HK1118061B - Process for preparing (alpha s, beta r)-6-bromo-alpha-[2-(dimethylamino)ethyl]-2-methoxy-alpha-1-naphthalenyl-beta-phenyl-3-quinolineethanol - Google Patents

Description

Process for the preparation of (α S, β R) -6-bromo- α - [2- (dimethylamino) ethyl ] -2-methoxy- α -1-naphthyl- β -phenyl-3-quinolineethanol

The present invention relates to the use of chiral 4-hydroxydinaphtho [2, 1-d: 1 ', 2' -f][1，3，2]Dioxaphosphanes4-oxide or its derivative as resolving agent, from 6-bromo-alpha- [2- (dimethylamino) ethyl by optical resolution]Separation of (alpha S, beta R) -6-bromo-alpha- [2- (dimethylamino) ethyl ] ethanol from a mixture of stereoisomeric forms of (2-methoxy-alpha-1-naphthyl-beta-phenyl-3-quinolineethanol]-2-methoxy- α -1-naphthyl- β -phenyl-3-quinolineethanol.

6-bromo-alpha- [2- (dimethylamino) ethyl ] -2-methoxy-alpha-1-naphthyl-beta-phenyl-3-quinolineethanol and its stereoisomeric forms are disclosed in WO2004/011436 as antimycobacterial agents useful for the treatment of mycobacterioses, in particular mycobacterioses caused by pathogenic mycobacteria, such as Mycobacterium tuberculosis, Mycobacterium bovis, Mycobacterium avium and Mycobacterium marinum.

The enantiomer (α S, β R) -6-bromo- α - [2- (dimethylamino) ethyl ] -2-methoxy- α -1-naphthyl- β -phenyl-3-quinolineethanol, corresponding to compound 12 in WO2004/011436 (or the a1 enantiomer), is the preferred compound for the treatment of mycobacteriosis, in particular tuberculosis. WO2004/011436 describes a process for separating it from the diastereoisomer a corresponding to a racemic mixture of (α S, β R) -6-bromo- α - [2- (dimethylamino) ethyl ] -2-methoxy- α -1-naphthyl- β -phenyl-3-quinolineethanol (enantiomer a 1) and (α R, β S) -6-bromo- α - [2- (dimethylamino) ethyl ] -2-methoxy- α -1-naphthyl- β -phenyl-3-quinolineethanol (enantiomer a 2) by chiral chromatography.

In order to ensure the supply of (α S, β R) -6-bromo- α - [2- (dimethylamino) ethyl ] -2-methoxy- α -1-naphthyl- β -phenyl-3-quinolineethanol for development and sale, a method is needed which can be synthesized efficiently on a large industrial scale.

It is therefore an object of the present invention to provide a process for the preparation (isolation) of (α S, β R) -6-bromo- α - [2- (dimethylamino) ethyl ] -2-methoxy- α -1-naphthyl- β -phenyl-3-quinolineethanol in high yield and high enantiomeric excess and in a manner suitable for large scale industrial operation.

The present invention relates to a process for the separation of (α S, β R) -6-bromo- α - [2- (dimethylamino) ethyl ] -2-methoxy- α -1-naphthyl- β -phenyl-3-quinolineethanol from a mixture of stereoisomeric forms of 6-bromo- α - [2- (dimethylamino) ethyl ] -2-methoxy- α -1-naphthyl- β -phenyl-3-quinolineethanol by optical resolution.

Chiral acids have been tested for several years as optical resolution agents for resolving (α S, β R) -6-bromo- α - [2- (dimethylamino) ethyl ] -2-methoxy- α -1-naphthyl- β -phenyl-3-quinolineethanol from a mixture of stereoisomeric forms of 6-bromo- α - [2- (dimethylamino) ethyl ] -2-methoxy- α -1-naphthyl- β -phenyl-3-quinolineethanol. It was found that optical resolution of (α S, β R) -6-bromo- α - [2- (dimethylamino) ethyl ] -2-methoxy- α -1-naphthyl- β -phenyl-3-quinolineethanol is not simple, since either the resulting chiral salt does not form crystals or an enantiomeric excess does not occur.

We have unexpectedly found that the use of chiral 4-hydroxydinaphtho [2, 1-d: 1 ', 2' -f][1，3，2]Dioxaphosphanes4-oxide or derivatives thereof as resolving agents successfully achieved the compound (. alpha.S,. beta.R) -6-bromo-alpha- [2- (dimethylamino) ethyl ] having two highly sterically hindered chiral centers in close proximity to each other]Optical resolution of-2-methoxy- α -1-naphthyl- β -phenyl-3-quinolineethanol, since the chiral salt crystallizes, which makes it possible to separate the chiral salt from the reaction mixture, and since a high enantiomeric excess can be achieved. The process of the invention makes it possible to obtain a mixture of all 4 pairsThe desired (α S, β R) enantiomer is isolated from a mixture of enantiomers. The process also removes other process impurities in the desired (α S, β R) enantiomer.

The term enantiomeric excess (e.e) is well known to the stereochemistry professional. For a mixture of (+) and (-) enantiomers of the indicated molar or weight fractions of ingredients F (+) and F (-) where F (+) + F (-) is 1, the enantiomeric excess of F (+) is defined as F (+) -F (-) and the percent corresponding excess is defined as 100 × [ F (+) -F (-) ].

Accordingly, the present invention relates to chiral 4-hydroxydinaphtho [2, 1-d: 1 ', 2' -f][1，3，2]DioxaphosphanesUse of 4-oxides or derivatives thereof for the separation from 6-bromo-alpha- [2- (dimethylamino) ethyl]Separation of (alpha S, beta R) -6-bromo-alpha- [2- (dimethylamino) ethyl ] ethanol from a mixture of stereoisomeric forms of (2-methoxy-alpha-1-naphthyl-beta-phenyl-3-quinolineethanol]-2-methoxy- α -1-naphthyl- β -phenyl-3-quinolineethanol.

6-bromo-alpha- [2- (dimethylamino) ethyl ] -2-methoxy-alpha-1-naphthyl-beta-phenyl-3-quinolineethanol is a compound of the formula

There are two chiral centers marked with the x number in the formula. It exists in four stereoisomeric forms, namely, (α S, β R) -6-bromo- α - [2- (dimethylamino) ethyl ] -2-methoxy- α -1-naphthyl- β -phenyl-3-quinolineethanol, (α R, β S) -6-bromo- α - [2- (dimethylamino) ethyl ] -2-methoxy- α -1-naphthyl- β -phenyl-3-quinolineethanol, (α R, β R) -6-bromo- α - [2- (dimethylamino) ethyl ] -2-methoxy- α -1-naphthyl- β -phenyl-3-quinolineethanol and (α S, β S) -6-bromo- α - [2- (dimethylamino) ethyl ] -2-methoxy- α -1-naphthyl- β -phenyl-3-quinolineethanol. These 4 stereoisomeric forms may be present in 2 diastereomers, namely, a racemic mixture of (α S, β R) -6-bromo- α - [2- (dimethylamino) ethyl ] -2-methoxy- α -1-naphthyl- β -phenyl-3-quinolineethanol and (α R, β S) -6-bromo- α - [2- (dimethylamino) ethyl ] -2-methoxy- α -1-naphthyl- β -phenyl-3-quinolineethanol, hereinafter referred to as diastereomer A, and (α R, β R) -6-bromo- α - [2- (dimethylamino) ethyl ] -2-methoxy- α -1-naphthyl- β -phenyl-3-quinolineethanol with (α R, β R) -6-bromo- α - [2- (dimethylamino) ethyl ] -2-methoxy- α -1-naphthyl- β -phenyl-3-quinolineethanol A racemic mixture of S, β S) -6-bromo- α - [2- (dimethylamino) ethyl ] -2-methoxy- α -1-naphthyl- β -phenyl-3-quinolineethanol, hereinafter referred to as diastereomer B.

Thus, whenever reference is made, before or after, to a mixture of stereoisomeric forms of 6-bromo- α - [2- (dimethylamino) ethyl ] -2-methoxy- α -1-naphthyl- β -phenyl-3-quinolineethanol, this refers to a mixture of 4 possible stereoisomeric forms, namely, (α S, β R) -6-bromo- α - [2- (dimethylamino) ethyl ] -2-methoxy- α -1-naphthyl- β -phenyl-3-quinolineethanol, (α R, β S) -6-bromo- α - [2- (dimethylamino) ethyl ] -2-methoxy- α -1-naphthyl- β -phenyl-3-quinolineethanol, (α R, β R) -6-bromo- α - [2- (dimethylamino) ethyl ] -2-methoxy- α -1-naphthyl- β -phenyl-3-quinolineethanol and (α S, β S) -6-bromo- α - [2- (dimethylamino) ethyl ] -2-methoxy- α -1-naphthyl- β -phenyl-3-quinolineethanol. Preferably, it refers to mixtures in which diastereomer a predominates, i.e. mixtures in which the content of diastereomer a is more than 50%, in particular 80% or more, especially 85% or more, or 90% or more, or to diastereomer a. Diastereomer a is a racemic mixture substantially free of diastereomer form B. Substantially free means herein that the other diastereomers are present in an amount of less than 5%, preferably less than 2%, more preferably less than 1%, or are substantially pure substances.

Mixtures in which diastereomer a predominates can be obtained by selective crystallization of diastereomer B from a mixture of diastereomers a and B. This can be accomplished by seeding the mixture of the a and B diastereomers with diastereomer B, thereby promoting crystallization of diastereomer B, which can then be removed from the mixture, for example, by filtration, to form a mixture in which diastereomer a predominates.

Diastereomer A (substantially free of diastereomer B) can be obtained from a mixture of diastereomers A and B by column chromatography and crystallization (cf. WO2004/011436, example B7).

Before or after, whenever a chiral 4-hydroxydinaphtho [2, 1-d: 1 ', 2' -f][1，3，2]Dioxaphosphanes4-oxides or derivatives thereof, all refer to chiral 4-hydroxydinaphtho [2, 1-d: 1 ', 2' -f][1，3，2]Dioxaphosphanes4-oxide, or a chiral 4-hydroxydinaphtho [2, 1-d: 1 ', 2' -f][1，3，2]Dioxaphosphanes4-oxide.

