JP4519912B2 - Process for the preparation of asymmetrically substituted biaryldiphosphines - Google Patents

Description

  The preparation of enantiomerically pure compounds is important to improve the effect of pharmaceutically active compounds and to limit unwanted side effects of “wrong” isomers. The present invention relates to a process for the preparation of asymmetrically substituted biaryldiphosphine ligands and their transition metal complexes for the hydrogenation of unsaturated prochiral compounds using the complexes.

  Asymmetric catalytic hydrogenation is one of the most efficient and convenient methods for preparing a wide range of enantiomerically pure compounds. Providing methods and precise provisions for precisely controlling the molecular chirality of pharmaceutically active compounds tends to play an increasingly important role in synthetic chemistry. Several diphosphine ligand families are commonly known under their trade names, such as BINAP, CHIRAPHOS, DIOP, DUPHOS, SEGPHOS, and TUNAPHOS.

Methods for preparing BINAP, SEGPHOS, and TUNAPHOS family biaryldiphosphine ligands are disclosed in EP-A-0256634 , EP-A-850945, and WO-A-01 / 21625, respectively. Furthermore, WO-A-03 / 029259 discloses the synthesis and use of fluorine derivatives of SEGPHOS.

  Pai, C.-C. et al., Tetrahedron Lett. 2002, 43, 2789-2792 includes methylenedioxo and ethylenedioxide for the asymmetric hydrogenation of ethyl 4-chloro-3-oxobutyrate. The use of oxo-substituted biaryldiphosphine ligands is described. Further examples of the preparation of biaryl diphosphines and asymmetric hydrogenation reactions using catalysts derived from biaryl diphosphine ligands are described in EP-A-0 926 152, EP-A-0 945 457, and EP-A-0 955 303. Is disclosed. Normally, both symmetrically and asymmetrically substituted biaryldiphosphines are claimed, but only examples of symmetrically substituted ligands are disclosed. With only a few special exceptions, a generally applicable synthetic route for asymmetrically substituted biaryldiphosphines and catalysts derived therefrom is not disclosed.

  Biaryl diphosphine ligands consist of three different parts: a strong biaryl core, substituents to prevent biaryl rotation, and usually two phosphine groups with large substituents to complex with transition metals . Known examples of ligand systems have a symmetrical substitution pattern of the core and the same phosphine group. As a rare example, WO-A-02 / 40492 used a catalyst containing (S) -6-methoxy-5 ′, 6′-benzo-2,2′-bis (diphenylphosphino) -biphenyl ligand. Disclosed is asymmetric hydrogenation of ethyl 4-chloro-3-oxobutyrate. (S) -alcohol is obtained with an enantiomeric excess (ee) of 83%.

  Although EP-A-0 647648 and WO-A-02 / 40492 claim a diphosphine having an asymmetrically substituted biaryl core, the disclosed synthetic principles are widely different asymmetrically substituted. It is not suitable for producing biaryl diphosphine ligands.

As shown in Scheme 1, major obstacles had to be overcome for the synthesis of the asymmetric biaryl diphosphines of the present invention. When a single fluorine, chlorine, or bromine atom or a single methoxy or dimethylamino group is attached to the 6-position, the 2′-diphenylphosphino-2-lithiobiphenyl produced as an intermediate is Asymmetrically substituted biaryldiphosphines could not be obtained by condensation with an organylphosphine moiety (Miyamoto, TK et al., J. Organomet. Chem. 1989, 373, C8-C12 ; Desponds, O., Schlosser, M., J. Organomet. Chem. 1996, 507, 257). The compound undergoes nucleophilic substitution and cyclization with a phosphorus atom to obtain 1H-benzo [b] phosphine dolole (9-phosphafluorene). A known failed approach to the ligands of the present invention is shown in Scheme 1 below.

  Here and hereinbelow, the term “enantiomerically pure compound” includes optically active compounds having an enantiomeric excess (ee) of at least 90%.

Here and hereinbelow, the term “C 1- _n -alkyl” means a straight-chain or branched alkyl group having 1 to n carbon atoms. C _1-6 -alkyl means, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl and hexyl.

Here and hereinafter, the term “C 1- _n -alkoxy” means a straight-chain or branched alkoxy group having 1-n carbon atoms. C _1-6 -alkoxy means for example methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy and hexyloxy.

Scheme 1: Failure approach for asymmetrically substituted diphosphine ligands

X = H, F, Cl, Br, OCH ₃ , N (CH ₃ ) ₂
Here and hereinafter, the term “C 3 _-n -cycloalkyl” means an alicyclic group having 3 to n carbon atoms. C _5-10 -cycloalkyl means monocyclic and polycyclic ring structures such as cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, adamantyl, or norbornyl.

Here and hereinafter, the term “C 3 _-n -cycloalkoxy” means a cycloalkoxy group having 3 to n carbon atoms. C _5-10 -cycloalkyl means, for example, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy, cyclooctyloxy, or cyclodecyloxy.

Here and hereinafter, the term “di-C _1-6 -alkylamino” means a dialkylamino group comprising two alkyl moieties independently having 1 to 6 carbon atoms. Di-C _1-6 -alkylamino is, for example, N, N-dimethylamino, N, N-diethylamino, N-ethyl-N-methylamino, N-methyl-N-propylamino, N-ethyl-N- It means hexylamino or N, N-dihexylamino.

Here and hereinbelow, the term “aryl” is an aromatic group, preferably one or more halogen atoms, nitro and / or amino groups, and / or optionally substituted C _1-6 − It means phenyl or naphthyl optionally further substituted with an alkyl, C _1-6 -alkoxy, or di-C _1-6 -alkylamino group.

Here and hereinbelow, the term “C _1-3 -alcohol” means methanol, ethanol, propanol, and isopropanol.

Here and hereinafter, the term “C _1-3 -alkanoic acid” means formic acid, acetic acid, and propionic acid.

  Considering the high steric regulation and efficient action of enzymes, ie natural catalysts, great efforts are expended in improving the selectivity and efficiency of artificial catalysts, especially for the production of compounds of pharmaceutical interest.

  The technical problem to be solved by the present invention was to provide a method for the desired synthesis of a series of biaryl diphosphines. A further problem to be solved was to establish the process in a robust manner in order to provide an appropriate amount of ligand for the pharmaceutical industry. Furthermore, the general concept should start with readily available compounds and include few reaction steps, allowing the synthesis of a wide range of ligands depending only on the reaction procedure.

  The problem can be solved according to the method of claim 1.

Methods for preparing asymmetrically substituted biaryldiphosphine ligands of the following formula are provided:

Wherein R ¹ is C _1-6 -alkyl or C _3-10 -cycloalkyl optionally substituted with one or more halogen atoms,
R ² and R ³ are the same and are selected from the group consisting of aryl, C _5-10 -cycloalkyl, and C _1-6 -alkyl, wherein each aryl moiety is optionally a halogen atom, nitro Substituted with one or more substituents selected from the group consisting of: amino, C _1-6 -alkyl, C _1-6 -alkoxy, and di-C _1-6 -alkylamino groups,
Or, R ² is C _1-6 -alkyl or C _5-10 -cycloalkyl, and R ³ is a halogen atom, nitro, amino, C _1-6 -alkyl, C _1-6 -alkoxy, and di- Aryl optionally substituted with one or more substituents selected from the group consisting of C _1-6 -alkylamino groups;
And each of C _1-6 -alkyl, C _1-6 -alkoxy, di-C _1-6 -alkylamino, and C _5-10 -cycloalkyl in R ² and R ³ is one or more halogen atoms. Optionally substituted.

