18 hours, and the precipitate was filtered off with suction, washed with a little ethanol and dried under 25 reduced pressure. 590 mg (1.02 mmol) of the corresponding mandelate salt (111) were obtained. HPLC analysis according to Example 1 delivered a ratio of the amide (IX A) to the amide (IX) of 47.9 to 52.1. The enantiomeric excess of the Mannich base (I) in the mandelate salt (11) was therefore only 4% ee. 30 Example 9: Synthesis of the imine (X) from the aldehyde (IV) and the amine (V)

[R

1 = o-nitrophenyl, R 2 = 2-pyridyl] 93 50 ml of toluene are added to 9.97 g (106 mmol) of 2-aminopyridine, 15.12 g (100 mmol) of 2-nitrobenzaldehyde and 190.3 mg (1 mmol) of 4-toluenesulfonic acid monohydrate, and the reaction mixture is heated to reflux for 1 h under nitrogen while azeotropically distilling off the toluene/water azeotrope on a water separator. The 5 mixture is then cooled to room temperature and the corresponding imine (X) where

R

1 = o-nitrophenyl and R 2 = 2-pyridyl crystallizes out. The product is filtered off with suction and dried under reduced pressure. 18.2 g (80 mmol, 80% of theory) of yellow crystals are obtained. According to 1 H NMR (300 MHz, CDCl3; measured immediately after dissolution), 80% of the product is the imine (X) [8 = 7.24 (m, 1H), 7.38 (d, 1H), 10 7.63 (td, 1H), 7.70- 7.83 (m, 2H), 8.06 (dd, 1H), 8.36 (dd, 1H), 8.53 (dm, 1H), 10.28 (s, 1H)] and 10% each are the reactants 2-aminopyridine and 2-nitrobenzaldehyde. IR (KBr): v = 1513 (s), 1435 (m), 1352 (m), 1339 (s), 788 (m) cm

"

. MS (DCI):

C

1 2

H

9

N

3 0 2 (M = 227), m/z = 228 (100%, M + H ). 15 Example 10: Synthesis of the aminal (XI) from the aldehyde (IV) and the amine (V)

[R

1 = o-nitrophenyl, R 2 = 2-pyridyl] 9.97 g (106 mmol) of 2-aminopyridine and 15.12 g (100 mmol) of 2 20 nitrobenzaldehyde are dissolved under nitrogen in 53 ml of dichloromethane in a 250 ml four-neck round-bottom flask equipped with a precision glass stirrer, thermometer, water separator and reflux condensor, and the internal temperature falls to 120C. 1.5 g of strongly acidic ion exchanger (Amberlite IR 120, Merck) are introduced and the reaction mixture is then heated to reflux at a bath temperature of 25 750C. In the water separator, approx. 1.5 ml of water collect (theory: 1.8 ml from the reaction plus 0.8 ml from the ion exchanger). After 5.5 hours, no more water separation can be discerned. When the stirrer is switched off, a clear solution which is hardly any darker than the original reactant solution can be seen above the settled ion exchange resin. After standing at RT overnight, a considerable amount of yellow 30 crystals have precipitated. The suspension is heated to reflux and sufficient dichloromethane is added (approx. 100 ml) to just completely dissolve the crystals in the heat of boiling. The batch is hot-filtered through a fluted filter in order to remove the ion exchanger. The filtrate is admixed with 250 ml of toluene and the dichloromethane is evaporated off under reduced pressure (beginning: 400 mbar, 94 end: 100 mbar) at a bath temperature of 40 0 C. Toward the end of the concentration, a pale yellow solid precipitates out. Improvement of the vacuum to 15 mbar then removes 2/3 of the toluene. The suspension is stored tightly sealed in a refrigerator at approx. 0*C overnight, which completes the crystallization of the product. The solid is 5 filtered off with suction, washed with 20 ml of cold toluene and dried under reduced pressure at 40*C. 14.50 g (45.1 mmol, 45.1% of theory) of pale yellow solid are obtained, melting point 134-135*C, after a further recrystallization from toluene, melting point 140-1420C. 'H NMR (300 MHz, DMSO-de): 5 = 6.53 (tm, 2H), 6.58 (d, 2H), 7.20 (d, 2H), 7.30 - 7.44 (m, 3H), 7.53 (td, 1H), 7.67 (td, 1H), 7.78 (dt, 1H), 7.88 10 (d, 1H), 7.94 (m, 2H). IR (KBr): v = 3227 (m), 3074 (m) and 3020 (m), 1599 (s), 1576 (m), 1532 (s), 1459 (m), 1435 (s), 1320 (m), 1149 (m), 771 (m) cm' 1 . MS (DCI):

C

17 HisN 5 0sO 2 (M= 321), m/z = 228.1 (100%, M + H* - aminopyridine), 94.8 (aminopyridine). 15 Example 11: Recovery of (S)-(+)-mandelic acid from the aqueous mother liquor of the liberation of Mannich base (I) from a Mannich salt of the formula (III) [R 1 = o-nitrophenyl,

R

2 = 2-pyridyl, R 3 = H, R 4 = 2-pyridyl, R s = phenyl, HY = (S)-(+)-mandelic acid] 20 The Mannich base (I) having the substituents specified in the title was liberated from 256.5 g (445.0 mmol) of the corresponding Mannich salt (Ill) in 1280 ml of water and 128 ml of ethanol using 222.0 ml of 2 N sodium hydroxide solution (444.0 mmol) at pH-stat 8.5, filtered off with suction, washed with 3 x 150 ml of water and dried under reduced pressure to obtain 188.52 g of (1) (444.1 mmol, 99.8% of theory). 25 The yellow aqueous mother liquor (pH 7.62) which had previously stood at room temperature for 5 days was washed initially with 2 x 250 ml of methyl tert-butyl ether, then with 250 ml of ethyl acetate. The washing phases mentioned were all distinctly yellow, and after concentrating to dryness under reduced pressure, contained 0.21 g, 0.06 g and 0.04 g of residue, and were all discarded. The aqueous mother liquor 30 (pH 7.83) which was now only very pale yellow was adjusted to the pKa value of mandelic acid (pH 3.85) (calibrated glass electrode) using 12 ml of 37% hydrochloric acid. The solution became cloudy, but no mandelic acid precipitated out. Extraction was effected using 500 ml of ethyl acetate. After concentrating to dryness under reduced pressure, this "extract 1" comprised 14.10 g (92.67 mmol, 20.8% of theory) 95 of residue. A further 19 ml of 37% hydrochloric acid were then added dropwise to the aqueous phase with stirring which resulted in the pH falling from 4.2 to 2.44 and cloudiness occurring again. Extraction was effected using 500 ml of ethyl acetate. After concentrating to dryness under reduced pressure, this "extract 2" comprised 5 29.57 g (194.35 mmol, 43.7% of theory) of residue. 18.5 ml of 37% hydrochloric acid were added dropwise to the aqueous phase with stirring, which resulted in the pH falling from 2.99 to 1.08. Extraction was effected using 500 ml of ethyl acetate. After concentrating to dryness under reduced pressure, this "extract 3" comprised 12.62 g (82.94 mmol, 18.6% of theory) of residue. The aqueous phase (pH 1.4) was extracted 10 once more with 500 ml of ethyl acetate. After concentrating to dryness under reduced pressure, this "extract 4" comprised 3.71 g (24.38 mmol, 5.5% of theory) of residue. The melting points (DSC measurements) of all four residues (extracts 1 to 4) were from 133.2*C to 133.5*C. According to 1 H NMR spectra (400 MHz, DMSO-de), all four residues consisted of mandelic acid of high purity. A sample of each residue was 15 derivatized to the methyl ester with a solution of diazomethane in diethyl ether, and analyzed by GC to find the enantiomeric excess using a capillary column with a chiral phase [50 m x 0.25 mm ID fused silica capillary column coated with 0.25 pm of Lipodex-E (Ser. No. 723369, column No. 20174-32). Oven temperature: 115°C isothermal, injector: 200 0 C, detector: 220 0 C, flow rate: 2.0 ml of He/min. Split: 1:100. 20 The retention time of the (S)-(+)-mandelic acid (as the methyl ester) was 24.73 min. A racemic comparative sample was used to determine that the retention time of (R)-(-) mandelic acid (as the methyl ester) was 25.90 min]. In none of the residues (extracts 1 to 4) could (R)-(-)-mandelic acid be detected. A total of 60.0 g (394.35 mmol, 88.6% of theory) of (S)-(+)-mandelic acid were therefore recovered at 100% ee. 25 For a recovery of (S)-(+)-mandelic acid on the industrial scale, there is thus the possibility of continuously extracting the aqueous mother liquor, for example in a countercurrent process with, for example, ethyl acetate, by maintaining the pH within the range from 2.5-1.0 by continuously adding 37% hydrochloric acid. 30 Example 12: Synthesis and isolation of the mixture of oxaborinanes having the main component of the formula (C) [R 1 = o-nitrophenyl, R 2 = 2-pyridyl, R 3 = H, R 4 = 2-pyridyl,

R

5 = phenyl] 96 In a 250 ml four-neck flask equipped with precision glass stirrer, internal thermometer and septum, the suspension of 6.37 g (15 mmol) of a Mannich base (I) [R 1 = o nitrophenyl, R 2 = 2-pyridyl, R 3 = H, R 4 = 2-pyridyl, R s = phenyl] in 75 ml of toluene was cooled to an internal temperature of +1*C using an ice bath. Within 2 minutes, 5 4.47 ml (45 mmol, 3.0 equiv.) of borane-dimethyl sulfide (95% in dimethyl sulfide) were added via a syringe which resulted in a maximum internal temperature increase of +3 0 C. The cooling bath was removed and the suspension heated to +180C within 15 minutes. The light yellow suspension was stirred vigorously at this temperature for 45 min. 10 HPLC analysis of the suspension [injection of 8.0 pl of a solution in acetonitrile onto a 250 x 4 mm steel column Nucleosil 100-5 C18, 5 pm, flow rate 1.0 ml/min., det. 254 nm, eluent A: water (900 ml)/acetonitrile (100 ml)/trifluoroacetic acid (1.00 ml), eluent B: water (100 ml)/acetonitrile (900 ml)/trifluoroacetic acid (0.75 ml); elution with 15 a linear gradient: 0-2 min (75% A, 25% B), 22-26 min (35% A, 65%. B), 27 min (75% A, 25% B)] showed that all but 2% of the Mannich base (I) had reacted ((I) and the retro-Mannich products forming on the column give a broad peak having shoulders at tret 3-4 min). In addition to the toluene peak (tret 20.8 min), several minor peaks and 3% of the 1,3-amino alcohol (II) (tret 12.4 min), two peaks of relatively long retention 20 time were detected ("peak 1" tret 25.5 min, "peak 2" tret 28.6 min) whose total peak area amounted to 93% of all peaks (apart from toluene). Between these two peaks, the base line was not reached again (remains on a plateau) which implies a conversion of the compound "peak 1" to the compound "peak 2" on the column. 25 The suspension was cooled to +5.C and rapidly admixed with 5 ml of water, then stirred at RT for 5 min. The suspension was filtered via a BOchner funnel. The very pale yellow solid was washed with toluene (2 x 10 ml) and dried at +45°C/150 mbar under nitrogen. 6.22 g (14.26 mmol based on the formula (C), 95% of theory) of colorless powder were obtained. 30 In DSC, this powder showed a weak endothermic peak at 104.6°C (-9.5 J/g) and a very strongly exothermic (1718 J/g) decomposition peak at 166.8*C (onset at 157*C).

