WO2012097510A1

WO2012097510A1 - Process for preparation of efavirenz by cyclisation

Info

Publication number: WO2012097510A1
Application number: PCT/CN2011/070396
Authority: WO
Inventors: Danmei Dai; Xiangtian LONG; Bing Luo; Anna KULESZA; Jens Reichwagen; Yanming Guo
Original assignee: Lonza Ltd; Lonza Guangzhou Research And Development Center Ltd
Priority date: 2011-01-19
Filing date: 2011-01-19
Publication date: 2012-07-26

Abstract

The invention disclosed a process for the preparation of the HIV drug Efavirenz, also known as DMP-266, starting from 1,4-dichlorobenzene, and its intermediates.

Description

PROCESS FOR PREPARATION OF EFAVIRENZ BY CYCLISATION

The invention disclosed a process for the preparation of the HIV drug Efavirenz, also known as DMP-266, starting from 1 ,4-dichlorobenzene, and its intermediates.

Efavirenz is an active pharmaceutical ingredient nowadays used as a HIV reverse transcriptase inhibitor in respective drugs.

WO 98/51676 A discloses the method for preparation of Efavirenz, which is currently used. This method starts from 4-chloro aniline. In this method, the amino group of the 4-chloro aniline needs to be protected prior to the addition of the

trifluoromethylketone moiety and afterwards deprotected, which represents additional process steps. Deprotection requires partially drastic conditions and reduces the overall yield and increases production costs.

Jiang, Wang and Yang in Tett. Lett (2001), 42 (24), 4083-4085 disclose a process which avoids protection and deprotection steps by application of a 5 step procedure starting from nitro-bromo-chloro benzene. This method requires reactions including the use of NaI0₄ and Os0₄, a Pd catalyzed coupling reaction and a Ni catalyzed reduction to obtain trifluoromethyl-(2-amino-5-chloro-phenyl)ketone.

The consecutive steps to obtain Efavirenz include the ring closure of

(S)-2-(2-amino-5-chlorophenyl)-4-cyclopropyl-l , 1 , 1 -trifluorobut-3-yn-2-ol under the application of phosgene or a phosgene derivative like diphosgene or triphosgene. Some of these reagents are explosive, some of these reagents are highly toxic, the application of some of these reagents is even prohibited in some countries. Therefore it is difficult, dangerous and expensive to carry out this method on large scale and its realization is geographically limited.

There was a need for a simplified process which does not have the protection and the deprotection steps of the known process, further there was a need for a process which does not use the mentioned explosive, toxic and/or prohibited substances, and which reduces the number of process steps. Further there was a need for a process with high yields, high stereoselectivity and/or reduced process complexity.

The following abbreviations are used, if not otherwise stated:

dppf 1 , 1 ' -bis(diphenylphosphino)ferrocene

OTf Trifluoromethanesulfonate, also known by the trivial name triflate, CF₃SO₃ Ts signifies a residue of formula (Ts), with the (*) denoting the connecting bond

(Ts)

XantPhos 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene

In the following, "halogen" means F, CI, Br or I, preferably F, CI or Br, more preferably CI; "halide" means fluoride, chloride, bromide or iodide, preferably fluoride, chloride or bromide, more preferably chloride; "halide ion" means F , CI , Br or I , preferably F , CI or Br , more preferably CI ; if not otherwise stated.

In the following, "mu" means the respective greek character of the greek symbol μ, if not otherwise stated.

In the following, "alkyl" means linear, branched or cyclic alkyl; if not otherwise stated. Examples of "alkyl" include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornyl, and the like; if not otherwise stated. In the following, "alkane" means linear, branched or cyclic alkane; if not otherwise stated.

In the following, "C5 8 alkane" means a linear, branched or cyclic aliphatic

hydrocarbon having 5 to 8 carbon atoms. In industrial chemistry, medium chained aliphatic hydrocarbons such as pentanes, hexanes, heptanes and octanes often are used as mixtures of the respective linear hydrocarbons together with its branched or cyclic, i.e. isomeric, forms.

In the following, "alkoxy" represents an alkyl group attached through an oxygen bridge, such as methoxy, ethoxy, n-propoxy, isopropoxy, iso-butoxy, sec-butoxy, tert-butoxy, pentyloxy and hexyloxy; if not otherwise stated.

In the following, "alkenyl" and "alkynyl" is intended to include hydrocarbon chains of a specified number of carbon atoms of either a straight- or branched- configuration and at least one double or triple bond respectively, which may occur at any point along the chain; if not otherwise stated. Examples of "alkenyl" include ethenyl (vinyl), propenyl, e.g. propen-2 yl, propen-3 yl (allyl), butenyl, e.g. buten-l-yl, pentenyl, dimethyl pentenyl, hexen-l-yl and the like, and includes E and Z forms, where applicable. Examples of "alkynyl" include ethynyl, propynyl, e.g. 1-propynyl and 3-propynyl, butynyl, pentynyl, dimethyl pentynyl, 1-hexynyl and the like.

In the following, "cycloalkyl" is intended to include a cycloaliphatic residue having at least 3 ring carbon atoms. Examples of "cycloalkyl" are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.

In the following, "dialkyl" means two alkyl groups attached to a connecting atom. For example in a dialkylzinc (II) compound, two alkyl groups are attached to zinc, whereas in dialkylamino the two alkyl groups are attached to nitrogen. In the following, "aryl" is defined as a phenyl, biphenyl, or naphthyl ring, preferably as phenyl, biphenyl, naphth-1 yl or naphth-2 yl, which is optionally substituted with the substituents as given in the text at any available carbon atoms; if not otherwise stated. The aryl may also be substituted with a fused 5-, 6- or 7-membered ring containing no, one or two oxygen atoms and the remaining ring atoms being carbon, the fused 5-, 6- or 7-ring being selected from the group consisting of dioxolanyl, dihydrofuranyl, dihydropyranyl and dioxanyl.

In the following, "heteroaryl" is intended to include a 5 or 6-membered aromatic ring substituted with one or two heteroatoms selected from the group consisting of O, S and N, and is unsubstituted or substituted with one, two or three identical or different substituents selected from the group consisting of halogen, Ci_₆ alkyl, Ci_₆ alkoxy, cyano, nitro, hydroxy, CHO, C0₂H, COCi_₆ alkyl, C0₂Ci_₆ alkyl, CON(R31)R32, N(R31)R32, N(R31)COCi_6 alkyl, any two adjacent substituents can be joined to form a 5-, 6- or 7-membered fused ring, said ring containing 1 or 2 endocyclic oxygen atoms and the remainder being carbon atoms, or any two adjacent substituents can be joined together to form a benzo-fused ring; if not otherwise stated, with

R31 and R32 being identical or different and independently from each other selected from the group consisting of halogen, CF₃, CN, N0₂, NH₂, NH(Ci_₆ alkyl), N(Ci_6 alkyl)₂, CONH₂, CONH(Ci_₆ alkyl), CON(Ci_₆ alkyl)₂, NHCONH₂, NHCONH(Ci_6 alkyl), NHCON(Ci_₆ alkyl)₂, aryl, C0₂Ci_₆ alkyl, Ci_₆ alkyl, C₂_6 alkenyl, C₂_₆ alkynyl, C₃_₇ cycloalkyl and Ci_₆ alkoxy, such that Ci_₆ alkyl is unsubstituted or substituted with 1 , 2 or 3 identical or different aryl, the substituting aryl being defined as phenyl, biphenyl, or naphthyl, the substituting aryl being unsubstituted or substituted by 1 , 2 or 3 identical or different substituents selected from the group consisting of with Ci_₆ alkyl, Ci_6 alkoxy, N0₂ and halogen;

if not otherwise stated.

Heteroaryl groups within the scope of this definition include but are not limited to acridinyl, carbazolyl, cinnolinyl, quinoxalinyl, pyrrazolyl, indolyl, benzotriazolyl, furanyl, thienyl, thiophen, benzothienyl, benzofuranyl, benzothiophen, quinolinyl, isoquinolinyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimid-5 inyl, and pyrrolyl, which are substituted or unsubstituted as defined above.

Preferred heteroaryl groups are furan-2 yl, furan-3 yl, thiophen-2 yl, thiophen-3 yl, benzo[b]furan-2 yl and benzo[b]thiophen 2 yl.

In the following, "Aralkyl" or "heteroaralkyl" is a aryl or a heteroaryl respectively with alkyl residue, preferably a Ci_g alkyl residue.

In the following, "C_n__m alkyl C₀__p carboxylate" represents an carboxylic acid ester consisting of C_n__m alkyl ester moiety and an acyl moiety, wherein the acyl moiety o to p C atoms.

In the following, "alkali metal" means Li, Na, and K, "alkaline earth metal" means Mg, Ca, Sr and Ba.

Subject of the invention is a method (4-alone) for the preparation of a compound of formula (4) or of a suitable salt of compound of formula (4),

the method (4-alone) comprises a step (4); step (4) comprises a method (4) for the preparation of the compound of formula (4) or of a suitable salt of compound of formula (4), method (4) comprises an intramolecular cyclisation of a compound of formula (3) or of a suitable salt of compound of formula (3), in the presence of a catalyst (4), a ligand (4) and a base (4);

catalyst (4) is selected from the group consisting of compounds derived from Cu(0), Cu(I), Cu(II), Pd(0) or Pd(II), and mixtures thereof;

ligand (4) is selected from the group consisting of diamine ligand, carbene ligand, phosphine ligand, phenanthroline ligand, hydroxyquinoline ligand, bis imine ligand, bipyridine ligand, salicylamide ligand, pyrollidine ligand, glycine ligand, proline ligand, beta diketone ligand, sparteine ligand, mono- or bidentate phosphor containing ligand and mixtures thereof;

base (4) is selected from the group consisting of alkali phosphate, alkali hydrogen phosphate, alkali dihydrogen phosphate, alkali carbonate, alkali bicarbonate, alkali alcoholate, alkali hydroxide, alkyl amine, alkali hexamethyldisilazide and alkali amide and mixtures thereof. Further subject of the invention is a method (3 -alone) for the preparation of a compound of formula (3) or of a suitable salt of compound of formula (3), with the compound of formula (3) being as defined above; the method (3-alone) comprises a step (3); step (3) comprises a method (3) for the preparation of the compound of formula (3) or of a suitable salt of compound of formula (3); method (3) comprises a step (3-1) and a step (3-2); step (3-1) comprises a reaction (3) of a compound of formula (2)

with a compound of formula (3 a);

ci- (3a)

N=C=0

O step (3-2) comprises the addition of a base (3) to the reaction mixture resulting from step (3-1); base (3) is selected from the group consisting of base (3-1), water and mixtures thereof;

base (3-1) is selected from the group consisting of N(R41)(R42)(R43), alkali or

alkaline earth metal carbonates, hydrogencarbonates and hydroxides, piperidine, Ci_₄ alkyl piperidine, pyridine, Ci_₄ alkyl-pyridines and

morpholine;

R41, R42 and R43 are identical or different and independently from each other hydrogen, phenyl or C_1-10 alkyl.

Further subject of the invention is a method (34) for the preparation of a compound of formula (4) or of a suitable salt of compound of formula (4), with the compound of formula (4) being as defined above, the method (34) comprises a step (3) and a step (4), with the step (3) and the step (4) being as defined above, also with all their preferred embodiments; wherein

a compound of formula (3) or a suitable salt of compound of formula (3) is prepared in step (3), and then

the compound of formula (4) or a suitable salt of compound of formula (4) is prepared in step (4) from the compound of formula (3) or from a suitable salt of compound of formula (3), the compound of formula (3) or the suitable salt of compound of formula (3) having been prepared in step (3);

with the compound of formula (3) being as defined above.

Further subject of the invention is a method (23) for the preparation of a compound of formula (3) or of a suitable salt of compound of formula (3), with the compound of formula (3) being as defined above; the method (23) comprises a step (2) and a step (3); step (2) comprises a method (2) for the preparation of a compound of formula (2), with the compound of formula (2) being as defined above, method (2) comprises a reaction (2), reaction (2) comprises a step (2-1), step (2-1) comprises a reaction (2-1) of a compound of formula (1) with a reagent (2),

reagent (2) is obtainable from a reaction (2a) of reagents (2a), reagents (2a) comprise a compound (2al), a compound (2a2) and a compound of formula (2a3);

M is selected from the group consisting of H, Ml, M2(X1) and M3(X1)(X2); Ml is selected from the group consisting of Li, Na and K;

M2 is selected from the group consisting of Zn, Mg and Cu;

M3 is B;

XI and X2 are identical or different and independently from each other selected from the group consisting of halogen, OTf and residue of formula (X-ac);

with the bond in formula (X-ac) denoted with (**) being the bond to M2 or M3; compound (2a 1) is a chiral additive; compound (2a2) is selected from the group consisting of compound (2a2a), compound (2a2b), compound (2a2c), compound (2a2d), compound (2a2e), compound (2a2f) and mixtures thereof;

compound (2a2a) is a diorganylzinc(II) compound;

compound (2a2b) is a compound derived from Cu(I) or Cu(II);

compound (2a2c) is a compound derived from Ti(IV);

compound (2a2d) is a compound derived from Li(I);

compound (2a2e) is a Grignard reagent;

compound (2a2f) is selected from the group consisting of Zn(OTf)2, Sn(OTf)2, InBr₃, AlMe₃, KOtBu, Zr(0-i-Pr)₄, [Rh(OH)(cod)]₂, [Rh(mu-OAc)C₂H₄]₂]2; with the step (3) being as defined above, also with all its preferred embodiments; wherein

the compound of formula (2) is prepared in step (2), and then

the compound of formula (3) or a suitable salt of compound of formula (3) is prepared in step (3) from the compound of formula (2), the compound of formula (2) having been prepared in step (2);

Further subject of the invention is a method (234) for the preparation of a compound of formula (4) or of a suitable salt of compound of formula (4), with the compound of formula (4) being as defined above, the method (234) comprises a step (2), a step (3) and a step (4), with the step (2), the step (3) and the step (4) being as defined above, also with all their preferred embodiments; wherein

a compound of formula (2) is prepared in step (2), and then

a compound of formula (3) or a suitable salt of compound of formula (3) is prepared in step (3) from the compound of formula (2), the compound of formula (2) having been prepared in step (2), and then

with the compound of formula (2) and the compound of formula (3) being as defined above.

