WO2010064212A1 - Method for obtaining an optically pure 1,2,3,4 tetrahydro-isoquinoline derivative - Google Patents

Abstract

The invention relates to a method for obtaining enantiomerically enriched 6,7-dimethoxy-1-[2-(4-trifluoromethyl-phenyl)-ethyl]-1,2,3,4-tetrahydro-isoquinoline from a mixture of (R)-6,7-dimethoxy-1-[2-(4-trifluoromethyl-phenyl)-ethyl]-1,2,3,4-tetrahydro-isoquinoline and (S)-6,7-dimethoxy-1-[2-(4-trifluoromethyl-phenyl)-ethyl]-1,2,3,4-tetrahydro-isoquinoline.

Description

METHOD FOR OBTAINING AN OPTICALLY PURE 1,2,3,4-TETRAHYDRO-ISOQUINOLINE DERIVATIVE

The present invention relates to a method for obtaining enantiomerically enriched (5)-6,7-dimethoxy-l-[2-(4-trifluoromethyl-phenyl)-ethyl]-l,2,3,4-tetrahydro-isoquinoline from a mixture of (i?)-6,7-dimethoxy-l-[2-(4-trifluoromethyl-phenyl)-ethyl]- 1 ,2,3 ,4-tetrahydro-isoquinoline and (5)-6,7-dimethoxy- 1 -[2-(4-trifluoromethyl-phenyl)- ethyl]- 1 ,2,3 ,4-tetrahydro-isoquinoline.

(5)-6,7-dimethoxy-l-[2-(4-trifluoromethyl-phenyl)-ethyl]-l,2,3,4-tetrahydro-isoquinoline is an important synthetic intermediate in the preparation of almorexant, a 1,2,3,4-tetrahydro-isoquinoline derivative with orexin antagonist properties which is currently in clinical development for the treatment of sleep disorders. 1,2,3,4-tetrahydro-isoquinoline derivatives with orexin antagonist properties and their preparation are described in WO 01/68609. Methods for preparing almorexant and (5)-6,7-dimethoxy-l-[2-(4-trifluoromethyl-phenyl)-ethyl]-l,2,3,4-tetrahydro-isoquinoline have furthermore been described in WO 2005/118548.

Besides, optical resolution methods using (2i?,Ji?)-2'-nitro-tartranilic acid have been described for certain 6,7-dimethoxy-l,2,3,4-tetrahydro-isoquinoline or 6-methoxy- 1,2,3,4-tetrahydro-isoquinoline derivatives (see US 3,378,561; US 3,389,140; US 3,389,141; T.A. Montzka et al, J. Org. Chem. (1968), 33(10), 3993-3995; WO 82/04049; and K.C. Rice and A. Brossi, J. Org. Chem. (1980), 45(4), 592-601).

According to the instant invention process, optical resolution of 6,7-dimethoxy- l-[2-(4-trifluoromethyl-phenyl)-ethyl]-l, 2,3, 4-tetrahydro-isoquino line is achieved with a high enantiomeric excess and a good yield. Various embodiments of the invention are thus presented hereafter: i) The invention relates to a process for obtaining enantiomerically enriched (5)-6,7-dimethoxy-l-[2-(4-trifluoromethyl-phenyl)-ethyl]-l,2,3,4-tetrahydro-isoquinoline from a mixture of (i?)-6,7-dimethoxy-l-[2-(4-trifluoromethyl-phenyl)-ethyl]- 1, 2,3, 4-tetrahydro-isoquino line and (5)-6,7-dimethoxy-l-[2-(4-trifluoromethyl-phenyl)- ethyl]-l,2,3,4-tetrahydro-isoquinoline, which process comprises the following sequential steps: either a) bringing to a given temperature T which may be up to the boiling temperature of the organic solvent(s) and optionally present water, a mixture of (7?)-6,7-dimethoxy- l-[2-(4-trifluoromethyl-phenyl)-ethyl]-l,2,3,4-tetrahydro-isoquinoline and

(5)-6,7-dimethoxy- 1 -[2-(4-trifiuoromethyl-phenyl)-ethyl]- 1 ,2,3 ,4-tetrahydro- isoquinoline in an organic solvent or organic solvent mixture optionally mixed with water, to which mixture is added a compound of formula I

I wherein R is nitro, methyl or methoxy, whereby the compound of formula I may be added as a solid or as a solution or a suspension either in the same organic solvent or organic solvent mixture optionally mixed with water as the one used for the enantiomer mixture or in a different organic solvent or organic solvent mixture optionally mixed with water, whereby the conditions are such that any solid components are dissolved in the organic solvent(s) and optionally present water; b) cooling down the solution obtained after step a) to a temperature that is at least 15°C lower than T and collecting the crystallised salt formed; and c) treating the crystallised salt collected at step b) with a base to obtain, after removal of possibly remaining compound of formula I, enantiomerically enriched (5)-6,7-dimethoxy- 1 -[2-(4-trifiuoromethyl-phenyl)-ethyl]- 1 ,2,3 ,4-tetrahydro- isoquinoline; or d) bringing to a given temperature T which may be up to the boiling temperature of the organic solvent(s) and optionally present water, a mixture of (7?)-6,7-dimethoxy- l-[2-(4-trifluoromethyl-phenyl)-ethyl]-l,2,3,4-tetrahydro-isoquinoline and

(5)-6,7-dimethoxy- 1 -[2-(4-trifiuoromethyl-phenyl)-ethyl]- 1 ,2,3 ,4-tetrahydro- isoquinoline in an organic solvent or organic solvent mixture optionally mixed with water, to which mixture is added a compound of formula F

r wherein R is nitro, methyl or methoxy, whereby the compound of formula F may be added as a solid or as a solution or a suspension either in the same organic solvent or organic solvent mixture optionally mixed with water as the one used for the enantiomer mixture or in a different organic solvent or organic solvent mixture optionally mixed with water, whereby the conditions are such that any solid components are dissolved in the organic solvent(s) and optionally present water; e) cooling down the solution obtained after step d) to a temperature that is at least 15⁰C lower than T and removing the crystallised salt formed, thus obtaining a solution of enantiomerically enriched (5)-6,7-dimethoxy- 1 -[2-(4-trifluoromethyl-phenyl)-ethyl]- 1, 2,3, 4-tetrahydro-isoquino line and possibly remaining compound of formula F in the organic solvent or organic solvent mixture optionally mixed with water; and f) removing the organic solvent or organic solvent mixture optionally mixed with water and treating the residue thus obtained with a base to obtain, after removal of possibly remaining compound of formula F, enantiomerically enriched (5)-6,7-dimethoxy- l-[2-(4-trifluoromethyl-phenyl)-ethyl]-l,2,3,4-tetrahydro-isoquinoline.

In this text, unless used regarding temperatures, the term "about" placed before a numerical value "X" refers in the current application to an interval extending from X minus 10% of X to X plus 10% of X, and preferably to an interval extending from X minus 5% of X to X plus 5% of X. In the particular case of temperatures, the term "about" or "around" placed before a temperature "Y" refers in the current application to an interval extending from the temperature Y minus 1O⁰C to Y plus 1O⁰C, and preferably to an interval extending from Y minus 5⁰C to Y plus 5⁰C.

Besides, the term "room temperature" as used herein refers to a temperature of about 25°C.

Moreover, the term "enantiomerically enriched (5)-6,7-dimethoxy-l-[2-(4-trifluoromethyl- phenyl)-ethyl]-l,2,3,4-tetrahydro-isoquinoline" as used in this text refers to a mixture of (i?)-6,7-dimethoxy-l-[2-(4-trifluoromethyl-phenyl)-ethyl]-l,2,3,4-tetrahydro-isoquinoline and (5)-6,7-dimethoxy-l-[2-(4-trifluoromethyl-phenyl)-ethyl]-l,2,3,4-tetrahydro- isoquinoline containing at least 70%, preferably at least 80% or 90% and more preferably at least 95% or 98% of (S)-6,7-dimethoxy-l-[2-(4-trifluoromethyl-phenyl)-ethyl]- 1 ,2,3 ,4-tetrahydro-isoquino line. ii) According to one variant of this invention, the process of embodiment i) above will be such that it comprises steps a) to c). iii) According to the other variant of this invention, the process of embodiment i) above will be such that it comprises steps d) to f). iv) According to a preferred embodiment of this invention, the process according to one of embodiments i) to iii) above will be such that R is methyl. v) According to one particular embodiment of this invention, the process according to one of embodiments i) to iv) above will be such that the method used for collecting the crystallised salt at step b) or removing the crystallised salt at step e) will consist in a filtration. vi) According to another particular embodiment of this invention, the process according to one of embodiments i), ii) and iv) above will be such that the method used for collecting the crystallised salt at step b) will consist in a decantation. vii) According to another particular embodiment of this invention, the process according to one of embodiments i), ii) and iv) above will be such that the method used for collecting the crystallised salt at step b) will consist in a centrifugation followed by a decantation. viii) According to another particular embodiment of this invention, the process according to one of embodiments i), iii) and iv) above will be such that the method used for removing the crystallised salt at step e) will consist in a decantation. ix) According to another particular embodiment of this invention, the process according to one of embodiments i), iii) and iv) above will be such that the method used for removing the crystallised salt at step e) will consist in a centrifugation followed by a decantation. x) According to one particular sub-embodiment of this invention, the process according to one of embodiments i) to ix) above will be such that the mixture of (i?)-6,7-dimethoxy- l-[2-(4-trifluoromethyl-phenyl)-ethyl]-l,2,3,4-tetrahydro-isoquinoline and

(5)-6,7-dimethoxy-l-[2-(4-trifluoromethyl-phenyl)-ethyl]-l,2,3,4-tetrahydro-isoquinoline and the compound of formula I or the compound of formula F will be in solution or in suspension in the same organic solvent or organic solvent mixture optionally mixed with water. xi) Preferably, the process of embodiment x) above will be such that the organic solvent or organic solvent mixture optionally mixed with water is selected from ethyl acetate, tetrahydrofurane, methyl ethyl ketone, acetone and a mixture of acetone with ethanol, whereby the organic solvent or organic solvent mixture is mixed with water in a proportion of a least 7 volumes of organic solvent per volume of water. xii) More preferably, the process of embodiment x) above will be such that the organic solvent or organic solvent mixture optionally mixed with water is selected from the following mixtures:

- a mixture of ethyl acetate and water, which contains about 20 volumes of ethyl acetate per volume of water;

- a mixture of 2-butanone and water, which contains about 10 volumes of 2-butanone per volume of water;

- a mixture of acetone and water, which contains from 8 to 20 (and preferably from 10 to 15) volumes of acetone per volume of water; and - a mixture of acetone, ethanol and water, which contains from 7 to 11 (and preferably from 8 to 10) volumes of acetone per volume of water and from 0.5 to 1.5 volumes of ethanol per volume of water.