Specifically, a chiral 4-hydroxydinaphtho [2, 1-d: 1 ', 2' -f][1，3，2]Dioxaphosphanes4-oxides or derivatives thereof represent chiral compounds of formula (1)

Wherein

n is an integer equal to 1 or 2;

R_1aand R_1bEach independently represents hydrogen, halogen, C optionally substituted by aryl_1-12Alkyl, aryl, naphthyl, Si (phenyl)₃；C_1-6Alkoxy, anthracenyl, C optionally substituted by aryl_2-6An alkynyl group;

R_2aand R_2bEach independently represents hydrogen, halogen, C optionally substituted by aryl_1-12Alkyl, aryl, C_2-12Alkenyl, C optionally substituted by phenyl_1-6Alkoxy, nitro, hydroxy;

in the presence of a compound represented by 4-hydroxydinaphtho [2, 1-d: 1 ', 2' -f][ 1，3，2]DioxaphosphanesR in the 14 and 15 positions of the 4-oxide_2aOr together with the two R_2aThe naphthalene rings to which the substituents are all attached together form 13-methyl-12, 13, 14, 15, 16, 17-hexahydro-11H-cyclopenta [ a]Phenanthrene;

in the presence of a compound represented by 4-hydroxydinaphtho [2, 1-d: 1 ', 2' -f][1，3，2]DioxaphosphanesR in the 8-and 9-positions of the 4-oxide_2bOr together with the two R_2bThe naphthalene rings to which the substituents are all attached together form 13-methyl-12, 13, 14, 15, 16, 17-hexahydro-11H-cyclopenta [ a]Phenanthrene;

aryl is phenyl or phenyl substituted with one, two or three substituents each independently selected from the group consisting of: c_1-6Alkyl, polyhalo C_1-6Alkyl, C substituted by phenyl_1-6Alkoxy, optionally selected from C_1-6Alkyl or naphthyl substituted by one, two or three substituents.

Interesting embodiments of the compounds of formula (1) are compounds wherein one or possibly more of the following conditions apply:

preferably R_1aThe substituents are placed in the position of 4-hydroxydinaphtho [2, 1-d: 1 ', 2' -f][1，3，2]Dioxaphosphanes1-or 2-position of the 4-oxide.

Preferably R_1bThe substituent being placed in the 4-hydroxydiNaphtho [2, 1-d: 1 ', 2' -f][1，3，2]Dioxaphosphanes6-or 7-position of 4-oxide.

Preferably R_2aThe substituents are placed in the position of 4-hydroxydinaphtho [2, 1-d: 1 ', 2' -f][1，3，2]Dioxaphosphanes14 or 15 of the 4-oxide.

Preferably R_2bThe substituents are placed in the position of 4-hydroxydinaphtho [2, 1-d: 1 ', 2' -f][1，3，2]Dioxaphosphanes8-or 9-position of the 4-oxide.

Preferably R_2aThe substituents are placed in the position of 4-hydroxydinaphtho [2, 1-d: 1 ', 2' -f][1，3，2]Dioxaphosphanes13 or 14 of the 4-oxide.

Preferably R_2bThe substituents are placed in the position of 4-hydroxydinaphtho [2, 1-d: 1 ', 2' -f][1，3，2]Dioxaphosphanes9 or 10 positions of the 4-oxide.

Chiral 4-hydroxydinaphtho [2, 1-d: 1 ', 2' -f][1，3，2]Dioxaphosphanes4-oxides or derivatives thereof or chiral compounds of formula (1) including:

(11bR) -4-hydroxy-2, 6-bis [2, 4, 6-tris (1-methylethyl) phenyl]Dinaphtho [2, 1-d: 1 ', 2' -f][1，3，2]Dioxaphosphanes4-oxide;

(11bR) -2, 6- [3, 5-bis (trifluoromethyl) phenyl]-4-hydroxydinaphtho [2, 1-d: 1 ', 2' -f][1，3，2]Dioxaphosphanes4-oxide;

(11bR) -9, 14-dibromo-4-hydroxy-2, 6-diphenyldinaphtho [2, 1-d: 1 ', 2' -f][1，3，2]Dioxaphosphanes4-oxide;

(11bR) -4-hydroxy-2, 6-bis (2 ', 4', 6 '-trimethyl [1, 1' -biphenyl)]-4-yl) dinaphtho [2, 1-d: 1 ', 2' -f][1，3，2]Dioxaphosphanes4-oxide;

(11bR) -4-hydroxy-2, 6-di-2-naphthyldinaphtho [2, 1-d: 1 ', 2' -f][1，3，2]Dioxaphosphanes4-oxide;

(11bR) -4-hydroxy-2, 6-bis (triphenylsilyl) dinaphtho [2, 1-d: 1 ', 2' -f][1，3，2]Dioxaphosphanes4-oxide;

(11bR) -2, 6-bis (2, 2 ', 4, 4', 6, 6 '-hexamethyl [1, 1': 3 ', 1' -terphenyl)]-5' -yl) -4-hydroxydinaphtho [2, 1-d: 1 ', 2' -f][1，3，2]Dioxaphosphanes4-oxide;

(11bR) -4-hydroxy-2, 6-di [4- (2-naphthyl) phenyl]A dinaphtho [2 ] derivative of a-naphthalene,1-d：1′，2′-f][1，3，2]dioxaphosphanes4-oxide;

(11bR) -4-hydroxy-2, 6-bis [2, 4, 6-trimethylphenyl]Dinaphtho [2, 1-d: 1 ', 2' -f][1，3，2]Dioxaphosphanes4-oxide;

(11bR) -4-hydroxy-2, 6-diphenyl]Dinaphtho [2, 1-d: 1 ', 2' -f][1，3，2]Dioxaphosphanes4-oxide;

(11bS) -4-hydroxy-1, 7, 9, 14-tetraoctyldinaphtho [2, 1-d: 1 ', 2' -f][1，3，2]Dioxaphosphanes4-oxide;

(11bS) -4-hydroxy-1, 7, 9, 14-tetrakis (2-phenylethyl) dinaphtho [2, 1-d: 1 ', 2' -f][1，3，2]Dioxaphosphanes4-oxide;

(11bS) -1, 7, 9, 14-tetrakis (4-butylphenyl) -4-hydroxydinaphtho [2, 1-d: 1 ', 2' -f][1，3，2]Dioxaphosphanes4-oxide;

(11bS) -4-hydroxy-1, 7, 9, 14-tetraphenyldinaphtho [2, 1-d: 1 ', 2' -f][1，3，2]Dioxaphosphanes4-oxide;

(4S, 14 β) - (14 ' β) - [4, 4 ' -dilestra-1, 3, 5, 7, 9-pentaene ] -3, 3 ' -diol, cyclic hydrogen phosphate;

(4R, 14 β) - (14 ' β) - [4, 4 ' -dilestra-1, 3, 5, 7, 9-pentaene ] -3, 3 ' -diol, cyclic hydrogen phosphate;

(11bR) -9, 14-dibromo-4-hydroxydinaphtho [2, 1-d: 1 ', 2' -f][1，3，2]Dioxaphosphanes4-oxide;

(11bR) -4-hydroxy-2, 6-bis ([1, 1 ': 3', 1 "-terphenyl)]-5' -yl) dinaphtho [2, 1-d: 1 ', 2' -f][1，3，2]Dioxaphosphanes4-oxide;

(11bS) -2, 6-di-9-anthracenyl-4-hydroxydinaphtho [2, 1-d: 1 ', 2' -f][1，3，2]Dioxaphosphanes4-oxide;

(11bR) -2, 6-di-9-anthracenyl-4-hydroxydinaphtho [2, 1-d: 1 ', 2' -f][1，3，2]Dioxaphosphanes4-oxide;

(11bR) -2, 6-diacetylene-4-hydroxydinaphtho [2, 1-d: 1 ', 2' -f][1，3，2]Dioxaphosphanes4-oxide;

(11bR) -9, 14-bis (2, 6-dimethylphenyl) -4-hydroxydinaphtho [2, 1-d: 1 ', 2' -f][1，3，2]Dioxaphosphanes4-oxide;

(11bR) -4-hydroxy-9, 14-dioctyldinaphtho [2, 1-d: 1 ', 2' -f][1，3，2]Dioxaphosphanes4-oxide;

(R) -9, 14-dibromo-4-hydroxy-10, 13-bis (phenylmethoxy) dinaphtho [2, 1-d: 1 ', 2' -f][1，3，2]Dioxaphosphanes4-oxide;

(S) -9, 14-dibromo-4-hydroxy-10, 13-bis (phenylmethoxy) dinaphtho [2, 1-d: 1 ', 2' -f][1，3，2]Dioxaphosphanes4-oxide;

4-hydroxy-10, 13-bis (phenylmethoxy) dinaphtho [2, 1-d: 1 ', 2' -f][1，3，2]Dioxaphosphanes4-oxide;

(S) -4-hydroxy-10, 13-bis (phenylmethoxy) dinaphtho [2, 1-d: 1 ', 2' -f][1，3，2]Dioxaphosphanes4-oxide;

(R) -4-hydroxy-10, 13-dimethoxydinaphtho [2, 1-d: 1 ', 2' -f][1，3，2]Dioxaphosphanes4-oxide;

(R) -4-hydroxydinaphtho [2, 1-d: 1 ', 2' -f][1，3，2]Dioxaphosphanes-10, 13-diol 4-oxide;

(R) -4-hydroxy-10, 13-bis (phenylmethoxy) dinaphtho [2, 1-d: 1 ', 2' -f][1，3，2]Dioxaphosphanes4-oxide;

(R) -4-hydroxy-2, 6-dimethyldinaphtho [2, 1-d: 1 ', 2' -f][1，3，2]Dioxaphosphanes4-oxide;

(S) -4-hydroxy-2, 6-dimethyldinaphtho [2, 1-d: 1 ', 2' -f][1，3，2]Dioxaphosphanes4-oxide;

(11bR) -4-hydroxydinaphtho [2, 1-d: 1 ', 2' -f][1，3，2]Dioxaphosphanes4-oxide;

(11bS) -4-hydroxydinaphtho [2, 1-d: 1 ', 2' -f][1，3，2]Dioxaphosphanes4-oxide;

preferably, the resolving agent is (11bR) -4-hydroxydinaphtho [2, 1-d: 1 ', 2' -f][1，3，2]Dioxaphosphanes4-oxide or (11bS) -4-hydroxydinaphtho [2, 1-d: 1 ', 2' -f][1，3，2]Dioxaphosphanes4-oxide.

