Process for the production of praziquantel and its precursors

Abstract

The present invention provides a method for preparing praziquantel, especially (R)-praziquantel and its analogs, in a stereoselective manner. One method involves the asymmetric hydrogenation of the following intermediate compound (I) and subsequent cyclization:

Description

Field of the Invention

[0001] The present invention relates to a process for the preparation of praziquantel and its precursors and analogues, in particular enantiomerically pure or enantiomerically enriched praziquantel and its precursors and / or analogues. Background of the Invention

[0003] Schistosomiasis is an acute and chronic disease caused by parasites. According to information from the WTO, it affects nearly 240 million people worldwide, and more than 700 million people live in endemic areas. Millions of people around the world suffer from severe morbidity due to schistosomiasis. Praziquantel is currently the only recommended drug for the infections and diseases caused by schistosome species infecting humans.

[0004] Praziquantel (PZQ) was registered, approved and commercialized as a racemic mixture in the early 1980s. However, it has been shown that only the (R)-enantiomer is active (the potent form) (P. Andrews, H. Thomas, R. Pohlke, J. Seubert Medical Research Reviews 3, 147 (1983)).

[0005]

[0006] Racemic praziquantel has an objectionable bitter taste. This leads to acceptance problems - especially in the treatment of young children. In addition to the difference in activity, the (R)-praziquantel potent form is also considered to have a smaller bitter taste than the (S)-praziquantel less potent form (T. Meyer et al. (2009) PLoS Negl Trop Dis 3(1): e357). Therefore, there is a need for an economical manufacturing process suitable for the preparation of enantiomerically enriched or preferably even pure (R)-praziquantel.

[0007] In the past few decades, many attempts have been made to develop a manufacturing process for (R)-praziquantel or its analogues. These attempts can be divided into two groups, firstly enantioselective synthesis routes, and secondly methods of generating a racemic mixture and combining chiral resolution. Given that the latter method necessarily involves additional method steps, a method that directly yields (R)-praziquantel may be mainly more attractive. However, it has proven very difficult to identify a suitable enantioselective synthesis route that is economically attractive. The search for such a synthesis and other methods for economically manufacturing (R)-praziquantel continues.

[0008] Description of the Invention

[0009] Accordingly, an object of the present invention is to provide an effective method for preparing praziquantel and its analogs, which method is suitable for providing enantiomerically enriched or enantiomerically pure (R)-praziquantel or its analogs, in particular a suitable stereoselective synthetic route which allows the preparation of enantiomerically enriched or even enantiomerically pure (R)-praziquantel or its analogs without requiring chiral separation. Nevertheless, another object of the present invention is to provide advantageous methods for preparing the desired enantiomers in terms of the final product and intermediate products, including enantiomeric mixtures having a more favorable percentage of the desired enantiomer compared to the starting materials.

[0010] This object is surprisingly solved by a new synthetic route which allows the stereoselective synthesis of (R)-praziquantel and its analogs. The new synthetic route has become possible due to the identification and preparation of new key intermediate compounds. In addition to the stereoselective synthesis, the key intermediate compounds also open up the possibility of non-stereoselective synthetic routes for racemic or enantiomerically enriched or pure praziquantel or its analogs which are considered to be advantageous. Of course, the present invention is not limited to praziquantel itself, but is equally applicable to its analogs. As described below, the present invention also provides an attractive recycling method for any reaction by-products or less desirable enantiomers or enantiomeric mixtures.

[0011] In particular, in a first aspect, the present invention provides a method for preparing:

[0012] (i) an optically active compound according to formula (X1)

[0013]

[0014] or

[0015] (ii) an optically active compound according to formula (X2)

[0016]

[0017] or

[0018] (iii) a mixture of both,

[0019] wherein in formula (X1) and formula (X2), R is selected from C 1 -C 8 alkyl, C 3 -C 8 cycloalkyl and optionally substituted aryl,

[0020] comprising: subjecting a compound according to formula (Y) having the above R:

[0021]

[0022] to a hydrogenation step.

[0023] Needless to say, part R is the same in the compounds according to formula (Y) and the compounds according to formulas (X1) and (X2).

[0024] C 1 -C 8 Alkyl, C 3 -C 8 Alkyl, cycloalkyl and aryl have their usual meanings in the art: C 1 -C 8 Alkyl includes straight-chain (unbranched) or branched alkyl groups having 1, 2, 3, 4, 5, 6, 7 or 8 C atoms, such as methyl, ethyl, n-propyl, isopropyl, butyl, tert-butyl, pentyl, hexyl, heptyl and octyl, where methyl and ethyl are most preferred. C 3 -C 8 Cycloalkyl includes saturated cyclic hydrocarbon ring systems having 3, 4, 5, 6, 7 or 8 ring C atoms, and includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl, where cyclohexyl is most preferred. Aryl includes aromatic carbocyclic systems, and phenyl is an exemplary embodiment, where the aryl may be unsubstituted or substituted, for example, substituted by one, two or more substituents selected from the following: amino, acylamino where the acyl group may contain up to four carbon atoms, halogen, hydroxy, methoxy or nitro.

[0025] In a preferred embodiment of the present invention, R is methyl or cyclohexyl, most preferably cyclohexyl. Cyclohexyl is clearly preferred because it allows for the subsequent direct synthesis of praziquantel. Similarly, for the synthesis of (R)-praziquantel, it is preferred to produce the compound according to formula (X1) having the (R) configuration, or a mixture of the compounds according to formulas (X1) or (X2) by the method according to claim 1, where the compound according to formula (X1) is present in excess (compared to the compound according to formula (X2)). Therefore, the method according to claim 1 preferably produces the compound of formula (X1) in an enantiomerically enriched or enantiomerically pure form.

[0026] In the most preferred embodiment of the present invention, in the method for preparing an optically active compound according to formula (X1) or formula (X2) or a mixture of both, the hydrogenation step is an asymmetric hydrogenation step in the presence of a catalyst, and if a mixture of optically active compounds according to formula (X1) or formula (X2) is obtained, the mixture contains an excess of the compound according to formula (X1) or the compound according to formula (X2). In other words, the asymmetric hydrogenation produces an enantiomerically enriched or enantiomerically pure compound according to formula (X1) or formula (X2).

[0027] Preferably, the compound according to formula (X1) or formula (X2) is present in the mixture with an enantiomeric excess of at least 10%, preferably at least 20%, more preferably at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80% or most preferably at least 85%, at least 90%, at least 95% or 100%. In the preparation of (R)-praziquantel, the compound of formula (X1) is generally the desired intermediate.

[0028] Advantageously, the catalyst used in the asymmetric hydrogenation is an iridium-based catalyst. However, it is also feasible to use other catalysts such as rhodium or ruthenium.