The method is a first reaction procedure in which one of the 2,2 ′, 6,6′-tetrabromobiphenyl bromine atoms is ORed by bromine-metal exchange followed by metal-hydroxy exchange followed by alkylation. Exchanged for ¹ ,

Obtaining a compound of the formula: wherein R ¹ is as defined above;

A further reaction procedure, each reaction procedure comprising at least one bromine-metal exchange followed by a metal-substituent exchange with each substituent, whereby each bromine atom is replaced with hydrogen, diarylphosphino, Exchange with a substituent selected from the group consisting of di-C _1-6 -alkylphosphino, and di-C _5-10 -cycloalkylphosphino;
Comprising.

  The bromine-metal exchange described in the present invention can be carried out at a temperature below -40 ° C. (“low temperature bromine-metal exchange”) or at least 0 ° C. (“high temperature bromine-metal exchange”). It may be performed using an organometallic compound.

Chiral biaryl diphosphine ligands having a biaryl skeleton permanently twisted about a central carbon-carbon bond have two atropisomers. Asymmetric hydrogenation with transition metal complexes is preferably carried out using one of the atropisomers and optionally further chiral auxiliaries. Therefore, a reference to a ligand of the following formula implicitly includes its atropisomer, unless otherwise specified, for example, by showing their positive (+) or negative (-) optical rotation. Should be acknowledged.

R ¹ , R ² , and R ³ in the formula are as defined above.

  The undesirable ring closure shown in Scheme 1 above can be surprisingly avoided by the method of the present invention. The reaction procedure of the method of the present invention for the preparation of the compound of formula I is shown in Scheme 2. The synthetic approach of Scheme 2 starts with 2,2 ', 6,6'-tetrabromo-1,1'-biphenyl (III), and one of the bromine atoms of III is substituted with an alkoxy or cycloalkoxy group. Compound III can be obtained by condensation of 1,3-dibromo-2-iodobenzene (II) according to Rajca A. et al., J. Am. Chem. Soc. 1996, 118, 7272-7279. According to Scheme 2, tailored preparation of ligands of formula I can be achieved with the required modifications of only 5 basic reactions (a to e), reaction temperatures, and corresponding amounts of reagents.

Scheme 2: Preparation of ligand I from 2,2 ', 6,6'-tetrabromobiphenyl (III) by replacing one bromine atom with an organyl group

R ¹ , R ² , and R ³ are as described herein,
[a-1] = 1 equivalent of low temperature bromine-metal exchange;
[a-2] = 2 equivalent low temperature bromine-metal exchange;
[a-3] = 1-2 equivalents of high temperature bromine-metal exchange;
[b] = borane oxidation;
[c] = alkylation;
[d] = hydrogen quenching;
[e-1] = 1 equivalent of metal-alkyl or -cycloalkylphosphine exchange;
[e-2] = 2 equivalents of metal-alkyl or -cycloalkylphosphine exchange;
[e-3] = 1 equivalent of metal-arylphosphine exchange;
[e-4] = 2 equivalent metal-arylphosphine exchange.

  In a preferred embodiment, the initial bromine-metal exchange of the compound of formula III is carried out with 1 equivalent of n-butyllithium in a polar solvent at a temperature below −40 ° C. (“1 equivalent of cold bromine— Metal exchange ") to obtain a metallized intermediate. Subsequent metal-hydroxy exchange is performed by reacting the metallated intermediate with borane or organoborate followed by reaction with a peroxy compound in the presence of alkali and / or alkaline earth hydroxide. Is carried out using an alkylating agent in the presence of a base.

  In a preferred embodiment, the borane or organoborate is a fluorodimethoxyborane diethyl ether adduct, triisopropyl borate, or trimethyl borate, preferably used in an ether solution.

  In another embodiment, the peroxy compound is selected from the group consisting of hydrogen peroxide, peracetic acid, m-chloroperbenzoic acid, and tert-butyl hydroperoxide.

In another embodiment, the alkali and / or alkaline earth hydroxide in the reaction with the peroxy compound is selected from the group consisting of LiOH, NaOH, KOH, Ca (OH) ₂ , and Mg (OH) _2. Is done.

In a further embodiment, the base of the alkylation reaction is an alkali and / or alkaline earth hydroxide and is selected from the group consisting of LiOH, NaOH, KOH, Ca (OH) ₂ , and Mg (OH) _2. The

In a preferred method, the alkylating agent is a C _1-6 -alkyl halide, a C _{5-10 -halogenated} cycloalkyl, or dimethyl sulfate. Preferably, the C _1-6 -alkyl halide is C _1-6 -alkyl bromide or C _1-6 -alkyl iodide. Particularly preferred alkylating agents are iodomethane or dimethyl sulfate.

In a preferred method, the further reaction procedure here is carried out by starting with a compound of formula IV above, and by a low temperature bromine-metal exchange of two bromine atoms followed by a metal-phosphine exchange, a compound of the formula And getting

[Wherein R ¹ is as defined above,
R ² and R ³ are the same and are selected from the group consisting of halogen atoms, nitro, amino, C _1-6 -alkyl, C _1-6 -alkoxy, and di-C _1-6 -alkylamino groups Aryl optionally substituted with one or more substituents, and C _1-6 -alkyl, C _5-10 -cycloalkyl, C _1-6 -alkoxy, and di-C _1- in R ² and R ³ Each ₆ -alkylamino group is optionally substituted with one or more halogen atoms]
Further, the remaining bromine atom of the compound of formula V is replaced with hydrogen by high temperature bromine-metal exchange followed by reaction with a proton donor to yield a ligand of the formula

[Wherein R ¹ , R ² , and R ³ are as defined above for compound V]
The following method is also provided, wherein the further reaction procedure is carried out by starting from the compound of formula IV above, followed by cold bromine-metal exchange of one bromine atom of an aryl moiety containing two bromine atoms followed by Obtaining a compound of the formula: wherein R ¹ is as defined above by metal-hydrogen exchange by reaction with a proton donor;

Further low temperature bromine-metal exchange of the remaining bromine atom followed by metal-phosphine exchange comprises obtaining a ligand of formula I, wherein R ¹ in formula I is as defined above, R ² and R ³ are the same and are selected from the group consisting of aryl, C _5-10 -cycloalkyl, and C _1-6 -alkyl, wherein each aryl moiety is optionally a halogen atom, nitro, amino, C _1-6 - alkyl, C _1-6 - alkoxy, and di -C _1-6 - substituted with one or more substituents selected from the group consisting of alkylamino groups and _{C. 1 to} the R ² and R ³ ₆ - alkyl, C _{5 to 10} - cycloalkyl, C _{1 to 6} - alkoxy, and di -C _{1 to 6} - alkylamino groups each are optionally substituted with one or more halogen atoms.