xiii) In a particularly preferred manner, the process of embodiment x) above will be such that the organic solvent or organic solvent mixture optionally mixed with water is selected from the following mixtures:

- a mixture of acetone and water, which contains about 10 volumes of acetone per volume of water; and - a mixture of acetone, ethanol and water, which contains about 9 volumes of acetone per volume of water and about 1 volume of ethanol per volume of water. xiv) According to another particular sub-embodiment of this invention, the process according to one of embodiments i) to ix) above will be such that the mixture of (i?)-6,7-dimethoxy-l-[2-(4-trifluoromethyl-phenyl)-ethyl]-l,2,3,4-tetrahydro-isoquinoline and (5)-6,7-dimethoxy-l-[2-(4-trifluoromethyl-phenyl)-ethyl]-l,2,3,4-tetrahydro- isoquinoline and the compound of formula I or the compound of formula F will be in solution or in suspension in different organic solvents each optionally mixed with water. xv) Preferably, the process of embodiment xiv) above will be such that: 1) the organic solvent or organic solvent mixture optionally mixed with water containing the mixture of enantiomers is selected from tetrahydrofurane and acetone, whereby said tetrahydrofurane or acetone is mixed with water in a proportion of a least 10 volumes of tetrahydrofurane or acetone per volume of water; and 2) the organic solvent or organic solvent mixture optionally mixed with water containing the compound of formula I or the compound of formula F is tetrahydrofurane, whereby said tetrahydrofurane is mixed with water in a proportion of a least 3 volumes of tetrahydrofurane per volume of water (and preferably in a proportion of 3 to 20 volumes of tetrahydrofurane per volume of water), it being understood that if for both the mixture of enantiomers and the compound of formula I or the compound of formula F the organic solvent is tetrahydrofurane, then the proportion of water optionally added is different. xvi) According to yet another particular sub-embodiment of this invention, the process according to one of embodiments i) to ix) above will be such that the compound of formula I or the compound of formula F will be added as a solid. xvii) Preferably, the process of embodiment xvi) above will be such that: - either the organic solvent or organic solvent mixture optionally mixed with water containing the mixture of (i?)-6,7-dimethoxy-l-[2-(4-trifluoromethyl-phenyl)-ethyl]- 1 ,2,3 ,4-tetrahydro-isoquinoline and (5)-6,7-dimethoxy- 1 -[2-(4-trifluoromethyl-phenyl)- ethyl]-l,2,3,4-tetrahydro-isoquinoline will be a mixture of 4-methyl-2-pentanone and water, whereby 4-methyl-2-pentanone is mixed with water in a proportion of a least 10 volumes of 4-methyl-2-pentanone per volume of water (and preferably such that said organic solvent or organic solvent mixture optionally mixed with water will be a mixture of 4-methyl-2-pentanone and water which contains about 12.5 volumes of 4-methyl- 2-pentanone per volume of water);

- or the organic solvent or organic solvent mixture optionally mixed with water containing the mixture of (i?)-6,7-dimethoxy-l-[2-(4-trifluoromethyl-phenyl)-ethyl]- 1, 2,3, 4-tetrahydro-isoquino line and (5)-6,7-dimethoxy-l-[2-(4-trifluoromethyl-phenyl)- ethyl]-l,2,3,4-tetrahydro-isoquinoline will be a mixture of acetone, ethanol and water, whereby acetone, ethanol and water are mixed in a proportion of at least 9 volumes of acetone per volume of water and per volume of ethanol (and preferably such that said organic solvent or organic solvent mixture optionally mixed with water will be a mixture of acetone, ethanol and water which contains about 9 volumes of acetone and about

1 volume of ethanol per volume of water). xviii) In particular, the process of embodiment xvi) above will be such that the organic solvent or organic solvent mixture optionally mixed with water containing the mixture of (i?)-6,7-dimethoxy-l-[2-(4-trifluoromethyl-phenyl)-ethyl]-l,2,3,4-tetrahydro-isoquinoline and (5)-6,7-dimethoxy- 1 -[2-(4-trifluoromethyl-phenyl)-ethyl]- 1 ,2,3 ,4-tetrahydro- isoquinoline will be a mixture of acetone, ethanol and water, whereby acetone, ethanol and water are mixed in a proportion of at least 9 volumes of acetone per volume of water and per volume of ethanol (and preferably such that said organic solvent or organic solvent mixture optionally mixed with water will be a mixture of acetone, ethanol and water which contains about 9 volumes of acetone and about 1 volume of ethanol per volume of water):. xix) Preferably, the organic solvent or organic solvent mixture(s) used in the process according to one of embodiments i) to xviii) above will have a boiling temperature T_B of at least 40⁰C (and in particular of at least 50⁰C). xx) Preferably, the temperature T used in step a) or step d) of the process according to one of embodiments i) to xix) above will be close to the boiling temperature T_B of the organic solvent or organic solvent mixture(s) optionally mixed with water used in said step, that is, between 0 and 10⁰C below T_B. xxi) In a general manner, step b) and step e) of the process according to one of embodiments i) to xx) above will be such that the time until the mixture obtained at step a) or d) reaches the cooling down temperature is not more than 24 hours, preferably not more than 16 hours, more preferably not more than 5 hours and in particular not more than 3 hours. xxii) Preferably, the cooling down temperature used at step b) or step e) of the process according to one of embodiments i) to xxi) above will be a temperature that is at least 20⁰C or 25°C lower, and in particular at least 30⁰C or 40⁰C lower, than the temperature T of step a) or step d) (and especially such a temperature that would be around room temperature). xxiii) Preferably, the base used in step c) or f) of the process according to one of embodiments i) to xxii) above will be selected from NaOH, KOH, LiOH, Ca(OH)₂, NaOMe, NaOEt, Na₂CO₃ and K₂CO₃. xxiv) More preferably, the base used in step c) or f) of the process according to one of embodiments i) to xxii) above will be selected from NaOH, KOH, LiOH and Ca(OH)₂ (and in particular from NaOH and KOH). xxv) According to a particular embodiment of this invention, the removal of possibly remaining compound of formula I or compound of formula F at step c) or at step f) of the process according to one of embodiments i) to xxiv) above is performed by an acid/base extraction procedure. xxvi) In a general manner, the quantity of compound of formula I or of compound of formula F used in step a) or in step d) of the process according to one of embodiments i) to xxv) above will preferably be from 0.9 to 1.6 equivalents (and in particular be from 1 to 1.4 equivalents) of compound of formula I or of compound of formula F per equivalent of (5)-6,7-dimethoxy-l-[2-(4-trifluoromethyl-phenyl)-ethyl]-l,2,3,4-tetrahydro-isoquinoline present in the mixture of (i?)-6,7-dimethoxy-l-[2-(4-trifluoromethyl-phenyl)-ethyl]- 1 ,2,3 ,4-tetrahydro-isoquinoline and (5)-6,7-dimethoxy- 1 -[2-(4-trifluoromethyl-phenyl)- ethyl]- 1 ,2,3 ,4-tetrahydro-isoquinoline. xxvii) According to another particular embodiment of this invention, the process according to one of embodiments i) to xxvi) above is followed by a recycling step, during which the enantiomerically enriched (i?)-6,7-dimethoxy- 1 -[2-(4-trifluoromethyl-phenyl)-ethyl]-

1,2,3,4-tetrahydro-isoquinoline contained in the filtrate collected after step b) or in the crystalline salt collected after step e) are converted into 6,7-dimethoxy- l-[2-(4-trifluoromethyl-phenyl)-ethyl]-3,4-dihydro-isoquinoline before being reduced into a mixture of (i?)-6,7-dimethoxy-l-[2-(4-trifluoromethyl-phenyl)-ethyl]- 1,2,3, 4-tetrahydro- isoquinoline and (5)-6,7-dimethoxy- 1 -[2-(4-trifluoromethyl-phenyl)-ethyl]-

1 ,2,3 ,4-tetrahydro-isoquinoline. xxviii) Preferably, in the recycling step of the process according to embodiment xxvii), the conversion into 6,7-dimethoxy- 1 -[2-(4-trifluoromethyl-phenyl)-ethyl]-3 ,4-dihydro- isoquinoline is carried out by reaction with either JV-chloro-succinimide under protection from light or NaOCl (and notably by reaction with NaOCl). xxix) According to a particular embodiment of this invention, the process according to embodiment xxvii) or xxviii) above will be such that the reduction step is carried out either by reaction with NaBH₄ or by catalytic hydrogenation (the catalyst used for this catalytic hydrogenation reaction being notably Pd/C). xxx) According to a particular embodiment of this invention, if the enantiomeric excess obtained for the product of the process according to one of embodiments i) to xxix) above is found to be insufficient, said process may be repeated once or twice to improve the enantiomeric excess.

The process according to the invention can be carried out using the general methods described hereafter.

GENERAL METHODS ACCORDING TO THE INVENTION

Abbreviations:

The following ; abbreviations are used throughout the specificatii aq. aqueous

CDI 1 , 1 ' -carbonyldiimidazole cone. concentrated

DCM dichloromethane

DEA diethylamine

DMF Λ/,Λ/-dimethylformamide

EA ethyl acetate e.e. enantiomeric excess eq. equivalent(s) e.r. enantiomeric ratio

Et ethyl ether diethyl ether

HPLC high performance liquid chromatography IT internal temperature iPrOH isopropanol

LOD loss on drying

Me methyl

MeCN acetonitrile

MEK methyl ethyl ketone (2-butanone)

MeOH methanol

MIBK methyl isobutyl ketone (4-methyl-2-pentanone) mol% % in mol

MS Mass Spectroscopy

NBS Λ/-bromosuccinimide

NCS JV-chlorosuccinimide org. organic

Pd/C palladium on charcoal prep. preparative

PTSA /?-toluenesulfonic acid monohydrate

RT room temperature

TBME tert-butyl methyl ether

TFA trifluoroacetic acid

THF tetrahydrofuran

TLC thin layer chromatography wt% % in weight

Preparation of the < compounds of formula I and the compounds of formula F:

The compounds of formula I and the compounds of formula F used in the invention process can be manufactured by standard methods well known to one skilled in the art.

For example, the compounds of formula I can be prepared according to the method summarised in Scheme 1 hereafter.

I

Scheme 1

In Scheme 1, Ar is a phenyl group substituted, in addition to the NH₂ group, with the R group as defined in formula I.

The reaction of the substituted aniline with acetic acid (J5',45)-4-acetoxy-2,5-dioxo- tetrahydro-furan-3-yl ester (obtained for example by reaction of D-(-)-tartaric acid with acetyl chloride or acetic anhydride in heated toluene) can notably be carried out in a solvent like DCM at a temperature preferably above RT (e.g. about 40⁰C). Subsequent cleavage of the ester groups can be performed by reacting the obtained intermediate with a base like KOH in a solvent like water.