97 For "peak 1", HPLC-MS (API positive) gave M+H : m/z = 437.3 which corresponds to the empirical formula C 25

H

2 1

BN

4 0 3 (molecular weight 436.28) of the formula (C). For "peak 2", the following mass peaks were detected: m/z= 488.3, 449.2 and 439.3. This is possibly the boric acid adduct of the 1,3-amino alcohol (11) [C 25

H

22

N

4 0 3 x H 3

BO

3 , 5 molecular weight 488.3]. Boric acid and amino alcohol (11) are the expected hydrolysis products of the oxazaborinane (C) in aqueous acidic medium. Finally, a sample of the colorless powder (C) is solvolyzed using 3.0 equiv. of methanesulfonic acid in an excess of methanol at +20'C. HPLC analysis of the 10 reaction mixture showed the virtually complete disappearance (< 1%) of "peak 1" and "peak 2" with simultaneous continuous growth of the peak of the amino alcohol (11) (94%) and its diastereomer dia-(ll) (tret 8.2 min, 4%). A similar workup to Example 19 delivered the dihydrochloride of the pure amino alcohol (II) (100% ee, 99.5% de) in a yield of 75% of theory. 15 Example 13: Synthesis of the optically active Mannich salt of the formula (111) [R 1 = o-nitrophenyl,

R

2 = 2-pyridyl, R 3 = H, R 4 = 2-pyridyl, R s = phenyl] by four-component coupling with dynamic optical resolution at room temperature; monitoring of the variation of ee with 20 time (Table 1); use of (+)-dipivaloyltartaric acid as the chiral auxiliary [HY = (+) DPTAJ and ethanol as solvent (Table 2, No. 5): 60 ml of ethanol (denatured with toluene) were initially charged with stirring into a 100 ml three-neck round-bottom flask equipped with a precision glass stirrer, nitrogen 25 feed and bubble counter, and 4,63 g (23.5 mmol, 1.00 equiv.) of 2-pyridylmethyl phenyl ketone, 2.77 g (29.4 mmol, 1.25 equiv.) of 2-aminopyridine, 4.26 g (28.2 mmol, 1.20 equiv.) of 2-nitrobenzaldehyde and 7.48 g (23.5 mmol, 1.00 equiv.) of (+)-dipivaloyltartaric acid were introduced in succession. After approx. 10 min, a clear, yellow solution was formed which began to become cloudy approx. 15 min. 30 later. Seed crystals (10 mg) of enantiomerically pure (+)-DPTA salt were added which resulted in a yellow suspension which was stirred at room temperature under a nitrogen atmosphere for 14 days. At each of the times visible from Table 1, small aliquots of the reaction suspension were withdrawn, the solids contained therein were separated from the mother liquor by microfiltration and derivatized with (-)- 98 camphanoyl chloride as described in Example 1, and analyzed by means of HPLC. The variation of ee with time observed is reported in Table 1. On the 14th day, the ratio of the desired enantiomer to the undesired enantiomer was 97.67:2.33, corresponding to 95.34% ee. The suspension which was now white was filtered, and 5 the filter residue was washed with the mother liquor and then twice with 10 ml of ethanol each time. The solid was dried at 45°C under high vacuum for 2 hours. 11.45 g (9.81 mmol, 83.6% of theory) of the white salt were obtained which, according to 1 H NMR and titration contained two Mannich base cations per DPTA dianion. It can be estimated that the actual yield was distinctly above 90% of theory, 10 since the 10 intermediate sample withdrawals consumed significant amounts of product. Example 14: Synthesis of the optically active Mannich salt of the formula (111) [R 1 = o-nitrophenyl, 15 R 2 = 2-pyridyl, R 3 = H, R 4 = 2-pyridyl, R s = phenyl] by four-component coupling with dynamic optical resolution at +40*C. Use of (+)-dipivaloyltartaric acid as the chiral auxiliary [HY = (+)-DPTA] and ethanol as solvent (Table 2, No. 6): In a 250 ml four-neck round-bottom flask equipped with a precision glass stirrer, 20 nitrogen feed, and reflux condensor with bubble counter, 5.06 g (25.65 mmol, 1.00 equiv.) of 2-pyridylmethyl phenyl ketone were dissolved in 60 ml of absolute ethanol. Within 10 min, 2.99 g (31.76 mmol, 1.24 equiv.) of 2-aminopyridine, 4.61 g (30.53 mmol, 1.19 equiv.) of 2-nitrobenzaldehyde and 8.08 g (25.38 mmol, 0.99 equiv.) of (+)-DPTA were added in succession at an internal temperature of 25 400C, and each addition was effected after waiting for just the amount of time required for the solid to go completely into solution. A clear yellow solution was obtained which transformed into a yellow suspension after 25 min. The reaction mixture was then stirred at 40°C overnight. Samples taken intermediately and derivatized showed that the enantiomeric excess of the solid was 55.7% ee after 4.16 30 hours and 93.0% ee after 20 hours. After 23 hours, the heating bath was removed and the suspension cooled to 23*C within 15 minutes, and the precipitate was filtered off with suction, washed twice with 10 ml of ethanol and then dried at 450C under high vacuum. 14.89 g (12.76 mmol, 25.52 mmol of the Mannich base (I) containing the substituents specified in the title, 99.5% of theory) were obtained as a very pale 99 yellow solid. According to 'H NMR and titration, the salt consisted of (I) and DPTA in a ratio of 2:1. The enantiomeric excess was 95.9% ee. Example 15: 5 Synthesis of the optically active Mannich salt of the formula (111) [R 1 = o-nitrophenyl,

R

2 = 2-pyridyl, R 3 = H, R 4 = 2-pyridyl, R 5 = phenyl] by four-component coupling with dynamic optical resolution at +60"C. Use of (S)-(+)-mandelic acid as the chiral auxiliary (HY = (+)-MDLA] and ethanol as the solvent (Table 3, No. 7): 10 in a 2 liter jacketed reactor (connected to a circulation thermostat) equipped with a temperature sensor and mechanical turbine stirrer, 97.2 g (492.8 mmol, 1.00 equiv.) of 2-pyridylmethyl phenyl ketone were dissolved in 1200 ml of ethanol (denatured with methyl ethyl ketone) at room temperature. Over the course of 15 min, the internal temperature was increased to 40C. At this temperature, 55.66 g 15 (591.4 mmol, 1.20 equiv.) of 2-aminopyridine, 89.37 g (591.4 mmol, 1.20 equiv.) of 2 nitrobenzaldehyde and 149.96 g (985.6 mmol, 2.00 equiv.) of (S)-(+)-mandelic acid were added in succession. Immediately afterwards, the internal temperature of the reaction mixture was increased to 60*C and a clear solution was obtained. This heating procedure lasted 30 min., and 15 min. later, the first precipitate formation 20 could be observed. Sample withdrawal/derivatization/HPLC analysis according to Example 1 allowed an enantiomeric excess of the precipitate of 91.5% ee after 2 h, 93.0% ee after 3.5 h and 94.4% ee after 4.5 h to be determined. The reaction mixture was cooled to 200C within 2 h. The precipitate was filtered off with suction, washed 3 times with 50 ml of ethanol, and then dried at 400C under a vacuum of 50 mbar to 25 constant weight. 262.4 g (455.2 mmol, 92.4% of theory) of the mandelate salt (Ill) with the substituents specified in the title were obtained. The melting point was 153-154°C. According to 1 H NMR, it contained the corresponding Mannich base (I) and mandelic acid in a ratio of 1:1. The enantiomeric purity was 94.4% ee by derivatization with camphanoyl chloride and 97.5% ee by the more exact method of 30 pivaloyl derivatization according to Example 2. Example 16: Synthesis of the optically active Mannich salt of the formula (111) [R 1 = o-nitrophenyl,

R

2 = 2-pyridyl, R 3 = H, R 4 = 2-pyridyl, R 5 = phenyl] by four-component coupling with 100 dynamic optical resolution at +400C. Use of (S)-(+)-mandelic acid as the chiral auxiliary [HY = (+)-MDLA] and acetone as the solvent (Table 3, No. 20): In a 2 liter jacketed reactor (connected to a circulation thermostat) equipped with a 5 temperature sensor and mechanical turbine stirrer, 97.2 g (492.8 mmol, 1.00 equiv.) of 2-pyridylmethyl phenyl ketone were dissolved at room temperature in 1200 ml of acetone. Over the course of 15 min, the internal temperature was increased to 400C. At this temperature, 55.66 g (591.4 mmol, 1.20 equiv.) of 2-aminopyridine, 89.37 g (591.4 mmol, 1.20 equiv.) of 2-nitrobenzaldehyde and 149.96 g (985.6 mmol, 10 2.00 equiv.) of (S)-(+)-mandelic acid were added in succession which resulted in a clear solution which was stirred further at 40C. After 4.5 h, the first formation of precipitate could be detected. After 24 h, sample withdrawat/derivatization/HPLC analysis according to Example 1 gave a 97.0% ee of the precipitate. The suspension was cooled to an internal temperature of 25°C within 2.5 h. The suspension was 15 filtered off with suction, washed 3 times with 50 ml of acetone and dried at 40*C under a vacuum of 50 mbar. 250.4 g (434.4 mmol, 88.2% of theory) of the mandelate salt (Ill) with the substituents specified in the title were obtained as an almost colorless solid having a melting point of 156-158°C. According to 1 H NMR, it contained the corresponding Mannich base (I) and mandelic acid in a ratio of 1:1. 20 The enantiomeric purity was 95.7% ee by derivatization with camphanoyl chloride (Example 1) and 97.0% ee by the more exact method of piv-derivatization (Example 2). Example 17: 25 Synthesis of the optically active Mannich salt of the formula (Ill) [R 1 = o-nitrophenyl,

R

2 = 2-pyridyl, R 3 = H, R 4 = 2-pyridyl, R s = phenyl] by coupling with Schiff base preformed in situ with dynamic optical resolution at 400-60oC; use of (S)-(+)-mandelic acid as the chiral auxiliary [HY = (+)-MDLA] and n-butyl acetate as the solvent (Table 3, No. 23): 30 in a 1 liter four-neck round-bottom flask equipped with a water separator with fitted reflux condenser, precision glass stirrer, nitrogen feed and vacuum connection, the solution of 25.87 g (275 mmol) of 2-aminopyridine and 37.75 g (250 mmol) of 2-nitrobenzaldehyde in 500 ml of n-butyl acetate was heated to reflux at 100 mbar 101 and a bath temperature of 70°C (50-60°C internal temperature) which resulted in approx. 4.7 ml of water separating in the water separator within 2.2 h. The mixture was then left to stand overnight at 220C under a nitrogen atmosphere. 49.2 g (250 mmol) of 2-pyridylmethyl phenyl ketone were then added with stirring 5 and, once it had all dissolved, 45.6 g (300 mmot) of (S)-(+)-mandelic acid were added and heated to an internal temperature of 400C. Precipitate formation was observed after 5 min. After 3 h at 40 0 C, further heating was effected to 600C and stirring was continued at this temperature for 24 h. The suspension was cooled to 250C with stirring, and the precipitate was filtered off with suction, washed twice with 50 ml of 10 n-butyl acetate and dried at 50'C under reduced pressure. 134.6 g (233.4 mmol, 93.4% of theory) of the mandelate salt (Ill) with the substituents specified in the title were obtained. According to 'H NMR, it contained the corresponding Mannich base (I) and mandelic acid in a ratio of 1:1. The enantiomeric purity was 95.4% ee by derivatization with camphanoyl chloride (Example 1) and 98.0% ee by the more exact 15 method of pivaloyl derivatization (Example 2). Example 18: Typical procedure for Table 8: diastereoselective reduction of the optically active free Mannich base (I) [R 1 = o-nitrophenyl, R 2 = 2-pyridyl, R 3 = H, R 4 = 2-pyridyl, R 5 = 20 phenyl, corresponding to a compound of the formula (XVII)] to the enantiomerically pure 1,3-amino alcohol (XIX) and subsequent workup (Table 8, No. 29): In a 500 ml four-neck flask equipped with a precision glass stirrer, dropping funnel and internal thermometer, 21.39 g (50.39 mmol, 1.0 equiv.) of the Mannich base 25 (XVII) (chem. purity > 99%, 95.6% ee, 0.36% of H 2 0) were suspended in 160 ml of toluene under a nitrogen atmosphere and cooled using an ice bath to an internal temperature of +1*C. At this temperature, 10.18 g (125.97 mmol, 2.5 equiv.) of borane-dimethyl sulfide complex (94% in dimethyl sulfide) were added dropwise within 25 min, and the internal temperature rose to +20C. Once addition had been 30 completed, the mixture was heated to +20°C within 30 min and stirred further at this temperature which resulted in the yellow suspension turning beige. Reaction monitoring after 15 min (HPLC as in Example 12) indicated the virtually complete consumption of (XVII) with the formation of an equilibrium of the corresponding oxazaborinanes of the general formula (C) and oligomers thereof. After a total stirring 102 time of 1.5 h at 20 0 C, 70 ml of methanol were added dropwise within 10 min at an internal temperature of the reaction mixture of between +150C and +22°C with ice bath cooling. During this addition, gas development was observed. 6.5 mi (100.78 mmol, 2.0 equiv.) of methanesulfonic acid were then added dropwise within 5 10 min at an internal temperature of +20*C with ice cooling, and vigorous gas development and exothermicity was observed. Toward the end of the addition, a yellow solution was formed which was stirred at average to high speed at an internal temperature of +40 to +45°C. After a stirring time of 1.25 h, reaction monitoring by HPLC at 254 nm indicated a total of 6.1% of "retro-Mannich" decomposition products, 10 complete disappearance of the intermediate oxazaborinanes and a diastereoselectivity of the reduction of 94.3:5.6. After a total of 1.75 h at 40-45"C, the mixture was concentrated on a rotary evaporator at a bath temperature of +40*C/350 to 150 mbar to remove 78 ml of distillate (methanol, trimethyl borate, some toluene). The resulting biphasic mixture (toluene and separated yellow oil) were admixed with 15 30 ml of 2N hydrochloric acid and extracted. The yellow, aqueous acidic phase was removed and the toluene phase re-extracted with 5 ml of 2N hydrochloric acid plus 10 ml of water. According to HPLC, the toluene phase then contained no more product (XIX) and was discarded. The combined aqueous acidic product-containing aqueous phases were dissolved in 200 ml of 1-butanol and admixed at an internal 20 temperature of +20*C within 10 min with 95 ml (190 mmol, 3.77 equiv.) of 2N sodium hydroxide solution in a 500 ml four-neck flask equipped with a precision glass stirrer and dropping funnel to obtain an orange-yellow emulsion which was stirred for a further 5 min. The product-containing, orange-yellow butanol phase (upper) was removed from the colorless, clear aqueous phase (lower, pH 10), and 85 ml of 1 25 butanol/water were distilled off azeotropically on a rotary evaporator at a bath temperature of +500C and from 250 to 45 mbar. The resulting concentrated solution of (XIX) in butanol was heated under nitrogen in a 500 ml four-neck flask equipped with a precision glass stirrer, dropping funnel and internal thermometer to an internal temperature of +45°C, and admixed within 5 min with 11.1 ml (110 mmol, 2.18 equiv.) 30 of 30% hydrochloric acid via the dropping funnel which resulted in an internal temperature rise to +480C and a yellow solution. This solution was cooled to an internal temperature of +20°C within 1 h, which resulted in the onset of the crystallization of the white dihydrochloride and the formation of a pasty suspension. The mixture was then further cooled to +5°C within 10 min and stirred for a further 103 15 min at this temperature. The viscous suspension was then filtered via a Buchner funnel to obtain a white filter cake and a yellow filtrate. The filter cake was washed with 2 x 20 ml of 1-butanol, suction-dried and then dried in a vacuum drying cabinet at 400C/100 mbar. 20.22 g (40.48 mmol calculated as (XIX) - 2 HCI) of white 5 crystalline solid were obtained. According to HPLC, it contained 99.8% of (XIX) and < 0.1% of the diastereomer dia-(XIX). The enantiomeric purity was 100% ee. According to titration (acid/base and also chloride titration) and 1 H NMR, (XIX) was present as the dihydrochloride. According to 1 H NMR, 11.5% by weight (corresponding to 87.5 mol%) of 1-butanol were present. Even on extended drying at 10 40-50*C under high vacuum, the butanol could not be removed. This behavior was observed in all dihydrochlorides of Table 8 which had been precipitated from 1 butanot. The butanol contents were without exception 85-97 mol%, so that the product may be regarded as the monobutanol solvate of (lI)-dihydrochloride. The yield was 80.3% of theory when the product weight was calculated as (XIX) 15 dihydrochloride neglecting the butanol content and is based on the weight of the reactant (XVII) used without taking into account its incomplete enantiomeric purity (93.4% ee) [known as the telquel yield]. Example 19: 20 Diastereoselective reduction of the optically active free Mannich base (I) [R' = o nitrophenyl, R 2 = 2-pyridyl, R 3 = H, R 4 = 2-pyridyl, R 5 = phenyl, corresponding to a compound of the formula (XVII)] to the enantiomerically pure 1,3-amino alcohol (XIX); use of borane-dimethyl sulfide complex as the reducing agent according to Table 8, No. 33; optimized workup. 25 In a 1 I four-neck round-bottom flask equipped with a precision glass stirrer, dropping funnel and internal thermometer, 63.63 g (150 mmol, 1.0 equiv.) of the Mannich base (XVII) (chem. purity > 99%, 93.4% ee, 0.02% of H 2 0) were suspended under a nitrogen atmosphere in 400 ml of toluene and cooled to an internal temperature of 30 +1°C using an ice bath. At this temperature, 31.60 g (391.1 mmol, 2.6 equiv.) of borane-dimethyl sulfide complex (94% in dimethyl sulfide) were added dropwise within 15 min which resulted in an internal temperature rise to +40C. Once addition had been completed, the mixture was heated to +20'C within 30 min and then stirred further at this temperature which resulted in the yellow suspension turning beige.