Further provided is the following method, wherein the further reaction procedure is carried out by starting from the compound of formula IV above, and includes cold bromine-metal exchange of one bromine atom of an aryl moiety containing two bromine atoms and Subsequent metal-hydrogen exchange by reaction with a proton donor yields a compound of formula VI where R ¹ is as defined above, followed by low-temperature bromine-metal exchange of one bromine atom followed by metal-phosphine exchange. To obtain a compound of the formula:

[Wherein R ¹ is as defined above, R ² is C _5-10 -cycloalkyl or C _1-6 -alkyl, and said C _1-6 -alkyl or C _5-10 -cyclo Alkyl is optionally substituted with one or more halogen atoms]
Furthermore, high temperature bromine-metal exchange of the remaining bromine followed by metal-phosphine exchange comprises obtaining a ligand of formula I, wherein R ¹ and R ² in formula I are as defined above. R ³ is one or more substituents selected from the group consisting of a halogen atom, nitro, amino, C _1-6 -alkyl, C _1-6 -alkoxy, and di-C _1-6 -alkylamino groups Each of C _1-6 -alkyl, C _5-10 -cycloalkyl, C _1-6 -alkoxy, and di-C _1-6 -alkylamino groups in R ³ is Optionally substituted with one or more halogen atoms.

  In a preferred embodiment, each low temperature bromine-metal exchange is performed at a temperature of −40 ° C. or less, preferably from −60 ° C., using an organometallic compound such as n-butyllithium, isopropylmagnesium chloride, or lithium tributylmagnesate It is carried out in the range of -90 ° C.

  In a preferred embodiment, each low temperature bromine-metal exchange is performed in a polar solvent, preferably in a solvent comprising tetrahydrofuran.

  As shown in Scheme 2, removing the last remaining bromine atom from the compounds of formulas V and VII requires different reaction conditions for the halogen-metal exchange. In a preferred embodiment in this reaction procedure, the halogen-metal exchange is performed at a temperature of at least 0 ° C. using an organometallic compound such as n-butyllithium, tert-butyllithium, isopropylmagnesium chloride, or lithium tributylmagnesate. It is preferably carried out in the range of 0 to + 40 ° C. The amount of organometallic compound (1-2 equivalents) depends on the substituent attached to the biaryl moiety. In most cases, one equivalent of an organometallic compound is sufficient to replace the halogen atom with a metal.

  In a preferred embodiment, the high temperature bromine-metal exchange is performed in a solution containing toluene and / or tetrahydrofuran.

In a preferred embodiment, the hydrogen donor is selected from the group consisting of C _1-3 alcohols, water, non-oxidizing inorganic protonic acids, and C _1-3 alkanoic acids. Preferably, the non-oxidizing inorganic protonic acid is HCl.

  Preferably, the non-oxidizing inorganic protonic acid is HCl.

  Preferably, the reaction with the hydrogen donor (hydrogen quenching) is carried out at a temperature in the range of −60 to −90 ° C.

In a preferred embodiment, the metal-phosphine exchange is performed using a halophosphine of the formula:

X in the formula is chlorine, bromine, or iodine, and the substituents R are the same and are R ² or R ³ , where R ² and R ³ are as defined above.

Depending on the intended substituent, the halophosphine of the formula VIII is a group consisting of halodiarylphosphine, halodi- (C _5-10 -cycloalkyl) phosphine, and halodi- (C _1-6 -alkyl) phosphine. More selected.

Each aryl substituent of the halodiarylphosphine moiety is optionally from the group consisting of a halogen atom, nitro, amino, C _1-6 -alkyl, C _1-6 -alkoxy, and di-C _1-6 -alkylamino groups Substituted with one or more selected substituents. Optionally, the C _1-6 -alkyl, C _1-6 -alkoxy, di-C _1-6 -alkylamino, and C _5-10 -cycloalkyl groups of the halophosphine of formula VIII are each one or more halogen atoms Is replaced by In a preferred embodiment, the halophosphine of formula VIII is selected from the group consisting of halodiarylphosphine and halodi- (C _5-10 -cycloalkyl) phosphine, more preferably chlorodicyclohexylphosphine, bromodicyclohexylphosphine, chlorodiphenylphosphine Or bromodiphenylphosphine.

A compound of the following formula is provided:

Wherein R ¹ is C _1-6 -alkyl or C _3-10 -cycloalkyl optionally substituted with one or more halogen atoms,
R ² and R ³ are the same and are selected from the group consisting of aryl, C _5-10 -cycloalkyl, and C _1-6 -alkyl, wherein each aryl moiety is optionally a halogen atom, nitro Substituted with one or more substituents selected from the group consisting of: amino, C _1-6 -alkyl, C _1-6 -alkoxy, and di-C _1-6 -alkylamino groups,
Or, R ² is C _5-10 -cycloalkyl or C _1-6 -alkyl, and R ³ is a halogen atom, nitro, amino, C _1-6 -alkyl, C _1-6 -alkoxy, and di- An aryl substituted with one or more substituents selected from the group consisting of C _1-6 -alkylamino groups;
And the C _1-6 -alkyl, C _5-10 -cycloalkyl, C _1-6 -alkoxy, and di-C _1-6 -alkylamino groups in R ² and R ³ are each one or more halogen atoms. Optionally substituted.

Further provided are compounds of the formula:

Wherein R ¹ is C _1-6 -alkyl or C _3-10 -cycloalkyl optionally substituted with one or more halogen atoms.

A compound of the following formula is provided:

Wherein R ¹ is C _1-6 -alkyl or C _3-10 -cycloalkyl optionally substituted with one or more halogen atoms,
R ² and R ³ are the same and are selected from the group consisting of aryl, C _5-10 -cycloalkyl, and C _1-6 -alkyl, wherein each aryl moiety is optionally a halogen atom, nitro Substituted with one or more substituents selected from the group consisting of: amino, C _1-6 -alkyl, C _1-6 -alkoxy, and di-C _1-6 -alkylamino groups,
Or, R ² is C _5-10 -cycloalkyl or C _1-6 -alkyl, and R ³ is a halogen atom, nitro, amino, C _1-6 -alkyl, C _1-6 -alkoxy, and di- Aryl optionally substituted with one or more substituents selected from the group consisting of C _1-6 -alkylamino groups;
And the C _1-6 -alkyl, C _5-10 -cycloalkyl, C _1-6 -alkoxy, and di-C _1-6 -alkylamino groups in R ² and R ³ are each one or more halogen atoms. Optionally substituted.

The present invention provides compounds of the formula:

Wherein R ¹ is C _1-6 -alkyl or C _3-10 -cycloalkyl optionally substituted with one or more halogen atoms,
R ² is selected from the group consisting of aryl, C _5-10 -cycloalkyl, and C _1-6 -alkyl, wherein each aryl moiety is optionally a halogen atom, nitro, amino, C _1-6 Substituted with one or more substituents selected from the group consisting of -alkyl, C _1-6 -alkoxy, and di-C _1-6 -alkylamino groups, and C _1-6 -alkyl in R ² , C ₅ Each of the _˜10 -cycloalkyl, C _1-6 -alkoxy, and di-C _1-6 -alkylamino groups is optionally substituted with one or more halogen atoms.