Further subject of the invention is a method (123) for the preparation of a compound of formula (3) or of a suitable salt of compound of formula (3), with the compound of formula (3) being as defined above; the method (123) comprises a step (1), a step (2) and a step (3); step (1) comprises a method (1) for the preparation of a compound of formula (1), with the compound of formula (1) being as defined above, method (1) comprises a reaction (1-1) or a reaction (1-2), the reaction (1-1) comprises a step (1-la),

step (1-la) comprises a reaction of a compound of formula (1-lal)

with a compound (l-la2); compound (l-la2) is selected from the group consisting of compound of formula (l-la2-l), compound of formula (l-la2-2) and compound of formula (l-la2-3);

reaction (1-2) comprises a step (l-2a) and a step (l-2b); step (l-2a) comprises a reaction (l-2a) of compound of formula (l-2a)

with the compound (l-la2) in the presence of a compound (l-2al); compound (l-2al) is a Friedel Crafts catalyst; step (l-2b) comprises the addition of an acid (1-2); with the step (2) and the step (3) being as defined above, also with all their preferred embodiments; wherein

the compound of formula (1) is prepared in step (1), and then

the compound of formula (2) is prepared in step (2) from the compound of formula

(1), the compound of formula (1) having been prepared in step (1), and then the compound of formula (3) or a suitable salt of compound of formula (3) is prepared in step (3) from the compound of formula (2), the compound of formula (2) having been prepared in step (2).

Further subject of the invention is a method (1234) for the preparation of a compound of formula (4) or of a suitable salt of compound of formula (4), with the compound of formula (4) being as defined above, the method (1234) comprises a step (1), a step (2), a step (3) and a step (4), with the step (1), the step (2), the step (3) and the step (4) being as defined above, also with all their preferred embodiments.

Further subject of the invention is a method (1234) for the preparation of a compound of formula (4) or of a suitable salt of compound of formula (4), with the compound of formula (4) being as defined above, the method (1234) comprises a step (1), a step (2), a step (3) and a step (4), with the step (1), the step (2), the step (3) and the step (4) being as defined above, also with all their preferred embodiments; wherein

a compound of formula (1) is prepared in step (1), and then

a compound of formula (2) is prepared in step (2) from the compound of formula (1), the compound of formula (1) having been prepared in step (1), and then a compound of formula (3) or a suitable salt of compound of formula (3) is prepared in step (3) from the compound of formula (2), the compound of formula (2) having been prepared in step (2),and then

with the compound of formula (1), the compound of formula (2) and the compound of formula (3) being as defined above.

Preferably, compound (l-la2) is compound of formula (l-la2-l).

Preferably, the reaction temperature of reaction (1-1) is from -78 to 100 °C, more preferably from -78 to 50 °C, even more preferably from -78 to 0 °C.

Preferably, reaction (1-1) is done at a pressure of from atmospheric pressure to 20 bar, more preferably of from atmospheric pressure to 10 bar, even more preferably of from atmospheric pressure to 5 bar.

Preferably, the reaction time of reaction (1-1) is from 15 min to 48 h, more preferably from 1 to 36 h, even more preferably from 4 to 24 h.

Reaction (1-1) can be done in a solvent (1-1).

Preferably, solvent (1-1) is selected from the group consisting of benzene, toluene, xylene, mesitylene, dioxane, R53-0-R55-0-R54, R58-0-R56-0-R57-0-R59, tetrahydrofurane, Ci_₄ alkyl tetrahydrofurane, halogenated Ci_₄ alkanes, R51-0-R52, C₅_i2 alkane and mixtures thereof;

R51 and R52 are identical or different and independently from each other C_1-10 alkyl or phenyl;

R53, R54, R58 and R59 are identical or different and independently from each other Ci_₄ alkyl;

R55, R56 and R57 are identical or different and independently from each other

-(CH2)_n55-;

n55 is 2, 3, 4, 5 or 6.

More preferably, solvent (1-1) is selected from the group consisting of toluene, dioxane, R58-0-R56-0-R57-0-R59, tetrahydrofurane, Ci_₄ alkyl tetrahydrofurane, halogenated Ci_₄ alkanes, R51-0-R52, C₅_i2 alkane and mixtures thereof.

Preferably, R51 and R52 are identical.

Preferably, R53 and R54 are identical.

Preferably, R56 and R57 are identical.

Preferably, R58 and R59 are identical.

Preferably, n55 is 2, 3 or 4, more preferably 2.

Preferably, the halogenated Ci_₄ alkanes are chlorinated, fluorinated, perchlorinated or perfluorinated Ci_₄ alkanes.

Especially, solvent (1-1) is selected from the group consisting of toluene, dioxane, diethylene glycol dimethyl ether, tetrahydrofurane, 2-methyltetrahydrofurane, dimethoxyethane, dichloroethane, diethyl ether, methyl-tert butyl ether, diisopropyl ether, biphenyl ether, pentane, hexane, heptane, octane, nonane, decane and mixtures thereof.

In particular, solvent (1-1) is toluene, tetrahydrofurane or hexane. Preferably, the amount of solvent (1-1) is from 1 to 200 fold, more preferably from 5 to 100 fold, even more preferably from 20 to 50 fold, of the weight of compound of formula (1-lal).

Preferably, in the reaction (1-1), from 1 to 3 mol equivalents, more preferably from 1 to 2 mol equivalents, even more preferably from 1.1 to 1.5 mol equivalents, of compound (l-la2) are used, the mol equivalents being based the mol of compound of formula (1-lal).

The reaction (1-1) optionally comprises a step (1-lb), which is done after step (1-la), the step (1-lb) being the addition of an acid (1-1) to the reaction mixture resulting from step (1-la).

Preferably, acid (1-1) is an acid (1-lb), water or mixture thereof.

Acid (1-lb) can be practically any acid.

Preferably, acid (1-lb) is selected from the group consisting of ammonium chloride, hydrochloric acid, sulphuric acid, nitric acid, phosphoric acid, Ci_₆ carboxylic acid, C₂-8 dicarboxylic acid, C₄_i2 tricarboxylic acid and mixtures thereof.

More preferably, acid (1-lb) is selected from the group consisting of ammonium chloride, hydrochloric acid, sulphuric acid, acetic acid, nitric acid, tartaric acid and mixtures thereof.

Preferably, when acid (1-1) is a mixture acid (1-lb) with water, acid (1-1) comprises from 1 to 30 % by weight, more preferably from 5 to 30 % by weight, even more preferably from 15 to 27 % by weight, of acid (1-lb), with the % by weight being based on the total weight of acid (1-1),

especially, when acid (1-1) is a mixture of acid (1-lb) with water, acid (1-1) is a saturated aqueous solution of acid (1-lb). Preferably, the amount of acid (1-1) is from 1 to 200 fold, more preferably from 5 to 100 fold, even more preferably from 10 to 50 fold, of the weight of compound of formula (1-lal).

Or, preferably, the amount of acid (1-1) is from 1 to 20 mol equivalents, more preferably from 1 to 10 mol equivalents, even more preferably from 1 to 5 mol equivalents, the mol equivalents are based on the mol of compound of formula (1-lal).

Preferably, the reaction (1-1) is done under inert atmosphere.

Preferably, compound of formula (1-lal) is prepared by a method (10) comprising a reaction (10) of a compound of formula (l-2a), with the compound of formula (l-2a) being as defined above; with a base (10) in a solvent (10); base (10) is Ci_₄ alkyl lithium.

Preferably, base (10) is selected from the group consisting of n-butyl lithium (BuLi), sec-butyl lithium, tert-butyl lithium and methyl lithium.

More preferably, base (10) is n-butyl lithium (BuLi).

Preferably, the reaction temperature of reaction (10) is from -78 to 50 °C, more preferably from -78 to 20 °C, even more preferably from -78 to 0 °C.

Preferably, the reaction (10) is done at a pressure of from atmospheric pressure to 20 bar, more preferably of from atmospheric pressure to 10 bar, even more preferably of from atmospheric pressure to 5 bar.

Preferably, the reaction time of reaction (10) is from 15 min to 48 h, more preferably from 1 to 36 h, even more preferably from 4 to 24 h. Preferably, solvent (10) is selected from the group consisting of benzene, toluene, xylene, mesitylene, dioxane, R53-0-R55-0-R54, R58-0-R56-0-R57-0-R59, tetrahydrofurane, Ci_₄ alkyl tetrahydrofurane, halogenated Ci_₄ alkanes, R51-0-R52, C₅_i2 alkane and mixtures thereof;

with R51 , R52, R53, R54, R58, R59, R55, R56 and R57 being as defined above, also with all their preferred embodiments.

More preferably, solvent (10) is selected from the group consisting of toluene, dioxane, R58-0-R56-0-R57-0-R59, tetrahydrofurane, Ci_₄ alkyl tetrahydrofurane, halogenated Ci_₄ alkanes, R51-0-R52, C₅_i2 alkane and mixtures thereof.

Especially, the solvent (10) is selected from the group consisting of toluene, dioxane, diethylene glycol dimethyl ether, tetrahydrofurane, 2-methyltetrahydrofurane, dimethoxyethane, dichloroethane, diethyl ether, methyl-tert butyl ether, diisopropyl ether, biphenyl ether, pentane, hexane, heptane, octane, nonane, decane, or mixtures thereof.

In particular, solvent (10) is toluene, tetrahydrofurane or hexane. Preferably, solvent (1-1) and solvent (10) are the identical.

Preferably reaction (10) and reaction (1-1) are done consecutively without isolating the compound of formula (1-1 al), preferably solvent (1-1) and solvent (10) are identical.

More preferably, reaction (10) and reaction (1-1) are done in one pot, and solvent (1-1) and solvent (10) are identical.

Preferably, the amount of solvent (10) is from 1 to 200 fold, more preferably from 5 to 100 fold, even more preferably from 20 to 50 fold, of the weight of compound of formula (l-2a). Preferably, from 1 to 3 mol equivalents, more preferably from 1 to 2 mol equivalents, even more preferably from 1.1 to 1.5 mol equivalents, of base (10) are used, the mol equivalents being based the mol of compound of formula (l-2a).

Preferably, the reaction (10) is done under inert atmosphere.

Preferably, compound (l-2al) is selected from the group of AICI₃, SnCl₄, Ce(OTf)3, BCI3, ZnCl₂, FeCl₃, TiCl₄, GaCl₃, AlBr₃, LiCl, BF₃ and mixtures thereof.

BF₃ can for example be BF3 as such or a BF₃ complex. A BF₃ complex is for example BF₃ acetonitrile complex, BF₃ diacetic acid complex, BF₃ diethyl ether complex, BF₃ dihydrate complex, BF₃ dimethyl ether complex, BF₃ dimethyl sulfide complex, BF₃ diphenol complex, BF₃ ethyl amine complex, BF₃ methanol complex, BF₃ phosphoric acid complex, BF₃ propanol complex, BF₃ propionic acid complex, BF₃ tert-butyl methyl ether complex, BF₃ tetrahydrofurane complex, silica supported BF₃.

The same, which is described for BF₃, can apply for BC1₃.

Preferably, the reaction temperature of reaction (1-2) is from -78 to 200 °C, more preferably from -48 to 150 °C, even more preferably from -25 to 100 °C.

Preferably, the reaction (1-2) is done at a pressure of from atmospheric pressure to 20 bar, more preferably of from atmospheric pressure to 10 bar, even more preferably of from atmospheric pressure to 5 bar.

Preferably, the reaction time of reaction (1-2) is 15 min to 48 h, more preferably from 1 to 36 h, even more preferably from 4 to 24 h.

Reaction (1-2) can be done in a solvent (1-2) or neat. Solvent (1-2) is preferably selected from the group consisting of benzene, toluene, xylene, mesitylene, dioxane, R53-0-R55-0-R54, R58-0-R56-0-R57-0-R59, tetrahydrofurane, Ci_₄ alkyl tetrahydrofurane, halogenated Ci_₄ alkanes, R51-0-R52, C₅_i2 alkane and mixtures thereof;

More preferably, solvent (1-2) is selected from the group consisting of toluene, dioxane, R58-0-R56-0-R57-0-R59, tetrahydrofurane, Ci_₄ alkyl tetrahydrofurane, halogenated Ci_₄ alkanes, R51-0-R52, C₅_i2 alkane and mixtures thereof.

Especially, solvent (1-2) is selected from the group consisting of toluene, dioxane, diethylene glycol dimethyl ether, tetrahydrofurane, 2-methyltetrahydrofurane, dimethoxyethane, dichloroethane, diethyl ether, methyl-tert butyl ether, diisopropyl ether, biphenyl ether, pentane, hexane, heptane, octane, nonane, decane and mixtures thereof.

In particular, solvent (1-2) is toluene, tetrahydrofurane or hexane.

Preferably, the amount of solvent (1-2) is from 1 to 200 fold, more preferably from 5 to 100 fold, even more preferably from 20 to 50 fold, of the weight of compound of formula (l-2a).

Preferably, in the reaction (1-2), from 1 to 3 mol equivalents, more preferably from 1 to 2 mol equivalents, even more preferably from 1.1 to 1.5 mol equivalents, of compound (l-la2) are used, the mol equivalents being based the mol of compound of formula (l-2a).

Preferably, acid (1-2) is an acid (l-2b) water of mixtures thereof.

Acid (l-2b) can be practically any acid. Preferably, acid (l-2b) is selected from the group consisting of ammonium chloride, hydrochloric acid, sulphuric acid, nitric acid, phosphoric acid, Ci_₆ carboxylic acid, C₂-8 dicarboxylic acid, C₄_i2 tricarboxylic acid and mixtures thereof.

More preferably, acid (l-2b) is selected from the group consisting of ammonium chloride, hydrochloric acid, sulphuric acid, acetic acid, nitric acid, tartaric acid and mixtures thereof.

Preferably, when acid (1-2) is a mixture of acid (l-2b) with water, acid (1-2) comprises from 1 to 30 % by weight, more preferably from 5 to 30 % by weight, even more preferably from 15 to 27 % by weight, of acid (1-lb), with the % by weight being based on the total weight of acid (1-2); especially, when acid (1-2) is a mixture of acid (l-2b) with water, acid (1-2) is a saturated aqueous solution of acid (l-2b).

Preferably, the amount of acid (1-2) is from 1 to 200 fold, more preferably from 5 to 100 fold, even more preferably from 10 to 50 fold, of the weight of compound of formula (l-2a).

