WO2012079235A1

WO2012079235A1 - Process for preparing efavirenz

Info

Publication number: WO2012079235A1
Application number: PCT/CN2010/079855
Authority: WO
Inventors: Danmei Dai (Joanna); Sea Long; Anna Kulesz; Bing Luo; Yanming Guo
Original assignee: Lonza Ltd; Lonza Guangzhou Research And Development Center Ltd.; Reichwagen
Priority date: 2010-12-16
Filing date: 2010-12-16
Publication date: 2012-06-21

Abstract

The invention disclosed a 4 step process for the preparation of Efavirenz, starting from 1,4-dichlorobenzene, and its intermediates.

Description

PROCESS FOR PREPARING EFAVIRENZ The invention disclosed a 4 step process for the preparation of Efavirenz, 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,l,l-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.

The following abbreviations are used, if not otherwise stated:

dppf 1 , 1 ' -bis(diphenylphosphino)ferrocene OTf Trifluoromethanesulfonate, also known by the trivial name triflate

Ts signifies a residue of formula (Ts), with the (*) denoting the connecting bond

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; 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, 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, "alkoxy" represents an alkyl group of indicated number of carbon atoms attached through an oxygen bridge, such as methoxy, ethoxy, propoxy, butoxy and pentoxy; 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, propenyl, butenyl, pentenyl, dimethyl pentenyl, and the like, and includes E and Z forms, where applicable. Examples of "alkynyl" include ethynyl, propynyl, butynyl, pentynyl, and dimethyl pentynyl. In the following, "aryl" is defined as a phenyl, biphenyl, or naphthyl ring 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 one or two oxygens 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, benzothienyl, benzofuranyl, quinolinyl, isoquinolinyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimid-5 inyl, and pyrrolyl, which are substituted or unsubstituted as defined above. Subject of the invention is a method for the preparation of a compound of formula (4)

comprising a step (1), a step (2), a step (3) and a step (4); step (1) comprises a method (1) for the preparation of a 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 (1-1 a) 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 Friedl Crafts catalyst;

step (l-2b) comprises the addition of an acid (1-2);

step (2) comprises a method (2) for the preparation of a 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 the compound of formula (1) with a reagent (2), reagent (2) is obtainable from a reaction (2a) of a compound (2al), a compound (2a2) and a compound of formula (2a3);

M is selected from the group consisting of H, Li, Na, K, Zn, Mg(Xl), Cu(Xl) and B(X1)₂; XI is halogen or CF₃SO₃; 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 [Ci_₆ alkyl]₂Zn;

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;

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; step (3) comprises a method (3) for the preparation of a compound of formula (3)

comprising 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 N(R41)(R42)(R43);

R41, R42 and R43 are identical or different and independently from each other hydrogen, phenyl or Ci_io alkyl; step (4) comprises a method (4) for the preparation of the compound of formula (4) comprising an intramolecular cyclisation of the 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 alkoholate, alkali hydroxide, alkyl amine, alkali hexamethyldisilazide and alkali amide and mixtures thereof.

Preferably, compound (1-1 a2) 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.

Expecially, solvent (1-1) is selected from the group consisting of toluene, dioxane,

diethyleneglycoldimethylether, tetrahydrofurane, 2-methyltetrahydrofurane, dimethoxyethane, dichloroethane, diethylether, methyl-tert butyl ether, diisopropylether, biphenylether, 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, tartric 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 equivalent, more preferably from 1 to 10 mol equivalent, even more preferably from 1 to 5 mol equivalent, the mol equivalent 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, Cs_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,

diethyleneglycoldimethylether, tetrahydrofurane, 2-methyltetrahydrofurane, dimethoxyethane, dichloroethane, diethylether, methyl-tert butyl ether, diisopropylether, biphenylether, 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-lal), 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. 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;

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

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 consiting of toluene, dioxane,

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, tartric 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 ( 1 -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 equivalent, more preferably from 1 to 10 mol equivalent, even more preferably from 1 to 5 mol equivalent, the mol equivalent being 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).