There is provided the use of a compound of the following formula for preparing a complex having a catalytic activity of a transition metal, preferably ruthenium, rhodium or iridium:

Wherein R ¹ is C _1-6 -alkyl or C _3-10 -cycloalkyl optionally substituted with one or more halogen atoms,
R ² and R ³ are the same and are selected from the group consisting of aryl, C _5-10 -cycloalkyl, and C _1-6 -alkyl, wherein each aryl moiety is optionally a halogen atom, nitro Substituted with one or more substituents selected from the group consisting of: amino, C _1-6 -alkyl, C _1-6 -alkoxy, and di-C _1-6 -alkylamino groups,
Or, R ² is C _5-10 -cycloalkyl or C _1-6 -alkyl, and R ³ is a halogen atom, nitro, amino, C _1-6 -alkyl, C _1-6 -alkoxy, and di- An aryl substituted with one or more substituents selected from the group consisting of C _1-6 -alkylamino groups, and C _1-6 -alkyl, C _5-10 -cycloalkyl in R ² and R ³ ; Each of the C _1-6 -alkoxy and di-C _1-6 -alkylamino groups is optionally substituted with one or more halogen atoms. The transition metal catalytic activity complex can be used for hydrogenation, preferably asymmetric hydrogenation, of compounds containing at least one unsaturated prochiral system. Preferably, the product obtained by said asymmetric hydrogenation is an enantiomerically pure compound.

  Some examples of generally applicable methods for the preparation of catalysts and catalyst solutions are Ashworth, TV et al. S. Afr. J. Chem. 1987, 40, 183-188, WO 00/29370 and Mashima, KJ Org. Chem. 1994, 59, 3064-3076.

In a preferred embodiment, the hydrogen pressure during the hydrogenation is in the range from 1 to 60 bar, particularly preferably in the range from 2 to 35 bar.
In a more preferred embodiment, the hydrogenation is performed at a temperature in the range of 0-150 ° C.

  In preferred embodiments, the compound comprising at least one unsaturated prochiral system is selected from the group consisting of compounds comprising a prochiral carbonyl group, a prochiral alkene group, or a prochiral imine group.

  In particularly preferred embodiments, said compound comprising at least one unsaturated prochiral carbonyl, alkene, or imine group is an aromatic ketone and an aldehyde α- and β-ketoester, α- and β-ketoamine, α- and β -Selected from the group consisting of keto alcohols, acrylic acid derivatives, acylated enamines, or N-substituted imines.

Preferably, the hydrogenation reaction, C _{1 to 4} - alcohol, water, dimethyl sulfoxide (DMSO), dimethylformamide (DMF), acetonitrile (MeCN), ethers or catalyst solution in a polar solvent such as a mixture of them, Done with. Preferably, the polar solvent includes methanol, ethanol, or isopropyl alcohol, or a mixture thereof. Particularly preferably, the solution further comprises an additive.

  The invention is illustrated by the following non-limiting examples.

Example 1: 1,3-dibromo-2-iodobenzene (II)
Diisopropylamine (0.14L, 0.10kg, 1.0mol) and 1,3-dibromobenzene (0.12L, 0.24kg, 1.0mol) were combined with n-butyllithium (1.0%) in tetrahydrofuran (2.0L) and hexane (0.64L). mol) solution was added continuously at −75 ° C. After 2 hours, a solution of iodine (0.26 kg, 1.0 mol) in tetrahydrofuran (0.5 L) was added at −75 ° C. The solvent was evaporated and the residue was dissolved in diethyl ether (1.0 L). After washing with a 10% aqueous solution of sodium thiosulfate (2 × 0.1 L), the organic layer was dried over sodium sulfate and evaporated to dryness. Crystallization from ethanol (1.0 L) gave 0.33 kg (91%) of colorless plate crystals;
mp 99-100 ° C;
¹ H-NMR (CHCl ₃ , 400 MHz): δ = 7.55 (d, J = 8.1 Hz, 2 H), 7.07 (t, J = 8.1 Hz, 2 H);
C ₆ H ₃ Br ₂ I (361.80): calculated (%) C 19.92, H 0.84; found C 19.97, H 0.80.

Example 2: 2,2 ', 6,6'-tetrabromo-1,1'-biphenyl (III)
At −75 ° C., butyl lithium (14 mmol) in hexane (5.6 mL) was added to a solution of 1,3-dibromo-2-iodobenzene (4.3 g, 12 mmol) in diethyl ether (0.18 L). . After the solution was stirred for 2 hours at −75 ° C., copper (II) chloride (9.7 g, 72 mmol) was added and the reaction mixture was allowed to reach 25 ° C. over 12 hours. Cold water was added to the reaction mixture and the organic layer was separated. The aqueous phase was extracted with ethyl acetate (2 × 0.10 L). The combined organic layer was dried over sodium sulfate and evaporated. By treating the residue with hexane cooled to −20 ° C., 2,2 ′, 6,6′-tetrabromo-1,1′-biphenyl is precipitated. The product (9.0 g, 33%) is sufficiently pure for further reaction;
mp 214-215 ° C;
¹ H NMR (CDCl ₃ , 400 MHz): δ = 7.67 (d, J = 8.3 Hz, 4H), 7.17 (t, J = 8.0 Hz, 2 H).

Example 3: 2,6,6'-tribromo-2'-methoxy-1,1'-biphenyl (IVa; R ¹ = Me)
N-Butyllithium (0.10 mol) in hexane (63 mL) was added to 2,2 ', 6,6'-tetrabromo-1,1'-biphenyl (47 g, 0.10 mol) solution. Treat the mixture sequentially with fluorodimethoxyborane diethyl ether adduct (19mL, 16g, 0.10mol), 3.0M aqueous solution of sodium hydroxide (36mL), and 30% hydrogen peroxide (10mL, 3.6g, 0.10mol) did. The reaction mixture was neutralized with 2.0 M hydrochloric acid (0.10 L) at 25 ° C. and extracted with diethyl ether (3 × 0.10 L). The combined organic layer was washed with a 10% aqueous solution of sodium sulfate (0.10 L), dried over sodium sulfate and evaporated. The oily residue was dissolved in dimethyl sulfoxide (0.20 L) and iodomethane (7.5 mL, 17 g, 0.12 mol) and potassium hydroxide powder (6.7 g, 0.12 mol) were added sequentially. After 1 hour, water (0.50 L) was added and the product was extracted with diethyl ether (3 × 0.10 L). The organic layer was dried over sodium sulfate and evaporated. Crystallization from ethanol (0.10 L) gave 35 g (82%) of product as colorless cubic crystals;
mp 184-185 ° C;
¹ H-NMR (CDCl ₃ , 400 MHz): δ = 7.64 (d, J = 8.3 Hz, 2 H), 7.3 (m, 2 H), 7.11 (t, J = 8.1 Hz, 1 H), 6.96 ( dd, J = 7.2, 2.2 Hz, 1 H), 3.77 (s, 3 H);
C ₁₃ H ₉ Br ₃ (420.92): calculated (%) C 37.09, H 2.16; found C 37.10, H2.03.

Example 4: 6-Bromo-2,6'-bis (diphenylphosphinyl) -2'-methoxy-1,1'-biphenyl (Va; R ¹ = Me and R ² = R ³ = phenyl)
At −75 ° C., n-butyllithium (0.10 mol) in hexane (57 mL) was added to a solution of compound IVa (21 g, 50 mmol) in tetrahydrofuran (0.25 L). The reaction mixture was treated with a 2.0 M solution of chlorodiphenylphosphine (18 mL, 22 g, 0.10 mol) in tetrahydrofuran (50 mL). The mixture was allowed to reach 25 ° C. and treated with a saturated aqueous solution of ammonium chloride (0.20 L). The reaction mixture was extracted with ethyl acetate (3 × 0.10 L) and the combined organic layer was dried over sodium sulfate. Evaporation of the solvent and crystallization from ethyl acetate (0.10 L) gave 23 g (71%) of colorless needle crystals;
mp 224-226 ° C (decomposition);
¹ H-NMR (CDCl ₃ , 400 MHz): δ = 7.56 (dd, J = 8.0, 1.3 Hz, 1 H), 7.38 (dt, J = 7.0, 1.6 Hz, 2 H), 7.3 (m, 12 H ), 7.1 (m, 6 H), 6.99 (ddd, J = 7.7, 2.9, 1.3 Hz, 1 H), 6.8 (m, 3 H), 6.63 (d, J = 8.6 Hz, 1 H), 3.01 ( s, 3 H);
³¹ P-NMR (CDCl ₃ , 162 MHz): δ = -10.1 (d, J = 24.6 Hz), -13.9 (d, J = 24.9 Hz);
C ₃₇ H ₂₉ BrOP ₂ (631.49): calculated (%) C 70.37, H 4.63; found C 69.13, H 4.60.