Or, preferably, the amount of acid (1-2) is from 1 to 20 mol equivalents, more preferably from 1 to 10 mol equivalents, even more preferably from 1 to 5 mol equivalents, the mol equivalents are based on the mol of compound of formula (l-2a).

Preferably, the reaction (1-2) is done under inert atmosphere.

After the reaction (1-1) or after the reaction (1-2), the compound of formula (1) can be isolated by standard methods such as washing, extraction, filtration, concentration and drying. Preferably, washing of any organic phase after the reaction (1-1) or after the reaction (1-2) during isolation can be done with water, with an aqueous solution of an acid (1-wash) or with brine.

Preferably, the acid (1-wash) is ammonium chloride

More preferably, acid (1-wash) is used as a saturated aqueous solution.

More preferably, the reaction mixture after the reaction (1-1) or after the reaction (1-2) is first washed with an aqueous solution of acid (1-wash), and then with brine.

Preferably, any aqueous phase after the reaction (1-1) or after the reaction (1-2) can be extracted, preferably the extraction if done with a solvent (1 -extract).

Solvent (1 -extract) is a suitable extraction solvent, preferably, solvent (1 -extract) is selected from the group consisting of solvent (1 -co-extract), C2-5 alkyl C2-5

carboxylate, C₅_8 alkane and mixtures thereof; more preferably consisting of solvent (1 -co-extract), C2-5 alkyl acetates, C2-5 alkyl propionate, C2-5 alkyl butyrate, C5-8 alkane and mixtures thereof; even more preferably solvent (1 -extract) is ethyl acetate or a mixture of ethyl acetate with solvent (1 -co-extract).

Solvent (1 -co-extract) is preferably selected from the group consisting of benzene, toluene, xylene, naphthalene, Ci_₄ alkyl substituted naphthalenes, decalin, tetralin and mixtures thereof. Preferably, the amount of solvent (1 -co-extract) is from 0.1 to 10 % by weight, more preferably from 0.1 to 5 % by weight, even more preferably from 0.1 to 2 % by weight, the % by weight based in the total weight of solvent (1 -extract).

Even more preferably, the reaction mixture after the reaction (1-1) or after the reaction (1-2) is first washed with an aqueous solution of acid (1-wash), then the resulting aqueous phase is extracted with solvent (1 -extract), and the resulting combined organic phase is washed with brine.

Concentration after the reaction (1-1) or after the reaction (1-2) is preferably done by distillation. The compound of formula (1) can be purified before or after isolation, preferably by chromatography or crystallization from an appropriate solvent.

Compound (l-la2) and compound of formula (l-2a) are known compounds and can be prepared according to known methods.

Preferably, compound (2a2) is selected from the group consisting of compound (2a2a), compound (2a2b), compound (2a2c), compound (2a2d), compound (2a2e), compound (2a2f) and mixtures thereof;

compound (2a2a) is selected from the group consisting of [Ci_₆ alkyl]₂Zn,

diphenyl-zinc and Zn(OTf)₂;

compound (2a2b) is a compound derived from Cu(I) or Cu(II);

compound (2a2c) is a compound derived from Ti(IV);

compound (2a2d) is an organolithium compound or a lithium halide;

compound (2a2e) is a Grignard reagent;

compound (2a2f) is selected from the group consisting of Zn(OTf)₂, Sn(OTf)₂, InBr₃, AlMe₃, KOtBu, Zr(0-i-Pr)₄, [Rh(OH)(cod)]₂, [Rh(mu-OAc)C₂H₄]₂]₂.

compound (2a2a) is selected from the group consisting of [Ci_₆ alkyl]₂Zn,

diphenyl-zinc and Zn(OTf)₂;

compound (2a2b) is selected from the group consisting of Cu(OTf), Cu(OTf)₂, Cul,

Cul₂, CuBr, CuBr₂, Cu(OAc)₂, CuCl and CuCl₂;

compound (2a2c) is Ti(halogen)_ni(0-Ci_6 alkyl)^;

compound (2a2d) is selected from the group consisting of Ci_₄ alkyl Li, lithium Ci_₆ alkoxide, lithium diisopropylamide (LDA), lithium hexamethyldisilazide (LiHMDS), phenyllithium, naphthyllithium, LiCl and LiBr; compound (2a2e) is a Grignard reagent;

compound (2a2f) is selected from the group consisting of Zn(OTf)2, Sn(OTf)2, InBr₃,

AlMe₃, KOtBu, Zr(0-i-Pr)₄, [Rh(OH)(cod)]₂, [Rh(mu-OAc)C₂H₄]₂]2, nl is 0, 1, 2, 3 or 4;

n2 is 4 - nl .

Preferably, the alkyl moiety of compound (2a2a) is selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl

More preferably, compound (2a2a) is selected from the group consisting of

dimethyl-Zn, diethyl-Zn, diphenyl-zinc and Zn(OTf)2.

Preferably, compound (2a2b) is selected from the group consisting of Cu(OTf),

Cu(OTf)₂, Cul, Cul₂, CuBr, CuBr₂, Cu(OAc)₂, CuCl and CuCl₂.

Preferably, compound (2a2c) is Ti(halogen)_ni(0-Ci_6 alkyl)^; more preferably,

Ti(halogen)_ni(0-Ci_₄ alkyl)^; even more preferably Ti(halogen)_ni(0-C₃_₄ alkyl)_n2.

nl is 0, 1, 2, 3 or 4;

n2 is 4 - nl .

Preferably, the halogen in the compound (2a2c) is CI.

Preferably, nl is 0, 1, 2 or 3; more preferably 0, 1 or 2, even more preferably, nl is 0 or 1.

Especially, compound (2a2c) is Ti(0-i-Pr)₄ or Ti(Cl)(0-i-Pr)₃.

Preferably, compound (2a2d) is Ci_₄ alkyl Li, lithium Ci_₆ alkoxide, lithium

diisopropylamide, lithium hexamethyldisilazide (LiHMDS), phenyllithium, naphthyllithium, LiCl or LiBr;

more preferably phenyllithium, n-butyl Li, sec-butyl Li, tert-butyl Li or MeLi. Preferably, compound (2a2e) is Ci_₄ alkyl Mg halogen, more preferably

Ci_2 alkyl Mg halogen.

Preferably, the halogen in compound (2a2e) is CI, Br or I, more preferably CI or Br. Especially, compound (2a2e) is MeMgCl, MeMgBr or MeMgl.

Preferably, compound (2a2f) is selected from the group consisting of Zn(OTf)2,

Sn(OTf)₂, InBr₃, AlMe₃, KOtBu, Zr(0-i-Pr)₄, [Rh(OH)(cod)]₂,

[Rh(μOAc)C₂H₄]₂]₂.

Preferably, compound (2al) is a protic chiral additive. The protic chiral additive induces the formation of the desired enantiomer during reaction (2-1). The expression "protic chiral additive" means that the chiral additive comprises at least one abstractable proton, preferably in form of a hydroxyl residue.

Preferably, compound (2a 1) is selected from the group consisting of compound of formula (2al-I), pyrrolidine-methanol and cinchonine;

R9 RIO or its enantiomer or a diastereomer;

R9 and RIO are identical or different and independently from each other H, OH, NH₂, NH(R17), N(R17)(R18) or a compound of formula (2al-II);

R7, R8, Rl 1 and R12 are identical or different and independently from each other

(a) H,

(b) CF₃,

(c) CN,

(d) CONH₂,

(e) CONH(Ci_6 alkyl),

(f) CON(Ci_6 alkyl)₂,

(g) C0₂-Ci_6 alkyl,

(h) C₃_7 cycloalkyl,

(i) Ci_6 alkyl, C₂_₆ alkenyl or C₂_₆ alkynyl, the Ci_₆ alkyl, C₂_₆ alkenyl or C₂_₆ alkynyl being unsubstituted or substituted by 1 or 2 identical or different substituents selected from the group consisting of halogen, CF₃, CN, N0₂, NH₂, NH(Ci_6 alkyl), N(Ci_6 alkyl)₂, CONH2, CONH(Ci_₆ alkyl), CON(Ci_₆ alkyl)₂, NHCONH₂, NHCONH(Ci_6 alkyl), NHCON(Ci_₆ alkyl)₂, C0₂-Ci_₆ alkyl, C₃_₇ cycloalkyl and Ci_₆ alkoxy;

(j) R7 and R8 or Rl 1 and R12 taken together can represent =0, thereby forming a ketone, amide, acid or ester group;

(k) compound of formula (2a 1 -III),

(1) COOH,

(m) C(0)OR17b,

(n) phenyl, naphthyl, naphthyl with 1 or 2 endocyclic N atoms, such that one and only one of R7, R8, Rl 1, or R12 can bear this definition, with the proviso, that at least one of the two carbons denoted with (1) and (2) and bearing R7, R8, R9, RIO, Rl 1 and R12 is a chiral center; or

RIO taken together with either Rl 1 or R12 represents a compound of formula (2al-IV) or compound of formula (2al-V), with the other of Rl 1 or R12 being hydrogen;

(*) Rl l or R12 (2al-IV) (2al-V) with the bond denoted (*) in formulae (2al-IV) and (2al-V) being the bond to the C atom denoted with (2) in formula (2al-I); or

R9 taken together with either R7 or R8 represents a compound of formula (2al-VI) or compound of formula (2al-VII), with the other of R7 or R8 being hydrogen;

(2al-VI) (2al-VII) with the bond denoted (*) in formulae (2al-IV) and (2al-V) being the bond to the C atom denoted with (2) in formula (2al-I);

R13 is H, Ci_6 alkyl or phenyl;

R14 is H; or R7 or R8 and R14 taken together can represent a carbon-carbon bond, when t is 1 or 2 and Rl 1 or R12 represents a compound of formula (2al-III); or

R7 or R8 and R14 taken together can represent -(CH₂)s, when t is 0 and Rl 1 or R12 represents a compound of formula (2a 1 -III);

R15 and R16 are identical or different and independently from each other selected from the group consisting of H, Ci_₆ alkyl, C₂_₆ alkenyl and C₂_₆ alkynyl, the Ci_6 alkyl, C₂_₆ alkenyl and C₂_₆ alkynyl being unsubstituted or substituted by 1 or 2 identical or different substituents selected from the group consisting of halogen, CF₃, CN, N0₂, NH₂, NH(Ci_₆ alkyl), N(Ci_₆ alkyl)₂, CONH2, CONH(Ci_6 alkyl), CON(Ci_₆ alkyl)₂, NHCONH₂, NHCONH(Ci_₆ alkyl), NHCON(Ci_6 alkyl)₂, C0₂-Ci_₆ alkyl, C₃_₇ cycloalkyl and Ci_₆ alkoxy;

with the proviso, that either R15 or R16 is hydrogen;

R17 and R18 are identical or different and independently from each other selected from the group consisting of Ci_₆ alkyl, phenyl, biphenyl, naphthyl and -S0₂-R17a, the Ci_₆ alkyl being unsubstituted or substituted with 1 or 2 substituents selected from the group consisting of phenyl, biphenyl or naphthyl;

or R17 and R18 form together with the N atom, to which they are connected, a 5 or 6 membered saturated, unsaturated or aromatic heterocyclic ring, the ring can have one or two further endocyclic hetero atoms selected from the group consisting of N, O and S;

R17a is Ci_4 alkyl, phenyl, tolyl or naphthyl;

R17b is Ci_4 alkyl;

Z is a connecting group with a formula selected from the group consisting of formula (2al-VIII), formula (2al-IX), formula (2al-X), formula (2al-XI), formula (2al-XII), formula (2al-XIII), formula (2al-XIV), formula (2al-XV), formula (2al-XVI), formula (2al-XVII) and formula (2al -XVIII);

(2al-XIV)

(2al-IX) '

(2al-XI) (2al-XII) (2al-XIII)

(2al-XIV)

(2al-XV) (2al-XVI)

(CHR13)m-

(2a 1 -XVII)

(2al -XVIII)

H

wherein represents a six-membered ring, the six-membered ring being unsaturated or saturated but non-aromatic, optionally one or two of the endocyclic C atoms of the six-membered ring are substituted by a heteroatom selected from the group consisting of N, O and S, optionally the six-membered ring is substituted with one or two Ci_₆ alkyl;

and wherein represents a five-membered ring, the five-membered ring being unsaturated or saturated but non-aromatic, optionally one or two of the endocyclic C atoms of the five-membered ring are substituted by a heteroatom selected from the group consisting of N, O and S, optionally the five -membered ring is substituted with one or two Ci_₆ alkyl; n is 1 , 2 or 3; m is 0 or 1 ; t is 0, 1 or 2; s is 1 or 2.

Preferably, when R17 and R18 form together with the N atom, to which they are

connected, a 5 or 6 membered saturated or aromatic heterocyclic ring, the ring can have one further endocyclic N atom.

More preferably, compound (2a 1) is selected from the group consisting of

2-amino- 1 -phenyl-propan- 1 -ol, 2-(C i_4-alkylamino)- 1 -phenyl-propan- 1 -ol,

2-(di-Ci_4-alkylamino)- 1 -phenyl-propan- 1 -ol,

2-(N,N-C4-6-alkylene)- 1 -phenyl-propan- 1 -ol, 2-(phenylamino)- 1 -phenyl-propan- 1 -ol, 2-(phenyl-(Ci_4-alkyl)amino)- 1 -phenyl-propan- 1 -ol,

2-(benzylamino)- 1 -phenyl-propan- 1 -ol, 2-(di-benzylamino)- 1 -phenyl-propan- 1 -ol, 2-(l-hetaryl)-l -phenyl-propan- l-ol, diethyl tartrate, pyrrolidine-methanol, cinchonine, compound of formula (2al-l 1), compound of formula (2al-12), compound of formula (2al-13), compound of formula (2al-14) and compound of formula (2al-15).

(2al-l l) (2al-12)

(2al-13) (2al-14) (2al-15)

Preferably, 2-(Ci_4-alkylamino)-l-phenyl-propan-l-ols is

2-(methylamino)- 1 -phenyl-propan- 1 -ol, 2-(ethylamino)- 1 -phenyl-propan- 1 -ol,

2-(isopropylamino)- 1 -phenyl-propan- 1 -ol or

2-(butylamino)- 1 -phenyl-propan- 1 -ol;

more preferably ephedrine.