Preferably, solvent (1 -extract) is ethyl acetate.

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 a [Ci_₆ alkyl]₂Zn;

compound (2a2b) is selected from the group consisting of Cu(OTf), Cu(OTf)₂, Cul, Cul₂, CuBr,

CuBr₂, Cu(OAc)₂;

compound (2a2c) is Ti(halogen)_ni(0-Ci_6 alkyl)_n2;

compound (2a2d) is Ci_₄ alkyl Li;

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 or 3;

n2 is 4 - nl .

Preferably, compound (2a2a) is dimethyl-Zn or diethyl-Zn. Preferably, compound (2a2b) is selected from the group consisting of Cu(OTf), Cu(OTf)2, Cul, Cul₂, CuBr, CuBr₂, Cu(OAc)₂.

Preferably, compound (2a2c) is Ti(halogen)_ni(0-Ci_6 alkyl)_n2; more preferably, Ti(halogen)_ni(0-Ci_

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

nl is 0, 1, 2 or 3;

n2 is 4 - nl.

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

Preferably, nl is 0, 1 or 2; n2 is 4 - nl.

More preferably, nl is 0 or 1; n2 is 4 - nl.

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

Preferably, compound (2a2d) is Ci_₄ alkyl Li, more preferably 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 selected from the group consisting of compound of formula (2al-I), pyrrolidine-methanol and cinchonine;

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)₂ 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 (2al-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 is selected from the group consisting of Ci_₆ alkyl, phenyl, biphenyl, naphthyl, -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;

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); (CHR13)m - (R13HC)m

- (CHR13)n

(2al-VIII) H H

(2al-XIV)

(2al-IX)

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

(R1

(2al-XIV)

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

(CHR13)m-

(

(2al-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;

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.

More preferably, compound (2al) is selected from the group consisting of (lR,2S)-N-pyrrolidinyl norephedrine (also referred to in the Chemical Abstract Registry as [R-(R*,S*)]-beta-methyl-alpha- phenyl-l-pyrrolidine-ethanol), N-methylephedrine, ephedrine, N,N-dibenzylnorephedrine, norephedrine, diethyl tartrate, pyrrolidine-methanol, (lR,2R)-pseudoephedrine, cinchonine, (1S,2S) N-methylpseudoephedrine, 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)

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

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 (2-1 -opt).

Compound (2-1 -opt) 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 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 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 (2-1 -opt) 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 (2-1 -opt) is the fact that compound (2-1 -opt) can also be chiral.

Preferably, M is selected from the group consisting of H, Li and Mg(Xl). It is postulated, that the reagent (2) comprises a chiral organometallic complex, which is formed from compound (2al), compound (2a2) and compound of formula (2a3), and which provides the chiral addition of the cyclopropylacetylene to compound of formula (1).

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 alkyleneglycols, C₂_₄ alkyleneglycol Ci_₄ alkyl monoether, C₂_₄ alkyleneglycol di-Ci_₄ alkyl ether, di-C₂_₄ alkyleneglycol mono-Ci_₄ alkyl ether, di-C₂_₄

alkyleneglycol 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 alkylsulfoxide, 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 Ci_io alkyl with the proviso, that at least one residues 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 residues of the R61, R62 and R63 is not hydrogen.

More preferably, solvent (2) is selected from the group consisting of ethylacetate, butylacetate, benzene, toluene, xylene, dimethylformamide, dimethylacetamide, N-methylpyrrolidone, pyridine, methylethylpyridine, dioxane, diethyleneglycoldimethylether, tetrahydrofurane, 2- methyltetrahydrofurane, dimethoxyethane, 0-, m-, p-dichlorobenzene, chlorobenzene,

dichloroethane, methanol, ethanol, n-propanol, 2-propanol, n-butanol, secondary butanol, n- pentanol, n-hexanol, tertiary butanol, dimethylsulfoxide, dimethylether, methyl-tert butyl ether, diisopropylether, biphenylether, 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 ethylacetate, butylacetate, toluene, dimethylformamide, dimethylacetamide, N-methylpyrrolidone, dioxane,

diethyleneglycoldimethylether, 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, more preferably from 0.01 to 0.25, even more preferably from 0.025 to 0.15 mol equivalents, of compound of formula (2al) 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, C_4-12 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, tartric 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).