Most preferably, the resolving agent is (11bR) -4-hydroxydinaphtho [2, 1-d: 1 ', 2' -f][1，3，2]Dioxaphosphanes4-oxide.

As used herein, C as a group or part of a group_1-6Alkyl is defined as a straight or branched chain saturated hydrocarbon group having 1 to 6 carbon atoms, such as methyl, ethyl, propyl, 1-methylethyl, butyl, pentyl, hexyl, 2-methylbutyl, and the like; c as a group or part of a group_1-12Alkyl is defined as a straight or branched chain saturated hydrocarbon group having 1 to 12 carbon atoms, such as defined for C1-6 alkyl and heptyl, octyl, nonyl, decyl, and the like; c_2-12Alkenyl is defined as straight and branched chain hydrocarbon radicals having from 2 to 12 carbon atoms containing one double bond such as ethenyl, propenyl, butenyl, pentenyl, hexenyl, methyleneoctyl and the like; c_2-6Alkynyl is defined as straight and branched chain hydrocarbon radicals containing one triple bond having from 2 to 6 carbon atoms, such as ethynyl, propynyl, butynyl, pentynyl, hexynyl and the like.

The term halogen is a generic term for fluorine, chlorine, bromine and iodine. Polyhalo C as a group or part of a group as used herein_1-6Alkyl is defined as mono-or polyhalo-substituted C_1-6Alkyl groups such as methyl having one or more fluorine atoms, e.g., difluoromethyl or trifluoromethyl, 1, 1-difluoroethyl, and the like. If in polyhalogen C_1-6More than one halogen atom within the definition of alkyl is attached to an alkyl group, which may be the same or different.

The compound of formula (1) may also be used in the form of a hydrate or a solvent adduct which the compound of formula (1) is capable of forming. Examples of such forms are hydrates, alcoholates and the like.

The present invention uses a chiral 4-hydroxydinaphtho [2, 1-d: 1 ', 2' -f][1，3，2]Dioxaphosphanes4-oxide or its derivative as resolving agent, from 6-bromo-alpha- [2- (dimethylamino) ethyl ester by optical resolutionBase of]Separation of (alpha S, beta R) -6-bromo-alpha- [2- (dimethylamino) ethyl ] ethanol from a mixture of stereoisomeric forms of (2-methoxy-alpha-1-naphthyl-beta-phenyl-3-quinolineethanol]The process for the preparation of (E) -2-methoxy- α -1-naphthyl- β -phenyl-3-quinolineethanol comprises two embodiments.

In a first embodiment, the salt of the desired (α S, β R) enantiomer with the resolving agent is crystallized.

In a second embodiment, the (α R, β S) enantiomer is crystallized with a salt of a resolving agent.

These two embodiments will be described in detail below.

First embodiment

The present invention relates to a method of using a chiral 4-hydroxydinaphtho [2, 1-d: 1 ', 2' -f][ 1，3，2]Dioxaphosphanes4-oxide or its derivative as resolving agent, from 6-bromo-alpha- [2- (dimethylamino) ethyl]Separation of (alpha S, beta R) -6-bromo-alpha- [2- (dimethylamino) ethyl ] ethanol from a mixture of stereoisomeric forms of (2-methoxy-alpha-1-naphthyl-beta-phenyl-3-quinolineethanol]Process for the preparation of (2-methoxy- α -1-naphthyl- β -phenyl-3-quinolineethanol, wherein (α S, β R) -6-bromo- α - [2- (dimethylamino) ethyl]-2-methoxy- α -1-naphthyl- β -phenyl-3-quinolineethanol in crystalline form with a resolving agent.

The invention also relates to a method for producing a compound using a chiral 4-hydroxydinaphtho [2, 1-d: 1 ', 2' -f][1，3，2]Dioxaphosphanes4-oxide or its derivative as resolving agent, from 6-bromo-alpha- [2- (dimethylamino) ethyl]Separation of (alpha S, beta R) -6-bromo-alpha- [2- (dimethylamino) ethyl ] ethanol from a mixture of stereoisomeric forms of (2-methoxy-alpha-1-naphthyl-beta-phenyl-3-quinolineethanol]Process for the preparation of (2-methoxy- α -1-naphthyl- β -phenyl-3-quinolineethanol, wherein (α S, β R) -6-bromo- α - [2- (dimethyl) -ethanolAlkylamino) ethyl]-2-methoxy- α -1-naphthyl- β -phenyl-3-quinolineethanol as a salt with a resolving agent, which process comprises:

a) reacting a mixture of stereoisomeric forms of 6-bromo- α - [2- (dimethylamino) ethyl ] -2-methoxy- α -1-naphthyl- β -phenyl-3-quinolineethanol with said resolving agent in a suitable solvent;

b) separating the salt of (α S, β R) -6-bromo- α - [2- (dimethylamino) ethyl ] -2-methoxy- α -1-naphthyl- β -phenyl-3-quinolineethanol with a resolving agent from the reaction mixture obtained in a);

c) optionally recrystallizing or slurrying the salt obtained in b) in a suitable solvent;

d) liberating (α S, β R) -6-bromo- α - [2- (dimethylamino) ethyl ] -2-methoxy- α -1-naphthyl- β -phenyl-3-quinolineethanol from the salt obtained in b) or c).

Since (11bR) -4-hydroxydinaphtho [2, 1-d: 1 ', 2' -f][1，3，2]Dioxaphosphanes4-oxide is a preferred resolving agent, so the present invention also relates to a method of resolving a compound using (11bR) -4-hydroxydinaphtho [2, 1-d: 1 ', 2' -f][1，3，2]Dioxaphosphanes4-oxide as resolving agent, from 6-bromo-alpha- [2- (dimethylamino) ethyl by optical resolution]Separation of (alpha S, beta R) -6-bromo-alpha- [2- (dimethylamino) ethyl ] ethanol from a mixture of stereoisomeric forms of (2-methoxy-alpha-1-naphthyl-beta-phenyl-3-quinolineethanol]Process for the preparation of (2-methoxy- α -1-naphthyl- β -phenyl-3-quinolineethanol, wherein (α S, β R) -6-bromo- α - [2- (dimethylamino) ethyl]-2-methoxy- α -1-naphthyl- β -phenyl-3-quinolineethanol and a salt of a resolving agent, which process comprises

a) 6-bromo-alpha- [2- (dimethylamino) ethyl]Mixture of stereoisomeric forms of (E) -2-methoxy-alpha-1-naphthyl-beta-phenyl-3-quinolineethanol with (11bR) -4-hydroxyDinaphtho [2, 1-d: 1 ', 2' -f][1，3，2]Dioxaphosphanes4-oxide in a suitable solvent;

b) separating the formed (alpha S, beta R) -6-bromo-alpha- [2- (dimethylamino) ethyl group from the reaction mixture obtained in a)]-2-methoxy- α -1-naphthyl- β -phenyl-3-quinolineethanol (11bR) -4-hydroxydinaphtho [2, 1-d: 1 ', 2' -f][1，3，2]Dioxaphosphanes4-oxide salts;

c) optionally recrystallizing or slurrying the salt obtained in b) in a suitable solvent;

d) the salt obtained from b) or c) does not release (α S, β R) -6-bromo- α - [2- (dimethylamino) ethyl ] -2-methoxy- α -1-naphthyl- β -phenyl-3-quinolineethanol.

Since the (α S, β R) -6-bromo- α - [2- (dimethylamino) ethyl ] -2-methoxy- α -1-naphthyl- β -phenyl-3-quinolineethanol and the salt of the resolving agent are crystallized in the above-described process, they can be isolated from the reaction mixture, for example, by filtration.

a) The solvent in (a) may also be a mixture of different solvents. In a preferred embodiment of the invention, the suitable solvent in a) is a ketone, an ester, a mixture of a ketone and a suitable aprotic polar solvent, or a mixture of an ester and a suitable aprotic polar solvent. Preferably the ketone is acetone or methyl ethyl ketone. The ester is preferably ethyl acetate or butyl acetate, more preferably butyl acetate. The aprotic polar solvent used in the mixture with the ketone is preferably dimethyl sulfoxide, N-dimethylformamide, N-dimethylacetamide or N-methylpyrrolidone. The aprotic polar solvent used to mix with the ester (preferably butyl acetate) is preferably dimethyl sulfoxide or N, N-dimethylformamide, most preferably dimethyl sulfoxide. Preferably the solvent in a) is a ketone or a mixture of ketones and aprotic polar solvent. More preferably, the solvent in a) is acetone or the solvent in a) is a mixture of acetone and dimethyl sulfoxide or N, N-dimethylformamide, in particular a mixture of acetone and dimethyl sulfoxide.

In a preferred embodiment of the invention, the sum of diastereomers A and B present in the mixture under a), i.e.the 6-bromo-. alpha. - [2- (dimethylamino) ethyl ] ethyl group present in the mixture under a), is used as calculation reference]-2-methoxy- α -1-naphthyl- β -phenyl-3-quinolineethanol, chiral 4-hydroxydinaphtho [2, 1-d: 1 ', 2' -f][1，3，2]Dioxaphosphanes4-oxide or derivative thereof, in particular (11bR) -4-hydroxydinaphtho [2, 1-d: 1 ', 2' -f][1，3，2]DioxaphosphanesThe amount of 4-oxide is from 0.5 to 1.5 equivalents, preferably 0.8 to 1.2 equivalents, most preferably 1 equivalent.