Preferably, 2-(di-Ci_4-alkylamino)-l -phenyl-propan- 1-ols is

2-(dimethylamino)- 1 -phenyl-propan- 1 -ol,

2-(diethylamino)- 1 -phenyl-propan- 1 -ol,

2-(diisopropylamino)- 1 -phenyl-propan- 1 -ol or

2-(dibutylamino)- 1 -phenyl-propan- 1 -ol;

more preferably N-methylephedrine, (lR,25)-2-(dimethyl- amino)-l -phenyl-propan- l-ol (CAS [552-79-4]), (15,2R)-2-(dimethyl- amino)-l -phenyl-propan- l-ol (CAS [42151-56-4]),

(lR,2R)-2-(dimethylamino)-l-phenyl-propan-l-ol (CAS [14222-20-9]) or

(1 S,2S)-2-(dimethylamino)- 1 -phenyl-propan- 1 -ol (CAS [51018-28-1]).

Preferably, 2-(N,N-C4-6-alkylene)-l -phenyl-propan- l-ol is

1 -phenyl-2-(piperidinyl)propan- 1 -ol or 1 -phenyl-2-(pyrrolidinyl)propan- 1 -ol; more preferably (lR,2S)-l-phenyl-2-(pyrrolidinyl)propan-l-ol (CAS [127641-25-2] or (lR,2S)-N-pyrrolidinyl norephedrine or (ϋ?,25)-ΡΝΕ),

(15,2R)-l-phenyl-2-(pyrrolidinyl)propan-l-ol (CAS [123620-80-4] or

(1S,2R)-PNE), (lR,2R)-l-phenyl-2-(pyrrolidinyl)propan-l-ol ((1R,2R)-PNE or ( 1 S,2S)- 1 -phenyl-2-(pyrrolidinyl)propan- 1 -ol (( 1 S,2S)-PNE) . Preferably, 2-(phenyl(Ci_4-alkyl)amino)-l-phenyl-propan-l-ol is

2-(phenyl(methyl)amino)- 1 -phenyl-propan- 1 -ol.

Preferably, 2-(l-hetaryl)-l -phenyl-propan- l-ol is l-phenyl-2-(l-pyridinyl)propan-l-ol or 1 -phenyl-2-(l -pyrrolyl)propan- 1 -ol.

Even more preferably, compound (2a 1) is selected from the group consisting of norephedrine, ephedrine, N-methylephedrine, N-dibenzylnorephedrine,

norpseudoephedrine, (lR,2R)-pseudoephedrine, (1 S,2S) N-methylpseudoephedrine, (lR,2S)-2-(dimethylamino)-l -phenyl-propan- l-ol (CAS [552-79-4]),

(lS,2R)-2-(dimethylamino)-l -phenyl-propan- l-ol (CAS [42151-56-4]),

( lR,2R)-2-(dimethylamino)- 1 -phenyl-propan- 1 -ol (CAS [ 14222-20-9]),

( 1 S,2S)-2-(dimethylamino)- 1 -phenyl-propan- 1 -ol (CAS [51018-28-1]),

( 1R,2S)- 1 -phenyl-2-(pyrrolidinyl)propan- 1 -ol (CAS [ 127641 -25-2]),

( 1 S,2R)- 1 -phenyl-2-(pyrrolidinyl)propan- 1 -ol (CAS [ 123620-80-4]),

( \R,2R)- 1 -pheny l-2-(pyrrolidinyl)propan- 1 -ol and ( 1 S,2S)- 1 -phenyl-2-(pyrrolidinyl)- propan-l-ol, diethyl tartrate, pyrrolidine -methanol, cinchonine, compound of formula (2al-l 1), compound of formula (2al-12), compound of formula (2al-13), compound of formula (2al-14) and compound of formula (2al-15).

Optionally, reaction (2-1) is done in the presence of a compound (2a4).

Optionally, reagent (2) is obtainable by a reaction (2a) of a compound (2al), a compound (2a2) and a compound of formula (2a3) and a compound (2a4).

Optionally, reagents (2a) comprise additionally a compound (2a4). Reagents (2a) can comprise more than one, preferably 2 or 3, more preferably 2 compounds (2a4).

Compound (2a4) is selected from the group consisting of R20OH, R20SH, R20CO₂H, R20SO₃H, HX2, R20CONH₂, phenyl-NH₂ and naphthyl-NH₂; X2 is halogen;

R20 is Ci_6 alkyl, C₂-6 alkenyl, C₂_₆ alkynyl, phenyl, biphenyl, naphthyl, and heteroaryl;

heteroaryl in the meaning of R20 is defined as a 5 or 6-membered aromatic ring

containing with one or two endocyclic heteroatoms selected from the group consisting of O, S and N;

with the Ci_6 alkyl, C₂_₆ alkenyl, C₂_₆ alkynyl, phenyl, the biphenyl, the naphthyl and the heteroaryl being unsubstituted or substituted with 1 , 2 or 3 identical or different substituents selected from the group consisting of N0₂, halogen, CF₃, Ci_6 alkyl, Ci_₆ alkoxy and N[Ci_₆ alky]₂.

Preferably, compound (2a4) is selected from the group consisting of MeOH, EtOH, n-propanol, iso-propanol, n-butanol, iso-butanol, sec-butanol, tBuOH, pentanol, such as (CH₃)₃CCH₂OH, (CH₃)₃CCH(CH₃)OH, Ph₃COH,

Cl₃CCH₂OH, F₃CCH₂OH, CH₂=CHCH₂OH, PhCH₂OH, (CH₃)₂NCH₂CH₂OH, 4-N0₂-phenol, CH₃C0₂H, CF₃C0₂H, and (CH₃)CC0₂H.

More preferably, compound (2a4) is selected from the group consisting of MeOH, tBuOH, (CH₃)₃CCH₂OH, (CH₃)₃CCH(CH₃)OH, Ph₃COH, Cl₃CCH₂OH, F₃CCH₂OH, CH₂=CHCH₂OH, PhCH₂OH, (CH₃)₂NCH₂CH₂OH, 4-N0₂-phenol, CH₃C0₂H, CF₃C0₂H, and (CH₃)CC0₂H.

Also within the scope of the definition of compound (2a4) is the fact that

compound (2a4) can also be chiral.

Preferably,

M is selected from the group consisting of H, Li, Na, K, Zn, Mg(Xl), Cu(Xl) and B(Xl)₂.

Preferably, XI is halogen or CF₃S0₃;

more preferably, M is selected from the group consisting of H, Li and Mg(Xl).

Preferably, the reaction temperature of reaction (2) is from -78 to 150 °C, more preferably from -20 to 100 °C, even more preferably from -20 to 70 °C. Preferably, the reaction (2) is done at a pressure of from atmospheric pressure to 20 bar, more preferably of from atmospheric pressure to 10 bar, even more preferably of from atmospheric pressure to 5 bar.

Preferably, the reaction time of reaction (2) is from 15 min to 72 h, more preferably from 1 to 36 h, even more preferably from 4 to 24 h.

Reaction (2) can be done in a solvent (2) or neat, solvent (2) is selected from the group consisting of Ci_₆ monocarboxylic acid Ci_₆ alkyl ester, benzene, toluene, xylene, mesitylene, N,N-di-Ci_₄ alkyl Ci_₄ monocarboxamide, N-methylpyrrolidone, pyridine, Ci_₄ alkyl pyridine, mixed and not-mixed di-Ci_₄ alkyl pyridine, dioxane, C₂-₄ alkylene glycols, C₂_₄ alkylene glycol Ci_₄ alkyl monoether, C₂_₄ alkylene glycol di-Ci_₄ alkyl ether, di-C₂_₄ alkylene glycol mono-Ci_₄ alkyl ether, di-C₂_₄ alkylene glycol di-Ci_₄ alkyl ether, tetrahydrofurane, Ci_₄ alkyl tetrahydrofurane,

R53-0-R55-0-R54, dichlorobenzene, chlorobenzene, halogenated Ci_₄ alkane, Ci_₆ alcohol, di-Ci_₂ alkyl sulfoxide, R51-0-R52, C5-12 alkane, N(R61)(R62)(R63), water or mixtures thereof;

R61, R62 and R63 are identical or different and independently from each other hydrogen, phenyl or C_1-10 alkyl with the proviso, that at least one residue of the R61 , R62 and R63 is not hydrogen;

with R51, R52, R53, R54, R55 and halogenated Ci_₄ alkanes being as defined above, also with all their preferred embodiments;

Preferably, R61, R62 and R63 are identical or different and independently from each other hydrogen, phenyl or Ci_₄ alkyl with the proviso, that at least one residue of the R61, R62 and R63 is not hydrogen.

More preferably, solvent (2) is selected from the group consisting of ethyl acetate, butyl acetate, benzene, toluene, xylene, dimethylformamide, dimethylacetamide, N-methylpyrrolidone, pyridine, methylethylpyridine, e.g. 2-methyl-5 -ethyl pyridine, dioxane, diethylene glycol dimethyl ether, tetrahydrofurane, 2-methyltetrahydrofurane, dimethoxyethane, o-, m-, p-dichlorobenzene, chlorobenzene, dichloroethane, methanol, ethanol, n-propanol, 2-propanol, n-butanol, secondary butanol, n-pentanol, n-hexanol, tertiary butanol, dimethyl sulfoxide, dimethyl ether, methyl-tert butyl ether, diisopropyl ether, biphenyl ether, pentane, hexane, heptane, octane, nonane, decane, cyclohexane, triethylamine, diisopropylethylamine, tri-n-propylamine,

tri-isopropylamine, tri-n-butylamine, triphenylamine, water or mixtures thereof.

Even more preferably, solvent (2) is selected from the group consisting of ethyl acetate, butyl acetate, toluene, dimethylformamide, dimethylacetamide,

N-methylpyrrolidone, dioxane, diethylene glycol dimethyl ether, tetrahydrofurane, 2-methyltetrahydrofurane, dimethoxyethane, dichloroethane, methanol, ethanol, n-propanol, 2-propanol, n-butanol, secondary butanol, n-pentanol, n-hexanol, tertiary butanol, hexane, cyclohexane, triethylamine, water or mixtures thereof.

Especially, solvent (2) is toluene, tetrahydrofurane or hexane.

Preferably, the amount of solvent (2) is from 1 to 200 fold, more preferably from 5 to 100 fold, even more preferably from 20 to 50 fold, of the weight of compound of formula (1).

Preferably, from 0.001 to 0.5 mol equivalents, more preferably from 0.01 to 0.25 mol equivalents, even more preferably from 0.025 to 0.15 mol equivalents, of compound of formula (2a 1) are used, the mol equivalents being based the mol of compound of formula (1).

Preferably, from 0.001 to 3, more preferably from 0.01 to 2, even more preferably from 0.025 to 1.5 mol equivalents, of compound of formula (2a2) are used, the mol equivalents being based the mol of compound of formula (1). Preferably, from 1 to 3, more preferably from 1 to 2, even more preferably from 1 to 1.5 mol equivalents, of compound of formula (2a3) are used, the mol equivalents being based the mol of compound of formula (1).

Preferably, the reaction (2) is done under inert atmosphere.

Reaction (2) comprises optionally a further step (2-2), which is done after step (2-1), step (2-2) being an addition of an acid (2) to the reaction mixture obtained from step (2-1).

Preferably, step (2-2) is done, when the reaction mixture obtained from a reaction (2-1) is so basic, that the compound of formula (1) is present in the reaction mixture in deprotonated state.

Preferably, acid (2) is an acid (2-2), water or a mixture thereof.

Acid (2-2) can be practically any acid.

Preferably, acid (2-2) is selected from the group consisting of ammonium chloride, hydrochloric acid, sulphuric acid, nitric acid, phosphoric acid, Ci_₆ carboxylic acid, C₂-8 dicarboxylic acid, C₄_i2 tricarboxylic acid and mixtures thereof.

More preferably, acid (2-2) is selected from the group consisting of ammonium chloride, hydrochloric acid, sulphuric acid, acetic acid, nitric acid, tartaric acid and mixtures thereof.

Preferably, when acid (2) is a mixture of acid (2-2) with water, acid (2) comprises from 1 to 30 % by weight, more preferably from 5 to 30 % by weight, even more preferably from 15 to 27 % by weight, of acid (2-2), with the % by weight being based on the total weight of acid (2);

especially, when acid (2) is a mixture of acid (2-2) with water, acid (2) is a saturated aqueous solution of acid (2-2). Preferably, the amount of acid (2) is from 1 to 200 fold, more preferably from 5 to 100 fold, even more preferably from 10 to 50 fold, of the weight of compound of formula (1).

Or preferably, the amount of acid (2) is from 1 to 20 mol equivalents, more preferably from 1 to 10 mol equivalents, even more preferably from 1 to 5 mol equivalents, the mol equivalent being base on the mol of compound of formula (1).

After the reaction (2), the compound of formula (2) can be isolated by standard methods such as washing, extraction, filtration, concentration and drying.

Preferably, the washing of any organic phase after the reaction during isolation can be done with water, with an aqueous solution of an acid (2 -wash) or with brine.

Preferably, the acid (2 -wash) is ammonium chloride.

More preferably, acid (2 -wash) is used as a saturated aqueous solution.

More preferably, the reaction mixture is first washed with an aqueous solution of acid (2 -wash), and then with brine.

When acid (2) is an aqueous solution of acid (2-2), it can function simultaneously to wash the organic phase, i.e. it acts as acid (2 -wash).

Preferably, any aqueous phase can be extracted, preferably the extraction if done with a solvent (2-extract).

Solvent (2-extract) is a suitable extraction solvent, preferably, solvent (2-extract) is selected from the group consisting of solvent (2-co-extract), C2-5 alkyl C2-5 carboxylate, C₅_8 alkane and mixtures thereof; more preferably consisting of solvent (2-co-extract), C2-5 alkyl acetates, C2-5 alkyl propionate, C2-5 alkyl butyrate, C5-8 alkane and mixtures thereof; even more preferably solvent (2-extract) is ethyl acetate or a mixture of ethyl acetate with solvent (2-co-extract).

Solvent (2-co-extract) is preferably selected from the group consisting of benzene, toluene, xylene, naphthalene, Ci_₄ alkyl substituted naphthalenes, decalin, tetralin and mixtures thereof. Preferably, the amount of solvent (2-co-extract) is from 0.1 to 10 % by weight, more preferably from 0.1 to 5 % by weight, even more preferably from 0.1 to 2 % by weight, the % by weight based in the total weight of solvent (2-extract).

