WO2004039779A1

WO2004039779A1 - Process for the preparation of pyridyl-aryl-sulphonic compounds

Info

Publication number: WO2004039779A1
Application number: PCT/IT2002/000626
Authority: WO
Inventors: Maurizio Paiocchi; Francesco Ponzini; Marco Nicolini
Original assignee: Euticals Prime European Therapeuticals Spa
Priority date: 2002-10-02
Filing date: 2002-10-02
Publication date: 2004-05-13
Also published as: AU2002349815A1; EP1546104A1

Abstract

A method is described for the preparation of pyridyl-aryl-sulphonic compounds of formula (I), by cross-coupling reaction, promoted by catalytic systems based on palladium or nickel between compounds of formulae (II, III), in which; a) Met represents Mg or Zn, b) Y represents C1, Br, I or acetoxy, c) Z represents I, Br, Cl, triflate, sulphonate and/or sulphone, d) R1, R2, R4, R5, which are the same as one another or different, represent H, a linear and/or branched C1-C4 alkyl, and/or an aryl, and/or a heteroaryl, or R1 and R2 and/or R4 and R5, taken together, form a heteroaryl, and e) R3 represents a linear, branched or cyclic C1-C8 alkyl and/or an aryl, and/or a heteroaryl.

Description

Process for the preparation of pyridyl-aryl-sulphonic compounds

The subject of the present invention is the preparation of compounds of formula 1 :

from compounds of formula 3 and formula 4.

in which:

• Met represents Mg or Zn,

• Y represents Cl, Br, I or acetoxy,

• Z represents I, Br, Cl, triflate, sulphonate and/or sulphone,

• Ri, R₂, R₄, R₅, which are the same as one another or different, represent H, a linear and/or branched Cι-C alkyl, and/or an aryl, and/or a heteroaryl, or Ri and R₂ and/or R and R5, taken together, form a C₃-C₈ ring, an aryl and/or a heteroaryl, and

• R3 represents a linear, branched or cyclic Cι-C₈ alkyl and/or an aryl, and/or a heteroaryl. The compounds of formula 1 are intermediates usable for the synthesis of various classes of active ingredients such as, for example: anti-inflammatories (WO 96/24584 and W096/24585), metalloproteinase inhibitors (WO 99/26909), anti- hypercholesteraemics, anti-hyperlipoproteinaemics, and anti-allergies (WO 98/04528), 2-cyclooxigenase inhibitors (WO 99/14195, WO 99/59635 and WO 00/38716), anti-arrythmics (EP-699666) and antibacterials (EP-481662), which are incorporated herein by reference. In particular, the compound of formula 2

is used in the preparation of new drugs for the treatment of disorders of the central nervous system associated with the activity of the dopamine receptors (WO

92/18475, WO 00/3714, US-5462947, which are also incorporated herein by reference).

STATE OF THE ART

As reported in the literature, the compound of formula 2 is normally prepared by a coupling reaction between 3-pyridyldiethyl borane and 3-bromophenylmethyl sulphone in THF, catalyzed by palladium tetrakistriphenyl phosphine in the presence of potassium hydroxide and tetrabutylammonium iodide (Sonesson, C. et al. T.L.

1994, 35, 9063), as given below.

A great disadvantage of this approach, however, is represented by the preparation of the pyridine derivative from 3-bromopyridine and methoxy-diethyl borane by low- temperature lithiation; both the low temperatures and the use of expensive and potentially dangerous raw materials such as alkyl lithium and methoxy-diethyl borane solutions in fact render this method of little interest from a commercial point of view; similar coupling reactions on boron derivatives to produce heteroaryl-aryl sulphones are described, for example, in WO99/14195 and EP-699666. Conventional cross-coupling reactions, which provide for the formation of a carbon- carbon bond between two partners, one carrying an leaving group (for example, a halogen) and the other a metallo-organic derivative (such as a Grignard reagent or a zinc derivative) are not, however, normally used for the preparation of compounds of formula 1 or 2; the acidity of the protons at ? on the sulphone group in fact represents a considerable deterrent to the use of metallo-organic reagents in the presence of alkyl sulphones (Magnus, P.D., Tetrahedron 1977, 33, 2019). A second disadvantage relates to the behaviour of the sulphone groups when they are subjected to the cross-coupling conditions; in fact several cases are known in the literature in which aryl-sulphonic and alkyl-sulphonic groups behave as leaving groups in cross-coupling reactions, thus promoting undesired competitive reactions (Julia M, et al, / Perk, Trans. 95, 7; Wenckert, E. et &\]CS Chem. Comm. 79, 637; German patent application DE 196 36 995 Al).