The compounds of formula F can be prepared according to the method summarised in Scheme 2 hereafter.

I¹ Scheme 2

In Scheme 2, Ar is a phenyl group substituted, in addition to the NH₂ group, with the R group as defined in formula F.

The reaction of the substituted aniline with acetic acid (3i?,4i?)-4-acetoxy-2,5-dioxo- tetrahydro-furan-3-yl ester (obtained for example by reaction of L-(+)-tartaric acid with acetyl chloride or acetic anhydride in heated toluene) can notably be carried out in a solvent like DCM at a temperature preferably above RT (e.g. about 40⁰C). Subsequent cleavage of the ester groups can be performed by reacting the obtained intermediate with a base like KOH in a solvent like water. _.Resp_.lution_.Erpcess_.according to_.the _.invention:

According to this invention, a process for obtaining enantiomerically enriched (5)-6,7-dimethoxy-l-[2-(4-trifluoromethyl-phenyl)-ethyl]-l,2,3,4-tetrahydro-isoquinoline from a mixture of (i?)-6,7-dimethoxy-l-[2-(4-trifluoromethyl-phenyl)-ethyl]- 1, 2,3, 4-tetrahydro-isoquino line and (5)-6,7-dimethoxy-l-[2-(4-trifluoromethyl-phenyl)- ethyl]-l,2,3,4-tetrahydro-isoquinoline can be carried out, which process comprises the following sequential steps: either a) bringing to a given temperature T which may be up to the boiling temperature of the organic solvent(s) and optionally present water, a mixture of (7?)-6,7-dimethoxy- l-[2-(4-trifluoromethyl-phenyl)-ethyl]-l,2,3,4-tetrahydro-isoquinoline and

(iS)-6,7-dimethoxy- 1 -[2-(4-trifluoromethyl-phenyl)-ethyl]- 1 ,2,3 ,4-tetrahydro- isoquinoline in an organic solvent or organic solvent mixture optionally mixed with water, to which mixture is added a compound of formula I

I wherein R is nitro, methyl or methoxy, whereby the compound of formula I may be added as a solid or as a solution or a suspension either in the same organic solvent or organic solvent mixture optionally mixed with water as the one used for the enantiomer mixture or in a different organic solvent or organic solvent mixture optionally mixed with water, whereby the conditions are such that any solid components are dissolved in the organic solvent(s) and optionally present water; b) cooling down the solution obtained after step a) to atemperature that is at least 15°C lower than T and collecting the crystallised salt formed; and c) treating the crystallised salt collected at step b) with a base to obtain enantiomerically enriched (5)-6,7-dimethoxy-l-[2-(4-trifluoromethyl-phenyl)-ethyl]-l,2,3,4-tetrahydro- isoquinoline; or d) bringing to a given temperature T which may be up to the boiling temperature of the organic solvent(s) and optionally present water, a mixture of (7?)-6,7-dimethoxy- l-[2-(4-trifluoromethyl-phenyl)-ethyl]-l,2,3,4-tetrahydro-isoquinoline and

(iS)-6,7-dimethoxy- 1 -[2-(4-trifluoromethyl-phenyl)-ethyl]- 1 ,2,3 ,4-tetrahydro- isoquinoline in an organic solvent or organic solvent mixture optionally mixed with water, to which mixture is added a compound of formula F

I' wherein R is nitro, methyl or methoxy, whereby the compound of formula F may be added as a solid or as a solution or a suspension either in the same organic solvent or organic solvent mixture optionally mixed with water as the one used for the enantiomer mixture or in a different organic solvent or organic solvent mixture optionally mixed with water, whereby the conditions are such that any solid components are dissolved in the organic solvent(s) and optionally present water; e) cooling down the solution obtained after step d) to a temperature that is at least 15⁰C lower than T and removing the crystallised salt formed, thus obtaining a solution of enantiomerically enriched (5)-6,7-dimethoxy-l-[2-(4-trifluoromethyl-phenyl)-ethyl]-

1, 2,3, 4-tetrahydro-isoquino line and possibly remaining compound of formula F in the organic solvent or organic solvent mixture optionally mixed with water; and f) removing the organic solvent or organic solvent mixture optionally mixed with water and treating the residue thus obtained with a base to obtain, after removal of possibly remaining compound of formula F, enantiomerically enriched (5)-6,7-dimethoxy- l-[2-(4-trifluoromethyl-phenyl)-ethyl]-l,2,3,4-tetrahydro-isoquinoline.

Should the same organic solvent or organic solvent mixture optionally mixed with water be used for step a) or step d) of the process above, then said organic solvent or organic solvent mixture optionally mixed with water may in particular be EA, THF, MEK, acetone or a mixture of acetone with EtOH, each of these organic solvents or organic solvent mixtures being preferably mixed with water in a proportion of a least 10 volumes of organic solvent per volume of water. Should different organic solvents or organic solvent mixtures optionally mixed with water be used for step a) or step d) of the process above, then: 1) the organic solvent or organic solvent mixture optionally mixed with water containing the mixture of enantiomers can be selected from THF and acetone, whereby said THF or acetone is mixed with water in a proportion of a least 10 volumes of THF or acetone per volume of water; and 2) the organic solvent or organic solvent mixture optionally mixed with water containing the compound of formula I can be THF, whereby said THF is mixed with water in a proportion of a least 3 volumes of THF per volume of water, it being understood that if for both the mixture of enantiomers and the compound of formula I or the compound of formula F the organic solvent is tetrahydrofurane, then the proportion of water optionally added is different.

Should the compound of formula I or the compound of formula F be added as a solid in step a) or step d) of the process above, then the organic solvent or organic solvent mixture optionally mixed with water containing the mixture of (7?)-6,7-dimethoxy- 1 -[2-(4-trifluoromethyl-phenyl)-ethyl]- 1 ,2,3 ,4-tetrahydro-isoquino line and

(5)-6,7-dimethoxy-l-[2-(4-trifluoromethyl-phenyl)-ethyl]-l,2,3,4-tetrahydro-isoquinoline can be a mixture of 4-methyl-2-pentanone and water, whereby 4-methyl-2-pentanone can be mixed with water in a proportion of a least 10 volumes of 4-methyl-2-pentanone per volume of water. Preferably, the quantity of compound of formula I or of compound of formula F used in step a) or in step d) of the process above will be from 0.9 to 1.5 equivalents of compound of formula I or of compound of formula F per equivalent of (5)-6,7-dimethoxy- l-[2-(4-trifluoromethyl-phenyl)-ethyl]-l, 2,3, 4-tetrahydro-isoquino line present in the mixture of (7?)-6,7-dimethoxy- 1 -[2-(4-trifluoromethyl-phenyl)-ethyl]- 1 ,2,3 ,4-tetrahydro- isoquinoline and (5)-6,7-dimethoxy-l-[2-(4-trifluoromethyl-phenyl)-ethyl]-

1,2, 3, 4-tetrahydro-isoquino line. The quantity of (5)-enantiomer present in the mixture can be determined by one skilled in the art using standard methods (e.g. measurement of rotatory power of the mixture and comparison with a known reference).

Preferably, the organic solvent or organic solvent mixture(s) used in the process above will have a boiling temperature of at least 40⁰C (and in particular of at least 50⁰C).

Preferably also, the mixture obtained at step a) or at step d) is heated at or close to the reflux temperature of the organic solvent or organic solvent mixture optionally mixed with water. In particular, if T_B is the boiling temperature of the organic solvent or organic solvent mixture(s) optionally mixed with water used in said step, the temperature used in step a) or step d) of the process will preferably be between 0 and 10⁰C below T_B.

Besides, the time until the mixture obtained at step a) or at step d) reaches the cooling down temperature should preferably not be more than 24 hours.

Moreover, the cooling down temperature used at step b) or step e) of the process above will preferably be a temperature that is at least 20⁰C or 25°C lower, and in particular at least 30⁰C or 40⁰C lower, than the temperature of step a) or the temperature of step d). Preferred embodiments will be such that the cooling down temperature used at step b) or step e) of the process above will be around RT.

If the enantiomeric excess obtained for the product of the resolution process according to the invention is found to be insufficient, said process may be repeated one or twice.

Preferably, the base used in step c) or step f) will be a stong base, for example NaOH, KOH, LiOH, Ca(OH)₂, NaOMe, NaOEt, Na₂CO₃ or K₂CO₃ (and in particular NaOH or KOH).

The separation of the (5)-6,7-dimethoxy-l-[2-(4-trifluoromethyl-phenyl)-ethyl]- 1,2,3,4-tetrahydro-isoquinoline from the compound of formula I or the compound of formula F can be carried out for example by chromatography over silica gel or using acid/base extraction methods known to one skilled in the art. Recycling _.process _.accprding to the invention _:

In order to increase the yield of the resolution process described above in the (iS)-enantiomer of 6,7-dimethoxy-l-[2-(4-trifluoromethyl-phenyl)-ethyl]-

1,2,3,4-tetrahydro-isoquinoline, it is possible to combine this resolution process with a recycling step as described in this section. In this recycling step, the (R)- and (S)- enantiomers of 6,7-dimethoxy- l-[2-(4-trifluoromethyl-phenyl)-ethyl]-l, 2,3, 4-tetrahydro-isoquino line contained in the filtrate collected after step b) are converted into 6,7-dimethoxy-l-[2-(4-trifluoromethyl- phenyl)-ethyl]-3,4-dihydro-isoquinoline before being reduced into an almost racemic mixture of (i?)-6,7-dimethoxy- 1 -[2-(4-trifluoromethyl-phenyl)-ethyl]- 1 ,2,3 ,4-tetrahydro- isoquinoline and (5)-6,7-dimethoxy-l-[2-(4-trifluoromethyl-phenyl)-ethyl]-

1 ,2,3 , 4-tetrahydro-isoquino line. Accordingly, in order to achieve conversion of the (R)- and (S)- enantiomers of 6,7-dimethoxy-l-[2-(4-trifluoromethyl-phenyl)-ethyl]-l,2,3,4-tetrahydro-isoquinoline into 6,7-dimethoxy-l-[2-(4-trifluoromethyl-phenyl)-ethyl]-3,4-dihydro-isoquinoline, the filtrate collected after step b) (rich in (i?)-6,7-dimethoxy-l-[2-(4-trifluoromethyl-phenyl)-ethyl]- 1,2,3,4-tetrahydro-isoquinoline) can be treated either with NCS under protection from light at a temperature of about 25°C in a solvent such as ether or with an aqueous NaOCl solution at a temperature between 10 and 30⁰C in a solvent such as DCM.