Even more preferably, the reaction mixture is first washed with an aqueous solution of acid (2-wash), then the resulting aqueous phase is extracted with solvent (2-extract), and the resulting combined organic phase is washed with brine.

Concentration is preferably done by distillation.

The compound of formula (2) can be purified before isolation, preferably by chromatography, distillation (preferably under reduced pressure) or crystallization.

It is postulated, that the reagent (2) comprises a chiral organometallic complex, which is formed from the reagents (2a), i.e. from compound (2al), compound (2a2) and compound of formula (2a3), and which provides the chiral addition of the

cyclopropylacetylene to compound of formula (1).

Reaction (2a) can be done in various ways with respect to the sequence of addition of the reagents (2a), and also with respect to the sequence of addition of any of the reagents (2a) and of compound of formula (1).

Reagent (2) can also be prepared in situ in the presence of compound of formula (1).

Reagents (2a) can comprise more than one, preferably 2 or 3, more preferably 2, compounds (2al); more than one, preferably 2 or 3, more preferably 2, compounds (2a2); and/or more than one, preferably 2 or 3, more preferably 2, compounds of formula (2a3).

Preferably, reagents (2a) comprise one, compound (2al), one or two compounds (2a2), and one compound of formula (2a3).

The following illustrates some possible embodiments of reaction (2a).

In one embodiment, reaction (2a) comprises step (2al), step (2a2), step (2a3) and step (2a4),

step (2al) being in a mixing (2al) of compound (2al) with compound (2a2);

step (2a2) being the mixing (2a2) of compound (2a3) with the mixture obtained by step (2al);

step (2a3) being the mixing (2a3) of compound of formula (1) with the mixture

obtained by step (2a2);

step (2a4) being the addition of acid (2) to the mixture obtained by step (2a3).

Preferably, the mixing (2al) is done at a temperature of from -78 to 100 °C, more preferably of from -20 to 100 °C, even more preferably of from -20 to 70 °C.

Preferably, the mixing (2a3) is done at a temperature of from -78 to 100 °C, more preferably of from -20 to 100 °C, even more preferably of from -20 to 70 °C.

Preferably, the mixing (2a 1) is done for a time of from 15 min to 72 h, more preferably of from 1 to 36 h, even more preferably of from 4 to 24 h.

Preferably, the mixing (2a2) is done for a time of from 15 min to 72 h, more preferably of from 1 to 36 h, even more preferably of from 4 to 24 h.

Preferably, the mixing (2a3) is done for a time of from 15 min to 72 h, more preferably of from 1 to 36 h, even more preferably of from 4 to 24 h. Between step (2a3) and step (2a4), a step (2a3-l) can be inserted, step (2a3-l) being a mixing (2a3-l) of compound (2a2) with the mixture obtained by step (2a3).

Preferably, the mixing (2a3-l) is done at a temperature of from -78 to 100 °C, more preferably of from -20 to 100 °C, even more preferably of from -20 to 70 °C.

Compound (2al), compound (2a2) and compound of formula (2a3) are known compounds and can be prepared according to known methods.

Preferably, the reaction (3) is done at a reaction temperature of from -78 to 100 °C, more preferably of from -20 to 80 °C, even more preferably of from -5 to 50 °C.

Preferably, the reaction (3) is done at a pressure of from atmospheric pressure to 20 bar, more preferably of from atmospheric pressure to 10 bar, even more preferably of from atmospheric pressure to 5 bar.

Preferably, the reaction time of reaction (3) is from 15 min to 48 h, more preferably from 1 to 36 h, even more preferably from 4 to 24 h.

Preferably, reaction (3) can be done in a solvent (3) or neat, solvent (3) is selected from the group consisting of Ci_₆ monocarboxylic acid Ci_₆ alkyl ester, benzene, toluene, xylene, mesitylene, N,N-di-Ci_₄ alkyl Ci_₄ monocarboxamide,

N-methylpyrrolidone, pyridine, Ci_₄ alkyl pyridine, mixed and not-mixed di-Ci_₄ alkyl pyridine, dioxane, C₂_₄ alkylene glycols, C₂_₄ alkylene glycol Ci_₄ alkyl monoether, C₂_₄ alkylene glycol di-Ci_₄ alkyl ether, di-C₂_₄ alkylene glycol mono-Ci_₄ alkyl ether, di-C₂_₄ alkylene glycol di-Ci_₄ alkyl ether, tetrahydrofurane, Ci_₄ alkyl

tetrahydrofurane, R53-0-R55-0-R54, dichlorobenzene, chlorobenzene, halogenated Ci_₄ alkane, Ci_₆ alcohol, di-Ci_₂ alkyl sulfoxide, R51-0-R52, C_5-12 alkane,

N(R61)(R62)(R63), water or mixtures thereof; with R51, R52, R53, R54, R55, R61, R62, R63 and halogenated Ci_₄ alkanes being as defined above, also with all their preferred embodiments;

More preferably, solvent (3) is selected from the group consisting of ethyl acetate, butyl acetate, toluene, xylene, dimethylformamide, dimethylacetamide,

N-methylpyrrolidone, pyridine, methylethylpyridine, e.g. 2-methyl-5 -ethyl pyridine, dioxane, diethylene glycol dimethyl ether, tetrahydrofurane, 2-methyltetrahydrofurane, dimethoxyethane, dichlorobenzene, chlorobenzene, dichloroethane, methanol, ethanol, n-propanol, 2-propanol, n-butanol, secondary butanol, n-pentanol, n-hexanol, tertiary butanol, dimethyl sulfoxide, dimethyl ether, methyl-tert butyl ether, diisopropyl ether, biphenyl ether, triethylamine, diisopropylethylamine, tri-n-propylamine,

Preferably, the amount of solvent (3) is from 1 to 200 fold, more preferably of from 5 to 100 fold, even more preferably of from 20 to 50 fold, of the weight of compound of formula (2).

Preferably, from 1 to 3 mol equivalents, more preferably from 1 to 2.0 mol

equivalents, even more preferably from 1 to 1.5 mol equivalents, of compound of formula (3 a) are used, the mol equivalents being based the mol of compound of formula (2).

Preferably, reaction (3) is done under inert atmosphere. Preferably, base (3-1) is N(R41)(R42)(R43).

Preferably, R41, R42 and R43 are identical or different and independently from each other hydrogen, phenyl or Ci_8 alkyl, more preferably hydrogen, phenyl or Ci_₄ alkyl, even more preferably hydrogen, phenyl, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl or tert-butyl. More preferably, R41, R42 and R43 are identical and independently from each other hydrogen, methyl, ethyl or phenyl.

Preferably, when base (3) is a mixture base (3-1) with water, base (3) comprises from 0.5 to 30 % by weight, more preferably from 1 to 20 % by weight, even more preferably from 4 to 10 % by weight, of base (3-1), with the % by weight being based on the total weight of base (3).

Preferably, the amount of base (3) is from 0.1 to 10 fold, more preferably from 0.2 to 5 fold, even more preferably from 0.4 to 2 fold, of the weight of compound of formula (2)·

Or, preferably, the amount of base (3) is from 1 to 20 mol equivalents, more preferably from 1 to 10 mol equivalents, even more preferably from 1 to 5 mol equivalents, the mol equivalents are based on the mol of compound of formula (3 a).

Preferably, the addition of base (3-1) is done, when the reaction mixture obtained from a reaction (3) is so acidic, that the compound of formula (3) is present in the reaction mixture in protonated state.

Preferably, suitable salts of compound of formula (3) are hydro chlorides, sulfonates, methanesulfonates, oxalates or tartrates, more preferably hydro chlorides.

After the reaction (3) the compound of formula (3) or suitable salts of compound of formula (3) can be isolated by standard methods such as washing, extraction, filtration, concentration and drying.

Preferably, the washing of any organic phase after the reaction during isolation can be done with an aqueous solution of a base (3-wash) and/or with brine.

Preferably, the base (3-wash) is an aqueous solution of triethylamine. Preferably, from 1 to 10 mol equivalents, more preferably from 1 to 5 mol equivalents, even more preferably from 1.5 to 2.5 mol equivalents, of base (3-wash) are used, the mol equivalents being based the mol of compound of formula (3 a).

More preferably, the reaction mixture is first washed with an aqueous solution of base (3-wash), and then with brine.

Preferably, any aqueous phase can be extracted, preferably the extraction if done with a solvent (3-extract).

Solvent (3-extract) is a suitable extraction solvent, preferably, solvent (3-extract) is selected from the group consisting of solvent (3 -co-extract), C2-5 alkyl C2-5

carboxylate, C₅_8 alkane and mixtures thereof; more preferably consisting of solvent (3 -co-extract), C2-5 alkyl acetates, C2-5 alkyl propionate, C2-5 alkyl butyrate, C5-8 alkane and mixtures thereof; even more preferably solvent (3-extract) is ethyl acetate or a mixture of ethyl acetate with solvent (3-co-extract).

Solvent (3-co-extract) is preferably selected from the group consisting of benzene, toluene, xylene, naphthalene, Ci_₄ alkyl substituted naphthalenes, decalin, tetralin and mixtures thereof. Preferably, the amount of solvent (3-co-extract) is from 0.1 to 10 % by weight, more preferably from 0.1 to 5 % by weight, even more preferably from 0.1 to 2 % by weight, the % by weight based in the total weight of solvent (3-extract).

Even more preferably, the reaction mixture is first washed with an aqueous solution of base (3-wash), then the resulting aqueous phase is extracted with solvent (3-extract), and the resulting combined organic phase is washed with brine.

Concentration is preferably done by distillation of a solvent (3) and/or solvent

(3-extract). The compound of formula (3) or of suitable salts of compound of formula (3) can be purified before final isolation preferably by chromatography or

crystallization from an appropriate solvent. Compound of formula (3 a) is a known compound and can be prepared according to known methods.

Preferably, compound of formula (3) is used for step (4) as such, i.e. in its neutral form and not as a salt.

Preferably, catalyst (4) is selected from the group consisting of Cu powder, Cul, CuBr, CuCl, CuSCN, CuCN, CuBF₄, CuPF₆, CuOTf (copper(I)

trifluoromethanesulfonate), CuC0₃, Cu(OAc)₂, Cu(OTf)₂ (copper(II) trifluoromethanesulfonate), Cu₂0, CuS0₄, Pd(OAc)₂, trisdibenzylideneacetone palladium(O), allylpalladium(II)chloride dimer, palladium(II)chloride, palladium(II)acetylacetonate, palladium(II)nitrate,

dichloro(bisbenzonitrile)palladium(II),

dichloro( 1 ,5-cyclooctadien)palladium(II),

tetrakis(triarylphosphino)palladium(0), dppfPdCl₂, Pd[(t-Bu)₃P]₂,

PdCl₂(A-Phos)₂, XantPhosPdCl₂, PdCl₂(t-DBPF), Pd(TFAc)₂ (palladium(II) trifluoroacetate) and mixtures thereof.

Preferably, ligand (4) is selected from the group consisting of

trans-Ν,Ν ' -dimethylcyclohexane- 1 ,2-diamine, N,N ' -dimethylethylenediamine, cis-Ν,Ν ' -dimethylcyclohexane- 1 ,2-diamine, trans-cyclohexane- 1 ,2-diamine and cis-cyclohexane- 1 ,2-diamine.

Base (4) comprises also respective mixed alkali compounds.

Preferably, the alkali of base (4) is Na or K.

Preferably, base (4) is selected from the group consisting of alkali phosphate, alkali hydrogen phosphate, alkali dihydrogen phosphate, alkali carbonate, alkali bicarbonate, alkali 0-Ci_₄ alkyl, alkali hydroxide, N(R71)(R72)(R73), alkali hexamethyldisilazide, alkali N(R81)(R82) and mixtures thereof; R71, R72 and R73 are identical or different and independently from each other hydrogen, phenyl or C_1-10 alkyl;

R81 and R82 are identical or different and independently from each other

hydrogen, phenyl or C_1-10 alkyl.

In particular, ligand (4) is trans-N,N'-dimethylcyclohexane-l,2-diamine, catalyst (4) is Cul and base (4) is K3PO4.

Preferably, the cyclisation of step (4) is done at reaction temperature of from -78 to 200 °C, more preferably of from 0 to 150 °C, even more preferably of from 100 to 150 °C.

Preferably, the cyclisation of step (4) is done at a pressure of from atmospheric pressure to 20 bar, more preferably of from atmospheric pressure to 10 bar, even more preferably of from atmospheric pressure to 5 bar.

Preferably, the cyclisation time of step (4) is from 15 min to 48 h, more preferably from 1 to 36 h, even more preferably from 4 to 24 h.

The cyclisation of step (4) is done in a solvent (4) or neat, preferably in a solvent. Solvent (4) is preferably selected from the group consisting of Ci_₆ monocarboxylic acid Ci_6 alkyl ester, benzene, toluene, xylene, mesitylene, N,N-di-Ci_₄ alkyl Ci_₄ monocarboxamide, N-methylpyrrolidone, pyridine, Ci_₄ alkyl pyridine, mixed and not-mixed di-Ci_₄ alkyl pyridine, dioxane, C₂_₄ alkylene glycols, C₂_₄ alkylene glycol Ci_₄ alkyl monoether, C₂_₄ alkylene glycol di-Ci_₄ alkyl ether, di-C₂_₄ alkylene glycol mono-Ci_₄ alkyl ether, di-C₂_₄ alkylene glycol di-Ci_₄ alkyl ether, tetrahydrofurane, Ci_₄ alkyl tetrahydrofurane, R53-0-R55-0-R54, dichlorobenzene, chlorobenzene, halogenated Ci_₄ alkane, Ci_₆ alcohol, di-Ci_₂ alkyl sulfoxide, R51-0-R52, C_5-12 alkane, N(R61)(R62)(R63), water or mixtures thereof; with R51, R52, R53, R54, R55, R61, R62, R63 and halogenated Ci_₄ alkanes being as defined above, also with all their preferred embodiments;

More preferably, the solvent (4) is selected from the group consisting of benzene, toluene, xylene, mesitylene, dimethylformamide, dimethylacetamide,

N-methylpyrrolidone, pyridine, methylethylpyridine, e.g. 2-methyl-5 -ethyl pyridine, dioxane, C₂_₄ alkylene glycols, C₂_₄ alkylene glycol Ci_₄ alkyl monoether, di-C₂_₄ alkylene glycol mono-Ci_₄ alkyl ether, di-C₂_₄ alkylene glycol di-Ci_₄ alkyl ether, tetrahydrofurane, 2-methyltetrahydrofurane, dimethoxyethane, dichlorobenzene, chlorobenzene, dichloromethane, chloroform, tetrachlorocarbon, dichloroethane, Ci_₆ alcohols, dimethyl sulfoxide, Ci_₄ alkyl ether, biphenyl ether, tertiary amines of formula N(R61)(R62)(R63), triphenylamine, water and mixtures thereof.