Example 5: 2 ', 6-bis (diphenylphosphinyl) -2-methoxy-1,1'-biphenyl (Ia; R ¹ = Me and R ² = R ³ = phenyl)
At 0 ° C., n-butyllithium (50 mmol) in hexane (30 mL) was added to a solution of compound Va (16 g, 25 mmol) in toluene (0.1 L). After 45 minutes, methanol (2 mL) was added at 25 ° C., followed by water (25 mL), and the organic layer was separated. The aqueous phase was extracted with dichloromethane (2 × 25 mL) and the combined organic layer was dried over sodium sulfate and evaporated. Crystallization from dichloromethane (50 mL) gave 7.9 g (57%) of colorless prismatic crystals;
mp 227-228 ° C (decomposition);
¹ H-NMR (CDCl3, 400 MHz): δ = 7.3 (m, 18 H), 7.15 (dt, J = 6.8, 2.6 Hz, 4 H), 7.06 (dt, J = 7.3, 1.7 Hz, 2 H) , 6.82 (dd, J = 7.6, 4.2 Hz, 1 H), 6.77 (d, J = 8.2 Hz, 1 H), 6.66 (dd, J = 7.9 Hz, 3.1, 1 H), 3.22 (s, 3 H );
³¹ P-NMR (CDCl ₃ , 162 MHz): δ = −13.1 (d, J = 17.8 Hz), −13.6 (d, J = 17.8 Hz);
C ₃₇ H ₃₀ OP ₂ (552.59): calculated (%) C 80.42, H 5.47; found C 80.53, H 5.52.

Example 6: 2 ', 6-dibromo-2-methoxy-1,1'-biphenyl (VIa; R ¹ = Me)
At −75 ° C., n-butyllithium (25 mmol) in hexane (13 mL) was added to a solution of compound IVa (11 g, 25 mmol) in tetrahydrofuran (0.20 L). Immediately after the addition was complete, methanol (2.0 mL) was added. After adding water (0.10 L), the organic phase was separated and the aqueous layer was extracted with ethyl acetate (3 × 30 mL). The combined organic layer was dried over sodium sulfate and evaporated. After crystallization from ethanol (25 mL), 7.9 g (92%) of 2 ′, 6-dibromo-2-methoxy-1,1′-biphenyl was obtained as colorless cubic crystals;
mp 93-95 ° C;
¹ H-NMR (CDCl ₃ , 400 MHz): δ = 7.67 (d, J = 8.0 Hz, 1 H), 7.38 (t, J = 7.5 Hz, 1 H), 7.3 (m, 4 H), 6.92 ( d, J = 8.1 Hz, 1 H), 3.73 (s, 3 H);
C ₁₃ H ₁₀ Br ₂ O (342.03): calculated (%) C 45.32, H 2.95; found C 45.32, H 2.85.

Example 7: 2 ', 6-bis (dicyclohexylphosphinyl) -2-methoxy-1,1'-biphenyl (Ib; R ¹ = Me, R ² = R ³ = cyclohexyl)
At −75 ° C., n-butyllithium (0.10 mol) in hexane (63 mL) was added to a solution of compound VIIa (17 g, 50 mmol) in tetrahydrofuran (0.25 L). After complete addition, the mixture was treated with a 2.0 M solution of chlorodicyclohexylphosphine (22 mL, 24 g, 0.10 mol) in tetrahydrofuran (50 mL). The mixture was allowed to reach 25 ° C. and treated with a saturated aqueous solution of ammonium chloride (0.10 L). The mixture was extracted with ethyl acetate (3 × 50 mL) and the combined organic layer was dried over sodium sulfate. Evaporation of the solvent and crystallization from methanol (0.10 L) gave 43 g (74%) of diphosphine as colorless cubic crystals;
mp 220 ~ 221 ° C (decomposition);
¹ H-NMR (CDCl ₃ , 400 MHz): δ = 7.56 (m sym., 1 H), 7.4 (m, 3 H), 7.16 (d, J = 7.5 Hz, 1 H), 7.08 (m sym. , 1 H), 6.88 (d, J = 7.8 Hz, 1 H), 3.66 (s, 3 H), 1.7 (m, 24 H), 1.2 (m, 20 H);
³¹ P-NMR (CDCl ₃ , 162 MHz): δ = −9.9 (d, J = 12.1 Hz), −11.5 (d, J = 12.2 Hz);
C ₃₇ H ₅₄ OP ₂ (576.79): calculated (%) C 77.05, H 9.44; found C 77.17, H 9.14.

Example 8: (2'-Bromo-6-methoxy-1,1'-biphenyl-2-yl) dicyclohexylphosphine (VIIa; R ¹ = Me and R ² = cyclohexyl)
At −75 ° C., n-butyllithium (0.10 mol) in hexane (63 mL) was added to a solution of compound VIa (34 g, 0.10 mol) in tetrahydrofuran (0.50 L). After the addition was complete, the mixture was treated with a 2.0 M solution of chlorodicyclohexylphosphine (22 mL, 24 g, 0.10 mol) in tetrahydrofuran (0.10 L). The mixture was allowed to reach 25 ° C. and treated with a saturated aqueous solution of ammonium chloride (0.20 L). The mixture was extracted with ethyl acetate (3 × 0.10 L) and the combined organic layer was dried over sodium sulfate. Evaporation of the solvent and crystallization from a 9: 1 mixture of hexane / ethyl acetate (v / v) (50 mL) gave 36 g (79%) of colorless needles;
mp 100-102 ° C;
¹ H NMR (CDCl ₃ , 400 MHz): δ = 7.61 (d, J = 7.8 Hz, 1 H), 7.38 (t, J = 7.9 Hz, 1 H), 7.33 (t, J = 7.3 Hz, 1 H ), 7.21 (dt, J = 7.9, 1.5 Hz, 2 H), 7.14 (dd, J = 7.6, 1.8 Hz, 1 H), 6.96 (d, J = 8.2 Hz, 1 H), 3.72 (s, 3 H), 1.7 (m, 12 H), 1.2 (m, 10 H);
³¹ P-NMR (CDCl ₃ , 162 MHz): δ = −13.8 (s);
C ₂₅ H ₃₂ BrOP (459.41): calculated (%) C 65.36, H 7.02; found C 65.52, H 7.07.