In a preferred embodiment of the invention, to the reaction mixture in a) is added a chiral 4-hydroxydinaphtho [2, 1-d: 1 ', 2' -f][1，3，2]Dioxaphosphanes4-oxide or derivative thereof, in particular (11bR) -4-hydroxydinaphtho [2, 1-d: 1 ', 2' -f][1，3，2]Dioxaphosphanes(alpha S, beta R) -6-bromo-alpha- [2- (dimethylamino) ethyl ] ethyl is added to the reaction mixture before the 4-oxide]-2-methoxy- α -1-naphthyl- β -phenyl-3-quinolineethanol and chiral 4-hydroxydinaphtho [2, 1-d: 1 ', 2' -f][1，3，2]DioxaphosphanesSalts of 4-oxides or derivatives thereof, especially (alpha S, beta R) -6-bromo-alpha- [2- (dimethylamino) ethyl]-2-methoxy-alpha-1-naphthyl-beta-phenyl-3-quinolineethaneAlcohol (11bR) -4-hydroxy-dinaphtho [2, 1-d: 1 ', 2' -f][1，3，2]DioxaphosphanesSeeds of 4-oxide salts.

In another preferred embodiment of the present invention, in the addition of chiral 4-hydroxydinaphtho [2, 1-d: 1 ', 2' -f][1，3，2]Dioxaphosphanes4-oxide or derivative thereof, in particular (11bR) -4-hydroxydinaphtho [2, 1-d: 1 ', 2' -f][1，3，2]DioxaphosphanesAfter 4-oxide addition of (. alpha.S,. beta.R) -6-bromo-. alpha. [2- (dimethylamino) ethyl ] to the reaction mixture]-2-methoxy- α -1-naphthyl- β -phenyl-3-quinolineethanol with a chiral 4-hydroxydinaphtho [2, 1-d: 1 ', 2' -f][1，3，2]DioxaphosphanesSalts of 4-oxides or derivatives thereof, in particular (α S, β R) -6-bromo- α - [2- (dimethylamino) ethyl]-2-methoxy- α -1-naphthyl- β -phenyl-3-quinolineethanol (11bR) -4-hydroxydinaphtho [2, 1-d: 1 ', 2' -f][1，3，2]DioxaphosphanesSeeds of 4-oxide salts.

More preferably, in the addition of a chiral 4-hydroxydinaphtho [2, 1-d: 1 ', 2' -f][1，3，2]Dioxaphosphanes4-oxide or derivative thereof, in particular (11bR) -4-hydroxydinaphtho [2, 1-d: 1 ', 2' -f][1，3，2]Dioxaphosphanes(alpha S, beta R) -6-bromo-alpha- [2- (dimethylamino) ethyl) is added to the reaction mixture before and after the 4-oxide]-2-methoxy- α -1-naphthyl- β -phenyl-3-quinolineethanol and chiral 4-hydroxydinaphtho [2, 1-d: 1 ', 2' -f][1，3，2]DioxaphosphanesSalts of 4-oxides or derivatives thereof, in particular (α S, β R) -6-bromo- α - [2- (dimethylamino) ethyl]-2-methoxy- α -1-naphthyl- β -phenyl-3-quinolineethanol (11bR) -4-hydroxydinaphtho [2, 1-d: 1 ', 2' -f][1，3，2]DioxaphosphanesSeeds of 4-oxide salts.

By seeding the reaction mixture in a) with a seed crystal of a chiral salt, the enantiomeric excess and filterability of the solid formed is improved.

(alpha S, beta R) -6-bromo-alpha- [2- (dimethylamino) ethyl]-2-methoxy- α -1-naphthyl- β -phenyl-3-quinolineethanol and chiral 4-hydroxydinaphtho [2, 1-d: 1 ', 2' -f][1，3，2]DioxaphosphanesSeeds of salts of 4-oxides or derivatives thereof, especially (alpha S, beta R) -6-bromo-alpha- [2- (dimethylamino) ethyl]-2-methoxy- α -1-naphthyl- β -phenyl-3-quinolineethanol (11bR) -4-hydroxydinaphtho [2, 1-d: 1 ', 2' -f][1，3，2]DioxaphosphanesThe seed crystals of the 4-oxide salt may be prepared by previously conducting the reaction using a chiral 4-hydroxydinaphtho [2, 1-d: 1 ', 2' -f][1，3，2]Dioxaphosphanes4-oxide or derivative thereof, in particular (11bR) -4-hydroxydinaphtho [2, 1-d: 1 ', 2' -f][1，3，2]Dioxaphosphanes4-oxide as resolving agent from 6-bromo-alpha- [2- (dimethylamino) ethyl]Preparation of (α S, β R) -6-bromo- α - [2- (dimethylamino) ethyl ] ethanol in a mixture of stereoisomeric forms of (2-methoxy- α -1-naphthyl- β -phenyl-3-quinolineethanol]-2-methoxy- α -1-naphthyl- β -phenyl-3-quinolineethanol, for example as obtained by the process of the invention.

In a preferred embodiment of the invention, 6-bromo-alpha- [2- (dimethylamino) ethyl]-a solution of a mixture of stereoisomeric forms of 2-methoxy- α -1-naphthyl- β -phenyl-3-quinolineethanol in a suitable solvent is added to a solution of chiral 4-hydroxydinaphtho [2, 1-d: 1 ', 2' -f][1，3，2]Dioxaphosphanes4-oxide or derivative thereof, in particular (11bR) -4-hydroxydinaphtho [2, 1-d: 1 ', 2' -f][1，3，2]Dioxaphosphanes4-oxide. The solvent is preferably an aprotic polar solvent, such as dimethylsulfoxide, N-dimethylformamide, N-dimethylacetamide or N-methylpyrrolidone, more preferably the aprotic polar solvent is dimethylsulfoxide or N, N-dimethylformamide, most preferably dimethylsulfoxide.

By adding a chiral 4-hydroxydinaphtho [2, 1-d: 1 ', 2' -f][1，3，2]Dioxaphosphanes4-oxide or derivative thereof, in particular (11bR) -4-hydroxydinaphtho [2, 1-d: 1 ', 2' -f][1，3，2]Dioxaphosphanes4-oxide, improving the efficiency of the reaction and the handling properties of the reagents.

In a preferred embodiment, the mixture of stereoisomeric forms of 6-bromo- α - [2- (dimethylamino) ethyl ] -2-methoxy- α -1-naphthyl- β -phenyl-3-quinolineethanol in a) of the above process is a mixture with a preponderance of one diastereomer A.

In a preferred embodiment of the invention, the (α S, β R) -6-bromo- α - [2- (dimethylamino) ethyl radical obtained is first reacted]-2-methoxy- α -1-naphthyl- β -phenyl-3-quinolineethanol and chiral 4-hydroxydinaphtho [2, 1-d: 1 ', 2' -f][1，3，2]DioxaphosphanesSalts of 4-oxides or derivatives thereof, especially (alpha S, beta R) -6-bromo-alpha- [2- (dimethylamino) ethyl]-2-methoxy- α -1-naphthyl- β -phenyl-3-quinolineethanol (11bR) -4-hydroxydinaphtho [2, 1-d: 1 ', 2' -f][1，3，2]Dioxaphosphanes4-oxide salt, recrystallization and/or slurrying, and then liberating the desired base from the chiral salt to increase ee and chemical purity. Recrystallization or slurrying is carried out in a suitable solvent, such as acetone, N-dimethylformamide, an N, N-dimethylformamide/water mixture, a dimethylsulfoxide/acetone mixture, a dimethylsulfoxide/alcohol mixture, or an N, N-dimethylformamide/alcohol mixture. Recrystallization in acetone is preferred.

In a preferred embodiment of the invention, starting from (. alpha.S,. beta.R) -6-bromo-. alpha. - [2- (dimethylamino) ethyl]-2-methoxy- α -1-naphthyl- β -phenyl-3-quinolineethanol and chiral 4-hydroxydinaphtho [2, 1-d: 1 ', 2' -f][1，3，2]DioxaphosphanesSalts of 4-oxides or derivatives thereof, in particular from (α S, β R) -6-bromo- α - [2- (dimethylamino) ethyl]-2-methoxy- α -1-naphthyl- β -phenyl-3-quinolineethanol (11bR) -4-hydroxydinaphtho [2, 1-d: 1 ', 2' -f][1，3，2]Dioxaphosphanes(alpha S, beta R) -6-bromo-alpha- [2- (dimethylamino) ethyl group released from 4-oxide salt]-2-methoxy- α -1-naphthyl- β -phenyl-3-quinolineethanol, by reacting the salt with a suitable base in a suitable solvent. Preferably the solvent is an organic solvent which is immiscible with water or an aqueous salt solution, for example toluene or tetrahydrofuran. More preferably, the solvent is toluene.

In a preferred embodiment of the invention, the (α S, β R) -6-bromo- α - [2- (dimethylamino) ethyl group is released from the above-mentioned salt]The base of the-2-methoxy- α -1-naphthyl- β -phenyl-3-quinolineethanol is a carbonate or a phosphate. Preferably the base is K₂CO₃，KHCO₃，Na₂CO₃，NaHCO₃，Na₃PO₄Or Na₂HPO₄. More preferably, the base is K₂C_O3。

To improve the purity, the obtained (α S, β R) enantiomer may be further recrystallized in a suitable solvent such as ethanol or toluene as described later.

The invention also relates to (alpha S, beta R) -6-bromo-alpha- [2- (dimethylamino) ethyl]-2-methoxy- α -1-naphthyl- β -phenyl-3-quinolineethanol and chiral 4-hydroxydinaphtho [2, 1-d: 1 ', 2' -f][1，3，2]DioxaphosphanesSalts of 4-oxides or derivatives thereof, especially (alpha S, beta R) -6-bromo-alpha- [2- (dimethylamino) ethyl]-2-methoxy- α -1-naphthyl- β -phenyl-3-quinolineethanol (11bR) -4-hydroxydinaphtho [2, 1-d: 1 ', 2' -f][1，3，2]Dioxaphosphanes4-oxide salt.