Preferably, solvent (3-extract) is ethyl acetate.

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. Reaction (2a) of the compound (2al), the compound (2a2) and the compound of formula (2a3) to obtain reagent (2) can be done in various ways. The following illustrates some possible

embodiments.

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 (2a 1); 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- 1) 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, C_2-4 alkyleneglycols, C₂_₄ alkyleneglycol Ci_₄ alkyl monoether, C₂_₄ alkyleneglycol di-Ci_₄ alkyl ether, di-C₂_₄ alkyleneglycol mono-Ci_₄ alkyl ether, di- C₂_₄ alkyleneglycol 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 alkylsulfoxide, R51-0-R52, Cs-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 ethylacetate, butylacetate, toluene, xylene, dimethylformamide, dimethylacetamide, N-methylpyrrolidone, pyridine, methylethylpyridine, dioxane, diethyleneglycoldimethylether, tetrahydrofurane, 2- methyltetrahydrofurane, dimethoxyethane, dichlorobenzene, chlorobenzene, dichloroethane, methanol, ethanol, n-propanol, 2-propanol, n-butanol, secondary butanol, n-pentanol, n-hexanol, tertiary butanol, dimethylsulfoxide, dimethylether, methyl-tert butyl ether, diisopropylether, biphenylether, triethylamine, diisopropylethylamine, tri-n-propylamine, tri-isopropylamine, tri-n- butylamine, triphenylamine, water or mixtures therof.

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 (3a) are used, the mol equivalents being based the mol of compound of formula (2).

Preferably, reaction (3) is done under inert atmosphere. Preferably, R41, R42 and R43 are identical or different and independently from each other

hydrogen, phenyl or Ci_s 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 equivalent, more preferably from 1 to 10 mol equivalent, even more preferably from 1 to 5 mol equivalent, the mol equivalent being based on the mol of compound of formula (3 a).

Preferably, the addition of base (3) 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.

After the reaction (3) or after the optional addition of base (3), the 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) being preferably ethylacetate.

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) can be purified before final isolation preferably by chromatography or crystallization from an appropriate solvent.

Compound of formula (3a) is a known compound and can be prepared according to known methods.

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, CuS0_4, 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,

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

Preferably, 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-l,2-diamine and cis-cyclohexane-l,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 Ci_io alkyl;

R81 and R82 are identical or different and independently from each other hydrogen, phenyl or Ci_ io alkyl.

In particular, ligand (4) is trans-N,N'-dimethylcyclohexane-l,2-diamine, catalyst (4) is Cul and base (4) is K₃P0₄.

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 alkyleneglycols, C₂_₄ alkyleneglycol Ci_₄ alkyl monoether, C₂_₄ alkyleneglycol di-Ci_₄ alkyl ether, di-C₂_₄ alkyleneglycol mono-Ci_₄ alkyl ether, di-C₂_₄ alkyleneglycol 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 alkylsulfoxide, 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, dioxane, C₂_₄ alkyleneglycols, C₂_₄ alkyleneglycol Ci_₄ alkyl monoether, di-C₂_ 4 alkyleneglycol mono-Ci_₄ alkyl ether, di-C₂_₄ alkyleneglycol di-Ci_₄ alkyl ether, tetrahydrofurane, 2-methyltetrahydrofurane, dimethoxy ethane, dichlorobenzene, chlorobenzene, dichloromethane, chloroform, tetrachlorocarbon, dichloroethane, Ci_₆ alkohols, dimethylsulfoxide, Ci_₄ alkyl ether, biphenylether, 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, dioxane, diethyleneglycoldimethylether, 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, dimethylsulfoxide,

dimethylether, methyl-tert butyl ether, diisopropylether, biphenylether, 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, more preferably from 0.01 to 0.25, 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, more preferably from 0.01 to 0.25, 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, nitric acid, phosphoric acid, Ci_₆ carboxylic acid, C₂_8 dicarboxylic acid, C_4-12 tricarboxylic acid and mixtures thereof.