In accordance with the foregoing, International patent application WO 01/27083 describes the preparation of aryl-pyridine compounds free of sulphonated substituents, in which a pyridyl halide is reacted with an aryl-magnesium halide in the presence of a catalytic quantity of a zinc salt and of a catalytic quantity of palladium. DESCRIPTION OF THE INVENTION It has now surprisingly been found that compounds of formula 1 can be produced with high yields and purity by cross-coupling reaction between compounds of formula 3 and compounds of formula 4, promoted by catalytic systems based on palladium or nickel, in accordance with the scheme given below.

in which:

• Met represents Mg or Zn,

• Y represents Cl, Br, I or acetoxy,

• Z represents I, Br, Cl, trifiate, sulphonate and/or sulphone,

• Ri, R₂, R₄, R5, which are the same as one another or different, represent H, a linear and/or branched Cι-C alkyl, and/or an aryl, and/or a heteroaryl, or Ri and R₂ and/or R₄ and R5, taken together, form a C₃-C₈ ring, an aryl and/or a heteroaryl, and

• R3 represents a linear, branched or cyclic Cι-C₈ alkyl and/or an aryl, and/or a heteroaryl.

Palladium and nickel are normally used in quantities of 0.01-10 moles, preferably 0.05-2 moles, per 100 moles of compound 3; the reaction is normally carried out by adding an organic solution of compound 3 to an organic solution containing compound 4 and the catalytic system.

The organic solvent is preferably an ethereal solvent (such as, for example, not to react with the Grignard compounds) such as THF, 1,2 dimethoxyethane, and/or 1,1- diethoxymethane; the reaction is carried out at a temperature of between 20 and 80°C, preferably between 40 and 60°C.

The reaction yield can be increased by operating in the presence of phosphines and/or phosphites, to be used preferably in a molar ratio of catalystphosphine/phosphite of between 1:1 and 1:6. The phosphines usable for the purposes of the present invention may be: triaryl phosphines, such as triphenyl phosphine, tritolyl phosphine, trixylyl phosphine, tri-2-furyl phosphine; diaryl alkylphosphines, such as methyldiphenyl phosphine, benzyldiphenyl phosphine, cyclohexyldiphenyl phosphine; dialkylaryl phosphines, such as 2-(di-t- butylphosphino)- biphenyl, 2-(dicyclohexylphosphino)biphenyl; trialkyl phosphines, such as 2-(di-t-butyl phosphino)biphenyl, 2-(dicyclohexylphosphino)biphenyl; trialkyl phosphines, such as triisopropyl phosphine, tricyclohexyl phosphine, tributyl phosphine, triisobutyl phosphine, di-t-butylmethyl phosphine; bidentate phosphines such as 2-2'bis(diphenylphosphino)-l,rbinaphthyl (racemic BINAP), 1,2- bis(dicyclohexylphosphino)ethane, l,l'bis(diphenyl- phosphino) ferrocene (dppf), 1,2- bis(diethylphosphino)- ethane, l,2-bis(dipentafluorophenylphosphino)ethane, 1,3- bis(diphenylphosphino)propane (dppp), l,4-bis(diphenyl- phosphino)butane (dppb). Palladium is generally added to the reaction medium in the form of complexes with phosphines such as, for example, palladium tetrakistriphenyl phosphine (Pd(PPh₃)₄) or as palladium salt, generally acetate or chloride, and a phosphine, preferably triphenyl phosphine; normally, one mole of palladium acetate or chloride is used in combination with 4 moles of triphenyl phosphine (Pd(OAc)₂ or PdCl₂ + 4PPh₃). Similarly, nickel is normally used in the form of complexes with phosphines, preferably bidentate phosphines, such as, for example, 1,3- bis(diphenylphosphino)propane (dppp) or l,4-bis(diphenylphosphino)butane (dppb); these complexes are added to the reaction solution as salts such as, for example, Ni(dppp)Cl₂ or Ni(dppb)Cl₂.

