ITMI20010772A1

ITMI20010772A1 - PROCESS FOR THE PREPARATION OF ARYL-PYRIDIN COMPOUNDS

Info

Publication number: ITMI20010772A1
Application number: IT2001MI000772A
Authority: IT
Inventors: Claudio Giordano; Luca Giannini
Original assignee: Norpharma Spa
Priority date: 2001-04-11
Filing date: 2001-04-11
Publication date: 2002-10-11
Also published as: ITMI20010772A0

Description

L'oggetto della presente invenzione riguarda la preparazione di composti di formula 1, The object of the present invention relates to the preparation of compounds of formula 1,

a partire da composti di formula 2 e formula 3. starting from compounds of formula 2 and formula 3.

dove where is it

• Met rappresenta Mg o Zn; • Met represents Mg or Zn;

• Y rappresenta C1, Br, 10 acetossi; • Y represents C1, Br, 10 acetoxy;

• Z rappresenta I, Br, C1, triflato, solfonato, fosfato; • Z represents I, Br, C1, triflate, sulfonate, phosphate;

• R1, R2, R3, R4 uguali o diversi tra loro rappresentano idrogeno, un alchile Ci-C4 lineare e/o ramificato, e/o un arile, e/o un eteroarile; oppure R1 ed R2 e/o R3 ed R4, presi insieme, formano un ciclo C3-C8, un arile e/o un eteroarile; • R1, R2, R3, R4 equal or different from each other represent hydrogen, a linear and / or branched C1-C4 alkyl, and / or an aryl, and / or a heteroaryl; or R1 and R2 and / or R3 and R4, taken together, form a C3-C8 cycle, an aryl and / or a heteroaryl;

• A rappresenta -COR5, dove R5 rappresenta idrogeno, un alchile C1-C4 lineare e/o ramificato, e/o un arile, e/o un eteroarile, oppure; • A represents -COR5, where R5 represents hydrogen, a linear and / or branched C1-C4 alkyl, and / or an aryl, and / or a heteroaryl, or;

• A rappresenta -CR5(OR6)(OR7) dove R5 ha il significato sopra descritto e R6 e R7, uguali o diversi tra loro, rappresentano un alchile C1-C4 lineare e/o ramificato, e/o un arile, e/o un eteroarile; oppure R6 e R7, uniti fra loro, rappresentano un alchile o un alchenile C1-Cs. • A represents -CR5 (OR6) (OR7) where R5 has the meaning described above and R6 and R7, equal or different from each other, represent a linear and / or branched C1-C4 alkyl, and / or an aryl, and / or a heteroaryl; or R6 and R7, joined together, represent a C1-Cs alkyl or alkenyl.

STATO DELL’ ARTE STATE OF THE ART

Le arii piridine sono comunemente utilizzate in sintesi organica quali intermedi per la preparazione di composti di vario genere. Arii pyridines are commonly used in organic synthesis as intermediates for the preparation of compounds of various kinds.

La 4-(2’-piridil)benzaldeide è un intermedio utile per la preparazione di farmaci antivirali e, in particolare, di farmaci efficaci nel trattamento dell’ AIDS quali per esempio i derivati eterociclici azaesanici descritti nella domanda di brevetto intemazionale WO 97/40029, qui incorporata per riferimento; tra i farmaci antivirali in questione, degni di nota sono per esempio BMS-232632 (Drugs of thè Future 1999, 24(4):375). 4- (2'-pyridyl) benzaldehyde is an intermediate useful for the preparation of antiviral drugs and, in particular, of drugs effective in the treatment of AIDS such as for example the azaesane heterocyclic derivatives described in the international patent application WO 97/40029 , incorporated herein by reference; among the antiviral drugs in question, noteworthy are for example BMS-232632 (Drugs of the Future 1999, 24 (4): 375).