Example 9: 6-dicyclohexylphosphanyl-2'-diphenylphosphanyl-2-methoxy-1,1'-biphenyl (Ic; R ¹ = Me, R ² = cyclohexyl, and R ³ = phenyl)
At 0 ° C., n-butyllithium (25 mmol) in hexane (30 mL) was added to a solution of compound VIIa (11 g, 25 mmol) in toluene (0.1 L). After 45 minutes, the mixture was cooled to −75 ° C. and a 1.0 M solution of chlorodiphenylphosphine (4.4 mL, 5.5 g, 25 mmol) in toluene (25 mL) was added. The mixture was allowed to reach 25 ° C. A saturated aqueous solution of ammonium chloride (50 mL) was added and the organic layer was separated. The aqueous phase was extracted with ethyl acetate (3 × 25 mL) and the combined organic layer was dried over sodium sulfate and evaporated. Crystallization from methanol (50 mL) gave 7.9 g (56%) of diphosphine as colorless cubic crystals;
mp 170-171 ° C;
¹ H-NMR (CDCl ₃ , 400 MHz): δ = 7.3 (m, 16 H), 6.78 (d, J = 7.9 Hz, 1 H), 3.23 (s, 3 H);
³¹ P-NMR (CDCl ₃ , 162 MHz): δ = −11.3 (d, J = 10.7 Hz), −14.0 (d, J = 10.8 Hz);
C ₃₇ H ₄₂ OP ₂ (564.69): calculated (%) C 78.70, H 7.50; measured C 78.59, H 7.43
Example 10: (-)-and (+)-6-dicyclohexylphosphanyl-2'-diphenylphosphinyl-2-methoxy-1,1'-biphenyl (Ic; R ¹ = Me, R ² = cyclohexyl, and R ³ = phenyl)
Racemic diphosphine Ic was separated into enantiomers by preparative chromatography using chiral steady state. The column used was Chiralcel (CHIRALCEL®), OD 20 μm, and the mobile phase was n-heptane / EtOH 2000: 1. From 360 mg of racemic material, 142 mg of (+)-6-dicyclohexylphosphanyl-2′-diphenylphosphanyl-2-methoxy-1,1′-biphenyl and 123 mg of (−)-6-dicyclohexylphosphanyl-2′- Diphenylphosphanyl-2-methoxy-1,1′-biphenyl was isolated. The enantiomeric purity of both compounds is 100% (determined by HPLC using an analytical chiral cell (CHIRALCEL®) and an OD 10 μm column) and the optical rotation of the (−) isomer is α _D ²⁴ ( In CH ₂ Cl ₂ , c = 0.5) = − 1.4.

Example 11: (-)-and (+)-2 ', 6-bisdicyclohexylphosphinyl-2-methoxy-1,1'-biphenyl (Ib; R ¹ = Me, R ² = R ³ = cyclohexyl)
Separation was performed as described in Example 10. The enantiomeric purity is 99.2% for the (-)-isomer and 96.9% for the (+)-isomer (measured by HPLC using an analytical chiral cell, OD 10 μm column), (+) The optical rotation of the isomer is α _D ²⁴ (c = 0.5 in CH ₂ Cl ₂ ) = 16.4.

Example 12: (-)-and (+)-2 ', 6-bisdiphenylphosphinyl-2-methoxy-1,1'-biphenyl (Ia; R ¹ = Me, R ² = R ³ = phenyl)
Separation was performed as described in Example 10. The optical rotation of the (+)-isomer is α _D ²⁰ (c = 0.5 in CHCl ₃ ) = 6.0.

Example 13: (S) -Ethyl 3-hydroxybutyrate
RuCl ₃ (5.3 mg, 0.026 mmol), (+)-ligand Ia (14.3 mg, 0.026 mmol), and ethyl acetoacetate (0.65 g, 5.0 mmol) were degassed in a 150 mL autoclave under an argon atmosphere. Dissolve in purified ethanol (30 mL). After washing the autoclave with argon, hydrogenation is carried out for 6 hours at 50 ° C. and 4 bar hydrogen pressure. After cooling to room temperature, the reaction solution is directly analyzed by GC for conversion (column: HP-101 25m / 0.2mm) and after derivatization with trifluoroacetic anhydride, the enantiomeric excess is analyzed (column: Lipodex-E 25 m / 0.25 mm). At 99.0% ee, the conversion is 99.7%.

Example 14: (R) -Ethyl 3-hydroxybutyrate
RuCl ₃ (1.5 mg, 0.007 mmol), (-)-ligand Ib (4.3 mg, 0.007 mmol), and ethyl acetoacetate (0.15 g, 1.1 mmol) were removed in a 15 mL autoclave under an argon atmosphere. Dissolve in vaporized ethanol (7 mL). The autoclave is washed with argon and then hydrogenated at 50 ° C. and 4 bar hydrogen pressure for 15 hours. After cooling to room temperature, the reaction solution was directly analyzed by GC for conversion (column: HP-101 25m / 0.2mm), and after derivatization with trifluoroacetic anhydride, the enantiomeric excess was analyzed (column: Lipodex-E 25 m / 0.25 mm). At 86.7% ee, the conversion is 98.3%.

Example 15: (R) -Ethyl 4-chloro-3-hydroxybutyrate
In a 150 mL autoclave under an argon atmosphere, bis (1-isopropyl-4-methylbenzene) dichlororuthenium (7.6 mg, 0.012 mmol), (+)-ligand Ia (14.0 mg, 0.025 mmol), and ethyl 4 -Chloro-3-oxobutyrate 98.4% (0.83 g, 5.0 mmol) is dissolved in degassed ethanol (30 mL). The autoclave is washed with argon and then hydrogenated at 80 ° C. and 4 bar hydrogen pressure for 4 hours. After cooling to room temperature, the reaction solution is directly analyzed by GC for conversion (column: HP-101 25 m / 0.2 mm) and ee (column: Lipodex-E 25 m / 0.25 mm). At 88% ee, the conversion is 99.9%.

Example 16: (S) -Ethyl 4-chloro-3-hydroxybutyrate
In a 150 mL autoclave under argon atmosphere, bis (1-isopropyl-4-methylbenzene) dichlororuthenium (7.5 mg, 0.012 mmol), (+)-ligand Ic (14.4 mg, 0.025 mmol), and ethyl 4 -Chloro-3-oxobutyrate (0.83 g, 5.0 mmol) is dissolved in degassed ethanol (30 mL). After washing the autoclave with argon, hydrogenation is carried out at 80 ° C. and 4 bar hydrogen pressure for 3 hours. After cooling to room temperature, the reaction solution is directly analyzed by GC for conversion (column: HP-101 25 m / 0.2 mm) and ee (column: Lipodex-E 25 m / 0.25 mm). At 80% ee, the conversion is 100%.

Example 17: N-acetyl-D-phenylalanine
In a 15 mL autoclave under an argon atmosphere, bis (benzene) dichloro-ruthenium (2.6 mg, 0.005 mmol), (+)-ligand Ia (6.0 mg, 0.011 mmol), and N-acetylaminocinnamic acid ( 0.53 g, 2.5 mmol) is dissolved in degassed methanol (5 mL). The autoclave is washed with argon and then hydrogenated at 40 ° C. and 50 bar hydrogen pressure for 16 hours. After cooling to room temperature, the reaction solution is evaporated and the residue is analyzed by HPLC for conversion (column: Bischoff Kromasil 100 C8) and enantiomeric excess (column: Nucleodex β-PM). At 43% ee, the conversion is 100%.