Optionally, the reaction may also be carried out in the presence of zinc salts such as, for example, zinc chloride (ZnCl₂), zinc bromide (ZnBr₂) and zinc acetate (Zn(OAc)₂); the zinc salt is normally used in quantities of 25-120 moles, preferably 35-70 moles, per 100 moles of compound 3. In order for the cross-coupling reaction to proceed with high yields and high selectivity in the presence of a minimum quantity of catalyst, it is preferable to prevent the accumulation of Grignard reagents in the reaction medium and they should therefore be in a dynamic deficiency relative to the zinc salt (that is, the Grignard reagent is added dropwise to a solution already containing compound 4, palladium, phosphine binder, and zinc salt). According to a preferred embodiment of the invention, 0.01-0.1 moles of palladium and 40-70 moles of zinc are used per 100 moles of compound 3; the molar ratio between palladium and compound 3 is less than 1:100. Alternatively, in a second embodiment, 0.01-2 moles of nickel per 100 moles of compound 3 are used (that is, in the absence of zinc salts).

The reaction according to the present invention may also be carried out both in the presence of alkyl halides (up to quantities greater than that which is equtmolar with the Grignard), and in the presence of variable quantities of alkyl Grignard; this result is particularly surprising if it is borne in mind that, in identical reaction conditions (Example 9), alkyl Grignards provide the product of homocoupling of the sulphonic derivative with yields greater than 60%, as illustrated in the following scheme:

It is also known that, in the presence of nickel complexes, the alkyl Grignards act as reducers on the sulphonic derivatives (Julia M, et al. JCS Perk. Trans. 95, 7). The fact that the present coupling reaction between compound 3 and compound 4 can be performed both in the presence of alkyl halides and of alkyl Grignard enables the organic solution of the pyridyl Grignard selected to be used directly for the subsequent cross-coupling reaction, that is, without the need for additional purification. In this connection, it should be borne in mind that the metallo-organic pyridine reagents are generally prepared by transmetallation from the corresponding halogen derivatives with alkyl Grignard, in accordance with the scheme given below:

in which:

• Met represents Mg,

• X represents Cl, Br or I,

• Y represents Cl, Br or I, and

• Ri and R₂ have the meanings given above

or by transmetallation from the corresponding halogen derivatives with alkyl lithium and subsequent treatment with zinc salts in accordance with the scheme given below

in which:

• Met represents Mg or Zn,

• X represents Cl, Br or I,

• Y represents Cl, Br, I or acetoxy, and • Ri and R₂ have the meanings given above.

According to the preferred embodiment of the present invention, they are prepared

(Example 1, Grignard A) by reaction of a halogeno(bromo, iodo)-pyridine with a catalytic quantity of alkyl halide in the presence of an at least stoichiometric quantity of magnesium; the alkyl halide is normally a Cι-C₈ alkyl chloride or bromide, preferably ethyl bromide or isopropyl bromide or chloride.

Very high yields and solutions of Grignard reagent which are less contaminated by undesired by-products than those which would be obtained with the use of pyridyl magnesium halides prepared by conventional methods such as, for example those reported in Tetrahedron 2000, 56, 1349 or in JOC 1959, 24, 504 and Red Trap. Chim.

Netherlands, 1965, 84, 439, are thus obtained.

Preferably, 100 moles of halogeno-pyridine are reacted with 10-20 moles of alkyl halide and 100-120 moles of magnesium. The reaction is generally carried out at a temperature of 0-60°C, preferably at 15-35°C, in an aprotic organic solvent which does not react with a Grignard reagent, preferably in tetrahydrofuran or mixtures of tetrahydrofuran and toluene; the solution thus obtained is then added dropwise to the solution containing compound 4 and the catalytic system.