[0029] Preferably, the iridium-based catalyst consists of or comprises a combination of iridium and a chiral ligand. More preferably, the iridium-based catalyst consists of or comprises a mixture of an iridium compound such as [Ir(COD)Cl] 2 and a chiral phosphine ligand. For the purposes of the present invention, chiral phosphine ligands will include any ligand containing a phosphine moiety and containing a chiral center. For example, the iridium-based catalyst consists of or comprises a mixture of an iridium compound such as [Ir(COD)Cl] 2 and a ligand selected from the Josiphos ligand family, the BoPhoz ligand family, the Taniaphoz ligand family, the BINAP patent family and other ligands, as described and illustrated below. Preferably, the iridium-based catalyst consists of or comprises a mixture of an iridium compound such as [Ir(COD)Cl] 2 and a mixture with one of the following ligands:

[0030]

[0031]

[0032]

[0033]

[0034] In the Josiphos patent family, the following ligands are preferred:

[0035]

[0036]

[0037] As general knowledge in the art, if a certain enantiomer in the catalyst system, for example the (R) enantiomer in the catalyst system, allows the production of a certain enantiomer of the hydrogenation product, for example the (S) enantiomer, then the corresponding other enantiomer of the catalyst system, for example the (S) enantiomer in this example, will result in the corresponding other enantiomer of the hydrogenation product, for example the (R) enantiomer in this example.

[0038] In the synthesis of the compound of formula (X1) in which R is cyclohexyl, the following ligands are preferably used:

[0039] (S)-Xyliphos, (R)-1-[(S p )-2-diphenylphosphino)-ferrocenyl]ethyl-diphenylphosphine, (R)-1-[(S p )-α-(dimethylamino-2-(diphenylphosphino)benzyl]-2-diphenylphosphino-ferrocene and (R)-Xyl-BINAP. These ligands are also preferably used in combination with additives such as iodine, for example in an amount of at least 5 mol%, more preferably at least 50 mol% or at least 100 mol%.

[0040] [Ir(COD)Cl] 2 represents cyclooctadiene iridium dichloride dimer and is represented by the following structure:

[0041] .

[0042] In an exemplary embodiment, the asymmetric hydrogenation step carried out in the presence of a catalyst involves at least one of the following:

[0043] - elevated temperature, which is preferably at least 60 °C, for example at least 80 °C, at least 90 °C or at least 100 °C;

[0044] - a solvent selected from dioxane, THF, Me-THF, IPA, DCE, DCM, ethyl acetate, toluene, α,α,α-trifluorotoluene; xylene, preferably m-xylene or p-xylene; mesitylene or any mixture of two or more thereof;

[0045] - at least one additive, which is preferably selected from iodine (I 2 ), iodide, phosphoric acid (H 3 PO 4 ), acetic acid (AcOH), HI, HBF 4 , preferably in an amount of at least 5 mol%, more preferably at least 50 mol%, more preferably at least 100 mol%;

[0046] - a substrate concentration of at least 0.05 mmol / l, for example at least 10 mmol / l, at least 100 mmol / l;

[0047] - a catalyst loading of at least 50 / 1 substrate / catalyst; for example at least 100 / 1, at least 250 / 1, at least 500 / 1 and

[0048] - normal to elevated pressure, which is preferably at least 1 bar H 2 , at least 5 bar H2 , at least 10 bar H 2 , at least 20 bar, at least 25 bar H 2 , at least 50 bar or at least 100 bar H 2 .

[0049] In a preferred embodiment, [Ir(COD)Cl] 2 is used in combination with (S)-Xyliphos in the presence of additives such as iodine (I 2 ). In a further preferred embodiment, [Ir(COD)Cl] 2 is used in combination with (R)-Xyl-BINAP in the presence of additives such as iodine (I 2 ). These catalysts / ligands are particularly preferred if R is cyclohexyl, i.e., for the preparation of praziquantel and its precursors.

[0050] The use of transfer hydrogenation reaction conditions may be a viable alternative for asymmetric hydrogenation reactions. For example, the transfer hydrogenation of compound (Y) to give compound (X1) with R = cyclohexyl can be carried out using (S,S)-Ts-DPEN RhCp*Cl (which represents N -[(1 S ,2 S )-2-(amino-κ N )-1,2-diphenylethyl]-4-methylbenzenesulfonato-κ N chloro[(1,2,3,4,5,6-η)-1-methyl-4-(1-methylethyl)benzene]-rhodium) and HCOOH, triethylamine 5 / 2 as an excess reducing agent. The following reaction conditions are used: additive KI (50 mol%), solvent-free, 40 °C, 0.1 mmol, catalyst loading 100 / 1 S / C, 16 h, to give 100% conversion with a moderate enantiomeric excess of 17% (R)-enantiomer (X1 vs. X2 compound).

[0051] In an alternative embodiment, the compound according to formula (Y) can be subjected to a hydrogenation step, in particular a non-selective hydrogenation step, to prepare a mixture of compounds, in particular a racemic mixture of compounds according to formula (X1) and (X2). Then the mixture of compounds can be used for the preparation of racemic praziquantel or its analogs, or subjected to chiral resolution to prepare the corresponding enantiomerically pure or enantiomerically enriched compounds of formula (X1) or (X2).

[0052] Such a hydrogenation step, in particular a non-stereoselective hydrogenation step, can be carried out using any known suitable conventional hydrogenation reaction method, for example those involving the use of hydrogen in the presence of a suitable catalyst such as Pt-C or Pd-C.

[0053] On the other hand, the present invention provides a method for preparing an enantiomerically pure or enantiomerically enriched compound according to formula (Q1) or formula (Q2).

[0054]

[0055] Comprising:

[0056] (a) preparing, by the method according to the present invention, (i) an optically active compound according to formula (X1) or (iii) a mixture of compounds according to formula (X1) and formula (X2), wherein the compound according to formula (X1) is present in excess in the mixture, for preparing a compound according to formula (Q1);

[0057] Or

[0058] (b) preparing, by the method according to the present invention, (i) an optically active compound according to formula (X2) or (iii) a mixture of compounds according to formula (X1) and formula (X2), wherein the compound according to formula (X2) is present in excess in the mixture, for preparing a compound according to formula (Q2).

[0059] In the compounds of formula (Q1) and (Q2), R is selected from C 1 -C 8 alkyl, C 3 -C 8 cycloalkyl and optionally substituted aryl. Preferably, R in formula (X1) and (X2) is the same as that in formula (Q1) and (Q2). However, it is possible to convert one R moiety into another, for example, changing a methyl group to a cyclohexyl group while maintaining chirality by methods known in organic chemistry (e.g., Houben-Weyl, Methods of organic chemistry). In this case, for clarity, R in formula (Q1) and (Q2) can be referred to as R'.

[0060] Preferably, the method for preparing an enantiomerically pure or enantiomerically enriched compound according to formula (Q1) or formula (Q2) as described above further comprises:

[0061] (a) reacting (i) an optically active compound according to formula (X1) or (iii) a mixture of compounds according to formula (X1) and formula (X2), wherein the compound according to formula (X1) is present in excess in the mixture, with a compound Y-CO-CH 2 -X, wherein Y is F, Cl or Br or -O-CO-alkyl and X is F, Cl or Br, most preferably reacting with chloroacetyl chloride (Cl-C(=O)-CH 2 Cl) to obtain a compound according to formula (Q1);

[0062] Or

[0063] (b) React an optically active compound according to formula (X2) or a mixture of compounds (iii) according to formula (X1) and formula (X2), in which the compound according to formula (X2) is present in excess, with the compound Y-CO-CH 2 -X, where Y is F, Cl or Br or -O-CO-alkyl, and X is F, Cl or Br, most preferably react with chloroacetyl chloride (Cl-C(=O)-CH 2 Cl) to obtain a compound according to formula (Q2).