104 Monitoring of the reaction after 2.5 h (HPLC system as in Example 12) indicated the virtually complete consumption of (XVII) with the formation of an equilibrium of oxazaborinanes. After a total stirring time of 4 h at 20*C, 190 mi of methanol were added dropwise within 10 min at an internal temperature of the reaction mixture 5 between +15 0 C and +22*C with ice bath cooling. During this addition, gas development was observed. 31.1 ml (478.9 mmol, 3.19 equiv.) of methanesulfonic acid were then added dropwise within 20 min, likewise within an internal temperature interval of from +150C to +22 0 C, and vigorous gas development was observed. Once 2/3 of the total amount of acid had been introduced, a yellow solution was obtained. 10 Once addition had been completed, the dropping funnel was rinsed using a further 53 ml of methanol and stirring was continued at from +200C to +220C. After a stirring time of 1 h, HPLC reaction monitoring at 254 nm indicated a total of 5.4% of Mannich base (XVII) and "retro-Mannich" decomposition products, 5.3% of dia-(XIX) and 88.4% of (XIX), and also complete disappearance of the intermediate 15 oxazaborinanes. The diastereoselectivity in the crude reaction solution was therefore 94.4:5.6. The mixture was stirred overnight at room temperature (internal temperature of +18 - +22*C) and concentrated the next day on a rotary evaporator at a bath temperature of +40*C and from 400 to 150 mbar to a final volume of 380 ml to remove methanol, trimethyl borate and some of the toluene. The resulting biphasic 20 mixture was admixed with 212 ml of water at an internal temperature of from +10°C to +250C. After stirring had been continued for 5 min, there was a phase separation. The toluene phase was discarded. The yellow, acidic product-containing aqueous phase (approx. 330 ml) was dissolved in 303 ml of 1-butanol and admixed within 10 min with 61.72 g (509.2 mmol, 3.39 equiv.) of 33% sodium hydroxide solution at 25 an internal temperature of from +10*C to +15°C in a 1 I four-neck flask equipped with a precision glass stirrer and dropping funnel to obtain an orange-yellow emulsion. Once the addition was complete, the mixture was stirred for a further 5 min. The product-containing, orange-yellow butanol phase (approx. 390 ml, upper) was removed from the virtually colorless clear aqueous phase (lower, approx. pH 9) and 30 concentrated on a rotary evaporator at a bath temperature of +500C and from 300 to 50 mbar to such an extent that 115 ml of distillate (1-butanol/water) were azeotropically removed. The resulting concentrated solution of (XIX) in butanol was heated to an internal temperature of +49*C under nitrogen in a 500 ml four-neck flask equipped with a precision glass stirrer, dropping funnel and internal thermometer and 105 admixed within 5 min via the dropping funnel with 39.24 g (322.9 mmol, 2.15 equiv.) of 30% hydrochloric acid which resulted in an internal temperature rise to +530C and a yellow solution. This solution was cooled to an internal temperature of +2 0 °C within 15 min which resulted in the onset of crystallization of the white dihydrochloride and 5 the formation of a pasty suspension. After a stirring time of 30 min at +20C, the mixture was cooled to +1*C within 30 min and stirred at this temperature for a further 1 h. Filtration was then effected through a BOchner funnel to obtain a white filter cake and a yellow filtrate. The filter cake was washed with 2 x 60 ml of 1-butanol, suction dried and then dried in a vacuum drying cabinet under a gentle nitrogen stream at 10 40 0 C and 50 mbar. 62.7 g (125.55 mmol) of (XIX) - 2 HCI were obtained as a white crystalline solid. According to HPLC, it contained 99.68% of (XIX) and 0.14% of the diastereomer dia-(XIX). The enantiomeric purity was 100% ee. According to titration and 'H NMR, (XIX) was present as dihydrochloride. According to 1 H NMR, 11.5% by weight (corresponding to 87.5 mol%) of 1-butanol were present. The yield was 83.7% 15 of theory when the product weight (62.7 g) is calculated as (XIX)-dihydrochloride neglecting the butanol content and is based on the weight of the reactant (XVII) used without taking into account its incomplete enantiomeric purity (93.4% ee) [known as the telquel yield]. When the butanol content of (XIX)-dihydrochloride is taken into account, and the racemic proportion (6.6%) of the reactant (XVII) used which had 20 been removed in the workup is subtracted, then the yield was 79.4% of theory. When the yield corrected for butanol is based on the all the reactant (XVII), then the yield was 74.1%. Example 20: 25 Diastereoselective reduction of the optically active free Mannich base (I) [R 1 = o nitrophenyl, R 2 = 2-pyridyl, R 3 = H, R 4 = 2-pyridyl, R 5 = phenyl, corresponding to a compound of the formula (XVII)] to the enantiomerically pure 1,3-amino alcohol (XIX) with borane generated in situ from chlorotrimethylsilane and sodium borohydride (Table 8, No. 34) 30 In a 500 ml four-neck round-bottom flask equipped with a precision glass stirrer, reflux condenser, internal thermometer and septum, 1.70 g (45.0 mmol, 3.0 equiv.) of sodium borohydride were suspended in 215 ml of tetrahydrofuran. After adding 4.89 g (45.0 mmol, 3.0 equiv.) of chlorotrimethylsilane (by syringe), the suspension 106 was stirred at average to high speed at an internal temperature of 500C for 45 min, and a finely crystalline white solid precipitated out. The suspension was then cooled to +1°C and admixed within 5 min with 6.36 g (15.0 mmol, 1.0 equiv.) of the Mannich base (XVII), which resulted in an internal temperature rise to +3 0 C and a pale yellow 5 suspension. The mixture was heated to 20°C within 15 min and stirring was continued at this temperature. HPLC monitoring after 30 min indicated virtually complete conversion of (XVII) to the oxazaborinane (C). After a total stirring time of 2 h at 200C, 25 ml of methanol were added dropwise to the mixture at from 10 to 15"C within 5 min. 3.1 ml (47.9 mmol, 3.19 equiv.) of methanesulfonic acid were then 10 added within 5 min. The mixture was then stirred further at an internal temperature of 20 0 C. HPLC monitoring after 15 min showed 23% of (XVII) and 72% of (C). After a stirring time of 30 min, a further 50 ml of methanol and 3.1 ml (47.9 mmol, 3.19 equiv.) of methanesulfonic acid were added to the mixture at 200C. The mixture was then stirred at an internal temperature of 40-43"C. Further HPLC monitoring after 15 30 min indicated the complete conversion of (C) to (XIX) (85.1%), dia-(XIX) (5.4%), and also (XVII) and retro-Mannich decomposition products (8.5% in total). After a total stirring time of 1 h at 40-43*C, the yellow suspension was filtered to remove salts and the filtrate fully concentrated on a rotary evaporator at 40°C and from 400 to 20 mbar. The remaining yellow, viscous oil was stored overnight at +4°C in 50 ml of 20 water. The aqueous product phase was dissolved in 60 ml of 1-butanol in a 250 ml four-neck round-bottom flask equipped with a precision glass stirrer, dropping funnel and internal thermometer under nitrogen and admixed within 5 min with 11.96 g (98.7 mmol, 6.58 equiv.) of 33% aqueous sodium hydroxide solution at from 15 to 220C. The orange-yellow suspension was stirred for 5 min and the yellow butanol 25 phase separated from the colorless aqueous phase (pH 13-14). The butanol phase was concentrated at 50'C and from 200 to 20 mbar to such an extent that 22 ml of distillate (butanol/water) were azeotropically removed. The resulting concentrated butanolic solution was heated to an internal temperature of 470C in a 100 ml four neck flask equipped with a precision glass stirrer, dropping funnel and internal 30 thermometer under nitrogen and admixed within 5 min with 4.00 g (33.0 mmol, 2.20 equiv.) of hydrochloric acid which resulted in an internal temperature rise to 500C and a clear orange-red solution. This was cooled to 150C within 15 min which resulted in the onset of crystallization of the white dihydrochloride and a pasty suspension being obtained. After a stirring time of 30 min, the mixture was cooled 107 further to 1°C within 15 min and stirring was continued at this temperature for one hour. The precipitate was filtered off with suction, washed twice with 10 ml of butanol and dried at 40 0 C and 50 mbar under a gentle nitrogen stream. 5.60 g (11.21 mmol, 74.8% of theory) of white solid were obtained which, according to HPLC, had 5 > 99% ee, and consisted of 99.6% of (XIX) and 0.2% of dia-(XIX). 1 H NMR indicated a 1-butanol content of 12.0%. The water content (Karl-Fischer titration) was 0.99%. The chloride titration gave 1.97 equiv. of chloride ions per mole of (XIX). Example 21: 10 Liberation of the Mannich base (I) [R 1 = o-nitrophenyl, R 2 = 2-pyridyl, R 3 = H, R 4 = 2-pyridyl, R s = phenyl, corresponding to a compound of the formula (XVII)] from the mandelate salt (XVIII) [Y'= (S)-(+)-mandelic salt] with NaHCO 3 in water/acetone according to Table 7, No. 23: 15 In a 2 liter jacketed reactor (connected to a circulation cryostat) equipped with a temperature sensor and mechanical turbine stirrer, 228.6 g (396.6 mmol, 1.0 equiv.) of mandelate salt (XViII) (95.6% ee of the Mannich base (XVII) present) were suspended at room temperature in 1143 ml of water under a nitrogen atmosphere and with stirring. The white suspension was then cooled to an internal temperature of 20 +10 0 C. 66.64 g (793.24 mmol, 2.0 equiv.) of sodium hydrogencarbonate were added, followed after 5 min by 114 ml of acetone. The suspension which was gradually becoming yellow was stirred at an internal temperature of +10°C. The conversion was monitored by taking samples, filtration and 1 H NMR of the solid. After 4.5 hours, 15.4% of mandelic acid were still present, and after 7.4 hours still 9.1%. After stirring 25 overnight, no more mandelic acid was detected. The suspension was filtered off with suction and the filter cake washed 3 times with 50 ml of water each time. The solid was dried in a vacuum drying cabinet at 40'C and approx. 50 mbar. 168.25 g (396.4 mmol, 99.95% of theory) of the free Mannich base (XVII) were obtained as a yellow powder, 96.8% ee (camph. method according to Example 1) or 96.2% ee (piv. 30 method according to Example 2), m.p. 153-154'C, residual water content according to Karl-Fischer titration: 0.32% by weight. 1 H NMR and HPLC confirm that it is a single compound which contains no more mandelic acid. 'H NMR also showed that the content of the anti-diastereomer of (XVII) was less than 1%.