These and further aspects of the invention will become clear from the following examples, which should be considered as illustrative and not limiting thereof.

PREPARATION OF THE GRIGNARD REAGENT EXAMPLE 1 - GRIGNARD A

Ethyl bromide (2.2 g 0.02 moles) was added to a suspension of magnesium (0.29g, 0.12 moles) in anhydrous tetrahydrofuran (58.5 g), kept at 20°C, with stirring, in an inert atmosphere, whilst the internal temperature was kept below 35°C. 3- bromopyridine (16.0 g, 0.101 moles) was added over 3 hours to the solution thus obtained, whilst the temperature was controlled at between 25 and 30°C. Stirring of the reaction mixture was continued at 25°C for a further 3 hours. EXAMPLE 2 - GRIGNARD B

A solution of 3-bromopyridine (16 g, 0.101 moles) in anhydrous tetrahydrofuran (5g) was added over 1 hour to a solution of 2-propyl-magnesium chloride (2M in tetrahydrofuran, 50.6 ml, Aldrich cat. 2000/2001) kept at 25°C. Stirring of the mixture was continued at 25°C for 4 hours. EXAMPLE 3 - GRIGNARD C

A solution of 2-propyl-magnesium chloride (2M in tetrahydrofuran, 49 g, 50.6 ml, Aldrich cat. 2000/2001) was added over 1 hour to a solution of 3-bromopyridine (16 g, 0.101 moles) in anhydrous tetrahydrofuran (5g), kept at 25°C. Stirring of the mixture was continued at 25°C for 4 hours. EXAMPLE 4 - GRIGNARD D

A solution of 2-proρyl-magnesium chloride (2M in tetrahydrofuran, 9,8 g 0.02 moles, Aldrich cat. 2000/2001) was added to a suspension of magnesium (1.96 g, 0.08 moles) in anhydrous tetrahydrofuran (53.2 g), kept at 20°C, with stirring, in an inert atmosphere. 3-bromopyridine (16.0 g 0.101 moles) was then added over 3 hours whilst the temperature was controlled at between 25 and 30°C. Stirring of the reaction mixture was continued at 25°C for 3 hours.

COUPLING REACTION EXAMPLE 5

3-bromophenylmethyl sulphone (19.5 g, 0.0825 moles) and palladium tetrakistriphenyl phosphine (0.095 g, 0.082 moles) were added to a mixture of anhydrous ZnCl₂ (4.0g, 0.0293 moles) in anhydrous tetrahydrofuran (45.0 g), kept at 50°C, with mechanical stirring, in an inert atmosphere. Grignard A solution (79.5 g) was added to the resulting suspension over 3 hours, still at 50°C. The reaction mixture was stirred for 1 hour.

The mixture was cooled to 25°C, treated with 120 g of 10% w/w hydrochloric acid solution and the phases were separated.

The aqueous phase was treated with 70g of a 28% w/w ammonia solution, toluene was added, and the phases were separated. The toluene phase was evaporated to oil at reduced pressure. Crystallization from 96g of isopropyl alcohol was then performed. 15.4 g of 3-(3'pyridyl)phenylmethyl sulphone (0.066 moles; yield 80% relative to 3-bromophenylmethyl sulphone) was obtained. M.P. = 86°C

Η-NMR (CDC1₃) (Bruker 400 MHz): 8.88 ppm (d, J=2.3 Hz, 1H), 8.68 ppm (dd, J= 4.8 Hz, 1.6 Hz, 1H), 8.15 ppm (t, J= 1.8 Hz, 1H), 7.98 ppm (dt, J=7.8 Hz,1.2 Hz, 1H), 7.92 ppm (dt, J= 8.0 Hz, 2.1 Hz, 1H), 7.88 ppm (dt, J= 7.8 Hz, 1.2 Hz, 1H), 7.70 ppm (t, J= 7.8 Hz, 1H), 7.42 ppm (dd, J= 7.9 Hz, 4.8 Hz, 1H), 3.11 ppm (s, 3H) EXAMPLE 6