Second embodiment

As already indicated above, according to the invention, a chiral 4-hydroxydinaphtho [2, 1-d: 1 ', 2' -f][1，3，2]Dioxaphosphanes4-oxide or its derivative as resolving agent, from 6-bromo-alpha- [2- (dimethylamino) ethyl by optical resolution]Separation of (α S, β R) -6-bromo- α - [2- (dimethylamino) ethyl ] ethanol from a mixture of stereoisomeric forms of (2-methoxy- α -1-naphthyl- β -phenyl-3-quinolineethanol]Another mode of the (E) -2-methoxy- α -1-naphthyl- β -phenyl-3-quinolineethanol is that wherein (α R, β S) -6-bromo- α - [2- (dimethylamino) ethyl]-2-methoxy-alpha-1-naphthyl-beta-phenyl-3-quinolineethanol and a salt of a resolving agent.

Accordingly, the present invention also relates to a method of using a 4-hydroxydinaphtho [2, 1-d: 1 ', 2' -f][1，3，2]Dioxaphosphanes4-oxide or its derivative as resolving agent, from 6-bromo-alpha- [2- (dimethylamino) ethyl]Separation of (α S, β R) -6-bromo- α - [2- (dimethylamino) ethyl ] ethanol from a mixture of stereoisomeric forms of (2-methoxy- α -1-naphthyl- β -phenyl-3-quinolineethanol]Process for the preparation of (2-methoxy- α -1-naphthyl- β -phenyl-3-quinolineethanol, wherein (α S, β R) -6-bromo- α - [2- (dimethylamino) ethyl]-2-methoxy- α -1-naphthyl- β -phenyl-3-quinolineethanol and a salt of a resolving agent, the process comprising:

a) reacting a mixture of stereoisomeric forms of 6-bromo- α - [2- (dimethylamino) ethyl ] -2-methoxy- α -1-naphthyl- β -phenyl-3-quinolineethanol with a resolving agent in a suitable solvent;

b) isolating the salt formed by (α R, β S) -6-bromo- α - [2- (dimethylamino) ethyl ] -2-methoxy- α -1-naphthyl- β -phenyl-3-quinolineethanol and the resolving agent from the reaction mixture in a);

c) (α S, β R) -6-bromo- α - [2- (dimethylamino) ethyl ] -2-methoxy- α -1-naphthyl- β -phenyl-3-quinolineethanol is isolated from the residual mother liquor obtained after separation of the formed salt from the reaction mixture.

For theThis alternative method, (11bS) -4-hydroxydinaphtho [2, 1-d: 1 ', 2' -f][1，3，2]Dioxaphosphanes4-oxide is the preferred resolving agent, and the invention therefore also relates to the use of (11bS) -4-hydroxydinaphtho [2, 1-d: 1 ', 2' -f][1，3，2]Dioxaphosphanes4-oxide as resolving agent, from 6-bromo-alpha- [2- (dimethylamino) ethyl by optical resolution]Separation of (α S, β R) -6-bromo- α - [2- (dimethylamino) ethyl ] ethanol from a mixture of stereoisomeric forms of (2-methoxy- α -1-naphthyl- β -phenyl-3-quinolineethanol]Process for the preparation of (2-methoxy- α -1-naphthyl- β -phenyl-3-quinolineethanol, wherein (α R, β S) -6-bromo- α - [2- (dimethylamino) ethyl]-2-methoxy- α -1-naphthyl- β -phenyl-3-quinolineethanol and crystalline salts of the resolving agent, said process comprising:

a) reacting a mixture of stereoisomeric forms of 6-bromo- α - [2- (dimethylamino) ethyl ] -2-methoxy- α -1-naphthyl- β -phenyl-3-quinolineethanol with said resolving agent in a suitable solvent;

b) separating (α R, β S) -6-bromo- α - [2- (dimethylamino) ethyl ] -2-methoxy- α -1-naphthyl- β -phenyl-3-quinolineethanol and the salt formed by the resolving agent from the reaction mixture obtained in a);

c) (α S, β R) -6-bromo- α - [2- (dimethylamino) ethyl ] -2-methoxy- α -1-naphthyl- β -phenyl-3-quinolineethanol is isolated from the residual mother liquor obtained after separation of the formed salt from the reaction mixture.

In the above-mentioned alternative process, the solvent used in a) and the resolving agent (in particular (11bS) -4-hydroxydinaphtho [2, 1-d: 1 ', 2' -f][1，3，2]Dioxaphosphanes4-oxide) in a similar manner as described above for the first embodiment. Therefore, what is needed isThe preferred embodiment with the above-mentioned amounts of solvent and resolving agent in a) also applies to the second embodiment.

The seeding step described above for the first embodiment is also applicable to the second embodiment, which means that a preferred embodiment of this alternative process comprises a process wherein (α R, β S) -6-bromo- α - [2- (dimethylamino) ethyl) -is added to the reaction mixture of a)]-2-methoxy- α -1-naphthyl- β -phenyl-3-quinolineethanol and chiral 4-hydroxydinaphtho [2, 1-d: 1 ', 2' -f][1，3，2]DioxaphosphanesSeeds of salts of 4-oxides or derivatives thereof, especially with (alpha R, beta S) -6-bromo-alpha- [2- (dimethylamino) ethyl]-2-methoxy- α -1-naphthyl- β -phenyl-3-quinolineethanol (11bS) -4-hydroxydinaphtho [2, 1-d: 1 ', 2' -f][[1，3，2]Dioxaphosphanes4-oxide salt seed crystal, and adding nucleus for crystallization. The seed crystals may be added before or after the addition of the resolving agent to the reaction mixture, or preferably both before and after, similar to that described for the first embodiment.

(alpha R, beta S) -6-bromo-alpha- [2- (dimethylamino) ethyl]-2-methoxy- α -1-naphthyl- β -phenyl-3-quinolineethanol and chiral 4-hydroxydinaphtho [2, 1-d: 1 ', 2' -f][1，3，2]DioxaphosphanesSeeds of salts of 4-oxides or derivatives thereof, especially (alpha R, beta S) -6-bromo-alpha- [2- (dimethylamino) ethyl]-2-methoxy- α -1-naphthyl- β -phenyl-3-quinolineethanol (11bS) -4-hydroxydinaphtho [2, 1-d: 1 ', 2' -f][1，3，2]DioxaphosphanesSeeds of the 4-oxide salt may be obtained by a method previously carried out according to the second embodiment.

For the second embodiment, it is also preferred to add the resolving agent to the reaction mixture in solution. The solvents described above for the first embodiment can also be used for the second embodiment.

In a preferred embodiment of this alternative process, the mixture of stereoisomeric forms of 6-bromo- α - [2- (dimethylamino) ethyl ] -2-methoxy- α -1-naphthyl- β -phenyl-3-quinolineethanol is diastereomer A.

Because of (alpha R, beta S) -6-bromo-alpha- [2- (dimethylamino) ethyl]-2-methoxy- α -1-naphthyl- β -phenyl-3-quinolineethanol with a chiral 4-hydroxydinaphtho [2, 1-d: 1 ', 2' -f][1，3，2]DioxaphosphanesSalts of 4-oxides or derivatives thereof, especially (alpha R, beta S) -6-bromo-alpha- [2- (dimethylamino) ethyl]-2-methoxy- α -1-naphthyl- β -phenyl-3-quinolineethanol (11bS) -4-hydroxydinaphtho [2, 1-d: 1 ', 2' -f][1，3，2]DioxaphosphanesThe 4-oxide salt, crystallizes out and can be separated from the reaction mixture, for example by filtration.

When diastereomer A is used as 6-bromo-alpha- [2- (dimethylamino) ethyl]Mixtures of the stereoisomeric forms of (E) -2-methoxy- α -1-naphthyl- β -phenyl-3-quinolineethanol, the desired (α S, β R) enantiomer can be separated from the remaining mother liquor, for example, by extraction with a suitable solvent. Examples of suitable extraction solvents are toluene and aqueous alkaline solutions, e.g. K₂CO₃The residual amount of resolving agent in the aqueous, mother liquor will remain in the basic aqueous layer, while the desired (α S, β R) enantiomer is present in the organic layer. After separation of the organic layer from the aqueous layer by methods well known to those skilled in the art, the organic layer may be concentrated to dryness, e.g., dried under vacuum, to provide the desired (α S, β R) enantiomer.

Alternatively, the (α S, β R) enantiomer may be separated from the residual mother liquor by the method of the first embodiment. The mother liquor is actually a mixture of stereoisomeric forms in which the desired (α S, β R) enantiomer is overwhelmingly dominant over the (α R, β S) enantiomer.

The resulting (α S, β R) enantiomer may be further recrystallized in a suitable solvent as described later.

6-bromo-alpha- [2- (dimethylamino) ethyl]-2-methoxy-alpha-1-naphthyl-beta Synthesis of a mixture of stereoisomeric forms of (E) -phenyl-3-quinolineethanol

The mixture of stereoisomeric forms of 6-bromo- α - [2- (dimethylamino) ethyl ] -2-methoxy- α -1-naphthyl- β -phenyl-3-quinolineethanol, which comprises diastereomer a, from which the desired enantiomer (α S, β R) -6-bromo- α - [2- (dimethylamino) ethyl ] -2-methoxy- α -1-naphthyl- β -phenyl-3-quinolineethanol can be isolated, can be prepared according to the protocol disclosed in WO2004/011436, which is incorporated herein by reference.

Alternatively, a mixture of stereoisomeric forms of 6-bromo- α - [2- (dimethylamino) ethyl ] -2-methoxy- α -1-naphthyl- β -phenyl-3-quinolineethanol may also be prepared by reacting 3-benzyl-6-bromo-2-methoxyquinoline with lithium diisopropylamide and (3-dimethylamino) -1' -ethylnaphthalenylmethanone in a suitable solvent, e.g. in a non-polar aprotic solvent such as an ether, preferably in tetrahydrofuran, preferably at low temperatures, e.g. below 0 ℃, more preferably at-70 to-80 ℃, followed by addition of a suitable acid, e.g. acetic acid.

The mixture of stereoisomeric forms of 6-bromo- α - [2- (dimethylamino) ethyl ] -2-methoxy- α -1-naphthyl- β -phenyl-3-quinolineethanol thus obtained can optionally be enriched in diastereomer a in the following manner: diastereomer B, prepared beforehand according to the process of the invention or obtained according to the scheme described in WO2004/011436, is added as seed to the reaction mixture in order to promote crystallization of diastereomer B, which is then filtered off. The resulting mixture of stereoisomeric forms may optionally be further enriched in diastereomer a by crystallization from a suitable solvent, e.g. ethanol. Enrichment (or purification) of a particular diastereomer or enantiomer in the reaction mixture means that the proportion of the particular diastereomer or enantiomer is increased.