108 Example 22: Liberation of the Mannich base (I) [R' = o-nitrophenyl, R 2 = 2-pyridyl, R 3 = H, R 4 = 2-pyridyl, R s = phenyl, corresponding to a compound of the formula (XVII)] from the mandelate salt (XVIII) [Y = (S)-(+)-mandelic acid salt] with 2N sodium hydroxide at 5 pH-stat 8.5 in water/ethanol according to Table 7, No. 21 The reaction was carried out in a 10 liter jacketed reactor (connected to a circulation cryostat) equipped with a temperature sensor and mechanical bell stirrer to which a Metrohm 718 STAT-Titrino autotitrator was connected. The autotitrator was filled with 10 1150 ml of 2.00 N sodium hydroxide solution, and was controlled via a glass electrode dipping into the reaction suspension and set to the following parameters: maximum metering rate 20 ml/min, minimum metering rate 4 ml/min, recording time interval every 60 sec., pHmax 8.5. The dropping tip of the autotitrator dipped into the reaction suspension. The jacket temperature of the reactor was controlled in such a 15 manner that the temperature of the reaction suspension was maintained within the 20-25 0 C range. At room temperature, 1311.3 g (2.274 mol, 1.0 equiv.) of mandelate salt (XVIII) (94.4% ee of the Mannich base (XVII) present, approx. 1.3% of the anti-diastereomer 20 of (XVII)) were suspended at room temperature in 5686 ml of water under a nitrogen atmosphere and with stirring, and 569 ml of ethanol (denatured with methyl ethyl ketone) were added. The pH of the suspension (before the beginning of the titration) was 4.8. After switching on the titrator, the pH briefly reached a maximum of pH 9.7. After only 30 sec., the reaction suspension had changed in color from pale yellow to 25 intense yellow. The initially high metering rate slowed appreciably with time. After 4 hours, 92% of the theoretical amount of sodium hydroxide solution had been metered in. The mixture was stirred overnight under pH-stat conditions (pH 8.5). The next morning, the metered addition had come to a standstill. The pH of the suspension was 8.72 and a total of 1139.6 ml (100.2% of theory) had been added by titration. 30 The suspension was filtered off with suction, and the filter cake was washed 4 times with 500 ml of water. The solid was dried in a vacuum drying cabinet under a nitrogen stream at 40 0 C and approx. 100 mbar for 28 hours, then at 25"C and 100 mbar for 70 hours and finally at 40"C for a further 20 hours under high vacuum (10