3-bromophenylmethyl sulphone (19.5 g, 0.0825 moles) and palladium tetrakistriphenyl phosphine (0.095 g, 0.082 mmoles) were added to a mixture of anhydrous ZnCl₂ (12.0 g 0.088 moles) in anhydrous tetrahydrofuran (45.0 g), kept at

50°C, with mechanical stirring, in an inert atmosphere. Grignard A solution (79.5 g) was added to the resulting suspension over 3 hours. The reaction mixture was stirred for 1 hour and then cooled to 25°C.

After treatment as in Example 1, an organic phase (136 g) containing compound 2

(HPLC titre 13.01%, equal to 17.7 g, 0.076 moles, yield 92% relative to 3- bromophenylmethyl sulphone) was obtained

EXAMPLE 7

Grignard A solution (79.5 g) was added over 5 hours to a mixture of 3- bromophenylmethyl sulphone (19.5 g, 0.0825 moles) and palladium tetrakistriphenyl phosphine (4.5 g, 0.0041 moles) in anhydrous tetrahydrofuran (45g), kept at 50°C, with mechanical stirring, in an inert atmosphere. The reaction mixture was stirred for 1 hour and then cooled to 25°C.

After treatment as in Example 1, an organic phase (120 g) containing compound 2

(HPLC titre 5.61%, equal to 6.73 g, 0.029 moles, yield 35% relative to 3- bromophenylmethyl sulphone) was obtained.

EXAMPLE 8

2-propyl magnesium chloride (2M in tetrahydrofuran, 0.045 g, 0.9 mmoles, Aldrich cat. 2000/2001) was added over 5' to a suspension of Ni(dppp)Cl₂ (0.231 g, 0.42 mmoles) in anhydrous tetrahydrofuran (3.5g), cooled to 0°C, in a 10 ml flask kept under inert atmosphere and with magnetic stirring. The temperature was allowed to rise to 20°C and stirring was continued for 10'.

The catalyst solution was added to a solution of 3-bromophenylmethyl sulphone (9.9 g, 0.042 moles) in anhydrous tetrahydrofuran (18.0 g), kept at 50°C, with mechanical stirring, in an inert atmosphere. Grignard A solution (44.0 g) was added over 4 hours. The reaction mixture was stirred for 1 hour and then cooled to 25°C.

After treatment as in Example 1, an organic phase (75 g) containing compound 2

(HPLC titre 12.1%, equal to 9.1 g, 0.039 moles, yield 93% relative to 3- bromophenylmethyl sulphone) was obtained. EXAMPLE 9

3-bromophenylmethyl sulphone (9.9 g, 0.042 moles) and palladium tetrakistriphenyl phosphine (0.047 g, 0.042 mmoles) were added to a mixture of anhydrous ZnCl₂

(1.72 g, 0.013 moles) in anhydrous tetrahydrofuran (22.5 g), kept at 50°C, with mechanical stirring, in an inert atmosphere.

Ethyl-magnesium bromide (1.5 M in tetrahydrofuran 28 ml) was added to the mixture over 3 hours. The reaction mixture was kept at 50°C for 1 hour and then cooled to 25°C.

After aqueous work-up, the product was isolated by flash chromatography. 8.5 g of

3,3'-bis(methansulphonyl)biphenyl (yield 65%) was obtained.

M.P. 205°C

'H-NMR (CDCb) (Bruker 400 MHz): 8.19 ppm (t, J= 1.8 Hz, 2H), 8.05 ppm (dt, J=

1.5, 8.3 Hz, 2H), 7.91 ppm (dt, J= 1.2, 7.9 Hz, 2H), 7.73 ppm (t, J= 7.9 Hz, 2H), 3.24 ppm (s, 6H).

EXAMPLE 10

3-bromophenylmethyl sulphone (19.5 g, 0.0825 moles) and palladium tetrakistriphenyl phosphine (0.095 g, 0.082 moles) were added to a mixture of ZnCl₂

(4.0 g, 0.0293 moles) in anhydrous tetrahydrofuran (45.0 g), kept at 50°C, with mechanical stirring, in an inert atmosphere.