Accordingly, the present invention also relates to a process for the preparation of (α S, β R) -6-bromo- α - [2- (dimethylamino) ethyl ] -2-methoxy- α -1-naphthyl- β -phenyl-3-quinolineethanol, which process comprises:

a) 3-benzyl-6-bromo-2-methoxyquinoline with lithium diisopropylamide and (3-dimethylamino) -1' -ethylnaphthalenylmethanone in a suitable solvent, e.g. an aprotic apolar solvent such as ether, preferably in tetrahydrofuran, at low temperature, e.g. at a temperature below 0 ℃, followed by addition of a suitable acid, e.g. acetic acid; and

b) using a chiral 4-hydroxydinaphtho [2, 1-d: 1 ', 2' -f][1，3，2]Dioxaphosphanes4-oxide or derivative thereof, in particular (11bR) -4-hydroxydinaphtho [2, 1-d: 1 ', 2' -f][1，3，2]Dioxaphosphanes4-oxide, 6-bromo-alpha- [2- (dimethylamino) ethyl group obtained from a) according to the process described hereinbefore, in particular according to the process of the first embodiment]Separation of (alpha S, beta R) -6-bromo-alpha- [2- (dimethylamino) ethyl ] ethanol from a mixture of stereoisomeric forms of (2-methoxy-alpha-1-naphthyl-beta-phenyl-3-quinolineethanol]-2-methoxy- α -1-naphthyl- β -phenyl-3-quinolineethanol.

In other words, the present invention also relates to a process for the separation of (α S, β R) -6-bromo- α - [2- (dimethylamino) ethyl ] -2-methoxy- α -1-naphthyl- β -phenyl-3-quinolineethanol from a mixture of stereoisomeric forms of 6-bromo- α - [2- (dimethylamino) ethyl ] -2-methoxy- α -1-naphthyl- β -phenyl-3-quinolineethanol according to the process described above, wherein the mixture of stereoisomeric forms is prepared as follows:

a) 3-benzyl-6-bromo-2-methoxyquinoline with lithium diisopropylamide and (3-dimethylamino) -1' -ethylnaphthylmethanone in a suitable solvent, e.g. in a non-polar aprotic solvent such as an ether, preferably in tetrahydrofuran, preferably at low temperature, e.g. below 0 ℃, followed by addition of a suitable acid, e.g. acetic acid.

The invention also relates to a method comprising

a) 3-benzyl-6-bromo-2-methoxyquinoline with lithium diisopropylamide and (3-dimethylamino) -1' -ethylnaphthalenylmethanone in a suitable solvent, e.g. in a non-polar aprotic solvent such as an ether, preferably in tetrahydrofuran, preferably at low temperature, e.g. below 0 ℃, followed by addition of a suitable acid, e.g. acetic acid;

b) enriching (or purifying) the (α S, β R) -6-bromo- α - [2- (dimethylamino) ethyl ] -2-methoxy- α -1-naphthyl- β -phenyl-3-quinolineethanol in the reaction mixture obtained in a) with (α R by removing from the reaction mixture a racemic mixture of (α R, β S) -6-bromo- α - [2- (dimethylamino) ethyl ] -2-methoxy- α -1-naphthyl- β -phenyl-3-quinolineethanol and (α S, β R) -6-bromo- α - [2- (dimethylamino) ethyl ] -2-methoxy- α -1-naphthyl- β -phenyl-3-quinolineethanol, a racemic mixture of β S) -6-bromo- α - [2- (dimethylamino) ethyl ] -2-methoxy- α -1-naphthyl- β -phenyl-3-quinolineethanol;

c) according to the process described hereinbefore, in particular the process of the first embodiment, the chiral 4-hydroxydinaphtho [2, 1-d: 1 ', 2' -f][1，3，2]Dioxaphosphanes4-oxide or derivative thereof, in particular (11bR) -4-hydroxydinaphtho [2, 1-d: 1 ', 2' -f][1，3，2]Dioxaphosphanes4-oxide, 6-bromo-alpha- [2- (dimethylamino) ethyl group obtained from b)]Stereoisomers of (E) -2-methoxy-alpha-1-naphthyl-beta-phenyl-3-quinolineethanolIsolation of (alpha S, beta R) -6-bromo-alpha- [2- (dimethylamino) ethyl group from the mixture of forms]-2-methoxy- α -1-naphthyl- β -phenyl-3-quinolineethanol.

Or in other words, the present invention also relates to a process for the separation of (α S, β R) -6-bromo- α - [2- (dimethylamino) ethyl ] -2-methoxy- α -1-naphthyl- β -phenyl-3-quinolineethanol from a mixture of stereoisomeric forms of 6-bromo- α - [2- (dimethylamino) ethyl ] -2-methoxy- α -1-naphthyl- β -phenyl-3-quinolineethanol obtained according to the process described above, wherein the mixture of stereoisomeric forms is prepared as follows:

a) 3-benzyl-6-bromo-2-methoxyquinoline with lithium diisopropylamide and (3-dimethylamino) -1' -ethylnaphthalenylmethanone in a suitable solvent, e.g. in a non-polar aprotic solvent such as an ether, preferably in tetrahydrofuran, preferably at low temperature, e.g. below 0 ℃, followed by addition of a suitable acid, e.g. acetic acid;

b) enriching (purifying) the mixture obtained in a) for (α S, β R) -6-bromo- α - [2- (dimethylamino) ethyl ] -2-methoxy- α -1-naphthyl- β -phenyl-3-quinolineethanol with (α R, a racemic mixture of β S) -6-bromo- α - [2- (dimethylamino) ethyl ] -2-methoxy- α -1-naphthyl- β -phenyl-3-quinolineethanol.

The invention also relates to a method comprising:

a) 3-benzyl-6-bromo-2-methoxyquinoline with lithium diisopropylamide and (3-dimethylamino) -1' -ethylnaphthylmethanone in a suitable solvent, e.g. in a non-polar aprotic solvent such as an ether, preferably in tetrahydrofuran, preferably at low temperature, e.g. below 0 ℃, followed by addition of a suitable acid, e.g. acetic acid;

b) enriching (or purifying) the reaction mixture obtained in a) for (α S, β R) -6-bromo- α - [2- (dimethylamino) ethyl ] -2-methoxy- α -1-naphthyl- β -phenyl-3-quinolineethanol and (α R, a racemic mixture of β S) -6-bromo- α - [2- (dimethylamino) ethyl ] -2-methoxy- α -1-naphthyl- β -phenyl-3-quinolineethanol;

c) crystallizing the stereoisomeric form of 6-bromo- α - [2- (dimethylamino) ethyl ] -2-methoxy- α -1-naphthyl- β -phenyl-3-quinolineethanol formed in the reaction mixture in a suitable solvent, e.g. in an alcohol or an ether/alcohol mixture, preferably in an alcohol, wherein the alcohol is preferably ethanol and the ether is preferably tetrahydrofuran;

d) according to the process described hereinbefore, in particular the process of the first embodiment, the chiral 4-hydroxydinaphtho [2, 1-d: 1 ', 2' -f][1，3，2]Dioxaphosphanes4-oxide or derivative thereof, in particular (11bR) -4-hydroxydinaphtho [2, 1-d: 1 ', 2' -f][1，3，2]Dioxaphosphanes4-oxide, 6-bromo-alpha- [2- (dimethylamino) ethyl group obtained from c)]Separation of (alpha S, beta R) -6-bromo-alpha- [2- (dimethylamino) ethyl ] ethanol from a mixture of stereoisomeric forms of (2-methoxy-alpha-1-naphthyl-beta-phenyl-3-quinolineethanol]-2-methoxy- α -1-naphthyl- β -phenyl-3-quinolineethanol.

Or put another way, the present invention also relates to a process for the separation of (α S, β R) -6-bromo- α - [2- (dimethylamino) ethyl ] -2-methoxy- α -1-naphthyl- β -phenyl-3-quinolineethanol from a mixture of stereoisomeric forms of 6-bromo- α - [2- (dimethylamino) ethyl ] -2-methoxy- α -1-naphthyl- β -phenyl-3-quinolineethanol according to the process described above, wherein the mixture of stereoisomeric forms is obtained by the following steps:

a) reaction of 3-benzyl-6-bromo-2-methoxyquinoline with lithium diisopropylamide and (3-dimethylamino) -1' -ethylnaphthalenylmethanone in a suitable solvent, e.g. an apolar aprotic solvent such as an ether, preferably in tetrahydrofuran, preferably at low temperature, e.g. at a temperature below 0 ℃, followed by addition of a suitable acid, e.g. acetic acid;

b) removing from the reaction mixture a racemic mixture of (α S, β S) -6-bromo- α - [2- (dimethylamino) ethyl ] -2-methoxy- α -1-naphthyl- β -phenyl-3-quinolineethanol and (α R, β R) -6-bromo- α - [2- (dimethylamino) ethyl ] -2-methoxy- α -1-naphthyl- β -phenyl-3-quinolineethanol, (α S, β R) -6-bromo- α - [2- (dimethylamino) ethyl ] -2-methoxy- α -1-naphthyl- β -phenyl-3-quinolineethanol and (α R, enrichment (purification) of the racemic mixture of β S) -6-bromo- α - [2- (dimethylamino) ethyl ] -2-methoxy- α -1-naphthyl- β -phenyl-3-quinolineethanol;

c) crystallizing the obtained stereoisomeric form of 6-bromo- α - [2- (dimethylamino) ethyl ] -2-methoxy- α -1-naphthyl- β -phenyl-3-quinolineethanol from the reaction mixture obtained in b) in a suitable solvent.