The reduction of 6,7-dimethoxy-l-[2-(4-trifluoromethyl-phenyl)-ethyl]-3,4-dihydro- isoquinoline can be achieved either by reaction with NaBH₄ or by catalytic hydrogenation. Catalysts that can be used for the catalytic hydrogenation include notably Pd/C. After this reduction step, almost racemic 6,7-dimethoxy-l-[2-(4-trifluoromethyl-phenyl)-ethyl]- 1,2,3,4-tetrahydro-isoquinoline is obtained.

Particular embodiments of the invention are described in the following Examples, which serve to illustrate the invention in more detail without limiting its scope in any way.

EXAMPLES

Column chromatography was performed on silica gel.

The compounds synthesised were characterised by ¹H-NMR or by chiral HPLC. Regarding ¹H-NMR (300 MHz: Varian Oxford or 400 MHz: Bruker Avance): the chemical shifts are given in ppm relative to the solvent used; - the multiplicities are mentioned as follows: s = singlet, d = doublet, t = triplet; q = quartet, m = multiplet, b = broad; the coupling constants J are given in Hz.

.?r.?Mr.?t|ons i.A . to .⁽C:...preparation Mp.P.WPPMds.of.fP.ζHϊ.u.l.?. !.'.-

General procedure for Preparations A to C: A solution of (+)-di-O-acetyl-L-tartaric anhydride (10.0 mmol) in DCM (1O mL) was added dropwise to a solution of the respective aniline derivative (11.0 mmol) in DCM (5.0 mL). The mixture was heated in a closed vial to 39°C (external temperature), stirred for 24 h and cooled to RT. A solution of KOH (32 mmol) in water (20 mL) was added, the layers were separated and the org. layer was extracted once with water (1O mL). The combined aq. layers were stirred for 2 h at RT and made acidic by dropwise addition of cone. HCl (3.5 mL). The obtained precipitate was filtered off and recrystallized from water to give the respective tartranilic acid derivative. Yields might be improved by further work-up of the aq. filtrate (due to the solubility of tartranilic acids in water).

Preparation A: (2R,3R)-2,3-dihydroxy-7V-(2-nitro-phenyl)-succinamic acid:

The title compound was obtained with 28% yield by reaction of (+)-di-O-acetyl-L-tartaric anhydride with 2-nitroaniline followed by recrystallisation from water (30 mL). 1H-NMR (DMSO-de) δ: 4.43 (m, 2H); 7.32 (ddd, J = 8.5, 7.2 Hz, 1.3 Hz, IH); 7.78 (ddd, J = 8.6, 7.1, 1.5 Hz, IH); 8.18 (dd, J = 8.4 Hz, 1.5 Hz, IH); 8.62 (dd, J = 8.4, 1.2 Hz, IH); 11.15 (s, IH).

Preparation B: (2R,3/f)-2,3-dihydroxy-7V-o-tolyl-succinamic acid:

B.I. First preparation method based on the general procedure described above:

The title compound was obtained with 27% yield by reaction of (+)-di-O-acetyl-L-tartaric anhydride with o-toluidine. Precipitation was however observed only after concentration of the aq. layer in vacuo to a volume of about 20 mL and no recrystallisation from water was carried out.

¹H-NMR (DMSO-de) δ: 2.22 (s, 3H); 4.41 (m, 2H); 7.05 (ddd, J = 7.4, 7.4, 1.1 Hz, IH); 7.18 (m, 2H); 7.70 (d, J = 7.2 Hz, IH); 9.02 (s, IH).

B.2. Second preparation method:

A solution of (+)-di-O-acetyl-L-tartaric anhydride (lOO mmol) in DCM (10O mL) was added to a solution of o-toluidine (110 mmol) in DCM (50 mL) at a rate to keep the DCM slightly refluxing. The mixture was stirred for 20 h, added to a solution of KOH (320 mmol) in water (200 mL) and shaken vigorously. The layers were separated and the org. layer was extracted once with water (100 mL). The combined aq. layers were stirred for 2 h at RT and made acidic by dropwise addition of cone. HCl (35 mL). Water (270 mL) was distilled off at 80⁰C, the mixture was cooled to RT and a seed crystal was added. After cooling to 4°C the obtained precipitate was filtered off and washed with TBME (80 mL). THF (500 mL) was added to the solid material, the suspension was filtered and the residue was washed with additional THF (250 mL). The filtrate was concentrated in vacuo to give the desired product (59 mmol) as a white powder. A second crop could be obtained in the following manner: acetone (40 mL) was added to the mother liquor, the suspension was filtered, the layers of the filtrate were separated and the org. layer was concentrated in vacuo; the residue was diluted with EA (50 mL) and water (100 mL), the layers were separated, the org. layer was extracted with water (100 mL), the combined aq. layers were concentrated in vacuo to a volume of 20 mL and the precipitate obtained was filtered off to give additional product (11.3 mmol). 1H-NMR (DMSO-de) δ: similar to that obtained for the product of B.1.

Preparation C: (2R,3R)-2,3-dihydroxy-7V-(2-methoxy-phenyl)-succinamic acid:

The title compound was obtained with 6% yield by reaction of (+)-di-O-acetyl-L-tartaric anhydride with o-anisidine followed by recrystallisation from water (5 mL). 1H-NMR (DMSO-d₆) δ: 3.86 (s, 3H); 4.40 (m, 2H); 6.92 (ddd, J = 8.2, 5.1, 3.3 Hz, IH); 7.85 (m, 2H); 8.31 (d, J = 7.6 Hz, IH); 9.24 (s, IH).

.?.r.^eP.?J.?t|on_I);___p_reparatioη qf a.cpmpound of formula I:

Preparation D: (2S,3S)-2,3-dihydroxy-7V-o-tolyl-succinamic acid:

DA. Acetic acid (3S,4S)-4-acetoxy-2,5-dioxo-tetrahydro-furan-3-yl ester:

Method_.1 :

A suspension of D-(-)-tartaric acid (33.3 mmol) in toluene (40 mL) was heated to 60⁰C and treated dropwise with acetyl chloride (133 mmol). The mixture was heated to reflux for 18 h and cooled slowly to 0⁰C. The obtained precipitate was filtered off to give 6.36 g of the desired product which was contaminated with an unknown, minor impurity. 1H-NMR (DMSO-d₆) δ: 2.17 (s, 6H); 6.27 (s, 2H).

Method_.2: PTSA (1.33 mmol) was added to a suspension of D-(-)-tartaric acid (133 mmol) in toluene (10O mL). The mixture was heated to 80⁰C, treated dropwise with acetic anhydride (533 mmol), stirred for additional 5 h and cooled to 0⁰C. The obtained precipitate was filtered off, washed twice with toluene (10 mL each) and dried in vacuo to give the desired product as a colourless solid (24.7 g, 85% yield). ¹H-NMR (CDCl₃) δ: 2.24 (s, 6H); 5.69 (s, 2H).

Method 3:

A 400 L glass lined reaction vessel was charged with toluene (200 L), D-(-)-tartaric acid (25.00 kg, 167 mol, 1.0 eq.) and PTSA (316.3 g, 1.67 mol, 0.01 eq.) at IT = 20⁰C and the suspension was heated to IT = 80 ⁰C. Acetic anhydride (62 L, 666 mol, 4 eq.) was added within 80 min, resulting in a clear orange solution. The solution was reacted at IT = 80⁰C for 3 h. The reaction mixture was cooled to IT = 30⁰C within 2 h and to IT = 1°C within further 3 h. The obtained suspension was stirred at this temperature for 1 h and filtered within 30 min. The filter cake was rinsed twice with pre-cooled (1-5°C) toluene (16.5 L each). The reactor was charged with THF (125 L) and cooled to IT = 20⁰C. The product was dissolved with THF yielding overall 150 L solution of acetic acid (3S,4S)-4-acetoxy- 2,5-dioxo-tetrahydro-furan-3-yl ester in THF. A sample was taken and the yield was determined by LOD (29.9 kg, 83% yield). 1H-NMR (CDCl₃) δ: 2.24 (s, 6H); 5.68 (s, 2H). DM. (2S,3S)-2,3-diαcetoxy-N-o-tolyl-succinαmic acid:

Method_.1 :

A slightly turbid solution of intermediate Di (7.0 g, 32.3 mmol) in toluene (35 mL) and DCM (35 mL) was treated with o-toluidine (3.64 g, 34.0 mmol). After 10 min, a precipitation was observed and the suspension was stirred for additional 16 h. The precipitate was filtered off to give the desired product (9.44 g, 90% yield).

Method_.2:

At 20⁰C a slightly turbid solution of intermediate Di (619 g, 2.86 mol) in toluene (1.86 L) and DCM (3.7 L) was treated with o-toluidine (322 g, 3.0 mol). After the addition had been finished, the resulting clear solution was stirred for 210 min at 20⁰C while the product precipitated. The mixture was diluted with toluene (1.86 L), stirred for additional 1O h, cooled to 1°C within 2 h and stirred for additional 60 min at 1°C. The precipitate was filtered off, washed twice with toluene (2 x 550 mL) and dried in vacuo to give the desired product (752 g, 81% yield). 1H-NMR (DMSO-de) δ: 2.11 (s, 3H); 2.12 (s, 3H), 2.15 (s, 3H); 2.15 (s, 3H); 5.66 (m, 2H); 7.17 (m, 3H); 7.25 (m, IH); 9.74 (s, IH); 13.73 (br. s, IH). M_.ethod 3:

A 640 L enameled reaction vessel was charged with a solution of intermediate Di

(118 mol, 0.0941 kg/kg solution) in DCM (271 kg solution). The solution was concentrated by distilling off DCM (32 L) under reduced pressure (530 mbar) at an IT of 25°C. The reaction mixture was diluted with toluene (70 L). At an IT of 20 to 22°C, o-toluidine

(121 mol, 12.9 kg) was added over a period of 25 min. The mixture was stirred for 225 min at 22°C. The obtained suspension was diluted with toluene (75 L), stirred for further 1O h, cooled to IT = 1°C over 2 h and stirred for further 2 h at IT = 1°C. The precipitate was filtered off, washed with cold toluene (44 L, 1°C) and dried to give the desired product as an off white powder (103 mol, 33.2 kg, 87% yield).

¹H-NMR (DMSO-de) δ: 2.11 (s, 3H); 2.12 (s, 3H); 2.15 (s, 3H); 5.66 (m, 2H); 7.17 (m, 3H); 7.23 (m, IH); 9.73 (s, IH); 13.73 (bs, IH).

D. Ui. (2S,3S)-2,3-dihydroxy-N-o-tolyl-succinamic acid:

Method_.1 : A suspension of intermediate D. ii (40O g, 1.24 mol) in water (2.8 L) was treated portionwise with KOH (270 g, 4.8 mol). The obtained clear solution was stirred for 2 h and made acidic by addition of cone. HCl (32%, 640 mL). EA (2.4 L) was added, the layers were separated and the aq. layer was extracted 4 times with EA (4 x 2.4 L). The combined org. layers were concentrated to a final volume of 2.6 L and diluted with toluene (3.0 L). Additional solvents (3.0 L) were distilled off and further toluene (2.0 L) was added to the residual mixture. The suspension was filtered and the residue was dried in vacuo to give the desired product (267 g, 88% yield).