[0064] In the said method, R in formula (X1) and (X2) is the same as that in formula (Q1) and (Q2).

[0065] In the "-O-CO-alkyl" moiety, the alkyl includes an alkyl having 1 to 6 carbon atoms or a cycloalkyl having 4 to 6 ring C atoms.

[0066] It is obvious from the above that in the reaction of the compound of formula (X1) or (X2) with the compound Y-CO-CH 2 -X, the stereochemistry / chirality is maintained such that the resulting product (Q1) or (Q2) has the same configuration at each ring C atom.

[0067] Of course, most preferably, the above method is used to prepare enantiomerically pure or enantiomerically enriched (R)-praziquantel:

[0068]

[0069] In this case, R is cyclohexyl in the compounds according to formula (X1) and (Q1), and in this case, each step (a) is used. Therefore, in a preferred embodiment, the present invention provides a method for preparing enantiomerically pure or enantiomerically enriched (R)-praziquantel, including the method described above for compounds (Q1) and (Q2), using an optically active compound according to formula (X1) or a mixture of compounds (iii) according to formula (X1) and formula (X2), in which the compound according to formula (X1) is present in excess, and in which R is cyclohexyl in the compounds according to formula (X1) and (Q1).

[0070] Expressed in a different way, the present invention provides a method for preparing enantiomerically pure or at least enantiomerically enriched (R)-praziquantel,

[0071]

[0072] including:

[0073] The method according to the invention as described above is used to prepare (i) an optically active compound according to formula (X1) or (iii) a mixture of compounds according to formula (X1) and formula (X2), wherein the compound according to formula (X1) is present in excess in the mixture, and wherein R is cyclohexyl.

[0074] Similar to what has been described previously, in a preferred embodiment, the method for preparing (R)-praziquantel further comprises reacting (i) an optically active compound according to formula (X1) or (iii) a mixture of compounds according to formula (X1) and formula (X2), wherein the compound according to formula (X1) is present in excess in the mixture, with the compound Y-CO-CH 2 -X, where Y is F, Cl or Br or -O-CO-alkyl, and X is F, Cl or Br, most preferably reacting with chloroacetyl chloride (Cl-C(=O)-CH 2 Cl) to obtain enantiopure or at least enantiomerically enriched (R)-praziquantel.

[0075] The use of Y-CO-CH 2 -X, especially chloroacetyl chloride (Cl-C(=O)-CH 2 Cl) for cyclization reaction itself is known in the prior art. For example, this reaction is described in DE 2504250 as a two-step method for converting a racemic mixture of compounds according to formula (X1) and (X2) into racemic praziquantel, and DE2504250 is incorporated herein by reference in its entirety. The reaction scheme starting from the compound of formula (X1) involving a one-step reaction with chloroacetyl chloride (Cl-C(=O)-CH 2 Cl) has been described previously, for example, by Sergovskaya and Chernyak (1991), and repeated by Roszkowski, P. et al. in Tetrahedron: Asymmetry 17 (2006) 1415-1419, the entire content of which is also incorporated herein by reference. The said reaction scheme includes reacting the compound of formula (X1) with chloroacetyl chloride under Schotten-Baumann conditions, for example, in a mixture of dichloromethane and 50% NaOH (aqueous solution) in the presence of TEBA chloride (benzyltriethylammonium chloride).

[0076] Although the preparation of praziquantel, especially (R)-praziquantel, is central to the present invention, its analogs themselves are also considered useful as drugs or as intermediate compounds of interest.

[0077] For the purposes of the present invention, "enantiopure" means that one enantiomer is present in an enantiomeric purity of at least 95% ee , preferably at least 98% ee , where ee represents enantiomeric excess as defined conventionally:

[0078]

[0079] m 1 and m 2 are the masses of enantiomers 1 and 2, respectively. As used herein, the term "enantiomerically enriched" refers to a mixture of two enantiomers in which the ratio of the enantiomers is greater than 50:50 (corresponding to ee > 0%), preferably at least 55:45 (ee ≥ 10%), at least 60:40 (ee ≥ 20%) or 70:30 (ee ≥ 40%) or 80:20 (ee ≥ 60%) or 90:10 (ee ≥ 80%), but less than 97.5:2.5 (ee < 95%). In a "racemic mixture", the enantiomer ratio is 50:50, and thus the enantiomeric excess ee is equal to zero. The term "mixture of enantiomers" includes racemic mixtures and mixtures of enantiomers in any other ratio from 50:50 to <100:0.

[0080] In a preferred alternative, the present invention provides a method for preparing an enantiomerically pure or enantiomerically enriched compound according to formula (Q1) or formula (Q2)

[0081]

[0082] comprising preparing a mixture of compounds according to formula (X1) or formula (X2) by the method according to the present invention, i.e., starting from compound Y,

[0083] separating the compound according to formula (X1) from the compound according to formula (X2),

[0084] and subjecting

[0085] (a) the compound according to formula (X1) to reaction with compound Y-CO-CH 2 -X, where Y is F, Cl or Br or -O-CO-alkyl and X is F, Cl or Br, most preferably to reaction with chloroacetyl chloride (Cl-C(=O)-CH 2 Cl), to obtain an enantiomerically pure or at least enantiomerically enriched compound according to formula (Q1);

[0086] or

[0087] (b) the compound according to formula (X2) to reaction with compound Y-CO-CH 2 -X, where Y is F, Cl or Br or -O-CO-alkyl and X is F, Cl or Br, most preferably to reaction with chloroacetyl chloride (Cl-C(=O)-CH 2 Cl), to obtain an enantiomerically pure or at least enantiomerically enriched compound according to formula (Q2).

[0088] Thus, in an alternative embodiment, a method for preparing enantiomerically pure or enantiomerically enriched (R)-praziquantel comprises:

[0089] preparing a mixture of compounds of formula (X1) and formula (X2) wherein R is cyclohexyl according to the method of the present invention as described above, separating the compound according to formula (X1) from the compound according to formula (X2),

[0090] and reacting the compound according to formula (X1) with Y-CO-CH 2 -X, where X and Y are as described above, most preferably reacting with chloroacetyl chloride (Cl-C(=O)-CH 2 Cl), to obtain enantiomerically pure or enantiomerically enriched (R)-praziquantel.

[0091] Separating the compound according to formula (X1) from the compound according to formula (X2) or vice versa may involve any suitable known chiral resolution method, such as chiral resolution by diastereomeric salt formation or chiral chromatography. Diastereomeric salt formation may involve known suitable optically active acids, such as the (+)- and (-)-forms of tartaric acid, dibenzoyl tartaric acid, diacetyl tartaric acid, di-neopentyl tartaric acid, mandelic acid, malic acid, lactic acid, 2-phenyl-butyric acid, camphoric acid, β-camphorsulfonic acid, dinitrodiphenolic acid or quinic acid. The diastereomeric salts are then crystallized from a suitable solvent such as ethanol, and then the diastereomeric salts are released under suitable conditions (e.g., basic or acidic conditions) and usually extracted with a suitable solvent such as dichloromethane or chloroform, and the desired enantiomer is separated.