Le aril piridine possono essere preparate per reazioni di “aril-aril cross coupling” (Lohse et al.; Synlett. 1999, Voi. 1; 45-48. Ei-ichi Negishi et al. Heterocycles 1982, Voi 18 117-122). Generalmente, il derivato piridinico reca il gruppo uscente, mentre il derivato arilico è il reattivo metalloorganico Aryl pyridines can be prepared by "aryl-aryl cross coupling" reactions (Lohse et al .; Synlett. 1999, Vol. 1; 45-48. Ei-ichi Negishi et al. Heterocycles 1982, Vol 18 117-122) . Generally, the pyridine derivative bears the leaving group, while the aryl derivative is the organometallic reactive

Esiste un numero limitato di esempi di cross-coupling arile-arile in cui la piridina costituisce il reagente organometallico (Kalinin, D.N. Synthesis 1992, 413 - 432; Tetrahedron 1998, 54, 263-303). There are a limited number of examples of aryl-aryl cross-coupling in which pyridine constitutes the organometallic reagent (Kalinin, D.N. Synthesis 1992, 413 - 432; Tetrahedron 1998, 54, 263-303).

Inoltre, negli esempi noti di questo tipo la piridina non è quasi mai presente sotto forma di Grignard, bensì come boro derivato. E’ riportato in letteratura un esempio nel quale si mostra come un Grignard piridinico, non dia un’efficace reazione di cross-coupling (Kumada, M. et al. Tetrahedron 1982, 38, 3347-3354). Moreover, in the known examples of this type, pyridine is almost never present in the form of Grignard, but as a derivative boron. An example is reported in the literature in which it is shown how a pyridine Grignard does not give an effective cross-coupling reaction (Kumada, M. et al. Tetrahedron 1982, 38, 3347-3354).

In particolare, la 4-(2’-piridil)benzaldeide viene normalmente preparata a partire da 4-bromobenzaldeide e 2-bromopiridina (Bold et al.; J.Med.Chem. In particular, 4- (2'-pyridyl) benzaldehyde is normally prepared starting from 4-bromobenzaldehyde and 2-bromopyridine (Bold et al .; J.Med.Chem.

1998, 41, 3387 e Drugs of thè Future, 1999, 24(4):375). D metodo prevede la conversione della bromobenzaldeide nel corrispondente acetale e quindi nel reattivo di Grignard il reattivo di Grignard viene poi fatto reagire con 2-bromopiridina in presenza di NiCl2 e di 1,3-bis(difenilfosfino)propano (Inorg.Chem. 1966, 1968) per dare, in seguito alla conversione della funzione acetalica in aldeidica per trattamento in ambiente acquoso acido, la 4-(2’-piridil)benzaldeide. Tale metodo presenta tuttavia il grosso inconveniente di una scarsa ripetibilità, tanto maggiore quanto minore è la quantità di catalizzatore impiegata. 1998, 41, 3387 and Drugs of the Future, 1999, 24 (4): 375). The method involves the conversion of bromobenzaldehyde into the corresponding acetal and then into the Grignard reagent the Grignard reagent is then reacted with 2-bromopyridine in the presence of NiCl2 and 1,3-bis (diphenylphosphino) propane (Inorg.Chem. 1966, 1968) to give, following the conversion of the acetal function into aldehyde by treatment in an aqueous acid medium, 4- (2'-pyridyl) benzaldehyde. However, this method has the major drawback of poor repeatability, the greater the smaller the quantity of catalyst used.

La domanda di brevetto EP 0,972,765 rivendica invece un metodo di sintesi di aril-piridine basato sull’uso di catalizzatori a base di ferrocenil fosfine e palladio a partire da alogeno piridine e Grignard ardici. Patent application EP 0,972,765, on the other hand, claims an aryl-pyridine synthesis method based on the use of catalysts based on ferrocenyl phosphines and palladium starting from halogen pyridines and Grignard ardici.

Scopo del lavoro che ha portato alla presente invenzione è stato quello di trovare un nuovo ed affidabile processo di aril-aril cross coupling in grado di portare alla formazione di arii piridine a partire da Grignard piridinici o da piridil-zinco derivati, con rese riproducibili ed industrialmente soddisfacenti anche in presenza di quantità di catalizzatore molto modeste. The aim of the work that led to the present invention was to find a new and reliable aryl-aryl cross coupling process capable of leading to the formation of ariy pyridines starting from pyridine Grignard or pyridyl-zinc derivatives, with reproducible and industrially satisfactory even in the presence of very modest quantities of catalyst.