¹H-NMR (DMSO-de) δ: 2.22 (s, 3H); 4.41 (m, 2H); 7.06 (ddd, IH); 7.20 (m, 2H); 7.72 (d, IH); 9.05 (s, IH). Method 2:

An enamelled reaction vessel was charged with water (350 L) and intermediate D.ii (49.8 kg, 154 mol). To the resulting suspension was added portionwise KOH (33.7 kg, 600 mol) over a period of 70 min (IT = 20-22⁰C). The reaction mixture was stirred for 21 h at IT = 20⁰C and made acidic by addition of HCl (32%, 80 L) via inlet vessel over 50 min and external cooling (IT = 17-20⁰C). EA (304 L) was added, the biphasic system was intensively stirred for 25 min and the layers were separated. The aq. layer was extracted additional 4 times at IT = 20⁰C with EA (4 x 300 L) and the combined org. layers were concentrated (jacket temperature 40-45⁰C, P < 200 mbar) to about l/5th of the original volume. Toluene (380 L) was added to the mixture and solvents (380 L) were distilled off. Additional toluene (250 L) was added and solvents (250 L) were distilled off. The suspension was filtered and the residue was dried within 16 h in a stream of nitrogen. The desired product was obtained as an off white powder (27.7 kg, 75% yield).

¹H-NMR (DMSO-de) δ: 2.22 (s, 3H); 4.41 (m, 2H); 7.06 (ddd, IH); 7.20 (m, 2H); 7.72 (d, IH); 9.05 (s, IH).

Method 3:

A 640 L enamelled reaction vessel was charged with a solution of intermediate D.i (29.9 kg, 138 mol) in THF (149 L). At an IT between 20⁰C to 25°C, o-toluidine (15.6 kg, 145 mol) was added via an inlet vessel over a period of 45 min. The mixture was stirred for 95 min at IT = 22°C and concentrated by distilling off THF (63 L) at IT = 25°C (jacket temperature: 40-45⁰C, pressure: 300 mbar, 5 h). Water (156 L) was added and the mixture was concentrated by distilling off solvent (60 L) at an IT = 25°C (jacket temperature: 40-45⁰C, pressure: 150 mbar, 7 h). Water (156 L) was added at IT = 24°C and the resulting suspension was treated portionwise with KOH (15.1 kg, 268 mol) over a period of 47 min. The reaction mixture was then stirred for 10 min at IT = 20⁰C and treated portionwise with additional KOH (15.0 kg, 268 mol) over a period of 20 min (IT = 21-22.5°C). The reaction mixture was stirred for 2 h at 20⁰C and diluted with methylcyclohexane (55 L). The biphasic system was stirred for 10 min, the layers were separated and the aq. layer was acidified by addition of H₂SO₄ (50%, 73 L) over 35 min with external cooling (IT = 20-22⁰C). EA (100 L) was added, the mixture was intensively stirred for 5 min, the layers were separated and the aq. layer was extracted additional nine times with EA (9 x 100 L). The combined org. layers were concentrated by distilling off EA (828 L) at IT = 25°C (jacket temperature: 40-45⁰C, pressure: 120 mbar). Toluene (332 L) was added and the mixture was concentrated by distilling off solvents (332 L) at IT = 30⁰C (jacket temperature: 40-45⁰C, pressure: 70 mbar). Additional toluene (210 L) was added, the suspension was filtered and the residue was washed with toluene (28 L) and dried in vacuo within 16 h in a stream of nitrogen. The desired product was obtained as an off-white powder (31.9 kg, 96% yield).

¹H-NMR (DMSO-de) δ: 2.22 (s, 3H); 4.40 (m, 2H); 7.06 (ddd, J = 7.4, 7.4, 1.1 Hz, IH); 7.19 (m, 2H); 7.71 (d, J = 7.2 Hz, IH); 9.05 (s, IH). ?r.ep.arat|pns i E .to.H: ...comparison .resolution. agent candidates: Preparation E: (2R,3R)-7V-(2-chloro-phenyl)-2,3-dihydroxy-succinamic acid:

Using the "General procedure for Preparations A to C", the title compound was obtained with 25% yield by reaction of (+)-di-O-acetyl-L-tartaric anhydride with 2-chloroaniline followed by recrystallisation from water (30 mL).

¹H-NMR (DMSO-de) δ: 4.43 (m, 2H); 7.13 (ddd, 1 = 1.1, 1.1, 1.5 Hz, IH); 7.35 (ddd, J = 7.8, 7.8, 1.4 Hz, IH); 7.51 (dd, J = 8.0, 1.4 Hz, IH); 8.32 (dd, J = 8.2, 1.5 Hz, IH); 9.39 (s, IH).

Preparation F: (2R,3R)-7V-(3-chloro-phenyl)-2,3-dihydroxy-succinamic acid: Using the "General procedure for Preparations A to C", the title compound was obtained with 33% yield by reaction of (+)-di-O-acetyl-L-tartaric anhydride with 3-chloroaniline followed by recrystallisation from water (20 mL).

¹H-NMR (DMSO-d₆) δ: 4.40 (m, 2H); 7.10 (ddd, J = 7.9, 2.0, 0.85 Hz, IH); 7.32 (dd, J = 8.1, 8.1 Hz, IH); 7.63 (ddd, J = 8.2, 1.8, 0.8 Hz, IH); 7.93 (dd, J = 2.0, 2.0 Hz, IH); 9.80 (s, IH).

Preparation G: (2R,3/?)-7V-(4-chloro-phenyl)-2,3-dihydroxy-succinamic acid:

Using the "General procedure for Preparations A to C", the title compound was obtained with 52% yield by reaction of (+)-di-O-acetyl-L-tartaric anhydride with 4-chloroaniline followed by recrystallisation from water (40 mL). 1H-NMR (DMSO-de) δ: 4.39 (m, 2H); 7.34 (d, J = 8.9 Hz, 2H); 7.76 (d, J = 8.9 Hz, 2H); 9.74 (s, IH).

Preparation H: (2R,3R)-7V-(2-carbamoyl-phenyl)-2,3-dihydroxy-succinamic acid:

Using the "General procedure for Preparations A to C", the title compound was obtained with 51% yield by reaction of (+)-di-O-acetyl-L-tartaric anhydride with 2-aminobenzonitrile. Precipitation was however observed only after concentration of the aq. layer in vacuo to a volume of about 20 mL and no recrystallisation from water was carried out.

¹H-NMR (DMSO-de) δ: 4.38 (m, 2H); 7.11 (ddd, J = 7.6, 7.6, 1.1 Hz, IH); 7.47 (ddd, J = 8.5, 7.1, 1.4 Hz, IH); 7.56 (bs, IH, NH); 7.73 (dd, J = 7.8, 1.4 Hz, IH); 8.13 (bs, IH, NH); 8.61 (dd, J = 8.3, 0.8 Hz, IH); 12.03 (s, IH). F. reparation I : preparation_, of .the. enantiomeric .mixture to be separated:.

Preparation I: rac-6,7-dimethoxy-l-[2-(4-trifluoromethyl-phenyl)-ethyl]-

1,2,3,4-tetrahydro-isoquinoline:

Li. 3-(4-trifluoromethyl-phenyl)-propionic acid: Method_.1 :

A mixture of 4-(trifluoromethyl)cinnamic acid (commercially available, 10.0 g, 46.3 mmol) and Pd/C (10 wt%, 250 mg) in EtOH (100 mL) was stirred under a hydrogen atmosphere (6 bar) for 21 h. After filtration through Celite and removal of the solvents in vacuo, the desired product was obtained as a white solid (10.1 g, 46.1 mmol, 100% yield). ¹H-NMR (CDCl₃) δ: 2.73 (t, J = 7.6 Hz, 2H); 3.03 (t, J = 7.6 Hz, 2H); 7.33 (d, J = 8.0 Hz, 2H); 7.56 (d, J = 8.1 Hz, 2H).

Method_.2:

A 400 L enameled reaction vessel was charged with 4-(trifluoromethyl)cinnamic acid

(40.1 kg, 185 mol) and THF (200 L). After stirring for 25 min, Pd/C (5 wt%, water damp -50%, 0.99 kg) was added at IT = 20⁰C. The mixture was hydrogenated under hydrogen atmosphere (1225 mbar) for 15 h at IT = 20-23⁰C. The mixture was filtered off over a Nutsch filter followed by an inline filter. The filter cake was washed with THF (25 L). The filtrates were transferred into a 640 L enameled reactor and concentrated by distilling off the solvent (206 L) at an external temperature of 40°C-50°C (IT = 26-43°C, pressure: 200 mbar). DCM (50 L) was added and the solution concentrated by distilling off the solvent (25 L) at IT = 30⁰C (jacket temperature: 40-45⁰C, pressure: 670 mbar). The reaction mixture was stripped 3 times by addition of DCM (3 x 25 L) and distillation of solvent (25, 26, 25 L) at IT = 27-30⁰C O^'acket temperature: 40-45⁰C, pressure: 580-600 mbar). DCM (235 L) was added and the solution was used in the next step (Preparation I, step I.iii, method 2) without further purification.

¹H-NMR (DMSO-d₆) δ: 2.60 (t, 2H); 2.92 (t, 2H); 7.33 (d, 2H); 7.47 (d, 2H); 12.23 (s, IH).

Method_.3:

A solution of 4-trifluoromethylcinnamic acid in MeOH is hydrogenated with Pd/C (5 wt%) at 2 bar until 4-trifluoromethylcinnamic acid has reacted completely. After removal of the catalyst by filtration, the 4-trifluoromethylhydrocinnamic acid was further reacted in the next step (Preparation I, step I.ii, method 2) without further purification. 1H-NMR (CDCl₃) δ: 7.5 (d, J = 8.0 Hz, 2H), 7.3 (d, J = 8.0 Hz, 2H), 3.0 (t, J = 7.6 Hz, 2H), 2.7 (t, J = 7.6 Hz, 2H). I.ii. 3-(4-trifluoromethyl-phenyl)-propionic acid methyl ester:

Method_.1 :

Caesium carbonate (19.0 g, 58.3 mmol) was added in one portion to a solution of intermediate Li (10.2 g, 46.8 mmol) in anhydrous DMF (150 ml). The suspension was stirred at RT for 15 min, cooled to 0⁰C and treated dropwise with iodomethane (4.4 mL, 70.5 mmol). The mixture was stirred at 0⁰C for 10 min and at RT for 18 h. EA (400 mL), water (300 mL), and brine (100 mL) were added to the reaction mixture and the layers were separated. The org. layer was washed with a mixture of water (100 mL) and brine (10O mL), dried over anhydrous MgSO₄, filtered and concentrated to dryness under reduced pressure to give a yellow oil which was purified by flash chromatography (DCM/MeOH 200/1). The desired product was obtained as a slightly yellow oil (10.7 g, 98% yield).