-

2 mbar). 960.9 g (2.26 mol, 99.5% of theory) of the free Mannich base (XVII) were obtained as 109 a fine light yellow powder, 95.6% ee (piv. method according to Example 2), m.p. 150 1520C, residual water content according to Karl-Fischer titration: 0.35% by weight. "H NMR and HPLC confirmed that it is a single compound which contains no more mandelic acid. 'H NMR also showed that the content of the anti-diastereomer of 5 (XVII) was approx. 1.2%. Example 23: Diastereoselective reduction of the optically active mandelate salt (Ill) [R 1 = o-nitrophenyl, R 2 = 2-pyridyl, R 3 = H, R 4 = 2-pyridyl, R s = phenyl, HY = (S)-(+) 10 mandelic acid, corresponding to a compound of the formula (XVIII)] to the 1,3-amino alcohol (XIX) according to Table 9, No. 18; solvolysis of the oxazaborinane using hydrochloric acid In a 1 I four-neck round-bottom flask equipped with a precision glass stirrer, dropping 15 funnel with fitted bubble counter, internal thermometer and nitrogen feed, 30.0 g (52.0 mmol, 1.0 equiv.) of the mandelate salt (XVIII) (96.5% ee of the Mannich base (XVII) present) were suspended in 400 ml of THF and cooled to +10C by means of an ice bath. 15.5 ml (156 mmol, 3.0 equiv.) of borane-dimethyl sulfide complex (95%) were added dropwise within 10 min under a nitrogen atmosphere at a reaction 20 temperature of from +1 to +3"C. Once the addition had been completed, the ice bath was removed and the reaction mixture brought to 23 0 C within 15 min, and then stirred for a further 1.5 hours. Sample taking/HPLC analysis showed that the conversion of (XVIII) to oxazaborinane (C) had been completed after only 1 hour. The reaction mixture was cooled again to 10C with the ice bath and then 25 ml of water 25 were slowly added dropwise at a maximum internal temperature of 120C. This resulted in vigorous gas development and the solution became pale yellow. Stirring was continued at room temperature until gas development was complete (30 min). A white solid precipitated out. The THF was distilled out of the reaction mixture at 40°C and approx. 100 mbar. Toward the end of distillation, a full water-jet vacuum (approx. 30 20 mbar) was applied for 5 min. After cooling to +5°C, 200 ml (2400 mmol) of conc. hydrochloric acid (37%) were slowly added dropwise at a maximum internal temperature of the reaction mixture of 200C, and the mixture was then stirred at 40°C for 1 hour. The 1,3-amino alcohol (XIX) went into solution as the hydrochloride and boric acid precipitated out. The suspension was left to stand overnight in a 110 refrigerator at 4°C in order to complete the crystallization. The boric acid was filtered off with suction and washed with 40 ml of water. After drying under reduced pressure, it weighed 7.23 g (116.9 mmol, 75% of theory). The acidic filtrate had a total volume of 250 ml. In a 1 I four-neck flask equipped with a precision glass stirrer and dropping 5 funnel, 96 g (2400 mmol) of sodium hydroxide solution were dissolved in 520 ml of water, cooled to 130C, and then said acidic filtrate was slowly added dropwise within 60 min at a maximum internal temperature of 15 0 C. The crude 1,3-amino alcohol (XIX) precipitated out in roughly crystalline form. The suspension was stirred at room temperature for a further 1 hour, and the precipitate was filtered off with suction and 10 washed with 250 ml of water (the precipitate which formed when the washing water ran into the filtrate consisted predominantly of polar impurities and was therefore discarded). The crude (XIX) was dried in a vacuum drying cabinet at 400C and approx. 100 mbar. 20.7 g (48.54 mmol, 93.4% of theory) of pale yellow solid was obtained. It was suspended in 100 ml of diisopropyl ether and stirred vigorously at 15 550C for 1 hour. The solid was filtered off with suction, washed with.100 ml of diisopropyl ether and dried under reduced pressure at 400C and approx. 100 mbar. 17.5 g (41.0 mmol, 78.9% of theory) of pale yellow powder were obtained which, according to HPLC analysis, was 95% pure and contained 3.1% of the diastereomer dia-(XIX) and 1.8% of by-products. 20 Example 24: Diastereoselective reduction of an optically active Mannich salt (Ill) [R 1 = o-nitrophenyl, R 2 = 2-pyridyl, R 3 = H, R 4 = 2-pyridyl, R 5 = phenyl, HY* = (+)-DPTA] to the 1,3-amino alcohol of the general formula (II), corresponding to a compound of the 25 formula (XIX) according to Table 10, No. 5; solvolysis of the oxazaborinane with hydrochloric acid. In a 250 ml four-neck round-bottom flask equipped with a precision glass stirrer, septum, bubble counter, internal thermometer and nitrogen feed, 10.0 g (8.57 mmol; 30 according to 'H NMR determination of the ratio of the compound (XVII) to DPTA, containing 16.08 mmol of (XVII); 1.0 equiv.)of the DPTA salt (11I) (95.1% ee of the Mannich base (XVII) present) were suspended in 100 ml of THF, then cooled to an internal temperature of from 0 to 50C. 7.63 ml (80.45 mmol, 5.0 equiv.) of borane dimethyl sulfide complex (95%) were added dropwise within 15 min by syringe under 111 nitrogen. The ice bath was then removed and the suspension heated to room temperature. After 20 min at room temperature, there was a clear solution. Taking a sample and HPLC analysis showed that (Ill) had been quantitatively converted to the oxazaborinane (C) and that only a few by-products had been formed. 45 ml of water 5 were added dropwise within 15 min (gas development, vigorous foaming), which resulted in an internal temperature rise to 40 0 C. 10 ml of 37% hydrochloric acid were added dropwise within 15 min, and then the internal temperature was increased to 60'C. After 15 min at 60'C, HPLC analysis indicated that no more boron compound was present and that (XIX) had formed as the main product. 30 ml of 33% sodium 10 hydroxide solution were used to adjust the pH to 13, and the reaction mixture was then cooled to room temperature and extracted twice with 100 ml of dichloromethane. The combined organic extracts were evaporated to dryness under reduced pressure and the residue (solid foam) was dried in a vacuum drying cabinet at 40'C and 50 mbar. 8.11 g of pale yellow powder were obtained which, according to an HPLC 15 assay, had a purity of 75.1%, based on a pure reference standard of (XIX). The yield of (XIX) was therefore 6.09 g (14.28 mmol, 88.8% of theory). The HPLC 100% purity was 94.8%, the ratio of (XIX) to dia-(XIX) was 97.8:2.2, and the enantiomeric purity was 96.8% ee. 20 Example 25: Diastereoselective reduction of an optically active Mannich salt (Ill) [R 1 = o-nitrophenyl, R 2 = 2-pyridyl, R 3 = H, R 4 = 2-pyridyl, R s = phenyl, HY* = (+)-DPTA] to the 1,3-amino alcohol of the general formula (II), corresponding to a compound of the formula (XIX) according to Table 10, No. 3; solvolysis of the oxazaborinane using 25 potassium hydroxide solution In a 250 ml four-neck round-bottom flask equipped with a precision glass stirrer, septum, bubble counter, internal thermometer and nitrogen feed, 10.0 g (8.57 mmol; according to 'H NMR determination of the ratio of the compound (XVII) to DPTA, 30 containing 16.08 mmol of (XVII); 1.0 equiv.) of the DPTA salt (111) (95.1% ee of the Mannich base (XVII) present) were suspended in 100 ml of THF, then cooled to an internal temperature of from 0 to 5 0 C. 7.63 ml (80.45 mmol, 5.0 equiv.) of borane dimethyl sulfide complex (95%) were added dropwise within 15 min by syringe under nitrogen. The ice bath was removed and the reaction mixture stirred while heating to 112 room temperature. After 30 min, there was a clear solution. Taking a sample and HPLC analysis showed the complete conversion of the reactant to 91% of oxazaborinane and 9% of (XIX). 45 ml of water were added dropwise within 15 min, followed by 45 ml of 20% aqueous potassium hydroxide solution within 15 min. This 5 resulted in gas development, vigorous foaming and an internal temperature rise to 400C. The reaction mixture was heated to 60'C and the solvolysis of the oxazaborinane to the 1,3-amino alcohol (XIX) was followed by HPLC monitoring. After 3 hours at 60'C, the ratio (C)/(XIX) was 53.3:46.7, after 10 hours 19.4:80.6, and after 16 hours 6.9:93.1. The solvolysis was aborted at this point and the reaction 10 mixture cooled to room temperature. Extraction was effected twice with 100 ml of dichloromethane and the combined organic extracts were washed with 50 ml of saturated sodium chloride solution. The dichloromethane solution was then evaporated to dryness under reduced pressure and the residue was dried under reduced pressure at 40*C and 50 mbar. 7.05 g of pale yellow powder were obtained 15 which, according to an HPLC assay, had a purity of 77.2% based on a pure reference standard of (XIX). The yield of (XIX) was therefore 5.44 g (12.76 mmol, 79.3% of theory). The HPLC 100% purity was 93.0%, the ratio of (XIX)/dia-(XIX) 98.5:1.5, and the enantiomeric purity 95.2% ee. 5.5% of unsolvolyzed oxazaborinane (C) were still present. 20 Example 26: Diastereoselective reduction of an optically active Mannich salt (Ill) [R 1 = o-nitrophenyl, R 2 = 2-pyridyl, R 3 = H, R 4 = 2-pyridyl, R 5 = phenyl, HY = (+)-DPTA] to the 1,3-amino alcohol of the general formula (II), corresponding to a compound of the 25 formula (XIX) according to Table 10, No. 9; solvolysis of the oxazaborinane using methanol/methanesulfonic acid In a 250 ml four-neck round-bottom flask equipped with a precision glass stirrer, septum, bubble counter, internal thermometer and nitrogen feed, 15.33 g 30 (13.13 mmol; according to 1 H NMR determination of the ratio of the compound (XVII) to DPTA, containing 25.30 mmol of (XVII); 1.0 equiv.) of the DPTA salt (111) (93.2% ee of the Mannich base (XVII) present) were suspended in 125 ml of THF, then cooled to an internal temperature of from 0 to 5°C. 4.86 ml (63.94 mmol, 2.5 equiv.) of borane-dimethyl sulfide complex (95%) were added dropwise within 15 min by 113 syringe under nitrogen. The ice bath was removed and the reaction mixture stirred while heating to room temperature. After 45 min, there was a clear solution. After 2 h, no more reactant could be detected by HPLC. At 5°C, 20.9 g of methanol were added dropwise within 15 min, immediately followed by 4.92 g of methanesulfonic acid. The 5 yellow solution was heated to an internal temperature of 350C and the solvolysis of the oxazaborinane (C) was followed by HPLC monitoring. After 4.5 h, 3.7% of (C), 94.2% of (XIX) and 2.1% of the diastereomer dia-(XIX) were detected. After 6.5 h at 350C and standing of the solution overnight at room temperature, 1.8% of (C), 96.9% of (XIX) and 1.8% of dia-(XIX) were detected. The yellow, clear solution was 10 evaporated under reduced pressure on a rotary evaporator to a residue of 22.95 g (yellow oil plus solid) and dissolved in 15 ml of methanol to give a clear solution (ultrasound bath, 350C). This highly concentrated methanol solution was added dropwise within 15 min into the solution of 10 ml of 25% ammonia solution in 75 ml of water (250C), and (XIX) precipitated out immediately. The suspension was stirred at 15 room temperature for 1 hour, then filtered off with suction. According to an HPLC assay against a pure reference standard of (XIX), this crude product had a purity of 88% and a (XIX)/dia-(XIX) ratio of 98.1:1.9. It was resuspended in a solution of 1 ml of conc. ammonia solution in 75 ml of water and stirred vigorously at room temperature for two hours, then filtered off with suction and dried at 450C and 20 150 mbar. 11.0 g (25.79 mmol, 101.9% of theory) of a light yellow powder which, according to an HPLC assay against a standard, had a purity of 96.1% (i.e. corrected yield: 97.9% of theory), 93.2% ee and an unchanged (XIX)/dia-(XIX) ratio of 98.1:1.9. This roughly purified (XIX) was stirred vigorously in 66 ml of boiling diisopropyl ether for 30 min, stirred for a further hour under ice bath cooling, then filtered off with 25 suction and dried at 500C under high vacuum (10 -2 mbar). 9.50 g (22.28 mmol, 88.1% of theory) of light yellow powder were obtained which, according to an HPLC assay against a standard, had 97.9% purity (i.e. corrected yield: 86.2% of theory), 95.2% ee and an (XIX)/dia-(XIX) ratio of 99.2:0.8. 30 Example 27: Synthesis of the optically active Mannich salt of the formula (Ill) [R 1 = p-tolyl, R 2 = 2-pyridyl, R 3 = H, R 4 = 2-pyridyl, R s = phenyl] by four-component coupling with dynamic optical resolution at room temperature; use of (S)-(+)-mandelic acid as the chiral auxiliary [HY* = (+)-MDLA)] and ethanol as the solvent: 114 In a 100 ml three-neck flask equipped with a precision glass stirrer, 30 ml of ethanol (denatured with methyl ethyl ketone) were initially charged. At room temperature (220C), 2.32 g (11.76 mmol, 1.00 equiv.) of 2-pyridylmethyl phenyl ketone, 1.40 g 5 (14.70 mmol, 1.25 equiv.) of 2-aminopyridine, 1.75 g (14.11 mmol, 1.20 equiv.) of 4-tolylaldehyde and 3.65 g (23.52 mmol, 2.00 equiv.) of (S)-(+)-mandelic acid were added in succession under an N 2 atmosphere. The mechanical stirrer was switched on and after a few minutes a clear yellow solution formed. After 1 h, considerable amounts of precipitate had formed. The suspension was stirred further at room 10 temperature. After 40 h and 64 h of reaction time, samples of the suspension (each containing approx. 50 mg of precipitate) were withdrawn and the precipitate in it filtered off with suction in each case. The syn/anti ratio was determined by 1 H NMR spectroscopy (measured immediately after dissolving the sample in DMSO-d6). The diastereomeric ratio can in principle be calculated from the integrals of a plurality of 15 signals, most simply from the methyl singlet which for the syn-isomer is at 6 = 2.15 ppm, and for the antiisomer at 5 = 2.11 ppm. The optical purity of the Mannich base was determined by chiral phase HPLC analysis after piv. derivatization using the procedure described at the end of Example 27. For both samples, the syn/anti ratio calculated from the NMR integrals was 95:5. 20 Taking into account the period of 3.5 min which was required after dissolving the sample for introducing the sample into the NMR instrument, sample shimming and data accumulation, an original syn/anti ratio of the precipitate of > 99: < 1 is extrapolated from the kinetics (Example 28) of the syn/anti-isomerization. In both cases, the molar ratio of Mannich base to mandelic acid was exactly 1:1. The 25 enantiomeric excess of the Mannich base was 96.0% ee in the sample after 40 h and 97.0% ee in the sample after 64 h. The precipitate of the reaction mixture was filtered off with suction, washed with mother liquor and then with a little ethanol, suction-dried and dried under high vacuum. 5.66 g (10.4 mmol, 88.2% of theory) of pale yellow powder were obtained. 30 Taking into account the two samples taken previously (approx. 100 mg), the yield was 90% of theory. "H NMR (400 MHz, DMSO-d 6 ): 8 = 2.15 (s, 3H), 5.02 (s, 1H, CHOH of the mandelate anion), 5.65 (d, 1H), 5.95 (t, 1H), 6.32 (d, 1H), 6.37 (t, 1H), 6.89 (d, 1H), 6.99 (d, 2H), 115 7.20 (m, 2H), 7.25-7.48 (m, 11H), 7.50-7.60 (m, 2H), 7.68 (td, 1H), 7.87 (d, 2H), 7.92 (~d, 1H), 8.46 (-d, 1H). 13C NMR (100.62 MHz, DMSO-d 6 ): 6 = 20.52 (CH 3 ), 55.20 (CH), 60.55 (CH), 72.44 (CHOH of the mandelate anion), 107.84 (CH), 111.87 (CH), 119.10 (CH), 121.80 5 (CH), 126.60-128.70 (12 signals, CH), 133.13 (CH), 135.40 (C), 136.50 (CH), 136.63 (CH), 138.95 (C), 140.20 (C), 147.25 (CH), 148.87 (CH), 156.10 (C), 157.90 (C), 174.20 (CO2-), 196.8 (C=O). Derivatization and ee determination: 10 20 p.l of pivaloyl chloride, followed by 10 pl of triethylamine are added to 2-5 mg of the Mannich salt in a Reacti-Vial. The solution is sonicated for 2 min in an ultrasound bath. 500 p1 of acetonitrile (HPLC grade) are added and 1 p1 of the solution is injected onto a Chiralpak AS 250 mm x 4.6 mm column. Isocratic elution at 25*C and 1.0 ml/min of the eluent 50% isopropanol/50% n-hexane/0.1% trifluoroacetic acid and 15 UV detection at 254 nm. The main isomer (98.5%) was eluted at t(ret) 12.14 min, and the mirror image (1.5%) at t(ret) 7.34 min. An appropriately derivatized racemic comparative sample delivered 50% of each peak. Example 28: 20 Syn/anti-isomerization of the Mannich base mandelate from Example 26 in DMSO-d 6 solution at 300K. Kinetics and equilibrium location of the retro-Mannich/Mannich reactions: 8 mg of the product from Example 27 were dissolved in DMSO-d 6 as rapidly as possible in a 1H NMR tube at room temperature. The sample was immediately 25 introduced into the NMR instrument (400 MHz, 300.0 K), shimmed rapidly and analyzed. The first spectrum was obtained 3.5 min after the sample dissolution. It showed the syn- and anti-isomers of the Mannich salt in a ratio of 95.1:4.9. Further spectra of the solution were each obtained at an interval of 3-4 min. They showed a continuous increase of the anti-isomer at the expense of the syn-isomer. The 30 variation can be seen from the graphics and the table of the appendix. 69 min after dissolution of the Mannich salt, the NMR monitoring was aborted at a syn/anti ratio of 50:50. A repeat measurement 20.5 hours after dissolution of the Mannich salt indicated a syn/anti ratio of 41.5:58.5. After a total of 44.5 hours, this ratio was unchanged. The thermodynamic equilibrium of the two isomers is thus achieved in 116 less than 20 h and the anti-isomer is preferred in solution. In contrast, the four component coupling (Example 27) results in the crystallization of virtually pure syn isomer, apparently owing to lower solubility. Even the spectrum obtained 3.5 min after sample dissolution indicates (in addition to the syn- and anti-isomers of the Mannich 5 salt) the presence of the retro-Mannich products 2-pyridylmethyl phenyl ketone (formula VI; singlet at 5 = 4.53 ppm) and tolylaldehyde (or corresponding imine) (formula IV or X, singlets at 5 = 2.40 and 9.12 ppm) in small but significant amounts. The best fit curve between the measurement points of the graph was obtained by 3rd order polynomial formation. Extrapolation of these curves to time t = 0 shows that the 10 solid had a syn/anti ratio of > 99:< 1. NMR Time after cis- trans Measurment sample isomer isomer No. dissolution [%] [%] [min] 1 3.5 95.1 4.9 2 6.5 92.5 7.5 3 10.5 89.0 11.0 4 13.5 85.0 15.0 5 17.5 81.7 18.3 6 20.5 77.3 22.7 7 24.5 76.8 23.2 8 27.5 71.8 28.2 9 31.5 68.0 32.0 10 34.5 66.2 33.8 11 37.5 63.8 36.2 12 41.5 61.7 38.3 13 44.5 60.1 39.9 14 48.5 58.7 41.3 15 51.5 56.8 43.2 16 55.5 54.5 45.5 17 58.5 53.6 46.4 18 61.5 52.9 47.1 19 65.5 52.0 48.0 20 68.5 50.5 49.5 21 1230 41.5 58.5 22 2670 41.6 58.4 Example 29: 15 Synthesis of the optically active Mannich salt of the formula (111) [R 1 = o-chlorophenyl,

R

2 = 2-pyridyl, R 3 = H, R 4 = 2-pyridyl, R 5 = phenyl] by four-component coupling with 117 dynamic optical resolution at room temperature; use of (S)-(+)-mandelic acid as the chiral auxiliary [HY* = (+)-MDLA)] and ethanol as the solvent: In a 50 ml two-neck flask equipped with a magnetic stirrer bar, 30 ml of ethanol 5 (denatured with methyl ethyl ketone) were initially charged. At room temperature (20'C), 2.32 g (11.76 mmol, 1.00 equiv.) of 2-pyridylmethyl phenyl ketone, 1.41 g (14.70 mmol, 1.25 equiv.) of 2-aminopyridine, 2.03 g (14.11 mmol, 1.20 equiv.) of 2-chlorobenzaldehyde and 3.65 g (23.52 mmol, 2.00 equiv.) of (S)-(+)-mandelic acid were added in succession under an N 2 atmosphere. The magnetic stirrer was 10 switched on and a yellow, slightly cloudy solution formed. After a reaction time of 30 min, the cloudiness had distinctly increased, and after 1 h, considerable amounts of precipitate had already appeared. The mixture was stirred at room temperature over the weekend. After a total of 3, 4, 5, 6 and 7 days of reaction time, samples (each of approx. 50 mg) were taken. Derivatization with pivaloyl chloride and similar 15 HPLC analysis to Example 27 gave the following enantiomeric excesses: 97.2% ee, 97.4% ee, 97.6% ee, 98.2% ee, 98.4% ee. The main isomer was eluted at t(ret) = 9.38 min, and the mirror image at t(ret) = 6.31 min. An appropriately derivatized racemic comparative sample delivered 50% of each of these peaks. In 1 H NMR spectra (400 MHz, DMSO-d6) of the samples, the anti-isomer could not be 20 detected (i.e. syn/anti >>99:1), and likewise no o-chlorobenzaldehyde or its imine. Traces of the retro-Mannich product 2-pyridylmethyl phenyl ketone could be detected. The precipitate of the reaction batch was filtered off with suction, washed with mother liquor and then with a little ethanol, suction-dried and dried under high vacuum. 5.77 g (10.19 mmol, 86.7% of theory) of pale yellow powder were obtained. Taking 25 into account the five previously taken samples (approx. 250 mg), the isolated yield was 90.4% of theory. 'H NMR (400 MHz, DMSO-d 6 ): 6 = 5.02 (s, 1H, CHOH of the mandelate anion), 5.73 (d, 1H), 6.22 (t, 1H), 6.38 (d, 1H), 6.40 (t, 1H), 6.90 (d, 1H), 7.14 (t, 2H), 7.18 (-td, 1H), 7.25-7.30 (m, 2H), 7.30-7.38 (m, 3H), 7.38-7.45 (m, 4H), 7.45-7.57 (m, 3H), 7.67 30 (td, 1H), 7.87 (m, 3H), 8.48 (dd, 1 H). 13C NMR (100,62 MHz, DMSO-d 6 ): 6 = 52.65 (CH), 58.92 (CH), 72.41 (CHOH of the mandelate anion), 107.37 (CH), 112.25 (CH), 122.35 (CH), 124.66 (CH), 126.60 129.29 (9 signals, CH), 132.83 (CH), 133.02 (C), 136.30 (C), 136.71 (CH), 136.77 118 (CH), 139.68 (C), 140.22 (C), 147.37 (CH), 148.90 (CH), 156.36 (C), 157.44 (C), 174.09 (CO 2 -), 196.43 (C=O). Example 30: 5 Synthesis of the racemic Mannich salt of the formula (111) [R 1 = phenyl, R 2 = 2-pyridyl,