[0092] A preferred example of separating the compounds of formula (X1) and (X2) in enantiomerically pure or enantiomerically enriched form to obtain the compound (X1) is by chiral resolution by forming diastereomeric salts (preferably with D-(-)-tartaric acid), preferably in combination with crystallization from ethanol. The diastereomeric salts are usually released under basic conditions (e.g., using sodium hydroxide), then extracted, for example, with dichloromethane, and evaporated in vacuo.

[0093] It is possible to recycle the residue of the chiral separation, i.e., the unwanted enantiomer, which may be mixed with some of the desired enantiomer, by dehydrogenation and subsequent hydrogenation, as shown in the following reaction scheme, which represents another aspect of the present invention:

[0094]

[0095] The compounds of formula (X1) and (X2) are subjected to a dehydrogenation step, for example using ethylene and Pd-C as a catalyst, to obtain a mixture of compound (Y) and its dehydrogenated derivative (Z). Then the mixture can be subjected to a hydrogenation reaction as described above, for example a non-selective hydrogenation reaction, for example using hydrogen and Pt-C as a catalyst, to obtain a mixture of the compounds of formula (X1) and (X2), usually a racemic mixture, which can be subjected to another chiral resolution step, for example.

[0096] Thus, on the other hand, the present invention provides a method for preparing a mixture of an optically active compound according to formula (X1) and an optically active compound according to formula (X2) or a salt thereof:

[0097]

[0098] wherein in formula (X1) and formula (X2), R is selected from C 1 -C 8 alkyl and C 3 -C 8 cycloalkyl;

[0099] wherein the compound or its salt is present in the mixture in a first ratio RM1 = X1:X2, and the first ratio is 0.8 - 1.2, preferably 0.9 - 1.1, most preferably 1;

[0100] comprising the steps of:

[0101] (a) dehydrogenating a mixture of compounds according to formula (X1) and (X2), wherein the compounds are present in the mixture in a second ratio RM2 = X1:X2 that is less than 0.8 or greater than 1.2, to produce a mixture of compounds or salts thereof according to the following formula (Y) and formula (Z)

[0102]

[0103] (b) hydrogenating the mixture of compounds or salts thereof according to formula (Y) and formula (Z) to obtain a mixture of compounds or salts of formula (X1) and (X2) having the first ratio RM1.

[0104] It is apparent from the ratio of the compounds of formula (X1) and (X2) that the purpose of the reaction is to reduce the amount of the unwanted compound (the compound of formula (X1) or (X2) in the mixture), and ideally to reach a racemic mixture, which has a more favorable amount of the desired compound and can thus be more suitably subjected to a (further) chiral resolution step.

[0105] Typically, the mixture of compounds of formula (X1) and (X2) or salts thereof at the second ratio RM2 will be the unwanted residue of the chiral resolution, i.e., the mixture will then be prepared by separating the mixture of compounds of formula (X1) and (X2) as a product or as a by-product. Less typically, the mixture of compounds of formula (X1) and (X2) or salts thereof at the second ratio RM2 can be the result of the asymmetric hydrogenation step of the compound of formula (Y) according to the process of the invention, especially if the asymmetric hydrogenation results in an excess of the unwanted enantiomer.

[0106] The salt can be any salt form of a compound that can be suitably subjected to the dehydrogenation and hydrogenation steps. If the initial mixture is the result or residue of a chiral resolution step, the salt can be a diastereomeric salt, i.e., a salt of the corresponding compound with a diastereomeric counterion.

[0107] These two steps can be carried out without separating the intermediate product. Alternatively, the intermediate products, i.e., the compounds of formula (Y) and (Z), can be separated.

[0108] On the other hand, the present invention relates to a compound according to the following formula (Y1),

[0109] .

[0110] This compound is considered to be a key intermediate in the synthesis of the present invention, especially allowing the preparation of (R)-praziquantel in a stereoselective manner.

[0111] Therefore, the present invention further provides the use of the compound of formula (Y1) for the preparation of (R)-praziquantel, or differently expressed, provides a method for preparing (R)-praziquantel using the compound (Y1) as a starting or intermediate compound.

[0112] More generally, the present invention further provides a compound of formula (Y)

[0113]

[0114] for the preparation of

[0115] (i) an optically active compound according to the following formula (X1),

[0116]

[0117] or

[0118] (ii) an optically active compound according to the following formula (X2)

[0119]

[0120] or

[0121] (iii) Use of a mixture of the two,

[0122] wherein R (in (Y) and (X1) and (X2)) is selected from C 1 -C 8 alkyl, C 3 -C 8 cycloalkyl and optionally substituted aryl, most preferably cyclohexyl.

[0123] The present invention also provides a method for preparing a compound of formula (Y1),

[0124]

[0125] comprising reacting [(isoquinolin-1-yl)-methyl]-amine

[0126]

[0127] with an acylating agent based on cyclohexanecarboxylic acid. There are different ways to couple a cyclohexanecarboxyl derivative with an amine, such as by forming an intermediate acylating agent and separating it, and then ammonolysis; forming a reactive acylating agent in separate steps and then immediately treating it with an amine; or in situ generating an acylating agent from cyclohexanecarboxylic acid in the presence of an amine by adding an activator or a coupling agent. The acylating agent based on cyclohexanecarboxylic acid can be, for example, cyclohexanecarboxylic acid in the presence of an activator or a coupling agent, or preferably a cyclohexanecarboxylic acid derivative selected from cyclohexanecarbonyl chloride, cyclohexanecarboxylic anhydride, and a mixed anhydride of cyclohexanecarboxylic acid and pivalic acid.

[0128] The mixed anhydride of cyclohexanecarboxylic acid and pivalic acid can be prepared in situ, for example, from cyclohexanecarboxylic acid and pivaloyl chloride in the presence of a tertiary amine as a base. The reaction with cyclohexanecarboxylic acid itself involves the use of an activator or a coupling agent or both. The formation of an amide starting from an amine is well established. Other examples of suitable reactants or reaction conditions, including condensing agents and activators, can be found in Montalbette C.A.G.N. et al., "Amide bond formation and peptide coupling” ,Terahedron 61 (2005) pp. 10827 - 10852, the entire content of which is incorporated herein by reference.

[0129] The reaction with cyclohexanecarbonyl chloride is preferred and is preferably carried out under basic conditions, for example, in a solvent system comprising THF and an aqueous basic solution such as an aqueous NaOH solution. Other suitable solvents include, for example, DCM, dioxane, toluene, and methyl tert-butyl ether.

[0130] Generally, the starting materials and catalysts used for preparing the compounds of the present invention can be prepared by the methods described in the following examples or by methods known per se, such as those described in the synthetic organic chemistry literature (e.g., Houben-Weil, Methods of Organic Chemistry), which are known to those skilled in the art or can be obtained commercially.

[0131] The following examples illustrate the compounds and methods of the present invention, which should not be construed as limiting the present invention. Unless otherwise specified, the variable factors (if any) shall have the same meanings as described above.