¹H-NMR (CDCl₃) δ: 2.66 (t, J = 7.5 Hz, 2H), 3.01 (t, J = 7.8 Hz, 2H), 3.67 (s, 3H), 7.32 (d, J = 7.8 Hz, 2H), 7.54 (d, J = 7.8 Hz, 2H).

Method_.2: To a solution of intermediate Li in MeOH (as obtained in Preparation I, step Li, method 3) was added 5 mol% sulfuric acid and heated. The formed water was distilled off together with MeOH until the esterification was complete. MeOH was then completely removed to yield the desired product.

¹H-NMR (CDCl₃) δ: 7.5 (d, J = 8.0 Hz, 2H), 7.3 (d, J = 8.0 Hz, 2H), 3.7 (s, 3H), 3.0 (t, J = 7.6 Hz, 2H), 2.6 (t, J = 7.6 Hz, 2H) I. Hi. N- [2-(3 ,4-dinιethoxy-phenyl)-ethyl] -3-(4-trifluoromethyl-phenyl)-propionamide:

Method_.1 :

A solution of homoveratrylamine (18.5 niL, 110 mmol) in toluene (350 mL) was treated with intermediate Li (23.9 g, 110 mmol), refluxed for 90 h in the presence of a Dean-Stark and cooled slowly to RT. The precipitate was filtered off and dried under vacuum to give the desired amide as a white solid (36.5 g, 95.7 mmol, 87% yield).

¹H-NMR (CDCl₃) δ: 2.44 (t, J = 7.5 Hz, 2H), 2.71 (t, J = 6.9 Hz, 2H), 3.02 (t, J = 7.5 Hz, 2H), 3.49 (dt, J = 6.2, 6.7 Hz, 2H), 3.85 (s, 3H), 3.86 (s, 3H), 5.34 (bs, IH), 6.61 (dd, J = 1.8, 8.1 Hz, IH), 6.67 (d, J = 1.8 Hz, IH), 6.77 (d, J = 8.1 Hz, IH), 7.29 (d, J = 8.0 Hz, 2H), 7.53 (d, J = 8.1 Hz, 2H).

Method_.2:

At IT = 20⁰C, CDI (31.5 kg, 194 mol) was added portionwise to a mixture of intermediate Li in DCM (235 L, prepared as described in Preparation I, step Li, method 2). To the reaction mixture was added homoveratrylamine (35.0 kg, 194 mol) within 80 min. In the inlet vessel, a crust was formed which was dissolved overnight with DCM (20 L). DCM (92.5 L) and sulfuric acid (1.0 M, 220 L) were added successively and the mixture was stirred for 10 min. The layers were separated and the org. layer was recharged into the reactor. Sulfuric acid (1.0 M, 220 L) was added and the mixture was stirred intensively for 10 min at IT = 20⁰C. The layers were separated and the org. layer was recharged into the reactor. An aq. NaHCO₃ solution (7.4 %, 185 L) was added and the mixture was stirred intensively for 10 min at IT = 20⁰C. The layers were separated and the org. layer was recharged into the reactor. Water (185 L) was added and the mixture was stirred intensively for 10 min at IT = 20⁰C. The layers were separated overnight and the yield of the desired amide was determined by LOD (68.5 kg, 180 mol, 97% over two steps). 1H-NMR (CDCl₃) δ: 2.43 (t, 2H), 2.70 (t, 2H), 3.01 (t, 2H), 3.48 (dt, 2H), 3.85 (s, 3H), 3.86 (s, 3H), 5.35 (bs, IH), 6.61 (dd, IH), 6.67 (d, IH), 6.77 (d, IH), 7.30 (d, 2H), 7.53 (d, 2H).

Method_.3:

Intermediate I.ii (see Preparation I, step I.ii, method 2) was dissolved in toluene, 2-(3,4-dimethoxy-phenyl)-ethylamine (commercial available; 1.05 eq.) and sodium methoxide (30% in MeOH; 1.1 eq.) were added. At normal pressure, the reaction mixture was heated to a maximum of 110 ⁰C and MeOH distilled until full conversion was reached. The reaction mixture was washed with water and sulfuric acid. During cooling of the org. layer, the desired amide crystallised and was filtered off, washed with cold toluene and dried in vacuo at 50⁰C.

¹H-NMR (CDCl₃) δ: 7.5 (d, J = 8.0 Hz, 2H), 7.3 (d, J = 8.0 Hz, 2H), 6.8 (d, J = 8.0 Hz, IH), 6.7 (d, J = 4.0 Hz, IH), 6.6 (m, IH), 5.5 (s, IH), 3.8 (s, 6H), 3.5 (m, 2H), 3.2 (t, J = 8.0 Hz, 2H), 2.7 (t, J = 8.0 Hz, 2H), 2.4 (t, J = 8.0 Hz, 2H).

/. z^'v. 6, 7-dimethoxy-l-[2-(4-trifluoromethyl-phenyl)-ethyl]-3, 4-dihydro-isoquinoline:

Method_.1 :

Intermediate I.iii (65 g, 170 mmol) was dissolved in acetonitrile (60O mL) at 60-70⁰C. Phosphorus oxy chloride (40 mL, 430 mmol) was added and the mixture was re fluxed for

45 min. The solvents were removed in vacuo and MeOH (400 mL) was added to the oily residue. After evaporation of the solvents ether (250 mL) and THF (250 mL) were added and the mixture was stirred vigorously at 45°C bath temperature to get a fine suspension.

The mixture was cooled to RT and the precipitate was filtered off to give the desired product as a hydrochloride salt (59.6 g, 87% yield). The free base (52.9 g) was obtained from the salt by extraction between a mixture of sat. NaHCO₃ and EA.

¹H NMR (free base, CDCl₃) δ: 2.60-2.67 (m, 2H), 2.98-3.13 (m, 4H), 3.63-3.71 (m, 2H),

3.87 (s, 3H), 3.93 (s, 3H), 6.70 (s, IH), 6.93 (s, IH), 7.34 (d, J = 8.2 Hz, 2H), 7.53 (d,

J = 8.2 Hz, 2H) 1U NMR (HCl salt, CDCl₃) δ: 2.89-2.97 (m, 2H), 3.22-3.29 (m, 2H), 3.56-3.64 (m, 2H),

3.81-3.87 (m, 2H), 3.87 (s, 3H), 4.01 (s, 3H), 6.79 (s, IH), 7.00 (s, IH), 7.40 (d, J = 8.2 Hz,

2H), 7.53 (d, J = 8.2 Hz, 2H).

Method_.2:

A 640 L enamelled reaction vessel was charged with a solution of intermediate I.iii (68.5 kg, 180 mol) in DCM (475 L, from Preparation I, step I.iii, method 2). The volume was reduced to 125 L by distilling off DCM (350 L) at IT = 30-32⁰C and reduced pressure (750-700 mbar). Toluene (682 L) was added in 50 min and IT = 32°C. The solution was concentrated by distilling off solvents (95 L) at IT = 42-55°C) and reduced pressure (200 mbar). After cooling to 20⁰C, a suspension was formed. Phosphorus oxychloride (35.8 kg, 233 mol) was added at IT = 20⁰C within 10 min. The mixture was heated with a ramp of l°C/min to IT = 45°C and subsequently with maximally 0.5°C/min to IT = 90⁰C. The suspension turned into a clear solution and the mixture was stirred for 4 h at 88°C. The solution was cooled to 50⁰C in 2 h and stirred for 1 h at 50⁰C. The solution was cooled to 20⁰C within 2 h whereby a turbid grey solution occurred which was further cooled to 0⁰C within 4 h. The obtained suspension was filtered off and the residue was washed with methylcyclohexane (134 L) and dried on a Nutsch filter in a stream of nitrogen for 17 h to give the desired crude product (76.5 kg) as a hydrochloride salt. To obtain the free base, DCM (468 L) and an aq. NaHCO₃ solution (7.4%, 555 L) were added slowly (strong CO₂- evolution). After stirring for 30 min, additional NaHCO₃ solution (7.4%, 150 L) was added within 15 min and the mixture was stirred for 30 min. The layers were separated and the aq. layer was extracted with DCM (270 L). The combined org. layers were washed with water (270 L) to give the desired product (52.9 kg, 146 mol, 81% yield determined by LOD) as a solution in DCM (total volume: 720 L).

¹H NMR (free base, DMSO-d₆) δ: 2.53 (m, 2H), 3.01 (m, 4H), 3.50 (m, 2H), 3.76 (s, 3H), 3.80 (s, 3H), 6.88 (s, IH), 7.10 (s, IH), 7.49 (d, 2H), 7.63 (d, 2H).

Method 3: Intermediate I.iii was suspended in toluene and heated to 80-100⁰C. After addition of 1.5 eq. phosphorus oxychloride the mixture was heated for 6 h to 80-100⁰C and then cooled within 3 h to 20 ⁰C. The obtained suspension (hydrochloride salt) was added to water while maintaining the pH of the aq. layer during addition and subsequent stirring between 7 and 8 by addition of a NaOH solution. The mixture was stirred until all precipitate was dissolved. After phase separation, residual water was removed by azeotropic distillation to give a solution of the desired product (free base) in toluene. Then 1.0 eq. of methanesulfonic acid was added, the formed suspension stirred for some time and then slowly cooled to 0 - 10 ⁰C and stirred at this temperature for another couple of hours. After filtration, the product (methanesulfonate salt) was washed with toluene and dried in vacuo.