Grignard B solution (79.5 g) was added over 3 hours. The reaction mixture was stirred for 1 hour and then cooled to 25°C.

After treatment as in Example 1, an organic phase (140 g) containing compound 2

(HPLC titre 12.3%, equal to 17.3 g, 0.074 moles, yield 90% relative to 3- bromophenylmethyl sulphone) was obtained.

EXAMPLE 11

2-propyl magnesium chloride (2M in tetrahydrofuran, 0.045 g, 0.9 mmoles Aldrich cat. 2000/2001) was added over 5' to a suspension of anhydrous NiCl₂ (0.055 g, 0.42 mmoles) and triphenyl phosphine (0.22 g, 0.84 mmoles) in anhydrous tetrahydrofuran (3.5 g), cooled to 0°C, in a 10 ml flask kept under an inert atmosphere and with magnetic stirring. The temperature was allowed to rise to 20°C and stirring was continued for 10'. The catalyst solution was added to a solution of 3-bromophenylmethyl sulphone (9.9 g, 0.042 moles) in anhydrous tetrahydrofuran (18.0 g), kept at 50°C with mechanical stirring, in an inert atmosphere. Grignard A solution (44.0 g) was added over 4 hours. The reaction mixture was stirred for 1 hour and then cooled to 25°C.

After treatment as in Example 1, an organic phase (65 g) containing compound 2

(HPLC titre 11.3%, equal to 7.3 g, 0.031 moles, yield 75% relative to 3- bromophenylmethyl sulphone) was obtained.

EXAMPLE 12

2-propyl magnesium chloride (2M in tetrahydrofuran, 0.045 g, 0.9 mmoles, Aldrich cat. 2000/2001) was added over 5' to a suspension of anhydrous NiCl₂ (0.055 g, 0.42 mmoles) and triphenyl phosphine (0.22 g, 0.84 mmoles) in anhydrous tetrahydrofuran (3.5 g), cooled to 0°C, in a 10 ml flask kept under inert atmosphere and with magnetic stirring. The temperature was allowed to rise to 20°C and stirring was continued for 10'.

The catalyst solution was added to a mixture constituted by anhydrous zinc chloride

(1.72 g) and 3-bromophenylmethyl sulphone (9.9 g, 0.042 moles) in anhydrous tetrahydrofuran (18.0 g), kept at 50°C, with mechanical stirring, in an inert atmosphere. Grignard A solution (44.0 g) was added over 4 hours. The reaction mixture was stirred for 1 hour and then cooled to 25°C.

After treatment as in Example 1, an organic phase (63 g) containing compound 2

(HPLC titre 10.8%, equal to 6.8 g, 0.029 moles, yield 70% relative to 3- bromophenylmethyl sulphone) was obtained.

EXAMPLE 13

3-bromophenylmethyl sulphone (19.5 g, 0.0825 moles) and palladium tetrakistriphenyl phosphine (0.095 g, 0.082 mmoles) were added to a mixture of anhydrous ZnCl₂ (4.0 g, 0.0293 moles) in anhydrous tetrahydrofuran (45.0 g), kept at

50°C, with mechanical stirring, in an inert atmosphere. Grignard B solution (79.5 g) was added to the resulting suspension over 3 hours. The reaction mixture was stirred for 1 hour and then cooled to 25°C.

A solution constituted by water (72 g) and 36% hydrochloric acid (32g) was added to the reaction mixture whilst the temperature was kept below 30°C. The mixture was stirred for 30 minutes and then toluene (30 g) was added and the phases were separated. Toluene (66 g) and 28% ammonia (49 g) were added to the aqueous phase, stirring was continued for 30 minutes, and then the phases were separated. The organic phase (140 g) contained compound 2 (HPLC titre 12.02%, equal to 16.8 g, 0.072 moles; yield relative to 3-bromophenylmethyl sulphone 88%).