[0132] Enantiomeric excess HPLC High performance liquid chromatography J Coupling constant m Multiplet mL Milliliter mp Melting point MS Mass spectrometry (S)-PZQ (S)-Praziquantel (R)-PZQ (R)-Praziquantel RT Room temperature Temp Temperature [S] Substrate concentration S Substrate C Catalyst s Singlet t Triplet THF Tetrahydrofuran <![CDATA[[Ir(COD)Cl] 2 > Iridium(III) chloride cyclooctadiene dimer <![CDATA[3,5-Me 2 -Ph]]> 3,5-Dimethylphenyl(dixylyl) Ph Phenyl t-Bu tert-Butyl 3,5-F-Ph 3,5-Difluorophenyl <![CDATA[Me 2 -Ph]]> Dimethylphenyl(dixylyl) Me Methyl Et Ethyl iPr Isopropyl Bn Benzyl c-Hex Cyclohexyl TEBAC Benzyltriethylammonium chloride Me-THF 2-Methyltetrahydrofuran IPA Isopropyl alcohol DCE Dichloroethane DCM Dichloromethane EtOAc Ethyl acetate

[0133] Example 1: Synthesis of (R)-Praziquantel: Route 1

[0134] Step 1: Preparation of Isoquinolinecarbonitrile (2)

[0135]

[0136] Isoquinolinecarbonitrile (2) is commercially available and can be prepared from isoquinoline (1) according to the reported procedures, such as the following reported procedures: J.M. Wefer, A. Catala, F.D. Popp, Chem. Ind. (London) 1965, 140-141; J.M. Wefer, A. Catala, F.D. Popp, J. Org. Chem. 1965, 30, 3075-3077; M.D. Rozwadowska, D. Brozda, Can. J. Chem. 1980, 58, 1239-1242 and D.L. Boger, C.E. Brotherton, J.S. Panek, D. Yohannes, J. Org. Chem. 1984, 49, 4056-4058, the entire contents of which are incorporated herein by reference.

[0137] Step 2: Preparation of [(Isoquinolin-1-yl)-methyl]-amine (3)

[0138]

[0139] Under stirring at room temperature, 18 g (0.117 mol) of isoquinolinecarbonitrile (2) was dissolved in ethanol (250 g) and 18.6 g of hydrochloric acid (32%). After adding 7.8 g of wet palladium-carbon (5%), hydrogen was applied at atmospheric pressure for 17 hours. Thereafter, the resulting mixture was filtered through diatomaceous earth and the filtrate was concentrated in vacuo. The residue was then dissolved in a biphasic mixture of dichloromethane (150 g) and 32% aqueous NaOH solution (55 g). The phases were separated and the aqueous layer was extracted three times with dichloromethane (200 g). Finally, the combined organic layers were evaporated to give [(isoquinolin-1-yl)-methyl]-amine (3) as a light brown solid (20.4 g, 90% yield).

[0140] Characterization of [(isoquinolin-1-yl)-methyl]-amine:

[0141]

[0142] Step 3: Preparation of N-(1-isoquinolin-1-yl-methyl)-cyclohexanecarboxamide (4)

[0143]

[0144] 58.9 g (0.372 mol) of [(isoquinolin-1-yl)-methyl]-amine (3) was dissolved in THF (250 g) under stirring at room temperature. 51.2 g (0.410 mol) of 32% aqueous NaOH solution and water (150 g) were added. The mixture was cooled to 10 °C and then a solution of 60 g (0.410 mol) of cyclohexanecarbonyl chloride in THF (50 g) was added dropwise over 2.5 hours at 10 - 15 °C. The resulting two-phase mixture was stirred at room temperature for 2 hours and then 2N HCl (191 g) was added. 300 g of methyltetrahydrofuran and 350 g of water were added to separate the phases. The aqueous layer was separated and the organic phase was extracted twice with 1N HCl (190 g). The aqueous phases were combined, washed with methyltetrahydrofuran (200 g) and then neutralized with 32% aqueous NaOH solution (106 g). Methyltetrahydrofuran (200 g) was added, the phases were separated, the aqueous phase was extracted twice with methyltetrahydrofuran (200 g), and finally the combined organic phases were evaporated. The crude solid residue was recrystallized from ethyl acetate and dried to give N-(1-isoquinolin-1-yl-methyl)-cyclohexanecarboxamide (4) as a white to pale yellow solid (69.9 g, 70% yield). A second batch of crystals could be separated by recrystallizing the mother liquor residue from ethyl acetate (15 g, 85% total yield).

[0145] Characterization of N-(1-isoquinolin-1-yl-methyl)-cyclohexanecarboxamide:

[0146]

[0147] Step 4: Preparation of [(R)-1-(1,2,3,4-tetrahydro-isoquinolin-1-ylmethyl)]-cyclohexanecarboxylic acid amide (5(R))

[0148]

[0149] In an inerted glove box, 11.51 mg (0.019 mmol) of the catalyst precursor [Ir(COD)Cl] 2 and 26.17 mg (0.041 mmol) of (S)-Xyliphos were mixed together and dissolved in THF (5 g). 0.2 g (0.75 mmol) of N-(1-isoquinolin-1-yl-methyl)-cyclohexanecarboxylic acid amide (4) was placed in an autoclave, under nitrogen, at room temperature, and dissolved in THF (25 g). The catalyst solution was added to the autoclave using a syringe, and then a hydrogen pressure of 100 bar was applied and heated to 75 °C. During the 24-hour reaction time, the pressure rose to 110 bar, giving a 56% conversion to the target [(R)-1-(1,2,3,4-tetrahydro-isoquinolin-1-ylmethyl)]-cyclohexanecarboxylic acid amide (5(R)), which is also referred to herein as (R)-PZQ-formamide, with an enantioselectivity of ee = 64%. The reaction mixture can ultimately be evaporated, purified by chromatography and finally crystallized from n-heptane / ethanol to increase the ee purity of (R)-PZQ-formamide (5(R)) to 96%.

[0150] Characterization of [(R)-1-(1,2,3,4-tetrahydro-isoquinolin-1-ylmethyl)]-cyclohexanecarboxylic acid amide:

[0151] C 17 H 24 N 2 O (272.39 g·mol -1 ), mp. 110 - 112 °C

[0152] The NMR data was fully consistent with that of the racemate (see below).

[0153] Step 5: Preparation of (R)-Praziquantel

[0154]

[0155] (R)-Praziquantel ((R)-PZQ) (6) can be prepared by cyclization of [(R)-1-(1,2,3,4-tetrahydro-isoquinolin-1-ylmethyl)]-cyclohexanecarboxylic acid amide (5(R)) ((R)-PZQ-formamide) with chloro-acetyl chloride according to known methods, such as the method described by Sergovskaya and Chernyak (1991), which was repeated by Roszkowski, P. et al. in Tetrahedron: Asymmetry 17 (2006) 1415-1419. To a stirred solution of the amine (1R)-7 [in this case (5(R))] (110 mg, 0.39 mmol) in 1.0 mL CH 2 Cl 2 was added a solution of 50% NaOH (0.12 mL, 1.33 mmol), and then a 0.15 mL CH 2 Cl 2 solution of chloroacetyl chloride (0.034 mL, 0.43 mmol). After 0.5 h, TEBAC (9 mg, 0.04 mmol) was added and the mixture was heated and stirred under reflux for 2 h. Thereafter, a portion of 3 mL of water was added and the mixture was extracted with CH 2 Cl 2 (2 × 3 mL). The organic phase was washed with water (2 × 2 mL), 5% HCl (2 mL), again with water (2 mL), and dried over Na 2 SO 4 . After evaporation of the solvent, the residue was purified by silica gel column chromatography using chloroform / methanol 0 - 0.3% MeOH as the solvent system to give 93 mg (77%) of (1R)-(-)-8 [in this case (R)-PZQ].