Experimental part

A.6-bromo-alpha- [2- (dimethylamino) ethyl]-2-methoxy-alpha-1-naphthyl-beta Preparation of a mixture of stereoisomeric forms of (E) -phenyl-3-quinolineethanol

Step A

(3-dimethylamino) -1' -ethylnaphthylmethanone hydrochloride (48.47g, 183.8mmol) was dissolved in water (157.5g), and stirred at room temperature for 5 to 10 minutes. A30% aqueous solution of sodium hydroxide (51.46g, 386mmol) was added and the reaction mixture was stirred for 10-15 minutes. Toluene (105g) was added, the mixture was stirred for 10-15 minutes, and then the layers were separated. Water (100g) was added to the organic layer, stirring was continued for 10-15 minutes, and then the two layers were separated. The organic layer was concentrated under reduced pressure at 50-60 ℃ to give 98.2% of (3-dimethylamino) -1' -ethylnaphthalenemenone.

Step B

In N₂To tetrahydrofuran (74g) was added a 25% solution of lithium diisopropylamide (92.4g, 228mmol) in tetrahydrofuran, heptane and ethylbenzene at 20-25 deg.C. The solution was cooled to-70 to-80 ℃ and 3-benzyl-6-bromo-2-methoxyquinoline (57.4g, 175mmol) in tetrahydrofuran (74g) was added dropwise over 90 minutes (80-150 minutes). The reaction mixture was stirred at-70 to-80 ℃ for 90 minutes (80 to 150 minutes).

To the reaction mixture was added dropwise a solution of (3-dimethylamino) -1' -ethylnaphthalenylmethanone (45.7g, 175mmol, prepared according to step A) in tetrahydrofuran (74g) at-70 ℃ to-80 ℃ over 90(80-150) minutes. The reaction mixture was stirred at-70 to-80 ℃ for 14 hours (8 to 15 hours).

Step C

The reaction mixture obtained in step B was added to a pre-cooled (-10 ℃ C.) solution of acetic acid (39g, 438mmol) in tetrahydrofuran (39g) over 10 to 30 minutes. 15 minutes after the addition, seed crystals of diastereomer B (0.05g, 0.1mmol) obtained in the previous preparation were added to the mixture, and the reaction mixture was stirred at 0 to 5 ℃ for 6 hours (5 to 7 hours). Water (200g) was added dropwise over 5 to 30 minutes and the reaction mixture was stirred at 0 to 5 ℃ for 30 to 40 minutes. Diastereomer B was filtered off and washed 2 times with tetrahydrofuran (20 g each time). The two layers were separated. The organic mother liquor layer was concentrated under reduced pressure at 50 to 55 ℃. Ethanol (250g) was added and the reaction mixture was further concentrated under reduced pressure at 50 to 60 ℃. The mixture is cooled to 0 ℃ (-5 to 5 ℃) in 0.5 to 1.5 hours, and stirred at this temperature for 1 to 2 hours, followed by filtration. The filter residue was washed 2 times with ethanol (50 g each time) and the product obtained was dried in vacuo at 80 deg.C (75 to 85 deg.C). 37.48g of a solid were obtained which contained 82.7% (w/w) diastereomer A and 7.7% (w/w) diastereomer B.

B. Using (11bR) -4-hydroxydinaphtho [2, 1-d: 1 ', 2' -f][1，3，2]Dioxaphosphanes 4 Separation of the specific enantiomer (α S, β R) -6 from the mixture of stereoisomeric forms -bromo-alpha- [2- (dimethylamino) ethyl]-2-methoxy-alpha-1-naphthyl-beta-benzene 3-quinolineethanol

The solid obtained in step C (30.45g, 50mmol, 1 eq.) was suspended in acetone (193.3g) at a temperature of 20 to 30 ℃. To this suspension was added (α S, β R) 6-bromo- α - [2- (dimethylamino) ethyl group obtained in the previous preparation]-2-methoxy- α -1-naphthyl- β -phenyl-3-quinolineethanol (11bR) -4-hydroxydinaphtho [2, 1-d: 1 ', 2' -f][1，3，2]Dioxaphosphanes4-oxide salt is added with nucleus for crystallization. Reacting (11bR) -4-hydroxydinaphtho [2, 1-d: 1 ', 2' -f][1，3，2]Dioxaphosphanes4-oxide (17.60g, 50mmol, 1 eq.) was dissolved in dimethyl sulfoxide (38.7g) at 40 to 50 ℃ and this solution was added to the above acetone suspension over 5 to 15 minutes via a funnel. The reaction mixture is then used again in the previous preparation process(alpha S, beta R) -6-bromo-alpha- [2- (dimethylamino) ethyl group obtained in (1)]-2-methoxy- α -1-naphthyl- β -phenyl-3-quinolineethanol (11bR) -4-hydroxydinaphtho [2, 1-d: 1 ', 2' -f][1，3，2]Dioxaphosphanes4-oxide salt (9mg, 0.016mmol) was subjected to crystallization by addition of nuclei. The resulting suspension was stirred for 60 minutes (45 to 75 minutes) and then heated to reflux. The suspension was stirred under reflux for 60 minutes (45 to 75 minutes), then cooled to 25 ℃ over 30 to 60 minutes (20 to 30 ℃) and stirred at 20 to 30 ℃ for 1 hour. The solid formed is filtered off and washed 2 times with acetone (62.5 g each time). The resulting residue (59g) was suspended in acetone (185.4g), and the suspension was heated to reflux, stirred under reflux for 2 hours (1.5 to 2.5 hours), then cooled to 25 ℃ over 30 to 45 minutes (20 to 30 ℃) and stirred for 45 to 75 minutes. The solid formed was filtered off and washed with acetone (47g) followed by toluene (55 g).

The resulting solid (54.96g) was suspended in toluene (40.3g) and dissolved in 10% potassium carbonate solution (4.23g K)₂CO₃In 38.02g of purified water). The mixture was heated to 80-85 ℃ and the aqueous layer was separated.

To the organic layer was added potassium carbonate solution (0.4 eq, 1.23g K)₂CO₃In 11.07g of purified water). After stirring for 5 to 15 minutes, the aqueous layer was separated and the organic layer was washed with purified water (11.8g) at 80 to 85 ℃.

The organic layer was concentrated under reduced pressure at 55 deg.C (50 to 60 deg.C). The residue was treated with ethanol (69g) at a temperature of 45 to 50 ℃ or more, followed by cooling to 0 to 5 ℃ over 0.5 to 1.5 hours, and stirring at this temperature for 0.5 to 1 hour. The solid formed is filtered off, washed twice with ethanol (18 g each), and dried in vacuo at 70 ℃ (65 to 75 ℃). Yield: (α S, β R) -6-bromo- α - [2- (dimethylamino) ethyl ] -2-methoxy- α -1-naphthyl- β -phenyl-3-quinolineethanol in an amount of 39% by weight (or 78% by weight calculated on the desired enantiomer) (HPLC purity: > 99.6%; enantiomeric excess > 99.8%; m.p.182-184 ℃ C.).

Purity was determined by HPLC using a YMC-Pack ODS-AQ (150X 4.6mm, 3 μm) column, mobile phase: mobile phase A: water/trifluoroacetic acid (1000mL/1 mL); mobile phase B: acetonitrile/trifluoroacetic acid (1000mL/0.8 mL); eluent gradient from 75% A and 25% B → 10% A and 90% B.

The enantiomeric excess was determined by HPLC using a Cyclobond I RSP (250X 4.6mm) column and the mobile phase was MeOH/water/ammonium acetate (60mL/40mL/0.154g) adjusted to pH 7 with acetic acid.

The resulting product (19.0g) was suspended in toluene (10.96g), heated to 90 ℃ and the mixture was filtered while hot, and the filter was washed with toluene (1.5 g). The solution was cooled to 70 ℃ and ethanol (22.16g) was added dropwise. During the addition of ethanol, the product starts to crystallize (optionally a few mg of (. alpha.S,. beta.R) 6-bromo-. alpha. - [2- (dimethylamino) ethyl ] -2-methoxy-. alpha. -1-naphthyl-. beta. -phenyl-3-quinolineethanol are added). Ethanol (32.31g) was added dropwise at 65 ℃ and the suspension was cooled to 0 ℃ and stirred for 1 hour. The residue was filtered off and washed with ethanol in two portions (52 g). The resulting product was dried (40-70 ℃ C.) to yield 17.07g (. alpha.S,. beta.R) -6-bromo-. alpha. [2- (dimethylamino) ethyl ] -2-methoxy-. alpha. -1-naphthyl-. beta. -phenyl-3-quinolineethanol.

Claims (31)

1. A method of using a chiral 4-hydroxydinaphtho [2, 1-d: 1 ', 2' -f][1，3，2]Dioxaphosphanes4-oxide as resolving agent, from 6-bromo-alpha- [2- (dimethylamino) ethyl by optical resolution]Separation of (α S, β R) -6-bromo- α - [2- (dimethylamino) ethyl ] ethanol from a mixture of stereoisomeric forms of (2-methoxy- α -1-naphthyl- β -phenyl-3-quinolineethanol]-2-methoxy-alpha-1-naphthyl-beta-phenyl-3-quinolineethanol,the method comprises

a) Reacting a mixture of stereoisomeric forms of 6-bromo- α - [2- (dimethylamino) ethyl ] -2-methoxy- α -1-naphthyl- β -phenyl-3-quinolineethanol with said resolving agent in a suitable solvent;

b) separating a crystalline salt of (α S, β R) -6-bromo- α - [2- (dimethylamino) ethyl ] -2-methoxy- α -1-naphthyl- β -phenyl-3-quinolineethanol formed with said resolving agent from the reaction mixture obtained in a);

c) optionally recrystallizing or slurrying the salt obtained in b) in a suitable solvent;

d) liberating (α S, β R) -6-bromo- α - [2- (dimethylamino) ethyl ] -2-methoxy- α -1-naphthyl- β -phenyl-3-quinolineethanol from the salt obtained in b) or c), wherein formula (1) is as follows

Wherein

n is an integer equal to 1 or 2;

R_1aand R_1bEach independently represents hydrogen, halogen, C optionally substituted by aryl_1-12Alkyl, aryl, naphthyl, Si (phenyl)₃；C_1-6Alkoxy, anthracenyl, C optionally substituted by aryl_2-6An alkynyl group;