Example 18: N-acetyl-L-phenylalanine
Bis (benzene) dichloro-ruthenium (2.6 mg, 0.005 mmol), (-)-ligand Ib (3.2 mg, 0.006 mmol), and 2- (N-acetylamino) in a 15 mL autoclave under an argon atmosphere -Dissolve cinnamic acid (0.53 g, 2.5 mmol) in degassed methanol (5 mL). The autoclave is washed with argon and then hydrogenated at 40 ° C. and 50 bar hydrogen pressure for 15 hours. After cooling to room temperature, the reaction solution is evaporated and the residue is analyzed by HPLC for conversion (column: Bischoff Kromasil 100 C8) and enantiomeric excess (column: Nucleodex β-PM). At 66% ee, the conversion is 34%.

Example 19: (S) -2-acetylamino-3-phenyl-propionic acid methyl ester
In a 15 mL autoclave under argon atmosphere, bis (1,5-cyclooctadiene) -rhodium (I) tetrafluoroborate (1.9 mg, 0.005 mmol), (+)-ligand Ic (2.8 mg, 0.005 mmol), and methyl 2- (N-acetylamino) -cinnamate (0.10 g, 0.5 mmol) are dissolved in degassed methanol (6 mL). The autoclave is washed with argon and then hydrogenated at 25 ° C. and 2 bar hydrogen pressure for 15 hours. After cooling to room temperature, evaporate the reaction solution and analyze the residue by HPLC for conversion (column: Bischoff Kromasil 100 C8) and GC for enantiomeric excess (column: Lipodex-E 25 m / 0.25 mm) To do. At 93.8% ee, the conversion is 100%.

Example 20: (R) -N-benzyl-1-phenylethylamine
Bis (1,5-cyclooctadiene) -di (iridium (I) dichloride) 98% (6.7 mg, 0.010 mmol), (+)-ligand Ia (11.0 mg) in a 15 mL autoclave under an argon atmosphere , 0.020 mmol), benzylamine (5.6 mg, 0.052 mmol), and N-benzyl-N- (1-phenylethylidene) amine (0.21 g, 1.0 mmol) were dissolved in degassed methanol (5 mL). Stir at room temperature for 1 hour. The autoclave is washed with argon and then hydrogenated for 17 hours at 30 ° C. and 50 bar hydrogen pressure. The reaction solution is directly analyzed by GC for conversion (column: HP-101 25 m / 0.2 mm) and enantiomeric excess (column: Macherey-Nagel, Nucleodex Beta-PM CC200 / 4). At 29% ee, the conversion is 100%.

Example 21: (S) -N-benzyl-1-phenylethylamine
Bis (1,5-cyclooctadiene) -di (iridium (I) dichloride) 98% (6.7 mg, 0.010 mmol), (+)-ligand Ic (5.7 mg) in a 15 mL autoclave under an argon atmosphere , 0.010 mmol), benzylamine (5.6 mg, 0.052 mmol), and N-benzyl-N- (1-phenylethylidene) amine (0.21 g, 1.0 mmol) were dissolved in degassed methanol (5 mL). Stir at room temperature for 1 hour. The autoclave is washed with argon and then hydrogenated at 30 ° C. and 50 bar hydrogen pressure for 15 hours. The reaction solution is analyzed directly by GC for conversion (column: HP-101 25 m / 0.2 mm) and enantiomeric excess (column: Macherey-Nagel, Nucleodex Beta-PM CC200 / 4). At 10% ee, the conversion is 100%.

Example 22: (R) -Dimethyl methyl succinate
Bis (1,5-cyclooctadiene) -rhodium (I) tetrafluoroborate (2.1 mg, 0.005 mmol) and ligand (+)-Ic (3.1 mg, 0.005) in a 15 mL autoclave under an argon atmosphere mmol) is dissolved in 5 mL of degassed methanol. Dimethyl itaconate (97%, 0.15 g, 0.9 mmol) is added using a syringe. The autoclave is flushed with argon and then hydrogenated at 23 ° C. and 2 bar hydrogen pressure for 15 hours. The reaction solution is analyzed directly by GC for conversion (column: HP-101 25 m / 0.2 mm) and enantiomeric excess (column: Macherey-Nagel, Nucleodex Beta-PM CC200 / 4). At 30% ee, the conversion is 100%.

Example 23: (R) -Dimethyl methyl succinate
Bis (1,5-cyclooctadiene) -rhodium (I) tetrafluoroborate (2.1 mg, 0.005 mmol) and (-)-ligand Ib (3.2 mg, 0.006) in a 15 mL autoclave under an argon atmosphere. mmol) is dissolved in 5 mL of degassed methanol. Dimethyl itaconate (97%, 0.15 g, 0.9 mmol) is added using a syringe. The autoclave is flushed with argon and then hydrogenated at 23 ° C. and 2 bar hydrogen pressure for 15 hours. The reaction solution is analyzed directly by GC for conversion (column: HP-101 25 m / 0.2 mm) and enantiomeric excess (column: Macherey-Nagel, Nucleodex Beta-PM CC200 / 4). At 24% ee, the conversion is 60%.

Claims (15)

A process for preparing an asymmetrically substituted biaryldiphosphine ligand of the formula:

[Wherein, R ¹ in the formula, C _{1 ~ 6,} which is optionally substituted with one or more halogen atoms - alkyl or C _{3 ~ 10} - cycloalkyl,
R ² and R ³ are the same, aryl, C _{5 ~ 10} - cycloalkyl, and C _{1 ~ 6} - is selected from the group consisting of alkyl, each aryl moiety herein is optionally halogen atom, a nitro , amino, C _{1 ~ 6} - or substituted with one or more substituents selected from the group consisting of alkylamino group, - alkyl, C _{1 ~ 6} - alkoxy, and di -C _{1 ~ 6}
Or, R ² is C _{1 ~ 6} - cycloalkyl, R ³ is a halogen atom, nitro, amino, C _{1 ~ 6} - - alkyl or C _{5 ~ 10} alkyl, C _{1 ~ 6} - alkoxy, and di - C _{1 ~ 6} - aryl optionally substituted with one or more substituents selected from the group consisting of alkyl group,
And, C _{1 ~ 6} in R ² and R ³ - alkyl, C _{1 ~ 6} - alkoxy, di -C _{1 ~ 6} - alkylamino, and C _{5 ~ 10} - each cycloalkyl groups, with one or more halogen atoms Optionally replaced]
The method is a first reaction procedure in which one of the following 2,2 ′, 6,6′-tetrabromobiphenyl bromine atoms is bromine-lithium exchange or bromine-magnesium exchange followed by lithium-hydroxy exchange: Or exchanged with OR ¹ by magnesium-hydroxy exchange followed by alkylation,

Obtaining a compound of the formula: wherein R ¹ is as defined above;