[0156] Characterization of (R)-PZQ:

[0157] C 19 H 24 N 2 O 2 (312.42 g·mol -1 ), mp. 110 - 111 °C

[0158] The analytical data are known and described.

[0159] Example 2: Synthesis of (R)-Praziquantel: Route 2

[0160] Steps 1 to 3 in the preparation of N-(1-isoquinolin-1-yl-methyl)-cyclohexanecarboxylic acid amide (4) are the same as in Route 1.

[0161] Step 4: Preparation of N-(1,2,3,4-tetrahydro-isoquinolin-1-ylmethyl)-cyclohexanecarboxylic acid amide (5)

[0162]

[0163] 21 g (0.078 mol) of N-(1-isoquinolin-1-yl-methyl)-cyclohexanecarboxylic acid amide (4) was dissolved in methanol (MeOH, 145 g) and glacial acetic acid (AcOH, 2.18 g, 0.036 mol) under stirring at room temperature. After addition of 11.8 g of wet platinum / activated carbon (5%) (Pt-C), hydrogen (H 2 ) was applied at a pressure of 2.6 bar and a temperature of 35 °C for 16 h. Then the mixture was filtered through diatomaceous earth and the filtrate was concentrated in vacuo. The residue was taken up in dichloromethane (200 g) and washed with NaOH (5%) until the pH reached 12 - 13. After phase separation, the aqueous layer was extracted with dichloromethane (90 g), and the combined organic phases were washed three times with water (75 g) until pH 7 and finally evaporated. The residue was recrystallized from ethyl acetate and dried to give the racemic mixture of N-(1,2,3,4-tetrahydro-isoquinolin-1-ylmethyl)-cyclohexanecarboxylic acid amide (5) as light yellow crystals (14.5 g, 68% yield).

[0164] Characterization of N-(1,2,3,4-tetrahydro-isoquinolin-1-ylmethyl)-cyclohexane-carboxylic acid amide:

[0165]

[0166] Step 5: Chiral resolution of racemic N-(1,2,3,4-tetrahydro-isoquinolin-1-ylmethyl)-cyclohexanecarboxylic acid amide (5)

[0167]

[0168] Racemic N-(1,2,3,4-tetrahydro-isoquinolin-1-ylmethyl)-cyclohexanecarboxylic acid amide (5) can be resolved by formation and crystallization from ethanol of the diastereomeric salt with D-(-)-tartaric acid. The diastereomeric salt was liberated under basic (NaOH) conditions, extracted with dichloromethane and evaporated in vacuo to give [(R)-1-(1,2,3,4-tetrahydro-isoquinolin-1-ylmethyl)]-cyclohexane-carboxylic acid amide (5(R)) as a white solid in 60% yield, ee with 96% ee.

[0169] Another suitable method is described, for example, in DE 2504250 (Example 91): A solution of 16.5 g of (D)-(-)-tartaric acid in 300 mL of methanol was added to a solution of 21.7 g of racemic N-(1,2,3,4-tetrahydro-isoquinolin-1-ylmethyl)-cyclohexanecarboxylic acid amide (prepared in a different manner in DE 2504250) in 300 mL of methanol. The solvent was distilled off, and the residue was recrystallized from ethanol until the melting point rose to about 207 °C. The salt was dissolved in water, the solution was made alkaline, and then extracted with chloroform or dichloromethane. After drying with magnesium sulfate and distilling off the solvent, [(R)-1-(1,2,3,4-tetrahydro-isoquinolin-1-ylmethyl)]-cyclohexanecarboxylic acid amide (5(R) was obtained.

[0170] Characterization of [(R)-1-(1,2,3,4-tetrahydro-isoquinolin-1-ylmethyl)]-cyclohexanecarboxylic acid amide:

[0171] C 17 H 24 N 2 O (272.39 g·mol -1 ), mp. 110-112 °C

[0172] Step 6 (optional): Recycling of [(S)-1-(1,2,3,4-tetrahydro-isoquinolin-1-ylmethyl)]-cyclohexanecarboxylic acid amide

[0173] [(S)-1-(1,2,3,4-tetrahydro-isoquinolin-1-ylmethyl)]-cyclohexanecarboxylic acid amide or a mixture of [(R)-1-(1,2,3,4-tetrahydro-isoquinolin-1-ylmethyl)]-cyclohexanecarboxylic acid amide with an excess of the (S)-configured compound can be recycled by dehydrogenation and rehydrogenation to produce a racemic mixture of the compounds for further chiral resolution, as follows:

[0174]

[0175] The mother liquor and washings from the above chiral resolution step 5 were evaporated and treated with dichloromethane and aqueous sodium hydroxide. After extracting the aqueous layer with dichloromethane, the combined organic layers were evaporated in vacuo to give a mixture of [(S)-1-(1,2,3,4-tetrahydro-isoquinolin-1-ylmethyl)]-cyclohexanecarboxylic acid amide and some residual [(R)-1-(1,2,3,4-tetrahydro-isoquinolin-1-ylmethyl)]-cyclohexanecarboxylic acid amide.

[0176] 5 g (0.018 mol) of the evaporation residue was dissolved in acetonitrile (30 g), 2.5 g of Pd-C (10%) was added, then an ethylene pressure of 10 bar was applied, and subsequently heated to 100 °C for 18 hours, with the internal pressure in the autoclave reaching a maximum of 20 bar. Finally, the mixture was filtered through diatomaceous earth, the catalyst was washed with warm acetonitrile, and the resulting filtrate was concentrated in vacuo to give 4.5 g of a light brown solid containing a mixture of N-(1-isoquinolin-1-yl-methyl)-cyclohexanecarboxamide (4) (53.6%) and its dehydrogenated derivative (7) (44.3%).

[0177] The residual mixture was used directly for hydrogenation and dissolved in methanol (63 g) and acetic acid (0.178 g, 0.003 mol). After adding 1.8 g (0.008 mol) of wet platinum / activated carbon (5%), a hydrogen pressure of 2.8 bar and a temperature of 36 °C were applied for 7 hours, then the mixture was filtered through diatomaceous earth and the filtrate was concentrated in vacuo. The residue was taken up in dichloromethane (40 g) and washed with NaOH (5%) until the pH reached 12 - 13. After phase separation, the aqueous layer was extracted with dichloromethane (20 g), the combined organic phases were washed three times with water (30 g) to reach pH 7, and finally evaporated. The residue was recrystallized from ethyl acetate and, after drying, gave 1-(1,2,3,4-tetrahydro-isoquinolin-1-ylmethyl)]-cyclohexanecarboxamide as pale yellow crystals (2.92 g, 65% yield). Subsequently, this substance can be used for further steps of chiral resolution.

[0178] Step 7: Preparation of (R)-Praziquantel

[0179] (R)-Praziquantel ((R)-PZQ) (6) can be prepared from [(R)-1-(1,2,3,4-tetrahydro-isoquinolin-1-ylmethyl)]-cyclohexanecarboxamide as described in Step 5 of Example 1.