R

3 = H, R 4 = 2-pyridyl, R 5 = phenyl] by four-component coupling at room temperature; use of (S)-(+)-mandelic acid as the chiral auxiliary [HY* = (+)-MDLA)] and ethanol as the solvent: 10 In a 100 ml three-neck flask equipped with a precision glass stirrer, 30 ml of ethanol (denatured with methyl ethyl ketone) were initially charged. At room temperature (22°C), 2.32 g (11.76 mmol, 1.00 equiv.) of 2-pyridylmethyl phenyl ketone, 1.41 g (14.70 mmol, 1.25 equiv.) of 2-aminopyridine, 1.51 g.(14.11 mmol, 1.20 equiv.) of benzaldehyde and 3.65 g (23.52 mmol, 2.00 equiv.) of (S)-(+)-mandelic acid were 15 added in succession under an N 2 atmosphere. The mechanical stirrer was switched on and after a few minutes a yellow, slightly cloudy solution formed. After 20 min, a precipitate had formed. The suspension was stirred further at room temperature for 3 days. A sample was taken in a similar manner to Example 27 and derivatized with pivaloyl chloride. The analysis was effected isocratically on a Chiralpak AD 20 250 mm x 4.6 mm column using a 25% isopropanol/75% n-hexane/0.1% trifluoroacetic acid eluent. The image and mirror image, as in an appropriately derivatized racemic reference sample, were eluted in a 50:50 ratio [t(ret) = 12.25 and 14.46 min]. 1 H NMR showed that the Mannich mandelate salt was present in high purity. Diastereomer and retro-Mannich products could be detected in very small 25 amounts in the NMR solution (DMSO-d 6 ). The reaction mixture was then heated to 60 0 C for 7 h, then allowed to cool to RT, and the solid was filtered off, washed with a little ethanol and dried under high vacuum. 5.55 g (10.44 mmol; 88.8% of theory) of pale yellow powder was obtained. The 1 H NMR spectrum was unchanged. Derivatization resulted in the Mannich base 30 remaining unchanged in racemic form. In contrast to Examples 27 and 29, (S)-(+) mandelic acid in an ethanol solvent does effect formation of the Mannich base from the reactants (IV), (V) and (VI), and also crystallization of the mandelate salt, but no dynamic optical resolution.

119 1 H NMR (400 MHz, DMSO-d 6 ): a = 5.02 (s, 1H, CHOH of the mandelate anion), 5.68 (d, 1H), 5.99 (t, 1H), 6.32 (d, 1H), 6.37 (t, 1H), 6.97 (d, 1H), 7.07 (t, 1H), 7.15-7.25 (m, 5H), 7.41 (t, 2H), 7.50-7.60 (m, 3H), 7.70 (t, 1H), 7.87 (d + m, 3H), 8.47 (d, 1H).

Claims (30)

1. A compound of the formula (I) or its enantiomer, R N /R 2 N H Rf Rs H(I R 4 5 where R 1 is 1. hydrogen,

2. a tert-butyl group or 10 3. a carbocyclic or heterocyclic aryl radical R 6 , where the aryl radical R 6 is a carbocyclic aryl radical having 5-14 carbon atoms or a heterocyclic aryl radical having 5-14 carbon atoms, where from 1 to 4 carbon atoms are replaced by N, O or S, where R 6 is unsubstituted or bears from 1 to 5 substituents which are each 15 independently (CI-C7)alkyl, (C 3 -C7)cycloalkyl, alkanoyl (-CO-(C-C7)alkyl), aroyl (-CO-(C 5 -C14)aryl), fluoro, chloro, bromo, iodo, hydroxyl, (Ci-C 7 )alkoxy, (C3-C 7 )Cycloalkoxy, (Cs-C 1 4)aryloxy, (C 1 -C7)alkanoyloxy, (C 5 -Ci4)aroyloxy, -O-CO-NHR, -O-CO-NRR', -O-CO-OR, -O-CO-SR, -O-CS-NHR, -O-CS NRR', -O-CS-OR, -O-CS-SR, -O-SO 2 -(C 1-C7)alkyl, -O-SO2-(Ca-C14)aryl, nitro, 20 -NH-CO-R, -NR'-CO-R, -NH-CO-OR, -NR'-CO-OR, -NH-CO-NHR, -NR' CO-NHR, -NR'-CO-NRR", di(C 1 -C7)alkylamino, di(Cs-C 1 4)arylamino, N-(CI-C 7 )alkyl-N-(C-C14)arylamino, (C1-C7)alkylthio, (Cs-C14)arylthio, (CI-C,)alkylsulfonyl, (C 5 -C14)arylsulfonyl, (Cs-C14)arylsulfoxidyl, or an unsubstituted aryl radical R 5 , 25 where R, R' and R" are each independently (C1-C7)alkyl, (C 3 -C7)cycloalkyl or (Cs-C 1 4)aryl, R 2 , R and R 4 are each independently 30 1. hydrogen, WO 03/093259 121 PCT/EPO3/04127 2. (Cl-C 7 )alkyl, where (C 1 -C7)alkyl is unsubstituted or substituted by an aryl radical R 6 ,

3. (C 3 -C7)cycloalkyl or

4. an aryl radical R 6 , and 5 R s is an aryl radical R 6 . 2. A compound of the formula (I) as claimed in claim 1, where R 6 is a carbocyclic aryl radical having 6-10 carbon atoms or a heterocyclic aryl radical having 6-10 10 carbon atoms, where from 1 to 4 carbon atoms are replaced by N, O or S. 3. A compound of the formula (I) as claimed in one of claims 1 and 2, where R 6 is a radical from the group of phenyl, naphthyl, anthracenyl, phenanthrenyl, pyridyl, quinolinyl, isoquinolinyl, benzoquinolinyl, pyridazinyl, pyrimidinyl, pyrazinyl, 15 triazinyl, tetrazinyl, benzopyridazinyl, benzopyrimidinyl, benzopyrazinyl (quinoxalinyl), benzotriazinyl, pyridopyridinyl, pyridoquinolinyl (phenanthrolinyl), benzoquinoxalinyl (phenazinyl), pyrrolyl, benzopyrrolyl (indolyl), benzoindolyl, pyrazolyl, benzopyrazolyl, imidazolyl, benzimidazolyl, triazolyl, benzotriazolyl, tetrazolyl, imidazopyrimidinyl (9H-purinyl), furanyl, benzofuranyl, dibenzofuranyl, 20 thiophene, benzothiophene, dibenzothiophene, isoxazolyl, benzisoxazolyl, oxazolyl, benzoxazolyl, oxadiazolyl, benzoxadiazolyl, thiazolyl, benzothiazolyl, isothiazolyl, benzisothiazolyl, thiadiazolyl or benzothiadiazolyl, where R 6 is unsubstituted or provided with up to 5 substituents which are each independently: (Ci-C7)alkyl, (C3-C7)cycloalkyl, fluoro, chloro, bromo, 25 (C-C7)alkoxy, (C 3 -C 7 )cycloalkoxy, (Cs-C 1 4)aryloxy, (Cl-C 7 )alkanoyloxy, (Cs-Ci4)aroyloxy, -O-CO-NHR, -O-CO-NRR', -O-CO-OR, nitro, phenyl, naphthyl, pyridyl, quinolinyl, isoquinolinyl or benzoquinolinyl. 4. A compound of the formula (I) as claimed in one of claims 1 to 3, where R 6 is a 30 radical R 7 which is defined as a radical from the group of phenyl, naphthyl, pyridyl, quinolinyl, isoquinolinyl or benzoquinolinyl, where R 7 is unsubstituted or is provided with up to 5 substituents which are each independently: (Cl-C 7 )alkyl, (C 3 -C7)cycloalkyl, fluoro, chloro, bromo, (C,-C7)alkoxy, (C 3 -C7)cycloalkoxy, (Cs-C 14 )aryloxy, (Cl-C7)alkanoyloxy, (Cr-C14)aroyloxy, -O-CO-NHR, -O-CO-NRR', WO 03/093259 122 PCT/EPO3/04127 -O-CO-OR, nitro, phenyl, naphthyl, pyridyl, quinolinyl, isoquinolinyl, benzoquinolinyl.

5. A compound of the formula (I) as claimed in one of claims 1 to 4, where R 6 is a 5 radical R3 which is defined as a radical from the group of phenyl, naphthyl, pyridyl or quinolinyl, and which is unsubstituted or provided with up to 5 substituents which are each independently: nitro, fluoro, chloro or bromo.

6. A compound of the formula (I) as claimed in one of claims 1 to 5, where R 2 , R 3 10 and R 4 are each independently hydrogen or a radical R 7 .

7. A compound of the formula (I) as claimed in one of claims 1 to 6, where R 2 , R 3 and R 4 are each independently hydrogen or an aryl radical R 8 . 15

8. A compound of the formula (1) as claimed in one of claims 1 to 7, where R 5 is a radical R 7 , preferably a radical R 8 . 20

9. A compound of the formula (II), RZ N -R 2 N ~H *OH (I R i .1, H R s R 4 25 where R 1 is 1. hydrogen, 2. a tert-butyl group or 3. a carbocyclic or heterocyclic aryl radical R 6 , where the aryl radical R 6 is a 30 carbocyclic aryl radical having 5-14 carbon atoms or a heterocyclic aryl WO 03/093259 123 PCT/EP03/04127 radical having 5-14 carbon atoms, where from 1 to 4 carbon atoms are replaced by N, O or S, where R 6 is unsubstituted or bears from 1 to 5 substituents which are each independently (Cl-C 7 )alkyl, (C 3 -C 7 )cyctoalkyl, alkanoyl (-CO-(C 1 -C7)alkyl), 5 aroyl (-CO-(Cs-C14)aryl), fluoro, chloro, bromo, iodo, hydroxyl, (Cl-C7)alkoxy, (C 3 -C 7 )cycloalkoxy, (Cs-C14)aryloxy, (Cl-C7)alkanoyloxy, (C-Ci4)aroyloxy, -O-CO-NHR, -O-CO-NRR', -O-CO-OR, -O-CO-SR, -O-CS-NHR, -O-CS NRR', -O-CS-OR, -O-CS-SR, -O-SO2-(C1-C7)alkyl, -O-SO2-(C5-C14)aryl, nitro, -NH-CO-R, -NR'-CO-R, -NH-CO-OR, -NR'-CO-OR, -NH-CO-NHR, -NR' 10 CO-NHR, -NR'-CO-NRR", di(Cj-C 7 )alkylamino, di(Cs-C 1 4)arylamino, N-(Cl-C7)alkyl-N-(Cs-C14)arylamino, (Cl-C7)alkylthio, (C 5 -C 1 4)arylthio, (C,-C7)alkylsulfonyl, (Cs-C14)arylsulfonyl, (C 5 -C 1 4)arylsulfoxidyl, or an unsubstituted aryl radical R 6 , 15 where R, R' and R" are each independently (CI-C7)alkyl, (C 3 -C7)cycloalkyl or (Cs-C 1 4)aryl, R , R 3 and R 4 are each independently 1. hydrogen, 20 2. (C 1 -C7)alkyl, where (C 1 -C7)alkyl is unsubstituted or substituted by an aryl radical R 6 , 3. (C 3 -C7)cycloalkyl or 4. an aryl radical R 6 , and 25 R s is an aryl radical R 6 , with the exception of a compound of the formula (II) where R' = o-aminophenyl, R 2 = H, R 3 = 2-pyridyl, R 4 = 2-pyridyl and R s = phenyl or 3,5-dimethylisoxazol-4-yl, 30 or an enantiomer of the compound of the formula (II) or a salt of the compound of the formula (II) or of an enantiomer of the compound of the formula (1l). WO 03/093259 124 PCT/EPO3/04127

10.A compound of the formula (II) as claimed in claim 9, where R 6 is a carbocyclic aryl radical having 6-10 carbon atoms or a heterocyclic aryl radical having 6-10 carbon atoms, where from 1 to 4 carbon atoms are replaced by N, O or S. 5

11.A compound of the formula (II) as claimed in one of claims 9 and 10, where R 6 is a radical from the group of phenyl, naphthyl, anthracenyl, phenanthrenyl, pyridyl, quinolinyl, isoquinolinyl, benzoquinolinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, tetrazinyl, benzopyridazinyl, benzopyrimidinyl, benzopyrazinyl (quinoxalinyl), benzotriazinyl, pyridopyridinyl, pyridoquinolinyl (phenanthrolinyl), 10 benzoquinoxalinyl (phenazinyl), pyrrolyl, benzopyrrolyl (indolyl), benzoindolyl, pyrazolyl, benzopyrazolyl, imidazolyl, benzimidazolyl, triazolyl, benzotriazolyl, tetrazolyl, imidazopyrimidinyl (9H-purinyl), furanyl, benzofuranyl, dibenzofuranyl, thiophene, benzothiophene, dibenzothiophene, isoxazolyl, benzisoxazolyl, oxazolyl, benzoxazolyl, oxadiazolyl, benzoxadiazolyl, thiazolyl, benzothiazolyl, 15 isothiazolyl, benzisothiazolyl, thiadiazolyl or benzothiadiazolyl, where R 6 is unsubstituted or provided with up to 5 substituents which are each independently: (Cl-C 7 )alkyl, (C 3 -C 7 )cycloalkyl, fluoro, chloro, bromo, (Cl-C 7 )alkoxy, (C3-C 7 )cycloalkoxy, (Cs-C14)aryloxy, (Cl-C 7 )alkanoyloxy, (Cs-C14)aroyloxy, -O-CO-NHR, -O-CO-NRR', -O-CO-OR, nitro, phenyl, naphthyl, 20 pyridyl, quinolinyl, isoquinolinyl or benzoquinolinyl.