More preferably, step (4)solvent (4) is selected from the group consisting of benzene, toluene, xylene, mesitylene, dimethylformamide, dimethylacetamide,

N-methylpyrrolidone, pyridine, methylethylpyridine, e.g. 2-methyl-5 -ethyl pyridine, dioxane, diethylene glycol dimethyl ether, tetrahydrofurane, 2-methyltetrahydrofurane, dimethoxyethane, dichlorobenzene, chlorobenzene, dichloromethane, chloroform, tetrachlorocarbon, dichloroethane, methanol, ethanol, n-propanol, 2-propanol, n-butanol, secondary butanol, n-pentanol, n-hexanol, tertiary butanol, dimethyl sulfoxide, dimethyl ether, methyl-tert butyl ether, diisopropyl ether, biphenyl ether, triethylamine, diisopropylethylamine, tri-n-propylamine, tri-isopropylamine, tri-n-butylamine, triphenylamine, water and mixtures thereof.

In particular, solvent (4) is toluene, tetrahydrofurane or hexane.

Preferably, the amount of solvent (4) is from 1 to 200 fold, more preferably of from 5 to 100 fold, even more preferably of from 20 to 50 fold, of the weight of compound of formula (3). Preferably, from 0.001 to 0.5 mol equivalents, more preferably from 0.01 to 0.25 mol equivalents, even more preferably from 0.025 to 0.1 mol equivalents, of catalyst (4) are used, the mol equivalents being based the mol of compound of formula (3).

Preferably, from 0.001 to 0.5 mol equivalents, more preferably from 0.01 to 0.25 mol equivalents, even more preferably from 0.025 to 0.2 mol equivalents, of ligand (4) are used, the mol equivalents being based the mol of compound of formula (3).

Preferably, from 1 to 3, more preferably from 1.1 to 2.5, even more preferably from 1.25 to 2 mol equivalents, of base (4) are used, the mol equivalents being based the mol of compound of formula (3).

Preferably, the cyclisation of step (4) is done under inert atmosphere.

Optionally, after the intermolecular cyclisation in method (4), an acid (4) is added to the reaction mixture resulting from the intramolecular cyclisation.

Preferably, this addition of acid (4) is done, when the reaction mixture obtained from the inramolecular cyclisation so basic, that the compound of formula (4) is present in the reaction mixture in deprotonated state.

Preferably, acid (4) is an acid (4-1), water or a mixture thereof.

Acid (4-1) can be practically any acid.

Preferably, acid (4-1) is selected from the group consisting of ammonium chloride, hydrochloric acid, sulphuric acid, sulfonic acid, nitric acid, phosphoric acid, Ci_₆ carboxylic acid, C₂_8 dicarboxylic acid, C₄_i₂ tricarboxylic acid and mixtures thereof.

More preferably, acid (4-1) is selected from the group consisting of ammonium chloride, hydrochloric acid, sulphuric acid, C₂_8 sulphonic acid, methanesulfonic acid, acetic acid, nitric acid, oxalic acid tartaric acid and mixtures thereof. Preferably, suitable salts of compound of formula (4) are the respective salts derived from compound of formula (4) and acid (4-1), more preferably hydro chloride, sulfonate, methanesulfonate, acetate, nitrate, oxalate or tartrate.

Preferably, when acid (4) is a mixture of acid (4-1) with water, acid (4) comprises from comprises from 1 to 30 % by weight, more preferably from 5 to 30 % by weight, even more preferably from 15 to 27 % by weight, of acid (4-1), with the % by weight being based on the total weight of acid (4).

Preferably, the amount of acid (4) is from 1 to 200 fold, more preferably from 5 to 100 fold, even more preferably from 10 to 50 fold, of the weight of compound of formula (3).

Or, preferably, the amount of acid (4) is from 1 to 20 mol equivalents, more preferably from 1 to 10 mol equivalents, even more preferably from 1 to 5 mol equivalents, the mol equivalents being based on the mol of compound of formula (3).

After the cyclisation of step (4) or after the optional addition of acid (4), the compound of formula (4) or its suitable salts can be isolated by standard methods such as washing, extraction, filtration, concentration and drying.

Preferably, the washing of any organic phase after the reaction during isolation can be done with water, with an aqueous solution of an acid (4-wash) or with brine.

Preferably, the acid (4-wash) is ammonium chloride.

More preferably, acid (4-wash) is used as a saturated aqueous solution.

The reaction mixture can first be washed with an aqueous solution of acid (4-wash), and then with brine. Preferably, any aqueous phase can be extracted, preferably the extraction if done with a solvent (4-extract).

Solvent (4-extract) is a suitable extraction solvent, preferably, solvent (4-extract) is selected from the group consisting of solvent (4-co-extract), C2-5 alkyl C2-5 carboxylate, C₅_8 alkane and mixtures thereof; more preferably consisting of solvent (4-co-extract), C2-5 alkyl acetates, C2-5 alkyl propionate, C2-5 alkyl butyrate, C5-8 alkane and mixtures thereof; even more preferably solvent (4-extract) is ethyl acetate or a mixture of ethyl acetate with solvent (4-co-extract).

Solvent (4-co-extract) is preferably selected from the group consisting of benzene, toluene, xylene, naphthalene, Ci_₄ alkyl substituted naphthalenes, decalin, tetralin and mixtures thereof. Preferably, the amount of solvent (4-co-extract) is from 0.1 to 10 % by weight, more preferably from 0.1 to 5 % by weight, even more preferably from 0.1 to 2 % by weight, the % by weight based in the total weight of solvent (4-extract).

Even more preferably, the reaction mixture is first washed with an aqueous solution of acid (4-wash), then the resulting aqueous phase is extracted with solvent (4-extract), and the resulting combined organic phase is washed with brine.

In case of filtration, the reaction mixture is preferably filtered with a Celite® filter. Concentration is preferably done by distillation of a solvent (4). The compound of formula (4) or its suitable salts can be purified before final isolation preferably by chromatography, crystallization from an appropriate solvent or distillation, preferably under reduced pressure.

Catalyst (4), ligand (4) and base (4) are known compounds and can be prepared according to known methods.

Step (1), step (2), step (3) and step (4) are done consecutively.

Where applicable, intermediates from the various steps and reactions can be used for the next step without isolation. Further subject of the invention is the use of compound of formula (2) for the preparation of compound of formula (3) or of suitable salts of compound of formula

(3);

with the compound of formula (3) and the compound of formula (2) being as defined above.

Further subject of the invention is the use of compound of formula (3) or of suitable salts of compound of formula (3) for the preparation of compound of formula (4) or of suitable salts of compound of formula (4);

with the compound of formula (3) and the compound of formula (4) being as defined above.

Further subject of the invention is the use of compound of formula (l-2a) or of compound of formula (l-lal) in a method for the preparation of compound of formula (3) or of suitable salts of compound of formula (3), which method prepares compound of formula (3) via the intermediate compounds of formula (1) and (2); with the compound of formula (l-2a), the compound of formula (1-lal), the compound of formula (1), the compound of formula (2) and the compound of formula (2) being as defined above, also with all their preferred embodiments.

Further subject of the invention is the use of compound of formula (1) or of compound of formula (2) as intermediates in a method for preparation of compound of formula (3) or of suitable salts of compound of formula (3), which method starts from compound of formula (l-2a) or from compound of formula (1-lal);

with the compound of formula (1), the compound of formula (2), the compound of formula (3), the compound of formula (l-2a) and the compound of formula (1-lal) being as defined above, also with all their preferred embodiments. Further subject of the invention is the use of compound of formula (2) in a method for the preparation of compound of formula (4) or of suitable salts of compound of formula (4), which method prepares compound of formula (4) via the intermediate compound of formula (3) or via intermediate suitable salts of compound of formula

(3);

with the compound of formula (2), the compound of formula (3) and the compound of formula (4) being as defined above.

Further subject of the invention is the use of compound of formula (3) or of suitable salts of compound of formula (3) as intermediates in a method for preparation of compound of formula (4) or of suitable salts of compound of formula (4), which method starts from compound of formula (2);

Further subject of the invention is the use of compound of formula (1) in a method for the preparation of compound of formula (3) or of suitable salts of compound of formula (3), which method prepares compound of formula (3) or suitable salts of compound of formula (3) via the intermediate compound of formula (2);

with the compound of formula (1), the compound of formula (2) and the compound of formula (3).

Further subject of the invention is the use of compound of formula (2) as intermediate in a method for preparation of compound of formula (3) or of suitable salts of compound of formula (3), which method starts from compound of formula (1);

Further subject of the invention is the use of compound of formula (1) in a method for the preparation of compound of formula (4) or of suitable salts of compound of formula (4), which method prepares compound of formula (4) via the intermediate compounds of formula (2) and (3) or via intermediate compound of formula (2) and suitable salts of compound of formula (3);

with the compound of formula (1), the compound of formula (2), the compound of formula (3) and the compound of formula (4) being as defined above.

Further subject of the invention is the use of compound of formula (2) or of compound of formula (3) or of suitable salts of compound of formula (3) as intermediates in a method for preparation of compound of formula (4) or of suitable salts of compound of formula (4), which method starts from compound of formula

(i);

Further subject of the invention is the use of compound of formula (l-2a) or of compound of formula (l-lal) in a method for the preparation of compound of formula (4) or of suitable salts of compound of formula (4), which method prepares compound of formula (4) via the intermediate compounds of formula (1), (2) and (3) or via intermediate compounds of formula (1) and (2) and suitable salts of compound of formula (3);

with the compound of formula (1), the compound of formula (2), the compound of formula (3), the compound of formula (4), the compound of formula (l-2a) and the compound of formula (1-lal) being as defined above, also with all their preferred embodiments.

Further subject of the invention is the use of compound of formula (1) or of compound of formula (2) or of compound of formula (3) or of suitable salts of compound of formula (3) as intermediates in a method for preparation of compound of formula (4) or of suitable salts of compound of formula (4), which method starts from compound of formula (l-2a) or from compound of formula (1-1 al);

The disclosed method has the advantage of not needing protection- and deprotection steps, which results in a simplified process with improved overall yield. The disclosed method furthermore avoids the use of explosive, highly toxic or even prohibited substances. The method can be realized geographically without the limitation of known processes.

Example

Abbreviations

ee enantiomeric excess, ((S)-(R))/((S)+(R))

n-BuLi n-butyl lithium

RT room temperature

THF tetrahydrofurane

Method description

A) HPLC method A analysis for the determination of the ee in examples 2b, and 4b

Detection in HPLC method A was done with a UV photodiode array detector.

Stepl Sample preparation:

A specific amount of sample in the range of 0.5 to 1 mg was dissolved in ca. from to 1 mL of isopropanol for example 2b or of ethanol for example 3b and 4b, the solution was filtered through a 0.45 micrometer size pore, 4 mm diameter PVDF hydrophobic filter.

Step2 Chromatography conditions:

Example 2b 3b 4b

Column Chiralpak AD-H, 4.6 x 250 mm Oven RT RT RT

Flow rate (mL/min) 0.5 0.8 1.0

Detector wavelength (nm)230 233 252

Run time (min) 20 30 30

Phase A/ Phase B (v/v) 11/89 15/85 2.5/97.5

Prior to the injection, the column was conditioned at initial conditions for 30 min.

Ste 3 Chromatographic profile analysis:

Measure of the area of all chromatography peaks related with the two enantiomers from the synthesis. The areas proportion is taken as a percentage of purity between the two enantiomers.

Example 1: l-(2,5-Dichloro-phenyl)-2,2,2-trifluoro-ethanone

A solution of 1 ,4-dichlorobenzene (20 g, 136 mmol) in anhydrous THF (200 mL) was cooled to -78 °C. n-BuLi (150 mmol in 60 mL hexane) was added. The mixture was stirred for 1 h, followed by addition of methyl trifluoroacetate (18 mL, 179 mmol) in 30 min. The mixture was allowed to warm up to 0 °C and then stirred for 2 h.

Pre-cooled saturated aqueous ammonium chloride solution (100 mL) was added. The phases were separated. The organic phase was concentrated under vacuum and the residue was dissolved in ethyl acetate (200 mL). The water phase was extracted with ethyl acetate (200 mL). The two ethyl acetate phases were combined and then washed with brine (200 mL). The phases were separated. The organic phase was dried over Na₂S0₄ and then filtrated. The filtrate was concentrated under vacuum. The residue was purified via column chromatography using silica gel eluting with ethyl acetate / hexane (1/10 v/v) to afford after isolation and drying

l-(2,5-Dichloro-phenyl)-2,2,2-trifluoro-ethanone as an orange oil (28.5 g, 86 % yield).

1H NMR (400 MHz, CDC1₃) delta 7.67 (s, 1H), 7.56 to 7.50 (m, 2H). Example 2a: 4-Cyclopropyl-2-(2,5-dichloro-phenyl)-l,l,l-trifluoro-but-3-yn-2-ol Anhydrous THF (400 mL) was cooled to -15 °C. n-BuLi (175 mmol in 70 mL hexane) was then charged in 20 min. Ethynylcyclopropane (22 mL, 260 mmol) was charged in 30 min to maintain the temperature at -15 to -12 °C. The mixture was warmed to 0 °C and then stirred at 0 °C for 30 min. The reaction mixture was cooled to -45 °C and a solution of l-(2,5-dichloro-phenyl)-2,2,2-trifluoro-ethanone (28 g, 115 mmol), prepared according to example 1, in anhydrous THF (40 mL) was charged over a period of 30 min. The reaction mixture was warmed to 0 °C and then stirred for 1 h. Pre-cooled saturated aqueous ammonium chloride solution (300 mL) was charged. The phases were separated. The organic phase was concentrated under vacuum and the residue was dissolved in ethyl acetate (50 mL). The water phase was extracted with ethyl acetate (2 times with 200 mL). The combined organic phase was washed with brine (100 mL) and dried over Na₂S0₄. The mixture was filtered and

concentrated under vacuum. The residue was purified via column chromatography using silica gel eluting with dichloromethane / hexane (1/10 v/v) to afford after isolation and drying

4-cyclopropyl-2-(2,5-dichloro-phenyl)-l,l,l-trifluoro-but-3-yn-2-ol (30 g, 84 % yield) as an orange oil.