[0180] Example 3: Synthesis of Racemic Praziquantel

[0181] Steps 1 to 4 are the same as in Example 2 (Route 2):

[0182]

[0183] Step 5: Preparation of Racemic Praziquantel

[0184] Racemic praziquantel (PZQ) was prepared in the same manner as described in Step 5 of Example 1 from racemic 1-(1,2,3,4-tetrahydro-isoquinolin-1-ylmethyl)]-cyclohexanecarboxamide.

[0185] Example 4: Synthesis of [(S)-1-(1,2,3,4-tetrahydro-isoquinolin-1-ylmethyl)]-cyclohexanecarboxamide

[0186] Steps 1 and 2 are the same as Steps 1 and 2 in Examples 1 to 3.

[0187] Step 3: Preparation of N - isoquinolin - 1 - yl - methyl - acetamide

[0188]

[0189] Similar to the preparation of N-(1 - isoquinolin - 1 - yl - methyl)-cyclohexanecarboxamide (4) (Step 3 in Example 1), N - isoquinolin - 1 - yl - methyl - acetamide (8) is synthesized by reacting [(isoquinolin - 1 - yl)-methyl]-amine (3) with acetyl chloride.

[0190] Characterization of N - isoquinolin - 1 - yl - methyl - acetamide:

[0191]

[0192] Step 4a: Preparation of [(S)-1-(1,2,3,4 - tetrahydro - isoquinolin - 1 - ylmethyl)]-acetamide

[0193]

[0194] In an inerted glove box, 15.30 mg (0.025 mmol) of the catalyst precursor [Ir(COD)Cl] 2 and 34.73 mg (0.054 mmol) of (R)-Xyliphos were mixed together and dissolved in THF (5 g). 0.2 g (0.99 mmol) of N - isoquinolin - 1 - yl - methyl - acetamide (8) was dissolved in THF (25 g) in a autoclave under nitrogen at room temperature. The catalyst solution was added to the autoclave with a syringe, then a hydrogen pressure of 100 bar was applied and heated to 100 °C. During the 17 - hour reaction time, the pressure rose to 110 bar, giving a 77.5% conversion to the target [(S)-1-(1,2,3,4 - tetrahydro - isoquinolin - 1 - ylmethyl)]-acetamide (9) with an enantioselectivity of ee = 84%. The reaction mixture can finally be evaporated, purified by chromatography and finally crystallized to increase the ee to 96% of the target [(S)-1-(1,2,3,4 - tetrahydro - isoquinolin - 1 - ylmethyl)]-acetamide (9).

[0195] [(S)-1-(1,2,3,4 - tetrahydro - isoquinolin - 1 - ylmethyl)]-acetamide characterization:

[0196] C 12 H 16 N 2 O (204.27 g·mol-1 ), mp. 55 °C

[0197] Step 4b: Preparation of [(R)-1-(1,2,3,4-tetrahydro-isoquinolin-1-ylmethyl)]-acetamide

[0198] Alternatively, [(R)-1-(1,2,3,4-tetrahydro-isoquinolin-1-ylmethyl)]-acetamide can be prepared using S-Xyliphos instead of R-Xyliphos, similar to Step 4a.

[0199] [(R)-1-(1,2,3,4-tetrahydro-isoquinolin-1-ylmethyl)]-acetamide and [(S)-1-(1,2,3,4-tetrahydro-isoquinolin-1-ylmethyl)]-acetamide can be used for the further synthesis of compounds that are very similar in structure to praziquantel, or further for the synthesis of praziquantel itself.

[0200] Example 5: Examples of suitable asymmetric hydrogenation conditions

[0201] Example 5.1: Preparation of 1-(1,2,3,4-tetrahydro-isoquinolin-1-ylmethyl)]-acetamide

[0202] Table 1 below illustrates suitable exemplary asymmetric hydrogenation conditions for the preparation of [(R)-1-(1,2,3,4-tetrahydro-isoquinolin-1-ylmethyl)]-acetamide and / or [(S)-1-(1,2,3,4-tetrahydro-isoquinolin-1-ylmethyl)]-acetamide:

[0203] Under an inert atmosphere, cyclooctadiene iridium(I) dichloride dimer (15.30 mg) and ligand (1 equivalent per iridium atom) were mixed in tetrahydrofuran (5.00 g). After stirring for 1 hour, the mixture was added to a solution of N-isoquinolin-1-ylmethyl-acetamide (200.00 mg) in tetrahydrofuran (30.00 g). The blend was stirred overnight at 100 °C under a hydrogen atmosphere of 110 bar. After evaporation of the solvent under reduced pressure, a mixture of (R)-(-)- and (S)-(+)-N-(1,2,3,4-tetrahydro-isoquinolin-1-ylmethyl)-acetamide was obtained.

[0204] Table 1

[0205]

[0206] Example 5.2: Preparation of 1-(1,2,3,4-tetrahydro-isoquinolin-1-ylmethyl)]-cyclohexanecarboxylic acid-amide

[0207] Table 2 below illustrates suitable asymmetric hydrogenation conditions (including catalysts) and also illustrates how the reaction conditions (such as the choice of solvent or additive) can be adjusted to optimize the conversion rate and / or stereoselectivity, particularly in the preparation of [(R)-1-(1,2,3,4-tetrahydro-isoquinolin-1-ylmethyl)]-cyclohexanecarboxylic acid-amide and / or [(S)-1-(1,2,3,4-tetrahydro-isoquinolin-1-ylmethyl)]-cyclohexanecarboxylic acid-amide:

[0208] Table 2

[0209]

[0210]

[0211]

[0212]

Claims

1. A method for preparing: (i) an optically active compound according to formula (X1) or (ii) an optically active compound according to formula (X2) or (iii) a mixture of both, wherein R is selected from C 1 -C 8 -alkyl, C 3 -C 8 -cycloalkyl and unsubstituted aryl or aryl substituted by amino, acylamino in which the acyl group contains up to four carbon atoms, halogen, hydroxy, methoxy or nitro, comprising: reacting a compound according to formula (Y) having R above: A hydrogenation step is carried out, wherein the mixture contains an excess of a compound according to formula (X1) or a compound according to formula (X2), and wherein the hydrogenation step is an asymmetric hydrogenation step in the presence of a catalyst, wherein the catalyst is [Ir(COD)Cl] 2 and a mixture of ligands or comprises such a mixture, the ligands being selected from 2. The method according to claim 1, wherein R is methyl or cyclohexyl.

3. The method according to claim 1, wherein the compound according to formula (X1) is present in the mixture with an enantiomeric excess of at least 10%.

4. The method according to claim 1, wherein the compound according to formula (X1) is present in the mixture with an enantiomeric excess of at least 20%.

5. The method according to claim 1, wherein the compound according to formula (X1) is present in the mixture with an enantiomeric excess of at least 30%.

6. The method according to claim 1, wherein the compound according to formula (X1) is present in the mixture with an enantiomeric excess of at least 40%.

7. The method according to claim 1, wherein the compound according to formula (X1) is present in the mixture with an enantiomeric excess of at least 50%.

8. The method according to claim 1, wherein the compound according to formula (X1) is present in the mixture with an enantiomeric excess of at least 60%.