¹H-NMR (CDCl₃) δ: 7.5 (d, J = 8.0 Hz, 2H), 7.3 (d, J = 8.0 Hz, 2H), 7.0 (s, IH), 6.8 (s, IH), 4.0 (s, 3H), 3.9 (s, 3H), 3.7 (m, 2H), 3.4 (t, J = 8.0 Hz, 2H), 3.2 (t, J = 8.0 Hz, 2H), 2.9 (t, J = 8.0 Hz, 2H), 2.8 (s, 3H) Lv. rac-6, 7-dimethoxy-l-[2-(4-trifluoromethyl-phenyl)-ethyl] -1,2,3, 4-tetrahydro- isoquinoline:

Method_.1 :

At 0⁰C, NaBH₄ (414 mg, 10.9 mmol) was added portionwise to a solution of intermediate I.iv (2.00 g, 5.50 mmol) in MeOH (50 mL). After 30 min, water (50 mL) was added and the mixture was extracted 3 times with EA. The combined org. layers were washed with water and brine, dried over Na₂SO₄ and concentrated in vacuo to give a crude product which was dissolved in iPrOH (1O mL). A solution of HCl in iPrOH (5-6 M, 2.0 mL) was added, the mixture was concentrated in vacuo and the residue was recrystallised from iPrOH to give the desired product (hydrochloride salt) as a white solid (1.45 g, 3.60 mmol, 66% yield). The mother liquor was concentrated in vacuo, EA was added and the suspension was stirred and filtered to give a second crop of product. 1U NMR (HCl salt, CDCl₃) δ: 2.30-2.52 (m, 2H), 2.94-3.10 (m, 3H), 3.16-3.33 (m, 2H), 3.55-3.68 (m, IH), 3.81 (s, 3H), 3.86 (s, 3H), 4.47-4.54 (m, IH), 6.48 (s, IH), 6.60 (s, IH), 7.40 (d, J = 8.1 Hz, 2H), 7.47 (d, J = 8.2 Hz, 2H), 9.83 (bs, IH), 10.53 (bs, IH).

Method_.2:

A 400 L enamelled reaction vessel was charged with intermediate I.iv (21.3 kg, 59 mol) as solution in DCM (290 L, from previous step) at IT = 13.2°C. The solution was concentrated by distilling off DCM (247 L) at an external temperature of 45°C (IT = 15.9-40⁰C) and reduced pressure (520-550 mbar). EtOH (70 L) was added at IT = 33°C and the solution was concentrated by distilling off solvent (55 L) at an external temperature of 55°C (IT = 32-36°C) and reduced pressure (120-225 mbar). The solution was diluted with EtOH (290 L) at IT = 20⁰C, Pd/C (5%, 0.352 kg) was added, the vessel was rinsed with EtOH (5 L) and the mixture was hydrogenated under H₂ atmosphere (1210 mbar) for 21 h at 20⁰C. To the solution was added EtOH (60 L) and the mixture was stirred for 15 min. The Pd/C catalyst was filtered off (24 h) to give the desired product (21.5 kg, 100% yield determined by LOD) as a solution in EtOH.

¹H NMR (free base, CDCl₃) δ: 2.00-2.15 (m, 2H), 2.64-2.93 (m, 4H), 2.99-3.03 (m, IH), 3.21-3.27 (m, IH), 3.83 (s, 3H), 3.85 (s, 3H), 3.97 (m, IH), 6.57 (d, 2H), 7.34 (d, 2H), 7.54 (d, 2H). Ref e.r ence Examples 1. to .4 : resolution. trials. using, tartr anilic .acid .derivatives:.

General procedure for Reference Examples 1 to 4 and for Examples 1 to 3:

A pre-heated solution (70⁰C) of the respective tartranilic acid (0.274 mmol, 1.0 eq.) in the given solvent / solvent mixture was added to a pre-heated solution (70⁰C) of rαc-6,7-dimethoxy-l-[2-(4-trifluoro-methyl-phenyl)-ethyl]-l,2,3,4-tetrahydro-isoquinoline (100 mg, 0.274 mmol) in EtOH (2.0 mL). The mixture was slowly cooled to RT and kept at this temperature until precipitation occurred. The precipitate was filtered off, washed with small volume of EtOH, dried in vacuo and analyzed by ¹H NMR. For determination of optical purity an aliquot (~ 2.0 mg) was diluted with EA (1.0 mL) and a NaOH solution (1.0 M, 1.O mL), the layers were separated, the org. layer was concentrated in vacuo and the residue was analysed by chiral HPLC. With (2i?,3i?)-configurated tartranilic acids the salt based on the (i?)-configurated 6,7-dimethoxy-l-[2-(4-trifluoro-methyl-phenyl)-ethyl]- 1,2,3,4-tetrahydro-isoquinoline precipitated preferably, which could be demonstrated by comparison with a reference of known configuration (WO 2005/118548). The characteristics of the chiral HPLC method used were as follows:

- column Chiralcel OD, 4.6 x 250 mm, 10 μm;

- eluent A: EtOH, 0.1% DEA; eluent B: n-hexane;

- eluent A / eluent B = 10 / 90 (isocratic); - flow rate: 0.8 mL/min; temperature: RT t_R ((iS)-isomer): 12.9 min; t_R ((i?)-isomer): 18.6 min.

Reference Example 1: resolution trial using (2R,3R)-7V-(2-chloro-phenyl)- 2,3-dihydroxy-succinamic acid:

(2i?,3i?)-JV-(2-chloro-phenyl)-2,3 dihydroxy-succinamic acid in EtOH (1.0 mL) was used in the General procedure described hereabove. No crystallisation was seen within 2 h and a precipitate (86% yield; 4% e.e.) was obtained after 2.5 days.

Reference Example 2: resolution trial using (2R,3R)-7V-(3-chloro-phenyl)- 2,3-dihydroxy-succinamic acid:

(2i?,3i?)-JV-(3-chloro-phenyl)-2,3 dihydroxy-succinamic acid in EtOH (1.0 mL) was used in the General procedure described hereabove. No crystallisation occurred. Reference Example 3: resolution trial using (2R,3R)-7V-(4-chloro-phenyl)- 2,3-dihydroxy-succinamic acid:

(2i?,3i?)-iV-(4-chloro-phenyl)-2,3 dihydroxy-succinamic acid in EtOH (1.0 niL) was used in the General procedure described hereabove. No crystallisation was seen within 2 h and a precipitate (72% yield; 14% e.e.) was obtained after 2.5 days.

Reference Example 4: resolution trial using (2R,3R)-7V-(2-carbamoyl-phenyl)- 2,3-dihydroxy-succinamic acid:

(2i?,3i?)-Λ/-(2-carbamoyl-phenyl)-2,3-dihydroxy-succinamic acid in EtOH / H₂O 10/3 (2.6 rnL) was used in the General procedure described hereabove. No crystallisation occurred.

E.^x.^a.^mP.l^e.?. l.t.o.3:...resolution .using compouηds.of formula l'.:

Example 1: resolution using the compound of Preparation C:

The compound of Preparation C in EtOH (1.O mL) was used in the General procedure described hereabove. No crystallisation was seen within 2 h, but crystallisation (41% yield; 76% e.e.) was obtained after 2.5 days.

Example 2: resolution using the compound of Preparation A:

The compound of Preparation A in EtOH / H₂O 5/1 (1.8 mL) was used in the General procedure described hereabove. Crystallisation (42% yield; 84% e.e.) was obtained after 30 min. Example 3: resolution using the compound of Preparation B:

The compound of Preparation B in EtOH / H₂O 5/1 (1.8 mL) was used in the General procedure described hereabove. Crystallisation (37% yield; 78% e.e.) was obtained after 10 min.

E.^x.^a.^mP.l?.?..4.to .20: :....resolution .usm Preparation D:

General procedure for Examples 4 to 19:

A solution of rac-6,7-dimethoxy- 1 -[2-(4-trifluoromethyl-phenyl)-ethyl]- 1 ,2,3 ,4-tetrahydro- isoquinoline (5.0 g, 13.7 mmol) in a given solvent (solvent A) was heated to reflux and treated with a solution/suspension of the compound of Preparation D (quantity of such compound: Q_D) in a given solvent (solvent B). After the addition was completed the mixture was allowed to reach RT within the given time (t). The precipitate was filtered off and dried to give the respective 6,7-dimethoxy-l-[2-(4-trifluoromethyl-phenyl)-ethyl]- 1,2,3,4-tetrahydro-isoquinoline in the given enantiomeric ratio (e.r.) which was determined after transfer to the free base by chiral HPLC. The yield (Y) is calculated based on the quantity of racemic starting material (maximum theoretical yield: 50%).

The characteristics of the chiral HPLC method used were as follows: column Chiralcel OD-H, 4.6 x 250 mm, 5 μm;

- eluent A: EtOH, 0.1% DEA; eluent B : n-hexane, 0.1% DEA; eluent A / eluent B = 10 / 90 (isocratic); flow rate: 0.8 mL/min; temperature: RT

- t_R ((5)-isomer): 12.1 min; t_R ((i?)-isomer): 18.6 min.

Examples 4 to 19:

The particular conditions and the results obtained for the processes carried out regarding Examples 4 to 19 are summarised in the table hereafter.

^ The tartranilic acid was added as a solid and solvent B was used to rinse the funnel. ^ The tartranilic acid was added as a solid.

Example 20:

A 640 L enamelled reaction vessel was charged with rαc-6,7-dimethoxy- l-[2-(4-trifluoromethyl-phenyl)-ethyl]-l,2,3,4-tetrahydro-isoquinoline (27.9 kg, 76.4 mol, determined by LOD) as solution in EtOH (400.8 kg; 500 L, as obtained following a protocol similar to that of Preparation I, step Lv, method 2). The solution was concentrated by distilling off EtOH (400 L) at an external temperature of 60⁰C and reduced pressure (170-120 mbar). Acetone (230 L) was added and the solution was concentrated by distilling off solvent (230 L) at an external temperature of 60⁰C and under reduced pressure (400-500 mbar). Acetone (372 L) was added to the solution and the EtOH content was determined by ¹H-NMR (acetone/EtOH = 92.11 / 7.89 w/w). The yellow solution was cooled to IT = 20⁰C and diluted with acetone (109.6 kg), EtOH (22.5 kg) and water (61 kg) to obtain a solvent ratio of 9/1/1 (v/v/v) with a concentration of 24 L solvent per kg of rαc-6,7-dimethoxy-l-[2-(4-trifluoromethyl-phenyl)-ethyl]-l,2,3,4-tetrahydro-isoquinoline. The mixture was heated to 80⁰C and a clear yellow solution was obtained. The compound of Preparation D (12.8 kg, 53.5 mol) was added and the mixture was stirred for 10 min at 80⁰C before cooling to 20⁰C within 2 h (ramp). The obtained suspension was filtered off and washed twice with acetone (76 L and 38 L). The precipitate was dried in a stream of nitrogen at 40⁰C to give the desired product (18.9 kg, 31.3 mol, 41% yield) in an enantiomeric ratio of S / R = 92 / 8 (chiral HPLC, see Examples 4 to 19).

EMffiP.l?.?..? A. M.d .22.L .. r.£?^^

Example 21: A solution of NCS (1.47 g, l l.O mmol) in ether (3O mL) was treated with rαc-6,7-dimethoxy-l-[2-(4-trifluoromethyl-phenyl)-ethyl]-l,2,3,4-tetrahydro-isoquinoline (2.O g, 5.50 mmol) under exclusion from light and stirred for 30 min at RT. A NaOH solution (1.0 M, 20 mL) was added and the mixture was vigorously stirred for further 30 min. The layers were separated and the aq. layer was extracted with DCM. The combined org. layers were washed with brine, dried over Na₂SO₄ and concentrated partially in vacuo. The residue was diluted with MeOH (50 mL) and residual DCM was removed in vacuo. LC-MS demonstrated full conversion. The obtained solution could be used without further manipulation in the next step (reduction with NaBH₄ to get back rαc-6,7-dimethoxy-l-[2-(4-trifluoromethyl-phenyl)-ethyl]-l,2,3,4-tetrahydro-isoquinoline; see Preparation I, step Lv, method 1).