R_2aand R_2bEach independently represents hydrogen, halogen, C optionally substituted by aryl_1-12Alkyl, aryl, C_2-12Alkenyl, C optionally substituted by phenyl_1-6Alkoxy, nitro, hydroxy;

in the presence of a compound represented by 4-hydroxydinaphtho [2, 1-d: 1 ', 2' -f][1，3，2]DioxaphosphanesR in the 14 and 15 positions of the 4-oxide_2aOr together with the two R_2aThe naphthalene rings to which the substituents are all attached together form 13-methyl-12, 13, 14, 15, 16, 17-hexahydro-11H-cyclopenta [ a]Phenanthrene;

in 4-hydroxydinaphthalenesAnd [2, 1-d: 1 ', 2' -f][1，3，2]DioxaphosphanesR in the 8-and 9-positions of the 4-oxide_2bOr together with the two R_2bThe naphthalene rings to which the substituents are all attached together form 13-methyl-12, 13, 14, 15, 16, 17-hexahydro-11H-cyclopenta [ a]Phenanthrene;

aryl is phenyl or phenyl substituted with one, two or three substituents each independently selected from the group consisting of: c_1-6Alkyl, polyhalo C_1-6Alkyl, C substituted by phenyl_1-6Alkoxy, optionally selected from C_1-6Alkyl or naphthyl, or phenyl substituted with one, two or three substituents,

wherein a suitable solvent in a) is a ketone, an ester, a mixture of a ketone and an aprotic polar solvent or a mixture of an ester and an aprotic polar solvent,

wherein the recrystallization or slurrying step of c) is carried out in acetone, N-dimethylformamide, an N, N-dimethylformamide/water mixture, a dimethyl sulfoxide/acetone mixture, a dimethyl sulfoxide/alcohol mixture or an N, N-dimethylformamide/alcohol mixture.

2. A process according to claim 1 wherein the resolving agent is (11bR) -4-hydroxydinaphtho [2, 1-d: 1 ', 2' -f][1，3，2]Dioxaphosphanes4-oxide.

3. The process of claim 1 or 2, wherein the suitable solvent in a) is a ketone or a mixture of a ketone and an aprotic polar solvent.

4. A process according to claim 3, wherein the ketone is acetone or methyl ethyl ketone and the aprotic polar solvent is dimethyl sulfoxide or N, N-dimethylformamide.

5. A process according to claim 3, wherein the solvent is acetone.

6. A process according to claim 3, wherein the solvent is a mixture of acetone and dimethyl sulfoxide.

7. The process of any of claims 1 to 6, wherein the reaction mixture in a) is seeded with (α S, β R) -6-bromo- α - [2- (dimethylamino) ethyl ] -2-methoxy- α -1-naphthyl- β -phenyl-3-quinolineethanol and a salt of the resolving agent before the resolving agent as defined in claim 1 or 2 is added.

8. The process of any of claims 1 to 6, wherein the reaction mixture in a) is, after addition of the resolving agent as defined in claim 1 or 2, additionally seeded with (α S, β R) -6-bromo- α - [2- (dimethylamino) ethyl ] -2-methoxy- α -1-naphthyl- β -phenyl-3-quinolineethanol and a salt of the resolving agent.

9. The process of any of claims 1 to 6, wherein the reaction mixture in a) is seeded with a salt of (α S, β R) -6-bromo- α - [2- (dimethylamino) ethyl ] -2-methoxy- α -1-naphthyl- β -phenyl-3-quinolineethanol with a resolving agent, both before and after addition of the resolving agent as defined in claim 1 or 2.

10. A process according to any one of claims 1 to 9, wherein the resolving agent is added to a solution of a mixture of stereoisomeric forms of 6-bromo- α - [2- (dimethylamino) ethyl ] -2-methoxy- α -1-naphthyl- β -phenyl-3-quinolineethanol in a suitable solvent, wherein the suitable solvent is an aprotic polar solvent.

11. A process according to claim 10, wherein the aprotic polar solvent is dimethyl sulfoxide, N-dimethylformamide, N-dimethylacetamide or N-methylpyrrolidone.

12. A process according to claim 11, wherein the aprotic polar solvent is dimethyl sulfoxide or N, N-dimethylformamide.

13. A process according to claim 12, wherein the aprotic polar solvent is dimethyl sulfoxide.

14. The process of claim 13, wherein the recrystallization or slurrying is performed in acetone.

15. The process of any one of claims 1 to 14 wherein the liberation of the base from the salt in d) is effected by reacting the salt with a suitable base in a suitable solvent, wherein the suitable solvent is an organic solvent immiscible with water or an aqueous salt solution, wherein the base is a carbonate or a phosphate.

16. A process according to claim 15 wherein the solvent is toluene or tetrahydrofuran.

17. A process according to claim 16, wherein the solvent is toluene.

18. The process of any one of claims 15 to 17, wherein the base is K₂CO₃，KHCO₃，Na₂CO₃，NaHCO₃，Na₃PO₄Or Na₂HPO₄。

19. A process according to claim 18In which the base is K₂CO₃。

20. The process of any of claims 1 to 19, wherein the resolving agent is used in an amount of 0.5 to 1.5 equivalents, calculated as the sum of the stereoisomeric forms of 6-bromo- α - [2- (dimethylamino) ethyl ] -2-methoxy- α -1-naphthyl- β -phenyl-3-quinolineethanol present in the mixture in a).

21. A process according to claim 20, wherein the resolving agent is used in an amount of 1 equivalent, calculated as the sum of the stereoisomeric forms of 6-bromo- α - [2- (dimethylamino) ethyl ] -2-methoxy- α -1-naphthyl- β -phenyl-3-quinolineethanol present in the mixture in a).

22. The process of any one of claims 1 to 21, wherein the mixture of stereoisomeric forms of 6-bromo- α - [2- (dimethylamino) ethyl ] -2-methoxy- α -1-naphthyl- β -phenyl-3-quinolineethanol is one in which the racemic mixture of (α S, β R) -6-bromo- α - [2- (dimethylamino) ethyl ] -2-methoxy- α -1-naphthyl- β -phenyl-3-quinolineethanol and (α R, β S) -6-bromo- α - [2- (dimethylamino) ethyl ] -2-methoxy- α -1-naphthyl- β -phenyl-3-quinolineethanol predominate.

23. A process for the separation of (α S, β R) -6-bromo- α - [2- (dimethylamino) ethyl ] -2-methoxy- α -1-naphthyl- β -phenyl-3-quinolineethanol from a mixture of stereoisomeric forms of 6-bromo- α - [2- (dimethylamino) ethyl ] -2-methoxy- α -1-naphthyl- β -phenyl-3-quinolineethanol as claimed in any of claims 1 to 22, wherein the mixture of stereoisomeric forms is obtained in the following manner

a) 3-benzyl-6-bromo-2-methoxyquinoline is reacted with lithium diisopropylamide and (3-dimethylamino) -1' -ethylnaphthalenylmethanone in a nonpolar aprotic solvent, followed by addition of an acid.

24. A process for the separation of (α S, β R) -6-bromo- α - [2- (dimethylamino) ethyl ] -2-methoxy- α -1-naphthyl- β -phenyl-3-quinolineethanol from a mixture of stereoisomeric forms of 6-bromo- α - [2- (dimethylamino) ethyl ] -2-methoxy- α -1-naphthyl- β -phenyl-3-quinolineethanol according to claim 23, wherein the mixture of stereoisomeric forms is obtained in the following manner

a) Reacting 3-benzyl-6-bromo-2-methoxyquinoline with lithium diisopropylamide and (3-dimethylamino) -1' -ethylnaphthalenylmethanone in a nonpolar aprotic solvent, followed by addition of an acid;

b) enriching the mixture obtained in a) in (α S, β R) -6-bromo- α - [2- (dimethylamino) ethyl ] -2-methoxy- α -1-naphthyl- β -phenyl-3-quinolineethanol with (α R, a racemic mixture of β S) -6-bromo- α - [2- (dimethylamino) ethyl ] -2-methoxy- α -1-naphthyl- β -phenyl-3-quinolineethanol.

25. A process according to claim 24, wherein the mixture of stereoisomeric forms is obtained by

a) Reacting 3-benzyl-6-bromo-2-methoxyquinoline with lithium diisopropylamide and (3-dimethylamino) -1' -ethylnaphthalenylmethanone in a nonpolar aprotic solvent, followed by addition of an acid;

b) enriching the reaction mixture obtained in a) for (α S, β R) -6-bromo- α - [2- (dimethylamino) ethyl ] -2-methoxy- α -1-naphthyl- β -phenyl-3-quinolineethanol and (α R, β R) -6-bromo- α - [2- (dimethylamino) ethyl ] -2-methoxy- α -1-naphthyl- β -phenyl-3-quinolineethanol by removing from the reaction mixture a racemic mixture of (α S, β S) -6-bromo- α - [2- (dimethylamino) ethyl ] -2-methoxy- α -1-naphthyl- β -phenyl-3-quinolineethanol and (α R, a racemic mixture of β S) -6-bromo- α - [2- (dimethylamino) ethyl ] -2-methoxy- α -1-naphthyl- β -phenyl-3-quinolineethanol; and

c) crystallizing the stereoisomeric form of 6-bromo-alpha- [2- (dimethylamino) ethyl ] -2-methoxy-alpha-1-naphthyl-beta-phenyl-3-quinolineethanol formed from the reaction mixture obtained in b) in a non-polar aprotic solvent,

wherein the nonpolar aprotic solvent in c) is an alcohol or an ether/alcohol mixture.

26. A process according to claim 25, wherein the non-polar aprotic solvent in c) is an alcohol.

27. A process according to claim 25 or 26, wherein the alcohol is ethanol.

28. A process according to any one of claims 23 to 27, wherein the apolar aprotic solvent is an ether.

29. A process according to claim 28 wherein the ether is tetrahydrofuran.

30. The process of any one of claims 23 to 29, wherein the reaction in a) is carried out at a temperature below 0 ℃.

31. Has the chemical formula of (alpha S, beta R) -6-bromo-alpha- [2- (dimethylamino) ethyl]-2-methoxy- α -1-naphthyl- β -phenyl-3-quinolineethanol (11bR) -4-hydroxydinaphtho [2, 1-d: 1 ', 2' -f][1，3，2]DioxaphosphanesA salt of 4-oxide.