More preferably, acid (4-1) is selected from the group consisting of ammonium chloride, hydrochloric acid, sulphuric acid, acetic acid, nitric acid, tartric acid and mixtures thereof. 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 equivalent, more preferably from 1 to 10 mol equivalent, even more preferably from 1 to 5 mol equivalent, the mol equivalent 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) can be isolated by standard methods such as filtration, concentration and drying or extraction. 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) can be purified before isolation preferably by chromatography, crystallization from an appropriate solvent or distillation preferably under vacuum.

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 without isolation for the next step.

Further subject of the invention is the use of compound of formula (l-2a) or of compound of formula (1-lal) for the preparation of compound of formula (4) via the intermediate compounds of formula (1), (2) and (3).

Further subject of the invention is the use of compound of formula (2) or of compound of formula (3) in a method for preparation of compound of formula (4), which method starts from compound of formula (l-2a) or from compound of formula (1-lal). 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, 3b and 4b Detection in HPLC method A was done with a UV photodiode array detector.

Ste l Sample preparation:

A specific amount of sample in the range of 0.5 to 1 mg was dissolved in ca. from 0.5 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.

Ste 2 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-Cyclopro yl-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-Cyclopro yl-2-(2,5-dichloro-phenyl)-l,l,l-trifluoro-but-3-yn-2-ol

Naphthalene- 1 -sulfonic acid ((R)-2-hydroxy-l-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 ehtynylcyclopropane (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)-l,l,l- 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, CDCI3) 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 cyclopropyl-(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 3a.

Example 4a: 6-Chloro-4-trifluoromethyl-4-(cyclopro ylethynyl)-lH-benzo[d]-l,3-oxazin-2- one

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, CDCI3) 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)- 1-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 HC1 (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, CDC1₃) 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-l-sulfonic acid ((R)-2-hydroxy-l-methyl-2,2- diphenyl-ethyl)-amide (27 g, 97 % yield) as a white solid.

1H NMR (400 MHz, CDCI3) 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 for the preparation of a compound of formula (4)

step (1 -1 a) comprises a reaction of a compound of formula (1 -1 a1 )

with a compound (1-1 a2); compound (1 -1 a2) is selected from the group consisting of compound of formula (1 -1 a2-1 ), compound of formula (1-1a2-2) and compound of formula (1-1a2-3);

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

with the compound (1-1 a2) in the presence of a compound (1-2a1);

compound (1-2a1) is a Friedl Crafts catalyst; step (1-2b) comprises the addition of an acid (1-2); step (2) comprises a method (2) for the preparation of a 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 the compound of formula (1 ) with a reagent (2), reagent (2) is obtainable from a reaction (2a) of a compound (2a1 ), a compound (2a2) and a compound of formula (2a3);

M is selected from the group consisting of H, Li, Na, K, Zn, Mg(X1 ), Cu(X1 ) and B(X1 )₂;

X1 is halogen or CF₃S0₃; compound (2a1 ) 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 [C^.₆ alkyl]₂Zn;

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

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

compound (2a2d) is an organolithium compound;

compound (2a2e) is a Grignard reagent;

compound (2a2f) is selected from the group consisting of Zn(OTf)₂, Sn(OTf)₂, lnBr₃, AIMe₃, KOtBu, Zr(0-i- Pr)₄, [Rh(OH)(cod)]₂, [Rh(mu-OAc)C₂H₄]₂]₂; step (3) comprises a method (3) for the preparation of a compound of formula (3)

comprising 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 N(R41 )(R42)(R43) ;

R41 , R42 and R43 are identical or different and independently from each other hydrogen, phenyl or CM₀ alkyl; step (4) comprises a method (4) for the preparation of the compound of formula (4) comprising an

intramolecular cyclisation of the 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(l), Cu(ll), Pd(0) or

Pd(ll), 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 alkoholate, alkali hydroxide, alkyl amine, alkali hexamethyldisilazide and alkali amide and mixtures thereof.