Example 22:

A solution of NaOCl in water (12.6%, 30.2 kg) was diluted with water (60 kg) and treated within 20 min with a solution of 6,7-dimethoxy-l-[2-(4-trifluoromethyl-phenyl)-ethyl]- 1,2,3,4-tetrahydro-isoquinoline (enriched in (i?)-enantiomer; 14.4 kg, 39.3 mol) in DCM (170 L) by keeping IT below 30⁰C. A solution of tetraethylammonium hydrogen sulfate (0.89 kg, 3.92 mol) in a NaOH solution (1.0 M, 4.31 L) was added and the mixture was stirred for 39 h at IT = 22°C, the layers were separated and the org. layer was washed with water (100 L). Solvents were partially distilled off (140 L) in vacuo, the mixture was diluted with EtOH (79 L) and additional solvents (35 L) were distilled off in vacuo. Again EtOH (37 L) was added and solvents (35 L) were distilled off in vacuo to give 6,7-dimethoxy-l-[2-(4-trifluoromethyl-phenyl)-ethyl]-3,4-dihydro-isoquinoline as a solution in EtOH. This solution could be used for the synthesis of almost racemic 6,7-dimethoxy-l-[2-(4-trifluoromethyl-phenyl)-ethyl]-l,2,3,4-tetrahydro-isoquinoline by hydrogenation in the presence of Pd/C (see Preparation I, step Lv, method 2).

Claims

Claims

1. A process for obtaining enantiomerically enriched (5)-6,7-dimethoxy- l-[2-(4-trifluoromethyl-phenyl)-ethyl]-l, 2,3, 4-tetrahydro-isoquino line from a mixture of (i?)-6,7-dimethoxy-l-[2-(4-trifluoromethyl-phenyl)-ethyl]-l,2,3,4-tetrahydro-isoquinoline and (5)-6,7-dimethoxy-l-[2-(4-trifluoromethyl-phenyl)-ethyl]-l,2,3,4-tetrahydro- isoquinoline, which process comprises the following sequential steps: either a) bringing to a given temperature T which may be up to the boiling temperature of the organic solvent(s) and optionally present water, a mixture of (7?)-6,7-dimethoxy- l-[2-(4-trifluoromethyl-phenyl)-ethyl]-l,2,3,4-tetrahydro-isoquinoline and (5)-6,7-dimethoxy- 1 -[2-(4-trifiuoromethyl-phenyl)-ethyl]- 1 ,2,3 ,4-tetrahydro- isoquinoline in an organic solvent or organic solvent mixture optionally mixed with water, to which mixture is added a compound of formula I

I wherein R is nitro, methyl or methoxy, whereby the compound of formula I may be added as a solid or as a solution or a suspension either in the same organic solvent or organic solvent mixture optionally mixed with water as the one used for the enantiomer mixture or in a different organic solvent or organic solvent mixture optionally mixed with water, whereby the conditions are such that any solid components are dissolved in the organic solvent(s) and optionally present water; b) cooling down the solution obtained after step a) to a temperature that is at least 15°C lower than T and collecting the crystallised salt formed; and c) treating the crystallised salt collected at step b) with a base to obtain, after removal of possibly remaining compound of formula I, enantiomerically enriched (iS)-6,7-dimethoxy- 1 -[2-(4-trifluoromethyl-phenyl)-ethyl]- 1 ,2,3 ,4-tetrahydro- isoquinoline; or d) bringing to a given temperature T which may be up to the boiling temperature of the organic solvent(s) and optionally present water, a mixture of (7?)-6,7-dimethoxy- l-[2-(4-trifluoromethyl-phenyl)-ethyl]-l,2,3,4-tetrahydro-isoquinoline and

(5)-6,7-dimethoxy- 1 -[2-(4-trifiuoromethyl-phenyl)-ethyl]- 1 ,2,3 ,4-tetrahydro- isoquinoline in an organic solvent or organic solvent mixture optionally mixed with water, to which mixture is added a compound of formula F

r wherein R is nitro, methyl or methoxy, whereby the compound of formula F may be added as a solid or as a solution or a suspension either in the same organic solvent or organic solvent mixture optionally mixed with water as the one used for the enantiomer mixture or in a different organic solvent or organic solvent mixture optionally mixed with water, whereby the conditions are such that any solid components are dissolved in the organic solvent(s) and optionally present water; e) cooling down the solution obtained after step d) to a temperature that is at least 15⁰C lower than T and removing the crystallised salt formed, thus obtaining a solution of enantiomerically enriched (5)-6,7-dimethoxy- 1 -[2-(4-trifluoromethyl-phenyl)-ethyl]- 1, 2,3, 4-tetrahydro-isoquino line and possibly remaining compound of formula F in the organic solvent or organic solvent mixture optionally mixed with water; and f) removing the organic solvent or organic solvent mixture optionally mixed with water and treating the residue thus obtained with a base to obtain, after removal of possibly remaining compound of formula F, enantiomerically enriched (5)-6,7-dimethoxy- l-[2-(4-trifluoromethyl-phenyl)-ethyl]-l,2,3,4-tetrahydro-isoquinoline.

2. The process of claim 1, which comprises steps a) to c).

3. The process of claim 1, which comprises steps d) to f).

4. The process of one of claims 1 to 3, in which R is methyl.

5. The process according to one of claims 1 to 4, wherein the mixture of (i?)-6,7-dimethoxy-l-[2-(4-trifluoromethyl-phenyl)-ethyl]-l,2,3,4-tetrahydro-isoquinoline and (5)-6,7-dimethoxy-l-[2-(4-trifluoromethyl-phenyl)-ethyl]-l,2,3,4-tetrahydro- isoquinoline and the compound of formula I or the compound of formula F are in solution or in suspension in the same organic solvent or organic solvent mixture optionally mixed with water.

6. The process according to claim 5, wherein the organic solvent or organic solvent mixture optionally mixed with water is selected from ethyl acetate, tetrahydrofurane, methyl ethyl ketone, acetone and a mixture of acetone with ethanol, whereby the organic solvent or organic solvent mixture is mixed with water in a proportion of a least 7 volumes of organic solvent per volume of water.

7. The process according to one of claims 1 to 4, wherein the mixture of (i?)-6,7-dimethoxy-l-[2-(4-trifluoromethyl-phenyl)-ethyl]-l,2,3,4-tetrahydro-isoquinoline and (5)-6,7-dimethoxy-l-[2-(4-trifluoromethyl-phenyl)-ethyl]-l,2,3,4-tetrahydro- isoquinoline and the compound of formula I or the compound of formula F are in solution or in suspension in different organic solvents each optionally mixed with water.

8. The process according to claim 7, wherein: 1) the organic solvent or organic solvent mixture optionally mixed with water containing the mixture of enantiomers is selected from tetrahydrofurane and acetone, whereby said tetrahydrofurane or acetone is mixed with water in a proportion of a least 10 volumes of tetrahydrofurane or acetone per volume of water; and 2) the organic solvent or organic solvent mixture optionally mixed with water containing the compound of formula I is tetrahydrofurane, whereby said tetrahydrofurane is mixed with water in a proportion of a least 3 volumes of tetrahydrofurane per volume of water.

9. The process according to one of claims 1 to 4, wherein the compound of formula I or the compound of formula F is added as a solid.

10. The process according to claim 9, wherein:

- either the organic solvent or organic solvent mixture optionally mixed with water containing the mixture of (i?)-6,7-dimethoxy-l-[2-(4-trifluoromethyl-phenyl)-ethyl]- 1, 2,3, 4-tetrahydro-isoquino line and (5)-6,7-dimethoxy-l-[2-(4-trifluoromethyl-phenyl)- ethyl]-l,2,3,4-tetrahydro-isoquinoline is a mixture of 4-methyl-2-pentanone and water, whereby 4-methyl-2-pentanone is mixed with water in a proportion of a least 10 volumes of 4-methyl-2-pentanone per volume of water;

- or the organic solvent or organic solvent mixture optionally mixed with water containing the mixture of (i?)-6,7-dimethoxy-l-[2-(4-trifluoromethyl-phenyl)-ethyl]-

1 ,2,3 ,4-tetrahydro-isoquinoline and (5)-6,7-dimethoxy- 1 -[2-(4-trifluoromethyl-phenyl)- ethyl]-l,2,3,4-tetrahydro-isoquinoline is a mixture of acetone, ethanol and water, whereby acetone, ethanol and water are mixed in a proportion of a least 9 volumes of acetone per volume of water and per volume of ethanol.

11. The process according to claim 10, wherein the organic solvent or organic solvent mixture optionally mixed with water containing the mixture of (7?)-6,7-dimethoxy- l-[2-(4-trifluoromethyl-phenyl)-ethyl]-l,2,3,4-tetrahydro-isoquinoline and

(5)-6,7-dimethoxy-l-[2-(4-trifluoromethyl-phenyl)-ethyl]-l,2,3,4-tetrahydro-isoquinoline is a mixture of acetone, ethanol and water which contains about 9 volumes of acetone and about 1 volume of ethanol per volume of water.

12. The process according to one of claims 1 to 11, which is followed by a recycling step, during which the (R)- and (S)- enantiomers of 6,7-dimethoxy-l-[2-(4-trifluoromethyl- phenyl)-ethyl]-l,2,3,4-tetrahydro-isoquinoline contained in the filtrate collected after step b) or step d) are converted into 6,7-dimethoxy-l-[2-(4-trifluoromethyl-phenyl)-ethyl]- 3,4-dihydro-isoquinoline before being reduced into a mixture of (7?)-6,7-dimethoxy- l-[2-(4-trifluoromethyl-phenyl)-ethyl]-l,2,3,4-tetrahydro-isoquinoline and

(5)-6,7-dimethoxy-l-[2-(4-trifluoromethyl-phenyl)-ethyl]-l,2,3,4-tetrahydro-isoquinoline.

13. The process of claim 12, wherein the conversion into 6,7-dimethoxy- l-[2-(4-trifluoromethyl-phenyl)-ethyl]-3,4-dihydro-isoquinoline is carried out by reaction with either JV-chloro-succinimide under protection from light or NaOCl.

14. The process of claim 13, wherein the conversion into 6,7-dimethoxy- l-[2-(4-trifluoromethyl-phenyl)-ethyl]-3,4-dihydro-isoquinoline is carried out by reaction with NaOCl.