9. The method according to claim 1, wherein the compound according to formula (X1) is present in the mixture with an enantiomeric excess of at least 70%.

10. The method according to claim 1, wherein the compound according to formula (X1) is present in the mixture with an enantiomeric excess of at least 80%.

11. The method according to claim 1, wherein the asymmetric hydrogenation step carried out in the presence of a catalyst involves at least one of the following: - an elevated temperature which is at least 60 °C; - a solvent selected from dioxane, THF, Me-THF, IPA, DCE, DCM, ethyl acetate, toluene, α,α,α - trifluorotoluene; xylene; mesitylene or a mixture of any two or more thereof; - At least one additive in an amount of at least 5 mol%, selected from iodine (I 2 ), iodide, phosphoric acid (H 3 PO 4 ), acetic acid (AcOH), HBF 4 ; - a substrate concentration of at least 0.05 mmol / l; - a catalyst loading of at least 50 / 1 substrate / catalyst; and - elevated pressure, the pressure being at least 1 bar H 2 .

12. The method according to claim 11, wherein the elevated temperature is at least 80 °C.

13. The method according to claim 11, wherein the elevated temperature is at least 90 °C.

14. The method according to claim 11, wherein the elevated temperature is at least 100 °C.

15. The method according to claim 11, wherein the xylene is meta-xylene or para-xylene.

16. The method according to claim 11, wherein the amount of the additive is at least 50 mol%.

17. The method according to claim 11, wherein the amount of the additive is at least 100 mol%.

18. The method according to claim 11, wherein the substrate concentration is at least 10 mmol / l.

19. The method according to claim 11, wherein the substrate concentration is at least 100 mmol / l.

20. The method according to claim 11, wherein the catalyst loading is at least 100 / 1 substrate / catalyst.

21. The method according to claim 11, wherein the catalyst loading is at least 250 / 1 substrate / catalyst.

22. The method according to claim 11, wherein the catalyst loading is at least 500 / 1 substrate / catalyst.

23. The method according to claim 11, wherein the elevated pressure is at least 5 bar H 2 .

24. The method according to claim 11, wherein the elevated pressure is at least 10 bar H 2 .

25. The method according to claim 11, wherein the elevated pressure is at least 20 bar H 2 .

26. The method according to claim 11, wherein the elevated pressure is at least 25 bar H 2 .

27. The method according to claim 11, wherein the elevated pressure is at least 50 bar H 2 .

28. The method according to claim 11, wherein the elevated pressure is at least 100 bar H 2 .

29. The method according to claim 11, wherein the iodide is HI.

30. A method for preparing an enantiomerically pure or enantiomerically enriched compound according to formula (Q1) or formula (Q2) comprising ： (a) preparing, by the method according to any one of claims 1-29, (i) an optically active compound according to formula (X1) or (iii) a mixture of compounds according to formula (X1) and formula (X2), wherein the compound according to formula (X1) is present in excess in the mixture, for preparing a compound according to formula (Q1); or (b) preparing, by the method according to any one of claims 1-29, (ii) an optically active compound according to formula (X2) or (iii) a mixture of compounds according to formula (X1) and formula (X2), wherein the compound according to formula (X2) is present in excess in the mixture, for preparing a compound according to formula (Q2), wherein R in formula (Q1) and (Q2) is selected from C 1 -C 8 -alkyl, C 3 -C 8 -cycloalkyl and aryl optionally substituted by amino, acylamino wherein the acyl group contains at most four carbon atoms, halogen, hydroxy, methoxy or nitro.

31. The method for preparing an enantiomerically pure or enantiomerically enriched compound according to formula (Q1) or formula (Q2) according to claim 30, which further comprises (c) React (i) an optically active compound according to formula (X1) or (iii) a mixture of a compound according to formula (X1) and a compound according to formula (X2), wherein the compound according to formula (X1) is present in excess in the mixture, with the compound Y-CO-CH 2 -X, where Y is F, Cl or Br or -O-CO-alkyl and X is F, Cl or Br, to obtain a compound according to formula (Q1); or (d) React an optically active compound according to formula (X2) or a mixture of compounds (iii) according to formula (X1) and formula (X2), in which the compound according to formula (X2) is present in excess, with the compound Y-CO-CH 2 -X, where Y is F, Cl or Br or -O-CO-alkyl and X is F, Cl or Br, to obtain a compound according to formula (Q2).

32. The method according to claim 31, wherein the compound Y-CO-CH 2 -X is chloroacetyl chloride (Cl-C(=O)-CH 2 Cl).

33. A method for preparing an enantiomerically pure or enantiomerically enriched compound according to formula (Q1) or formula (Q2) comprising preparing a mixture of compounds according to formula (X1) or formula (X2) by the method according to claim 1, separating the compound according to formula (X1) from the compound according to formula (X2), and subjecting (a) A compound according to formula (X1) is reacted with a compound Y-CO-CH 2 -X, where Y is F, Cl or Br or -O-CO-alkyl and X is F, Cl or Br, to obtain an enantiomerically pure or enantiomerically enriched compound according to formula (Q1); or (b) A compound according to formula (X2) is reacted with a compound Y-CO-CH 2 -X, where Y is F, Cl or Br or -O-CO-alkyl and X is F, Cl or B, to obtain an enantiopure or enantiomerically enriched compound according to formula (Q2), wherein R in formula (Q1) and (Q2) is the same as that in formula (X1) and (X2).

34. The method according to claim 33, wherein the compound Y-CO-CH 2 -X is chloroacetyl chloride (Cl-C(=O)-CH 2 Cl).

35. A method for preparing enantiomerically pure or enantiomerically enriched (R)-praziquantel comprising the method according to any one of claims 31-34, using an optically active compound according to formula (X1) or (iii) a mixture of compounds according to formula (X1) and formula (X2), wherein the compound according to formula (X1) is present in excess in the mixture, and wherein R in the compound according to formula (X1) is cyclohexyl.

36. A method for preparing a mixture of an optically active compound according to the following formula (X1) and an optically active compound according to the following formula (X2) or a salt thereof wherein R is selected from C 1 -C 8 alkyl and C 3 -C 8 cycloalkyl; wherein the compound or its salt is present in the mixture at a first ratio RM1 = X1:X2, and the first ratio is 0.8-1.2; comprising the following steps: (a) dehydrogenating a mixture of compounds according to formula (X1) and (X2), wherein the compounds are present in the mixture at a second ratio RM2 = X1:X2 less than 0.8 or greater than 1.2, to produce a mixture of compounds according to the following formula (Y) and formula (Z) or salts thereof, wherein R is the same as that in formula (X1) and (X2), and (b) Hydrogenating the mixture of the compounds of formula (Y) and formula (Z) or their salts to obtain a mixture of compounds of formula (X1) and (X2) or their salts at a first ratio RM1, wherein a mixture of compounds of formula (X1) and (X2) or their salts at a second ratio RM2 is prepared by asymmetric hydrogenation of the compound of formula (Y) by the method according to any one of claims 1 to 7 or by separating the mixture of compounds of formula (X1) and (X2), and the mixture is prepared by the method according to claim 1.

37. The method according to claim 36, wherein the first ratio X1:X2 is 0.9 - 1.

1.

38. The method according to claim 36, wherein the first ratio X1:X2 is 1.

Images