A further reaction procedure, each reaction procedure comprising at least one bromine-lithium exchange or bromine-magnesium exchange followed by a lithium-substituent exchange or a magnesium-substituent exchange with the respective substituent, thereby the respective bromine atom hydrogen, diarylphosphino, di -C _{1 ~ 6} - include be substituted with substituents selected from the group consisting of cycloalkyl phosphino - alkylphosphino and di -C _{5 ~ 10} How to 2. The method of claim 1, wherein the initial bromine-lithium exchange is performed with 1 equivalent of n-butyllithium at a temperature of -40 ° C. or less, and the lithium-hydroxy exchange is performed with borane or organoborate. A process in which the reaction is carried out with a peroxy compound in the presence of an alkali and / or alkaline earth hydroxide and the alkylation is carried out with an alkylating agent in the presence of a base. .   3. The method according to claim 2, wherein the borane or organoborate is a fluoromethoxyborane ethyl ether adduct or trimethylborate.   4. The method according to claim 2 or 3, wherein the peroxy compound is selected from the group consisting of hydrogen peroxide, peracetic acid, m-chloroperbenzoic acid, and tert-butyl peroxide. A method according to any one of claims 2-4, wherein the alkylating agent, C _{1 ~ 6} - alkyl halide, C _{5 ~ 10} - halogenated cycloalkyl, or dimethyl sulfate method. 6. The method according to any one of claims 1-5, wherein the further reaction procedure is carried out by starting from a compound of formula IV, wherein two bromine atoms are cooled at -90 to -40 <0> C. Obtaining a compound of the formula by bromine-lithium exchange or bromine-magnesium exchange followed by lithium-phosphine exchange or magnesium-phosphine exchange ;

[R ¹ in the formula is as defined above, R ² and R ³ are the same, a halogen atom, nitro, amino, C _{1 ~ 6} - alkyl, C _{1 ~ 6} - alkoxy, and di - C _{1 ~ 6} - is one or more aryl optionally substituted with substituents selected from the group consisting of alkylamino group, C _{1 ~ 6} in and R ² and R ³ - alkyl, C _{5 ~ 10} - cyclo alkyl, C _{1 ~ 6} - alkoxy, and di -C _{1 ~ 6} - alkylamino groups each are optionally substituted with one or more halogen atoms]
Further, the remaining bromine atom of the compound of formula V is replaced with hydrogen by high temperature bromine-lithium exchange or bromine-magnesium exchange at 0-40 ° C. and subsequent reaction with a hydrogen donor to give a ligand of the formula A method comprising that.

[Wherein R ¹ , R ² , and R ³ are as defined in Compound V above] 6. A process according to any one of claims 1-5, wherein the further reaction procedure is carried out by starting from a compound of formula IV, wherein one bromine atom is cooled at -90 to -40C. Bromine-lithium exchange or bromine-magnesium exchange followed by lithium-hydrogen exchange or magnesium-hydrogen exchange by reaction with a hydrogen donor to obtain a compound of the formula wherein R ¹ is as defined above;

A process comprising obtaining a ligand of formula I by further cold bromine-lithium exchange or bromine-magnesium exchange followed by lithium-phosphine exchange or magnesium-phosphine exchange of the remaining bromine atoms at −90 to −40 ° C. :
Here, in the ligand of formula I, R ¹ is as defined above, R ² and R ³ are the same, aryl, C _{5 ~ 10} - consisting of alkyl - cycloalkyl, and C _{1 ~ 6} is selected from the group, each aryl moiety herein is optionally halogen atom, nitro, amino, C _{1 ~ 6} - consisting of alkylamino groups - alkyl, C _{1 ~ 6} - alkoxy, and di -C _{1 ~ 6} substituted with one or more substituents selected from the group, C _{1 ~ 6} in and R ² and R ³ - alkyl, C _{5 ~ 10} - cycloalkyl, C _{1 ~ 6} - alkoxy and di -C _{1 ~ 6,} Each -alkylamino group is optionally substituted with one or more halogen atoms. 6. The method according to any one of claims 1 to 5, wherein the further reaction procedure is carried out by starting from a compound of formula IV, wherein one bromine atom is cooled at -90 to -40 <0> C. Obtaining a compound of formula VI wherein R ¹ is as defined above by bromine-lithium exchange or bromine-magnesium exchange followed by lithium-hydrogen exchange or magnesium-hydrogen exchange by reaction with a hydrogen donor;
Low temperature bromine-lithium exchange or bromine-magnesium exchange at −90 to −40 ° C. of one bromine atom followed by lithium-phosphine exchange or magnesium-phosphine exchange to obtain a compound of the formula

[R ¹ in the formula is as defined above, R ² is C _{5 ~ 10} - an alkyl, said C _{1 ~ 6} - - cycloalkyl or C _{1 ~ 6} alkyl or C _{5 ~ 10} - cyclo The alkyl group is optionally substituted with one or more halogen atoms]
Further, a process comprising obtaining a ligand of formula I by high temperature bromine-lithium exchange or bromine-magnesium exchange at 0-40 ° C. of the remaining bromine atoms followed by lithium-phosphine exchange or magnesium-phosphine exchange :
Here, in the ligand of formula I, R ¹ and R ² are as defined above, R ³ is a halogen atom, nitro, amino, C _{1 ~ 6} - alkyl, C _{1 ~ 6} - alkoxy, and di -C _{1 ~ 6} - is one or more aryl optionally substituted with substituents selected from the group consisting of alkylamino group, C _{1 ~ 6} in and R ³ - alkyl, C _{5 ~ 10} - cycloalkyl, C _{1 ~ 6} - alkoxy, and di -C _{1 ~ 6} - alkylamino groups each are optionally substituted with one or more halogen atoms. The method according to any one of claims 6 to 8, wherein each of the low-temperature bromine-lithium exchanges is performed using n-butyllithium at a temperature of -40 ° C or lower . 9. The method according to claim 6 or 8, wherein the high temperature bromine-lithium exchange is performed with n-butyllithium or tert-butyllithium at a temperature of at least + 0 ° C. A method according to any one of claims 6-8, wherein the hydrogen donor is, C _{1 ~ 3} - is selected from the group consisting of alkanoic acids - alcohols, water, HCl, and C _{1 ~ 3} Method. 9. The method according to any one of claims 6 to 8, wherein the lithium-phosphine exchange or magnesium-phosphine exchange is carried out using a halophosphine of the formula:

Here, X in the formula is chlorine, bromine, or iodine, R is the same and is R ² or R ³ , where R ² and R ³ are as defined above. The method of claim 12, halophosphine of the formula VIII is Haroji - (C _{5 ~ 10} - cycloalkyl) phosphines and halo - a method selected from the group consisting of diaryl phosphines. Compounds of the following formula:

Here, R ¹ in the formula is 1 or more C ₁ optionally substituted with halogen atom _1-6 - cycloalkyl - alkyl or C _{3 - 10.} Methods for using compounds of formula I for the preparation of complexes having catalytic activity of transition metals:

Here, R ¹ in the formula, C _{1 ~ 6,} which is optionally substituted with one or more halogen atoms - alkyl or C _{3 ~ 10} - cycloalkyl,
R ² and R ³ are the same, aryl, C _{5 ~ 10} - cycloalkyl, and C _{1 ~ 6} - is selected from the group consisting of alkyl, each aryl moiety herein is optionally halogen atom, a nitro , amino, C _{1 ~ 6} - or substituted with one or more substituents selected from the group consisting of alkylamino group, - alkyl, C _{1 ~ 6} - alkoxy, and di -C _{1 ~ 6}
Or, R ² is C _{5 ~ 10} - alkyl, R ³ is a halogen atom, nitro, amino, C _{1 ~ 6} - - cycloalkyl or C _{1 ~ 6} alkyl, C _{1 ~ 6} - alkoxy, and di - C _{1 ~ 6} - aryl optionally substituted with one or more substituents selected from the group consisting of alkyl group,
C _{1 ~ 6} in and R ² and R ³ - alkyl, C _{5 ~ 10} - optionally alkylamino groups respectively, one or more halogen atoms - cycloalkyl, C _{1 ~ 6} - alkoxy, and di -C _{1 ~ 6} Is replaced by