12.A compound of the formula (II) as claimed in one of claims 9 to 11, where R 6 is a radical R 7 which is defined as a radical from the group of phenyl, naphthyl, pyridyl, quinolinyl, isoquinolinyl or benzoquinolinyl, where R 6 is unsubstituted or is 25 provided with up to 5 substituents which are each independently: (Cl-C7)alkyl, (C3-C7)cycloalkyl, fluoro, chloro, bromo, (Cl-C7)alkoxy, (C 3 -C7)cycloalkoxy, (Cs-C 1 4)aryloxy, (C 1 -C7)alkanoyloxy, (Cs-C 1 4)aroyloxy, -O-CO-NHR, -O-CO-NRR', -O-CO-OR, nitro, phenyl, naphthyl, pyridyl, quinolinyl, isoquinolinyl, benzoquinolinyl. 30

13. A compound of the formula (II) as claimed in one of claims 9 to 12, where R 6 is a radical R 8 which is defined as a radical from the group of phenyl, naphthyl, pyridyl or quinolinyl, and which is unsubstituted or provided with up to 5 substituents which are each independently: nitro, fluoro, chloro or bromo. WO 03/093259 125 PCT/EPO3/04127

14.A compound of the formula (II) as claimed in one of claims 9 to 13, where R 2 , R 3 and R are each independently hydrogen or a radical R 7 . 5

15.A compound of the formula (II) as claimed in one of claims 9 to 14, where R 2 , R 3 and R 4 are each independently hydrogen or an aryl radical R 8 .

16.A compound of the formula (11) as claimed in one of claims 9 to 15, where R 5 is a radical R 7 , preferably a radical R 8 . 10

17.A process for preparing a compound of the formula (11l) or its diastereomer Y* H N 0 R R 5 R 4 H (Ill) 15 where R' is 1. hydrogen, 2. a tert-butyl group or 20 3. a carbocyclic or heterocyclic aryl radical R 6 , where the aryl radical R 6 is a carbocyclic aryl radical having 5-14 carbon atoms or a heterocyclic aryl radical having 5-14 carbon atoms, where from 1 to 4 carbon atoms are replaced by N, O or S, where R 6 is unsubstituted or bears from 1 to 5 substituents which are each 25 independently (C,-C7)alkyl, (C 3 -C7)cycloalkyl, alkanoyl (-CO-(Cl-C 7 )alkyl), aroyl (-CO-(Cs-C 1 4)aryl), fluoro, chloro, bromo, iodo, hydroxyl, (C 1 -C7)alkoxy, (C 3 -C7)cycloalkoxy, (Cs-C 1 4)aryloxy, (CI-C7)alkanoyloxy, (Cs-C 14 )aroyloxy, -O-CO-NHR, -O-CO-NRR', -O-CO-OR, -O-CO-SR, -O-CS-NHR, -O-CS NRR', -O-CS-OR, -O-CS-SR, -O-SO 2 -(Cl-C7)alkyl, -O-SO 2 -(C 5 -C 1 4)aryl, nitro, WO 03/093259 126 PCT/EPO3/04127 -NH-CO-R, -NR'-CO-R, -NH-CO-OR, -NR'-CO-OR, -NH-CO-NHR, -NR' CO-NHR, -NR'-CO-NRR", di(Cl-C7)alkylamino, di(Cs-C14)arylamino, N-(C1-C 7 )alkyl-N-(Cs-C1 4 )arylamino, (CI-C7)alkylthio, (C 5 -C14)arylthio, (C 1 -C7)alkylsulfonyl, (Cs-C14)arylsulfonyl, (Cs-C14)arylsufoxidyl, or an 5 unsubstituted aryl radical R 6 , where R, R' and R" are each independently (Cl-C 7 )alkyl, (C 3 -C7)cycloalkyl or (C 5 -C14)aryl, 10 R , R 3 and R 4 are each independently 1. hydrogen, 2. (Ci-C,)alkyl, where (C 1 -C 7 )alkyl is unsubstituted or substituted by an aryl radical R 6 , 3. (C 3 -C7)cycloalkyl or 15 4. an aryl radical R 6 , and R 5 is an aryl radical R 6 , and where the anion Y - is the conjugated base of an optically active, organic 20 Brensted acid (protic acid), which comprises converting the compounds of the formulae (IV), (V), (VI) and (VII) 25 O 0 N R R s HY R 1 H H 4 (IV) (V) (VI) (Vll) where the R', R 2 , R 3 , R 4 and R 5 radicals in the compounds of the formulae (IV), (V), (VI) and (VII) are defined as above, 30 WO 03/093259 127 PCT/EPO3/04127 in a suitable solvent to the compound of the formula (111), by either reacting the compounds of the formulae (IV), (V), (VI) and (VII) at the same time in a direct Mannich reaction, 5 or initially reacting the compounds of the formulae (IV) and (V) to give an imine of the formula (X) or to an aminal of the formula (Xl) which can optionally be isolated N, 2 H N, 2 R H (X) (Xl) 10 and then converting the compound of the formula (X) or (XI) with the addition of the compounds of the formula (VI) and (VII) to a compound of the formula (Ill).

18. The process as claimed in claim 17, where Y*- is an optically active, naturally 15 occurring or industrially prepared carboxylic acid, preferably from the group of (R)-(-)-mandelic acid, (S)-(+)-mandelic acid, D-(-)-tartaric acid, L-(+)-tartaric acid, (+)-di-O,O'-pivaloyl-D-tartaric acid [(+)-DPTA], (-)-di-O,O'-pivaloy-L-tartaric acid, [(-)-DPTA], (+)-O,O'-dibenzoyl-D-tartaric acid, (-)-O,O'-dibenzoyl-L-tartaric acid, (-)-di-O,O'-benzoyl-L-tartaric mono(dimethylamide), (+)-O,O'-dianisoyl-D-tartaric 20 acid [(+)-DATA], (-)-O,O0'-dianisoyl-L-tartaric acid [(-)-DATA], (+)-di-O,0'-p-tolyl-D tartaric acid, (-)-di-O,O'-p-tolyl-L-tartaric acid, D-(+)-malic acid, L-(-)-malic acid, L-(+)-lactic acid, D-(-)-lactic acid, (S)-(-)-2-(phenylaminocarbonyloxy)propionic acid, (R)-(+)-2-(phenylaminocarbonyloxy)propionic acid, D-(+)-gluconic acid, (-) 2,3,4,6-di-O-isopropylidene-2-keto-L-gulonic acid, (D)-(-)-quinic acid, (-)-3,4,5 25 trihydroxy-1 -cyclohexene-1 -carboxylic acid [shikimic acid], (S)-(+)-(2,2-dimethyl 5-oxodioxolan-4-yl)acetic acid, (+)-camphoric acid, (-)-camphoric acid, (1 R)-(+) camphanic acid, (1S)-(-)-camphanic acid, (R)-(-)-O-acetylmandelic acid, (S)-(+) O-acetylmandelic acid, (R).-2-phenoxypropionic acid, (S)-2-phenoxypropionic acid, (S)-(+)-ct-methoxyphenylacetic acid, (R)-(-)-c-methoxyphenylacetic acid, 30 (R)-(+)-a-methoxy-a-trifluoromethylphenylacetic acid, (S)-(-)-a-methoxy-a- WO 03/093259 128 PCT/EPO3/04127 trifluoromethylphenylacetic acid, (S)-(+)-2-phenylpropionic acid, (R)-(-)-2 phenylpropionic acid, (R)-(+)-2-chloropropionic acid, (S)-(-)-2-chloropropionic acid, (R)-(+)-N-(a-methylbenzyl)phthalic monoamide, (S)-(-)-N-(a methylbenzyl)phthalic monoamide, (R)-(-)-5-oxotetrahydrofuran-2-carboxylic acid, 5 (S)-(+)-5-oxotetrahydrofuran-2-carboxylic acid, D-(+)-3-phenyllactic acid, L-(-)-3 phenyllactic acid, L-(+)-a-hydroxyisovalec acid, D-(-)-a-hydroxyisovaleric acid, (+)-menthyloxyacetic acid, (-)-menthyloxyacetic acid, (+)-mono-(l S)-menthyl phthalate, (-)-mono-(1R)-menthyl phthalate, (+)-trans-5-norbomene-2,3 dicarboxylic acid, (-)-trans-5-norbornene-2,3-dicarboxylic acid, (R)-(+) 10 methylsuccinic acid, (S)-(-)-methylsuccinic acid, (R)-(+)-6-hydroxy-2,5,7,8 tetramethylchroman-2-carboxylic acid [(R)-(+)-Troloxt, (S)-(-)-6-hydroxy-2,5,7,8 tetramethylchroman-2-carboxylic acid [(S)-(-)-Trolox], (S)-(+)-2-(4-isobutyl phenyl)propionic acid [(S)-ibuprofen], (R)-(-)-2-(4-isobutylphenyl)propionic acid [(R)-ibuprofen], (+)-2-(6-methoxy-2-naphthyl)propionic acid [(+)-naproxen], (-)-2 15 (6-methoxy-2-naphthyl)propionic acid [(-)-naproxen], and also the available natural or unnatural a- or P-amino acids and their readily accessible derivatives, in particular N-acylated derivatives, or an optically active sulfonic acid, preferably (1S)-(+)-camphor-10-sulfonic acid, 20 (1R)-(-)-camphor-10-sulfonic acid, (-)-3-bromocamphor-8-sulfonic acid or (+)-3 bromocamphor-10-sulfonic acid, or an optically active phosphoric acid, phosphinic acid or phosphonic acid derivative, preferably (R)-(-)-1,1'-binaphthalene-2,2'-diyl hydrogenphosphate, (S) 25 (+)-1, 1'-binaphthalene-2,2'-diyl hydrogenphosphate, (+)-phosphinothricin or (-) phosphinothricin, or an optically active phenol, preferably (R)-(+)- or (S)-(-)-binaphthol. 30

19.The process as claimed in one of claims 17 and 18, wherein the suitable solvent is water or an organic solvent, or a mixture of water with an organic solvent, optionally comprising a solubility-enhancing additive, where organic solvents may be present in 100% purity or technical quality, preferably a Ci-Cr-alcohol, branched or unbranched, more preferably methanol, ethanol, n-propanol, WO 03/093259 129 PCT/EPO3/04127 isopropanol or n-butanol, or a ketonic solvent, more preferably acetone or methyl ethyl ketone (MEK), or an ester, more preferably ethyl acetate or n-butyl acetate, or an ether, more preferably tetrahydrofuran, methyl tert-butyl ether, diisopropyl ether, 1,2-dimethoxyethane or diethylene glycol dimethyl ether (diglyme), or a 5 hydrocarbon, aliphatic or aromatic, more preferably toluene, or a supercritical medium, more preferably supercritical carbon dioxide or a halogenated hydrocarbon, more preferably dichloromethane, or a polar, aprotic solvent, more preferably DMF, DMSO or NMP. 10

20.The process as claimed in one of claims 17 to 19, wherein water present in the reaction is removed by azeotropic distillation or by adding water-binding additives, preferably magnesium sulfate or activated molecular sieves. 15