2. Method according to claim 1 , wherein compound (1 -2a1 ) is selected from the group of AICI₃, SnCI₄, Ce(OTf)₃, BCI₃, ZnCI₂, FeCI₃, TiCI₄, GaCI₃, AIBr₃, LiCI, BF₃ and mixtures thereof.

3. Method according to claim 1 or 2, wherein compound (2a1 ) is selected from the group consisting of compound of formula (2a1 -l), pyrrolidine-methanol and cinchonine;

R9 RIO or its enantiomer or a diastereomer;

R9 and R10 are identical or different and independently from each other H, OH, NH₂, NH(R17), N(R17)₂ or a compound of formula (2a1 -ll);

R7, R8, R1 1 and R12 are identical or different and independently from each other

(a) H,

(b) CF₃,

(c) CN,

(d) CONH₂,

(e) CONH(d.₆ alkyl),

(f) CON(d.₆ alkyl)₂,

(g) C0₂-d.₆ alkyl,

(h) C3-7 cycloalkyl,

(i) C1-6 alkyl, C₂.₆ alkenyl or C₂.₆ alkynyl, the d-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(d.₆ alkyl)₂, CONH2, CONH(d.₆ alkyl), CON(d.₆ alkyl)₂, NHCONH₂, NHCONH(d.₆ alkyl), NHCON(d.₆ alkyl)₂, C0₂-d.₆ alkyl, C₃.₇ cycloalkyl and C_{1 -6} alkoxy;

(j) R7 and R8 or R1 1 and R12 taken together can represent =0, thereby forming a ketone, amide, acid or ester group;

(k) compound of formula (2a1 -lll),

(CH2)_t

(I) 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, R1 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, R10, R1 1 and R12 is a chiral center; or

R10 taken together with either R1 1 or R12 represents a compound of formula (2a1 -IV) or compound of formula (2a1 -V), with the other of R1 1 or R12 being hydrogen;

(*) Rll or R12

(2al-IV) (2al-V) with the bond denoted (^*) in formulae (2a1 -IV) and (2a1 -V) being the bond to the C atom denoted with (2) in formula (2a1 -l); or

R9 taken together with either R7 or R8 represents a compound of formula (2a1 -VI) or compound of formula (2a1 -VII), with the other of R7 or R8 being hydrogen;

(2al-VI) (2al-VII) with the bond denoted (^*) in formulae (2a1 -IV) and (2a1 -V) being the bond to the C atom denoted with (2) in formula (2a1 -l);

R13 is H, d-e 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 R1 1 or R12 represents a compound of formula (2a1 -lll); or

R7 or R8 and R14 taken together can represent -(CH₂)s, when t is 0 and R1 1 or R12 represents a compound of formula (2a1 -lll);

R15 and R16 are identical or different and independently from each other selected from the group consisting of H, d-e alkyl, C₂.₆ alkenyl and C₂.₆ alkynyl, the d-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(d_-6 alkyl), N(d.₆ alkyl)₂, CONH2, CONH(d.₆ alkyl), CON(d.₆ alkyl)₂, NHCONH₂, NHCONH(d.₆ alkyl), NHCON(d.₆ alkyl)₂, C0₂-d.₆ alkyl, C₃.₇ cycloalkyl and d_₆ alkoxy;