Claims

1. A method for the preparation of compounds of formula 1 ,

by reaction between compounds of formula 3 and formula 4

in which:

• Met represents Mg or Zn,

• Y represents Cl, Br, I or acetoxy,

Z represents I, Br, Cl, triflate, sulphonate and/or sulphone, • Ri, R₂, Rt, R5, which are the same as one another or different, represent H, a linear and/or branched Cι-C₄ alkyl, and/ or an aryl, and/or a heteroaryl, or Ri and R₂ and/or 4 and R5, taken together, form a C3-CS ring, an aryl and/or a heteroaryl, and

• R3 represents a linear, branched or cyclic Cι-C₈ alkyl and/or an aryl, and/or a heteroaryl, in the presence of catalytic systems based on palladium or nickel.

2. A method according to Claim 1, characterized in that the palladium and/or the nickel are used in quantities of 0.01-10 moles, preferably 0.05-2 moles, per 100 moles of compound 3.

3. A method according to Claim 1, characterized in that an organic solution of compound 3 is added to an organic solution containing compound 4 and the catalytic system.

4. A method according to Claim 3, characterized in that the solvent is an ethereal solvent, preferably THF, 1,2 dimethoxyethane, and/or 1,1-diethoxymethane.

5. A method according to Claim 1, characterized in that it is performed at a temperature of between 20 and 80°C, preferably between 40 and 60°C.

6. A method according to Claim 1, characterized in that it is performed in the presence of phosphines and/or phosphites.

7. A method according to Claim 6, characterized in that the phosphines and/or phosphites are used in a molar ratio of metabphosphine/phosphite of between 1:1 and 1:6.

8. A method according to Claim 7, characterized in that the phosphines are selected from triaryl phosphines, diarylalkyl phosphines, trialkyl phosphines, and bidentate phosphines.

9. A method according to Claim 8, characterized in that palladium is used in the form of complexes with phosphines, preferably as Pd(PPh₃) .

10. A method according to Claim 8, characterized in that palladium is used in salt form, generally in acetate or chloride form, in combination with a phosphine, preferably triphenyl phosphine.

11. A method according to Claim 8, characterized in that nickel is used in the form of complexes with phosphines, preferably bidentate phosphines.

12. A method according to Claim 1, characterized in that it is performed in the presence of zinc salts, preferably ZnCl₂, ZnBr₂ or Zn(OAc)₂.

13. A method according to Claim 12, characterized in that the zinc salt is used in quantities of 25-120 moles, preferably 35-70 moles, per 100 moles of compound 3.

14. A method according to Claim 13 in which Met is magnesium, characterized in that 0.01-0.1 moles of palladium and 40-70 moles of zinc are used per 100 moles of compound 3.

15. A method according to Claim 14, characterized in that the molar ratio between palladium and compound 3 is less than 1:100.

16. A method according to Claim 12, characterized in that compound 3 is used in a dynamic deficiency relative to the zinc salt.

17. A method according to Claim 1, characterized in that compound 3 is prepared by reaction of the corresponding halogeno-pyridine with a catalytic quantity of alkyl halide, in the presence of an at least stoichiometric quantity of magnesium.

18. A method according to Claim 17, characterized in that 100 moles of the halogeno-pyridine are reacted with 10-20 moles of alkyl halide and 100-120 moles of magnesium.

19. A method according to Claims 1-16, characterized in that a solution produced in accordance with Claims 17-18 is added dropwise to a solution containing compound 4 and the catalytic system.

20. A method according to Claim 19, characterized in that the reaction is carried out in the presence of alkyl halides and/or alkyl-magnesium halides.

21. A method according to Claim 1, characterized in that 0.5-1.2 moles, preferably 1 mole, of compound 3 are used per 1 mole of compound 4.

22. A method for the preparation of anti-inflammatories, metalloproteinase inhibitors, anti-hypercholesteraemics, anti-hyperlipoproteinaemics, anti-allergies, 2- cyclooxygenase inhibitors, anti-arrythmics, antibacterials, and drugs for the treatment of disorders of the central nervous system, the method being characterized in that it comprises a method according to Claims 1-21.