1H NMR (400 MHz, CDC1₃) delta 7.90 (d, J = 2.4 Hz, 1 H), 7.34 (d, J = 8.8 Hz, 1 H), 7.27 (dd, J = 8.8, 2.4 Hz, 1 H), 4.43 (s (br), 1 H), 1.37 to 1.31 (m, 1 H), 0.87 to 0.77 (m, 4 H).

Example 2b:

(S)-4-Cyclopr o yl-2-(2,5-dichlor o-phenyl)- 1,1,1 -tr ifluor o-but-3-yn-2-ol

Naphthalene- 1 -sulfonic acid ((R)-2 -hydroxy- 1 -methyl-2,2-diphenyl-ethyl)-amide (130 mg, 0.31 mmol) was charged followed by addition of anhydrous toluene (5 mL) and dimethylzinc (3.1 mmol in 3.1 mL heptane) at RT under inert atmosphere. The reaction mixture was stirred at RT for 0.5 h followed by addition of

ethynylcyclopropane (260 mg, 2.8 mmol). The reaction mixture was stirred at RT for 1.5 h. A solution of l-(2,5-dichloro-phenyl)-2,2,2-trifluoro-ethanone (500 mg, 2.1 mmol), prepared according to example 1, in anhydrous toluene (5 mL) was charged at RT over a period of 2 h. The reaction mixture was then stirred at RT for 18 h followed by addition of saturated aqueous ammonium chloride solution (20 mL). The phases were separated. The water phase was extracted with ethyl acetate (2 times with 20 mL). The combined organic phase was washed with brine (20 mL) and dried over Na₂S0₄. The mixture was filtered and concentrated under vacuum. The residue was purified via column chromatography using silica gel eluting with dichloromethane / hexane (1/10 v/v) to afford after isolation and drying

(S)-4-cyclopropyl-2-(2,5-dichloro-phenyl)- 1,1,1 -trifluoro-but-3-yn-2-ol (500 mg, 78% yield) as a light yellow oil. The ee measured was 46 % (HPLC method description A).

1H NMR (400 MHz, CDC1₃) delta 7.90 (d, J = 2.4 Hz, 1 H), 7.38 (d, J = 8.8 Hz, 1 H), 7.30 (dd, J = 8.8, 2.4 Hz, 1 H), 3.52 (s (br), 1 H), 1.39 to 1.36 (m, 1 H), 0.89 to 0.83 (m, 4 H).

Example 3a: Carbamic acid

cyclopro yl-(2,5-dichloro-phenyl)-trifluoromethyl-prop-2-ynyl ester

A mixture of 4-cyclopropyl-2-(2,5-dichloro-phenyl)-l,l,l-trifluoro-but-3-yn-2-ol (1.0 g, 3.2 mmol), prepared according to example 2a, and ethyl acetate (10 mL) was cooled to 0 °C followed by addition of chlorosulfonyl isocyanate (0.37 mL, 4.25 mmol). The mixture was warmed to RT and then stirred for 5 h. The mixture was cooled to 0 °C and water (10 mL) was charged in 10 min followed by addition of triethylamine (0.9 mL, 6.49 mmol) over a period of 10 min. The reaction mixture was warmed to RT for 18 h. The phases were separated. The water phase was extracted with ethyl acetate (2 times with 20 mL). The combined organic phase was washed with brine (10 mL) and dried over Na₂S0₄. The mixture was filtered and concentrated under vacuum. The residue was purified via column chromatography using silica gel eluting with ethyl acetate/ hexane (1/10 v/v) to afford after isolation and drying carbamic acid cyclopropyl-(2,5-dichloro-phenyl)-trifluoromethyl-prop-2-ynyl ester (1.1 g, 98 % yield) as a white solid. 1H NMR (400 MHz, CDC1₃) delta 7.89 (s, 1H), 7.33 to 7.27 (m, 2H), 5.22 (s (br), 2H), 1.45 to 1.34 (m, 1H), 0.92 to 0.90 (m, 4H).

Example 3b: (S)-Carbamic acid

cyclopropyl-(2,5-dichloro-phenyl)-trifluoromethyl-prop-2-ynyl ester

A mixture of (S)- 4-cyclopropyl-2-(2,5-dichloro-phenyl)-l,l,l-trifluoro-but-3-yn-2-ol (0.92 mg, 3.0 mmol), prepared according to example 2b, and ethyl acetate (8 mL) was cooled to 0 °C followed by addition of chlorosulfonyl isocyanate (0.39 mL, 4.5 mmol). The mixture was warmed to RT, stirred for 1.5 h, and then cooled to 0 °C. Water (10 mL) was charged in 10 min followed by addition of triethylamine (0.83 mL, 6.0 mmol)) over a period of 10 min. The reaction mixture was warmed to RT for 18 h. The phases were separated and the water phase was extracted with ethyl acetate (2 times with 20 mL). The combined organic phase was washed with brine (10 mL) and dried over Na₂S0₄. The mixture was filtered and concentrated under vacuum. The residue was purified via column chromatography using silica gel eluting with ethyl acetate/ hexane (1/10 v/v) to afford after isolation and drying (S)-carbamic acid cyclopropyl-(2,5-dichloro-phenyl)-trifluoromethyl-prop-2-ynyl ester (1.02 g, 98 % yield) as a white solid. The ee measured was 46 % (HPLC method description A). The 1H NMR (400 MHz, CDCI3) measurement of the compound prepared according to example 3b was identical as the 1H NMR (400 MHz, CDCI3) measured in the example 3 a.

Example 4a:

6-Chloro-4-trifluoromethyl-4-(cyclopropylethynyl)-lH-benzo[d]-l,3-oxazin-2-on e

Trans-N,N'-dimethylcyclohexane-l,2-diamine (17 mg, 0.12 mmol) and toluene (8 mL) were added to carbamic acid

cyclopropyl-(2,5-dichloro-phenyl)-trifluoromethyl-prop-2-ynyl ester (210 mg, 0.6 mmol), prepared according to example 3a, Cul (5.7 mg, 0.03 mmol) and K₃PO₄ (266 mg, 1.25 mmol) under inert atmosphere. The mixture was heated to 120 °C and stirred for 24 h at 120 °C. The mixture was cooled down to RT and filtered. The filtrate was concentrated under vacuum. The residue was purified via column chromatography using silica gel eluting with ethyl acetate/ hexane (1/3 v/v) to afford after isolation and drying

6-chloro-4-trifluoromethyl-4-(cyclopropylethynyl)-lH-benzo[d]-l,3-oxazin-2-one (76 mg, 40 % yield) as a white solid.

1H NMR (400 MHz, CDC1₃) delta 9.73 (s, 1 H), 7.50 (d, J = 2.0 Hz, 1 H), 7.38 (dd, J = 8.4, 2.4 Hz, 1 H), 6,92 (d, J = 8.8 Hz, 1 H), 1.45 to 1.33 (m, 1 H), 0.97 to 0.96 (m, 4 H).

Example 4b:

(S)-6-Chloro-4-trifluoromethyl-4-(cyclopropylethynyl)-lH-benzo[d]-l,3-oxazin-2 -one

Trans-N,N'-dimethylcyclohexane-l,2-diamine (26 mg, 0.18 mmol) and toluene (8 mL) were added to (S)-carbamic acid

cyclopropyl-(2,5-dichloro-phenyl)-trifluoromethyl-prop-2-ynyl ester (300 mg, 0.8 mmol) prepared according to example 3b, Cul (8.4 mg, 0.04 mmol) and K₃PO₄ (390 mg, 1.8 mmol) under inert atmosphere. The mixture was heated to 120 °C and stirred for 24 h at 120 °C. The mixture was cooled down to RT and filtered. Saturated aqueous ammonium chloride solution (10 mL) was added to the reaction mixture and the phases were separated. The water phase was extracted with ethyl acetate (2 times with 10 mL). The combined organic phase was washed with brine (10 mL) and dried over Na₂S0₄. The mixture was filtered and concentrated under vacuum. The residue was purified via column chromatography using silica gel eluting with ethyl acetate/ hexane (1/3 v/v) to afford after isolation and drying

(S)-6-chloro-4-trifluoromethyl-4-(cyclopropylethynyl)-lH-benzo[d]-l,3-oxazin-2-one as a white solid (120 mg, 45 % yield). The ee measured was 45 % (HPLC method description A). 1H NMR (400 MHz, CDC1₃) delta 9.58 (s, 1 H), 7.51 (s, 1 H), 7.37 (dd, J = 8.8, 2.4 Hz, 1 H), 6.88 (d, J = 8.4 Hz, 1 H), 1.45 to 1.39 (m, 1 H), 0.97 to 0.94 (m, 4 H).

Example 5: (R)-2-amino-l,l-diphenyl-propan-l-ol

A solution of PhMgBr (0.87 mol in 287 mL THF) was cooled to 0 °C under inert atmosphere. (R)-l-Methoxycarbonyl-ethyl-ammonium chloride (20 g, 140 mmol) was charged in portions over a period of 90 min to maintain the temperature between 0 and 5 °C. The reaction mixture was stirred for 30 min between 0 and 5 °C and then allowed to warm to RT. After 4 h at RT, the mixture was cooled to 0 °C. Aqueous HCl (100 mL, 10 % w/w) was added over a period of 60 min between 0 and 5 °C. The mixture was warmed to RT. Ethyl acetate (300 mL) and water (400 mL) were charged. The phases were separated and the water phase was extracted with ethyl acetate (200 mL). The combined organic phase was washed successively with water (50 mL) and brine (50 mL). The organic phase was concentrated under vacuum to afford a residue (about 50 g). Hexane (30 mL) was charged in 30 min. The mixture was cooled down to 0 °C in 3 h and then aged for 1 h at 0 °C. The mixture was filtered to afford after isolation and drying (R)-2-amino-l,l-diphenyl-propan-l-ol (30.4 g, 80 % yield) as a yellow solid.

1H NMR (400 MHz, CDCI3) delta 7.64 (dd, J = 7.6, 4.0 Hz, 2 H), 7.51 (dd, J = 7.6, 1.4 Hz, 2 H), 7.37 to 7.28 (m, 4 H), 7.24 to 7.17 (m, 2 H), 4.18 (q, J = 6.3 Hz, 1 H), 0.99 (d, J = 6.3 Hz, 3 H).

Example 6: Naphthalene-l-sulfonic acid

((R)-2-hydroxy-l-methyl-2,2-diphenyl-ethyl)-amide

A mixture of (R)-2-amino-l,l-diphenyl-propan-l-ol (15.3 g, 67 mmol), prepared according to example 5, and dichloromethane was cooled to 0 °C followed by addition of triethylamine (20.4 g, 202 mmol) within 15 min. A solution of

naphthalene- 1-sulfonyl chloride (16.8 g, 74 mmol) in dichloromethane was charged over a period of 2 h at 2 to 8 °C. The mixture was allowed to warm to RT and then stirred for 4 h at RT. Water (40 mL) was charged and the phases were separated. The water phase was extracted with dichloromethane (20 mL). The combined organic phase was washed with brine (20 mL). The mixture was filtered and concentrated under vacuum. The residue was purified via column chromatography using silica gel eluting with ethyl acetate/ hexane (1/3 v/v) to afford after isolation and drying naphthalene- 1 -sulfonic acid ((R)-2-hydroxy-l-methyl-2,2-diphenyl-ethyl)-amide (27 g, 97 % yield) as a white solid.

1H NMR (400 MHz, CDC1₃) delta 8.35 (m, 1 H), 8.21 (d, J = 7.2 Hz, 1 H), 8.21 (d, J = 8.1 Hz, 1 H), 7.89 (d, J = 8.1 Hz, 1 H), 7.57 to 6.9 (m, 10 H), 6.86 to 6.81 (m, 3 H), 5.18 to 5.05 (m, 1 H), 4.51 to 4.42 (m, 1 H), 2.81 (d(br), 1 H), 1.13 (m, 3 H).

Claims

1. A method (4-alone) for the preparation of a compound of formula (4) or of a suitable salt of compound of formula (4),

the method (4-alone) comprises a step step (4) comprises a method (4) for the preparation of the compound of formula (4) or of suitable salts of compound of formula (4), method (4) comprises an intramolecular cyclisation of a compound of formula (3) or of a suitable salt of compound of formula (3), in the presence of a catalyst (4), a ligand (4) and a base (4);

base (4) is selected from the group consisting of alkali phosphate, alkali hydrogen phosphate, alkali dihydrogen phosphate, alkali carbonate, alkali bicarbonate, alkali alcoholate, alkali hydroxide, alkyl amine, alkali hexamethyldisilazide and alkali amide and mixtures thereof.

2. Method according to claim 1, wherein

the compound of formula (3) or a suitable salt of compound of formula (3) is prepared in a step (3), and then

the compound of formula (4) of a suitable salt of compound of formula (4) is prepared in step (4) from the compound of formula (3) or from a suitable salt of compound of formula (3), the compound of formula (3) having been prepared in step (3); wherein

step (3) comprises a method (3) for the preparation of the compound of formula (3) or of a suitable salt of compound of formula (3); method (3) comprises a step (3-1) and a step (3-2); step (3-1) comprises a reaction (3) of a compound of formula (2)

with a compound of formula (3a);

step (3-2) comprises the addition of a base (3) to the reaction mixture resulting from step (3-1);

base (3) is selected from the group consisting of base (3-1), water and mixtures thereof;

base (3-1) is selected from the group consisting of N(R41)(R42)(R43), alkali or alkaline earth metal carbonates, hydrogencarbonates and hydroxides, piperidine, C_1-4 alkyl piperidine, pyridine, C_1-4 alkyl-pyridines and morpholine;

R41, R42 and R43 are identical or different and independently from each other hydrogen, phenyl or Ci_io alkyl.