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

R17 is selected from the group consisting of d-6 alkyl, phenyl, biphenyl, naphthyl, -S0₂-R17a, the d-6 alkyl being unsubstituted or substituted with 1 or 2 substituents selected from the group consisting of phenyl, biphenyl or naphthyl;

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

R17b is C_{1 4} alkyl;

Z is a connecting group with a formula selected from the group consisting of formula (2a1 -VIII), formula (2a1 - IX), formula (2a1 -X), formula (2a1 -XI), formula (2a1 -XII), formula (2a1 -XIII), formula (2a1 -XIV), formula (2a1 -XV), formula (2a1 -XVI), formula (2a1 -XVII) and formula (2a1 -XVIII);

(2al-XIV)

(2al-IX)

(2al-XI) (2al-XD) (2al-Xni)

(2al-XIV)

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

(CHR13)m-

(

(2al-XVn)

(2al-XVin)

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 O, 1 or 2; s is 1 or 2.

4. Method according to one or more of claims 1 to 3, 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 [C^.₆ alkyl]₂Zn;

compound (2a2b) is selected from the group consisting of Cu(OTf), Cu(OTf)₂, Cul, Cul₂, CuBr, CuBr_2,

Cu(OAc)₂;

compound (2a2c) is

alkyl)_n2;

compound (2a2d) is Ci_₄ alkyl Li;

compound (2a2e) is a Grignard reagent;

compound (2a2f) is selected from the group consisting of Zn(OTf)₂, Sn(OTf)₂, lnBr₃, AIMe₃, KOtBu, Zr(0-i-

Pr)₄, [Rh(OH)(cod)]₂, [Rh(mu-OAc)C₂H₄]₂]₂,

n1 is O, 1 , 2 or 3;

n2 is 4 - n1 .

5. Method according to one or more of claims 1 to 4, wherein R41 , R42 and R43 are identical or different and independently from each other hydrogen, phenyl or d-₈ alkyl.

6. Method according to one or more of claims 1 to 5, wherein catalyst (4) is selected from the group

consisting of Cu powder, Cul, CuBr, CuCI, CuSCN, CuCN, CuBF4, CuPF6, CuOTf (copper(l) trifluoromethanesulfonate), CuC0₃, Cu(OAc)₂, Cu(OTf)₂ (copper(ll) trifluoromethanesulfonate), Cu₂0, CuS0_4i Pd(OAc)₂, trisdibenzylideneacetone palladium(O), allylpalladium(ll)chloride dimer,

palladium(ll)chloride, palladium(ll)acetylacetonate, palladium(ll)nitrate,

dichloro(bisbenzonitrile)palladium(ll), dichloro(1 ,5-cyclooctadien)palladium(ll),

tetrakis(triarylphosphino)palladium(0), dppfPdCI₂, Pd[(t-Bu)₃P]₂, PdCI₂(A-Phos)₂, XantPhosPdCI₂, PdCI₂(t-DBPF), Pd(TFAc)₂ (palladium(ll) trifluoroacetate) and mixtures thereof.

7. Method according to one or more of claims 1 to 6, wherein ligand (4) is selected from the group

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

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-C^ -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 CM ₀ alkyl;

R81 and R82 are identical or different and independently from each other hydrogen, phenyl or C,.₁₀ alkyl.

9. Method according to one or more of claims 1 to 8, wherein the alkali of base (4) is Na or K.

10. Use of compound of formula (1 -2a) or of compound of formula (1 -1 a1 ) for the preparation of compound of formula (4) via the intermediate compounds of formula (1 ), (2) and (3), with the compounds of formula (1 ), (1 -2a), (1 -1 a1 ), (2), (3) and (4) as defined in claim 1 .

1 1 . Use of compound of formula (2) or of compound of formula (3) in a method for preparation of compound of formula (4), which method starts from compound of formula (1 -2a) or from compound of formula (1 -

1 a1 ), with the compounds of formula (1 ), (1 -2a), (1 -1 a1 ), (2), (3) and (4) as defined in claim 1 .