21.A process for preparing a compound of the formula (I) or its enantiomer RK NR 2 N 0 R R5 R 4 H (1) 20 where R 1 is 1. hydrogen, 2. a tert-butyl group or 3. a carbocyclic or heterocyclic aryl radical R 6 , where the aryl radical R 8 is a 25 carbocyclic aryl radical having 5-14 carbon atoms or a heterocyclic aryl radical having 5-14 carbon atoms, where from 1 to 4 carbon atoms are replaced by N, O or S, where R 6 is unsubstituted or bears from 1 to 5 substituents which are each independently (CI-C 7 )alkyl, (C 3 -C 7 )cycloalkyl, alkanoyl (-CO-(C 1 -C7)alkyl), 30 aroyl (-CO-(Cs-C14)aryl), fluoro, chloro, bromo, iodo, hydroxyl, (C 1 -C 7 )alkoxy, WO 03/093259 130 PCT/EPO3/04127 (C 3 -C7)cycloalkoxy, (C5-C14)aryloxy, (Cil-C 7 )alkanoyloxy, (Cs-C14)aroyloxy, -O-CO-NHR, -O-CO-NRR', -O-CO-OR, -O-CO-SR, -O-CS-NHR, -O-CS NRR', -O-CS-OR, -O-CS-SR, -O-SO2-(Cl-C7)alkyl, -O-SO2-(C5-C1 4 )aryl, nitro, -NH-CO-R, -NR'-CO-R, -NH-CO-OR, -NR'-CO-OR, -NH-CO-NHR, -NR' 5 CO-NHR, -NR'-CO-NRR", di(Cl-C7)alkylamino, di(C 5 -C 1 4 )arylamino, N-(C 1 l-C7)alkyl-N-(Cs-C14)arylamino, (Cl-C7)alkylthio, (C 5 -C14)arylthio, (C 1 -C7)alkylsulfonyl, (Cs-C 1 4)arylsulfony, (Cs-C14)arylsulfoxidyl, or an unsubstituted aryl radical R 6 , 10 where R, R' and R" are each independently (C,-C 7 )alkyl, (C 3 -C 7 )cycloalkyl or (Cs-C 1 4 )aryl, R 2 , R 3 and R 4 are each independently 1. hydrogen, 15 2. (Cl-C7)alkyl, where (Cl-C7)alkyl is unsubstituted or substituted by an aryl radical RS, 3. (C 3 -C7)cycloalkyl or 4. an aryl radical R 6 , and 20 R 5 is an aryl radical R 6 , which comprises converting a compound of the formula (Ill) Y N 0* R R5 R 4 H 25 (111) where the R 1 , R 2 , R 3 , R 4 and R 5 radicals are as defined above, by adding a suitable base in a suitable solvent. WO 03/093259 131 PCT/EPO3/04127

22.The process as claimed in claim 21, wherein a suitable base is an organic amine, preferably a (Cl-Co 10 )tdrialkylamine, more preferably a (C-C 3 )trialkylamine, especially preferably triethylamine, diisopropylethylamine, or an alkali metal 5 hydrogencarbonate, carbonate or hydroxide, or an alkaline earth metal hydrogencarbonate, carbonate or hydroxide, preferably sodium hydrogencarbonate or sodium hydroxide.

23.The process as claimed in claim 22, wherein a suitable solvent is water or an 10 organic solvent, or a mixture of water with an organic solvent, optionally comprising a solubility-enhancing additive.

24.The process as claimed in one of claims 22 and 23, wherein the organic solvent is a Cl-Cs-alcohol, branched or unbranched, preferably methanol, ethanol, n 15 propanol, isopropanol or n-butanol, or a ketonic solvent, preferably acetone or methyl ethyl ketone (MEK), or an ester, preferably ethyl acetate or n-butyl acetate, or an ether, preferably tetrahydrofuran, methyl tert-butyl ether, diisopropyl ether, 1,2-dimethoxyethane or diethylene glycol dimethyl ether (diglyme), or a hydrocarbon, aliphatic or aromatic, preferably toluene, or a supercritical medium, 20 preferably supercritical carbon dioxide or a halogenated hydrocarbon, preferably dichloromethane, or a polar, aprotic solvent, preferably DMF, DMSO or NMP.

25. A process for preparing a compound of the formula (11) or its enantiomer, N H OH R R 5 R 4 H 25 (ll) where R 1 is 1. hydrogen, 30 2. a tert-butyl group or WO 03/093259 132 PCT/EPO3/04127 3. a carbocyclic or heterocyclic aryl radical R 6 , where the aryl radical R 6 is a carbocyclic aryl radical having 5-14 carbon atoms or a heterocyclic aryl radical having 5-14 carbon atoms, where from 1 to 4 carbon atoms are replaced by N, OorS, 5 where R 6 is unsubstituted or bears from 1 to 5 substituents which are each independently (Cl-C 7 )alkyl, (C 3 -C7)cycloalkyl, alkanoyl (-CO-(C 1 -C7)alkyl), aroyl (-CO-(Cs-C14)aryl), fluoro, chloro, bromo, iodo, hydroxyl, (Ci-C7)alkoxy, (C3-C7)cycloalkoxy, (Cs-C14)aryloxy, (Cl-C7)alkanoyloxy, (C 5 -C14)aroyloxy, -O-CO-NHR, -O-CO-NRR', -O-CO-OR, -O-CO-SR, -O-CS-NHR, -O-CS 10 NRR', -O-CS-OR, -O-CS-SR, -O-SO 2 -(CI-C7)alkyl, -O-SO2-(Cs-C14)aryl, nitro, -NH-CO-R, -NR'-CO-R, -NH-CO-OR, -NR'-CO-OR, -NH-CO-NHR, -NR' CO-NHR, -NR'-CO-NRR", di(Ci-C 7 )alkylamino, di(C 5 -C,4)arylamino, N-(Cl-C7)alkyl-N-(C 5 -C14)arylamino, (C 1 -CT)alkylthio, (C 5 -C 1 4)arylthio, (C 1 -C 7 )alkylsulfonyl, (Cs-C14)arylsulfonyl, (Cs-C,4)arylsulfoxidyl, or an 15 unsubstituted aryl radical R 6 , where R, R' and R" are each independently (CI-C7)alkyl, (C 3 -C7)cycloalkyl or (C 5 -C 1 4)aryl, 20 R 2 , R 3 and R 4 are each independently 1. hydrogen, 2. (Cl-C7)alkyl, where (Cl-C 7 )alkyl is unsubstituted or substituted by an aryl radical R 6 , 3. (C 3 -C 7 )cycloalkyl or 25 4. an aryl radical R 6 , and R s is an aryl radical R 6 , which comprises 30 reducing a compound of the formula (I11) WO 03/093259 133 PCT/EP03/04127 Y H R, | .,R2 N 0 R - R R4 H (Ill) where the R', R 2 , R 3 , R' and R 5 radicals are each as defined above, 5 or a compound of the formula (1) N 0 Ri ' R5 R 4 with a suitable reducing agent, and then optionally working up and isolating. 10

26.The process as claimed in claim 25, wherein the reducing agent is a borane or borohydride reagent, optionally in the presence of a chiral catalyst.

27.The process as claimed in one of claims 25 and 26, wherein the reducing agent is an achiral reducing agent, preferably 15 1. a borane-sulfide complex, more preferably borane-dimethyl sulfide or borane-1,4-thioxane complex; 2. a borane etherate, for example boron-tetrahydrofuran complex; 3. catecholborane; 4. a borane-sulfide complex or a borane etherate or catecholborane in the 20 presence of a Lewis acid, more preferably titanium chloride triisopropoxide (iPrO) 3 TiCI; 5. a borane-amine complex, more preferably borane-ammonia, borane-tert butylamine, borane-N,N-diethylaniline, borane-N-ethyldiisopropylamine, borane-N-ethylmorpholine, borane-N-methylmorpholine, borane-morpholine, WO 03/093259 134 PCT/EPO3/04127 borane-piperidine, borane-pyridine, borane-triethylamine or borane trimethylamine complexes; 6. a borane-amine complex in the presence of a Lewis acid, more preferably titanium chloride trilsopropoxide (iPrO)3TiCI; 5 7. a borane-phosphine complex, more preferably borane-tributylphosphine or borane-triphenylphosphine complexes; 8. a combination of a borohydride, more preferably sodium borohydride or tetraalkylammonium borohydride, with a reagent which leads to in situ generation of borane, especially preferably sodium borohydride/iodine, 10 sodium borohydride/boron trifluoride diethyletherate, sodium borohydride/chlorotrimethylsilane; tetraalkylammonium borohydride/alkyl halide (for example methyl iodide) in dichloromethane or the biphasic mixture of an alkyl bromide and a saturated aqueous solution of sodium borohydride and catalytic amounts of a quaternary onium salt as a phase transfer 15 catalyst; 9. a borohydride of a mono- or bivalent metal cation, more preferably sodium borohydride, lithium borohydride or zinc borohydride, or a tetraalkylammonium borohydride, in the presence or absence of a cerium(lll) salt as an additive; 20 10. diborane (B 2 He), or a reducing agent comprising one or more optically active catalysts, preferably 1. a borohydride of a mono- or bivalent metal cation, more preferably sodium borohydride, in the presence of catalytic amounts of an optically active 25 aldiminato cobalt(II) complex, for example (1S,2S)-N,N'-bis[3-oxo-2-(2,4,6 trimethylbenzoyl)butylidene]-1,2-diphenylethylenediaminato cobalt(l I) (S) MPAC, in the presence or absence of tetrahydrofurfuryl alcohol as a coligand; 2. a borohydride of a mono- or bivalent metal cation, more preferably sodium 30 borohydride, catalyzed by a rhodium complex which results from the coordination of two molecules of optically pure 1,3-amino alcohol (II) per molecule of [(p )-pentamethylcyclopentadienyl]rhodium dichloride dimer; 3. CATHy T m - catalysts composed of the cyclopentadienylrhodium chloride dimer and chiral 1,2-amino alcohols. WO 03/093259 135 PCT/EPO3/04127

28.The process as claimed in one of claims 25 to 27, wherein the reducing agent is a borane-sulfide complex, a borane etherate, sodium borohydride or an asymetric sodium borohydride reducing agent comprising an in situ catalyst which is 5 obtained by the coordination of the [(p 5 )-pentamethylcyclopentadienyl]rhodium dichloride dimer to the optically active 1,3-amino alcohol (II).

29.The process as claimed in one of claims 25 to 28, wherein the reducing agent is a borane-dimethyl sulfide or borane-tetrahydrofuran complex. 10

30. The process as claimed in one of claims 25 to 29, wherein the compound of the formula (11) is worked up by acidic solvolysis and/or by crystallization. WO 03/093259 136 PCT/EP03/04127 Figure 1 AVENTIS Process-Develoument Analytical Laboratory Building : D-729 mamm mma ama m m nn m mm mammm ummR WWW--m-m una sm BR a m -- = ----- um===am mu ma ma ............... a ......... .. ................... ........... Daerator : J. Ortica Data file name : C:\HPCHE\I\DATA1DATE\LC040402.D Date / Time : 04.04.2001 14:36:27 Injection : 2.00 Il Vial - Number : 2 Sample Name : 2955 Method Name : C: \HPCHEHI\INETHODS\POSITIVE\CHIRADEXHMIX17. SAMPLE INFO : Charge 4 Probe 3.1 Hethod Info : COLUMN: CHIRADEX 5 um 250*4 mm MOBILE PHASE: A: 1% TEA-CH3COOH PH 4,1 B: CH3CN A:B 82,5:17,5 UV - 254 nm nm FLOW : I al/min DAD1 B. Sig=254.10 Ref=300.100 (DATE\LC040402.D) mAU 40 30 20 10 0. .. .. .. . ... .. .. .. DAD1 B, Sig-254,16 Ref-360,100 Peak RT Area Area 4 Name Number raminl counts 1 7.42 40.18 2.33 2 9.25 1685.66 97.67 Result: 1725.85 100.00 5 WO 03/093259 137 PCT/EP03/04127 Figure 2 AVENTIS Process-DevelooDment Analytical Laboratory Building : D-729 . a -- as..............................................no ............. ....................... DOperator : J. Ortioa Data file name : C:1HPCHEH\DATA\DATE1LC040401.D Date / Time : 04.04.2001 14:20:10 Injection 2.00 p1 Vial - Number : 1 Sample Name : 1453 SPS Piv. Method Name : C:\HPCHEN\I\EThODS\ POSITIVE CHIRADEX\HIXl17. N SAMPLE INFO : Racenat Method Info : COLUMN: CHIRADEX 5 um 250*4 m MOBILE PHASE: A: l% TEA-CH3C00H PH 4,1 B: CH3CN A:B 82,5:17,5 UV - 254 nm nm FLD : 1 ml/min DHTERWWWW~an=ammandmmanna=um m=== ---- =mmumana=manamm=munmammum ummma----mmam=u=maaman ............. f l C * S S tl C . C O a...........l DAD1 8, Sig=254.10 Re1=360,100(DATE\LC040 1.D) mAU 40 35 30 25 20) 15 10 5 DADI B, 5ig=254,16 Ret=360,100 Peak RT Area Area & Name Number rain1 counts 1 7.34 1613.82 49.49 2 9.25 1646.89 50.51 Result: 3260.71 100.00 5