3. Method according to claim 1 or 2, wherein

the compound of formula (2) is prepared in a step (2), and then the compound of formula (3) or a suitable salt of compound of formula (3) is prepared in step (3) from the compound of formula (2), the compound of formula (2) having been prepared in step (2), and then

the compound of formula (4) or a suitable salt of compound of formula (4) is prepared in step (4) from the compound of formula (3) or from a suitable salt of compound of formula (3), the compound of formula (3) or the suitable salt of compound of formula (3) having been prepared in step (3); wherein

step (2) comprises a method (2) for the preparation of the compound of formula (2), method (2) comprises a reaction (2), reaction (2) comprises a step (2-1), step (2-1) comprises a reaction (2-1) of a compound of formula (1) with a reagent (2),

M2 is selected from the group consisting of Zn, Mg and Cu; M3 is B;

compound (2a2a) is a diorganylzinc(II) compound;

compound (2a2b) is a compound derived from Cu(I) or Cu(II);

compound (2a2c) is a compound derived from Ti(IV);

compound (2a2d) is a compound derived from Li(I);

compound (2a2e) is a Grignard reagent;

compound (2a2f) is selected from the group consisting of Zn(OTf)₂, Sn(OTf)₂, InBr₃, AlMe₃, KOtBu, Zr(0-i-Pr)₄, [Rh(OH)(cod)]₂, [Rh(mu-OAc)C₂H₄]₂]2.

4. Method according to one or more of claims 1 to 3, wherein

the compound of formula (1) is prepared in a step (1), and then

the compound of formula (2) is prepared in step (2) from the compound of formula (1), the compound of formula (1) having been prepared in step (1), and then the compound of formula (3) or a suitable salt of compound of formula (3) is prepared in step (3) from the compound of formula (2), the compound of formula (2) having been prepared in step (2), and then

step (1) comprises a method (1) for the preparation of the compound of formula (1), method (1) comprises a reaction (1-1) or a reaction (1-2), the reaction (1-1) comprises a step (1-1 a),

step (1-la) comprises a reaction of a compound of formula (1-lal)

with a compound (l-la2); compound (l-la2) is selected from the group consisting of compound of formula (l-la2-l), compound of formula (l-la2-2) and compound of formula

(l-la2-3);

with the compound (l-la2) in the presence of a compound (l-2al); compound (l-2al) is a Friedel Crafts catalyst; step (l-2b) comprises the addition of an acid (1-2).

5. Method according to one or more of claims 1 to 4, wherein

catalyst (4) is selected from the group consisting of Cu powder, Cul, CuBr, CuCl, CuSCN, CuCN, CuBF₄, CuPF₆, CuOTf (copper(I) tnfluoromethanesulfonate), CuC0₃, Cu(OAc)₂, Cu(OTf)₂ (copper(II) tnfluoromethanesulfonate), Cu₂0, CuS0₄, Pd(OAc)₂, trisdibenzylideneacetone palladium(O), allylpalladium(II)chloride dimer,

palladium(II)chloride, palladium(II)acetylacetonate, palladium(II)nitrate,

dichloro(bisbenzonitrile)palladium(II), dichloro(l,5-cyclooctadien)palladium(II), tetrakis(triarylphosphino)palladium(0), dppfPdCl₂, Pd[(t-Bu)₃P]₂, PdCl₂(A-Phos)₂, XantPhosPdCli, PdCl₂(t-DBPF), Pd(TFAc)₂ (palladium(II) trifluoroacetate) and mixtures thereof.

6. Method according to one or more of claims 1 to 5, wherein

ligand (4) is selected from the group consisting of

trans-N,N'-dimethylcyclohexane-l,2-diamine, N,N'-dimethylethylenediamine, cis-Ν,Ν' -dimethylcyclohexane- 1 ,2-diamine, trans-cyclohexane- 1 ,2-diamine and cis-cyclohexane- 1 ,2-diamine.

7. Method according to one or more of claims 1 to 6, wherein the alkali of base (4) is Na or K.

8. Method according to one or more of claims 1 to 7, wherein base (4) is selected from the group consisting of alkali phosphate, alkali hydrogen phosphate, alkali dihydrogen phosphate, alkali carbonate, alkali bicarbonate, alkali O-C₁-₄ alkyl, alkali hydroxide, N(R71)(R72)(R73), alkali hexamethyldisilazide, alkali N(R81)(R82) and mixtures thereof;

R71, R72 and R73 are identical or different and independently from each other hydrogen, phenyl or C_MO alkyl;

R81 and R82 are identical or different and independently from each other

hydrogen, phenyl or C_MO alkyl.

9. Method according to one or more of claims 3 to 8, wherein

compound (2a2) is selected from the group consisting of compound (2a2a), compound (2a2b), compound (2a2c), compound (2a2d), compound (2a2e), compound (2a2f) and mixtures thereof;

compound (2a2a) is selected from the group consisting of [Ci-₆ alkyl] ₂Zn,

diphenyl-zinc and Zn(OTf)₂;

compound (2a2b) is a compound derived from Cu(I) or Cu(II);

compound (2a2c) is a compound derived from Ti(IV); compound (2a2d) is an organolithium compound or a lithium halide;

compound (2a2e) is a Grignard reagent;

10. Method according to one or more of claims 3 to 9, wherein

compound (2a2) is selected from the group consisting of compound (2a2a), compound

(2a2b), compound (2a2c), compound (2a2d), compound (2a2e), compound

(2a2f) and mixtures thereof;

compound (2a2a) is selected from the group consisting of [C_1-6 alkyl]₂Zn,

diphenyl-zinc and Zn(OTf)₂;

Cul₂, CuBr, CuBr_2, Cu(OAc)₂, CuCl and CuCl₂;

compound (2a2c) is Ti(halogen)_ni(0-Ci-6 alkyl)_n2;

compound (2a2d) is selected from the group consisting of C_1-4 alkyl Li, lithium C_1-6 alkoxide, lithium diisopropylamide (LDA), lithium hexamethyldisilazide (LiHMDS), phenyllithium, naphthyllithium, LiCl and LiBr;

compound (2a2e) is a Grignard reagent;

compound (2a2f) is selected from the group consisting of Zn(OTf)₂, Sn(OTf)₂, InBr₃,

AlMe₃, KOtBu, Zr(0-i-Pr)₄, [Rh(OH)(cod)]₂, [Rh(mu-OAc)C₂H₄]₂]₂, nl is 0, 1, 2, 3 or 4;

n2 is 4 - nl .

11. Method according to one or more of claims 3 to 10, wherein

compound (2a 1) is a pro tic chiral additive.

12. Method according to one or more of claims 3 to 11, wherein

compound (2al) is selected from the group consisting of compound of formula (2al-I), pyrrolidine-methanol and cinchonine;

R9 RIO or its enantiomer or a diastereomer;

R7, R8, Rl l and R12 are identical or different and independently from each other

(a) H,

(b) CF₃,

(c) CN,

(d) CONH₂,

(e) CONH(Ci-6 alkyl),

(f) CON(Ci-6 alkyl)₂,

(g) C0₂-Ci-6 alkyl,

(h) C₃-7 cycloalkyl,

(i) Ci-6 alkyl, C₂-₆ alkenyl or C₂-₆ alkynyl, the Ci-₆ alkyl, C₂-₆ alkenyl or C₂-₆ alkynyl being unsubstituted or substituted by 1 or 2 identical or different substituents selected from the group consisting of halogen, CF₃, CN, N0₂, NH₂, NH(Ci-₆ alkyl), N(Ci_-6 alkyl)₂, CONH2, CONH(Ci-₆ alkyl), CON(Ci-₆ alkyl)₂,

NHCONH₂, NHCONH(Ci-6 alkyl), NHCON(Ci-₆ alkyl)₂, C0₂-Ci-₆ alkyl, C₃.₇ cycloalkyl and Ci-₆ alkoxy; (j) R7 and R8 or Rl 1 and R12 taken together can represent =0, thereby forming a ketone, amide, acid or ester group;

(k) compound of formula (2a 1 -III),

(1) COOH,

(m) C(0)OR17b,

(n) phenyl, naphthyl, naphthyl with 1 or 2 endocyclic N atoms, such that one and only one of R7, R8, Rl 1, or R12 can bear this definition, with the proviso, that at least one of the two carbons denoted with (1) and (2) and

bearing R7, R8, R9, RIO, Rl l and R12 is a chiral center; or

RIO taken together with either Rl l or R12 represents a compound of formula (2al-IV) or compound of formula (2al-V), with the other of Rl 1 or R12 being hydrogen;

(*) Rl l or R12

(2al-IV) (2al-V) with the bond denoted (*) in formulae (2al-IV) and (2al-V) being the bond to the C atom denoted with (2) in formula (2al-I); or

(2al-VI) (2al-Vn) with the bond denoted (*) in formulae (2al-IV) and (2al-V) being the bond to the C atom denoted with (2) in formula (2al-I);

R13 is H, Ci-6 alkyl or phenyl;

R14 is H; or R7 or R8 and R14 taken together can represent a carbon-carbon bond, when t is 1 or 2 and Rl l or R12 represents a compound of formula (2al-III); or

R7 or R8 and R14 taken together can represent -(CH₂)s, when t is 0 and Rl l or R12 represents a compound of formula (2a 1 -III); R15 and R16 are identical or different and independently from each other selected from the group consisting of H, C_1-6 alkyl, C₂-6 alkenyl and C₂-₆ alkynyl, the Ci-6 alkyl, C₂-₆ alkenyl and C₂-₆ alkynyl being unsubstituted or substituted by 1 or 2 identical or different substituents selected from the group consisting of halogen, CF₃, CN, N0₂, NH₂, NH(Ci_-6 alkyl), N(Ci_-6 alkyl)₂, CONH2, CONH(Ci-6 alkyl), CON(Ci-₆ alkyl)₂, NHCONH₂, NHCONH(Ci-₆ alkyl), NHCON(Ci-6 alkyl)₂, C0₂-Ci-₆ alkyl, C₃.₇ cycloalkyl and Ci_-6 alkoxy;

with the proviso, that either R15 or R16 is hydrogen;

R17 and R18 are identical or different and independently from each other selected from the group consisting of C_1-6 alkyl, phenyl, biphenyl, naphthyl and -S0₂-R17a, the C_1-6 alkyl being unsubstituted or substituted with 1 or 2 substituents selected from the group consisting of phenyl, biphenyl or naphthyl;

or

R17 and R18 form together with the N atom, to which they are connected, a 5 or 6 membered saturated, unsaturated or aromatic heterocyclic ring, the ring can have one or two further endocyclic hetero atoms selected from the group consisting of N, O and S;

R17a is Ci-4 alkyl, phenyl, tolyl or naphthyl;

R17b is Ci-4 alkyl;

Z is a connecting group with a formula selected from the group consisting of formula (2al-VIII), formula (2al-IX), formula (2al-X), formula (2al-XI), formula (2al-XII), formula (2al-XIII), formula (2al-XIV), formula (2al-XV), formula (2al-XVI), formula (2al-XVII) and formula (2al-XVIII);

(2al-XIV)

(2al-IX)

(2al-XI) (2al-XII) (2al-Xni)

(2al-XIV)

(2al-XV) (2al-XVI)

(CHR13)m-

(

(2al-XVII)

(2al-XVin) wherein

represents a six-membered ring, the six-membered ring being unsaturated or saturated but non-aromatic, optionally one or two of the endocyclic C atoms of the six-membered ring are substituted by a heteroatom selected from the group consisting of N, O and S, optionally the six-membered ring is substituted with one or two C_1-6 alkyl;

represents a five-membered ring, the five-membered being unsaturated or saturated but non-aromatic, optionally one or two of the endocyclic C atoms of the five-membered ring are substituted by a heteroatom selected from the group consisting of N, O and S, optionally the five -membered ring is substituted with one or two C_1-6 alkyl; n is 1, 2 or 3; m is 0 or 1 ; t is 0, 1 or 2; s is 1 or 2.

13. Method according to one or more of claims 4 to 12, wherein

compound (l-2al) is selected from the group of A1C1₃, SnCl₄, Ce(OTf)₃, BC1₃, ZnCl₂, FeCl₃, TiCl₄, GaCl₃, AlBr₃, LiCl, BF₃ and mixtures thereof.

14. Use of compound of formula (3) or of suitable salts of compound of formula (3) for the preparation of compound of formula (4) or of suitable salts of compound of formula (4); with the compound of formula (3) and the compound of formula (4) being as defined in claim 1.

15. Use of compound of formula (2) in a method for the preparation of compound of formula (4) or of suitable salts of compound of formula (4), which method prepares compound of formula (4) via the intermediate compound of formula (3) or via intermediate suitable salts of compound of formula (3);

with the compound of formula (2), the compound of formula (3) and the compound of formula (4) being as defined in claim 2.

16. Use of compound of formula (3) or of suitable salts of compound of formula (3) as intermediates in a method for preparation of compound of formula (4) or of suitable salts of compound of formula (4), which method starts from compound of formula (2);

17. Use of compound of formula (1) in a method for the preparation of compound of formula (4) or of suitable salts of compound of formula (4), which method prepares compound of formula (4) via the intermediate compounds of formula (2) and (3) or via intermediate compound of formula (2) and suitable salts of compound of formula (3);

with the compound of formula (1), the compound of formula (2), the compound of formula (3) and the compound of formula (4) being as defined in claim 3.

18. Use of compound of formula (2) or of compound of formula (3) or of suitable salts of compound of formula (3) as intermediates in a method for preparation of compound of formula (4) or of suitable salts of compound of formula (4), which method starts from compound of formula (1); with the compound of formula (1), the compound of formula (2), the compound of formula (3) and the compound of formula (4) being as defined in claim 3.

19. Use of compound of formula (l-2a) or of compound of formula (1-lal) in a method for the preparation of compound of formula (4) or of suitable salts of compound of formula (4), which method prepares compound of formula (4) via the intermediate compounds of formula (1), (2) and (3) or via intermediate compounds of formula (1) and (2) and suitable salts of compound of formula (3);

with the compound of formula (1), the compound of formula (2), the compound of formula (3), the compound of formula (4), the compound of formula (l-2a) and the compound of formula (1-lal) being as defined in claim 4.

20. Use of compound of formula (1) or of compound of formula (2) or of compound of formula (3) or of suitable salts of compound of formula (3) as intermediates in a method for preparation of compound of formula (4) or of suitable salts of compound of formula (4), which method starts from compound of formula (l-2a) or from compound of formula (1-lal);