DESCRIZIONE DELL’INVENZIONE DESCRIPTION OF THE INVENTION

E’ stato ora sorprendentemente trovato che i composti di formula 1 possono essere ottenuti con rese e purezze elevate per reazione di cross-coupling tra composti di formula 2 e composti di formula 3, promossa da sistemi catalitici a base di palladio o nichel, secondo lo schema qui sotto riportato It has now been surprisingly found that the compounds of formula 1 can be obtained with high yields and purities by cross-coupling reaction between compounds of formula 2 and compounds of formula 3, promoted by catalytic systems based on palladium or nickel, according to diagram below

dove: where is it:

• Met rappresenta Mg, Zn; • Met represents Mg, Zn;

• Y rappresenta C1, Br, I o acetossi; • Y represents C1, Br, I or acetoxy;

• Z rappresenta I, Br, Cl, trillato, solfonato, fosfato; • Z represents I, Br, Cl, trillate, sulfonate, phosphate;

• R1 R2, R3, R4 uguali o diversi tra loro rappresentano idrogeno, un alchile lineare e/o ramificato, e/o un arile, e/o un eteroarile; oppure ed R4, presi insieme, formano un ciclo C3-C8, un arile e/o un eteroarile; • R1 R2, R3, R4 equal or different from each other represent hydrogen, a linear and / or branched alkyl, and / or an aryl, and / or a heteroaryl; or and R4, taken together, form a C3-C8 cycle, an aryl and / or a heteroaryl;

• A rappresenta -COR5, dove R5 rappresenta idrogeno, un alchil C1-C4 lineare e/o ramificato, e/o un arile, e/o un eteroarile, oppure; • A represents -COR5, where R5 represents hydrogen, a linear and / or branched C1-C4 alkyl, and / or an aryl, and / or a heteroaryl, or;

• A rappresenta dove R5 ha il significato sopra descritto e R6 e R7, uguali o diversi tra loro, rappresentano un alchile C1-C4 lineare e/o ramificato, e/o un arile, e/o un eteroarile; oppure R6 e R7, uniti fra loro, rappresentano un alchile o un alchenile C1 -C8 (ad esempio nel caso in cui una funzione carbonilica viene protetta come chetale ciclico). • A represents where R5 has the meaning described above and R6 and R7, equal or different from each other, represent a linear and / or branched C1-C4 alkyl, and / or an aryl, and / or a heteroaryl; or R6 and R7, joined together, represent a C1 -C8 alkyl or alkenyl (for example in the case in which a carbonyl function is protected as a cyclic ketal).

Il palladio ed il nichel sono normalmente impiegati in quantità di 0.01-10 moli, preferibilmente 0.05-2, per 100 moli di composto 2; la reazione viene normalmente condotta aggiungendo una soluzione organica del composto 2 ad una soluzione organica contenente il composto 3 ed il sistema catalitico. Il solvente organico è preferibilmente un solvente etereo (tale ad esempio da non reagire con i composti di Grignard), quale il THF, il 1,2 dimetossietano e/o Ι,Ι-dietossimetano oppure una miscela di solventi quale THF/toluene; la reazione viene condotta ad una temperatura compresa tra 20 e 100 °C, preferibilmente tra 40 e 80°C. Palladium and nickel are normally used in quantities of 0.01-10 moles, preferably 0.05-2, per 100 moles of compound 2; the reaction is normally carried out by adding an organic solution of compound 2 to an organic solution containing compound 3 and the catalytic system. The organic solvent is preferably an ethereal solvent (such as for example not reacting with Grignard compounds), such as THF, 1,2-dimethoxyethane and / or Ι, Ι-diethoxymethane or a mixture of solvents such as THF / toluene; the reaction is carried out at a temperature comprised between 20 and 100 ° C, preferably between 40 and 80 ° C.

La resa di reazione può essere aumentata operando in presenza di fosfine e/o fosfiti, da utilizzarsi preferibilmente in un rapporto molare catalizzatorerfosfina/fosfito compreso tra 1:1 ed 1:6. Le fosfine utilizzabili per gli scopi della presente invenzioni possono essere: triarilfosfine, quali The reaction yield can be increased by operating in the presence of phosphines and / or phosphites, to be used preferably in a catalyst rphosphine / phosphite molar ratio between 1: 1 and 1: 6. The phosphines that can be used for the purposes of the present invention can be: triarylphosphines, such as

quantità di 25-120 moli, preferibilmente 35-70, per 100 moli di composto 2. Affinché la reazione di cross-coupling proceda con alte rese ed elevata selettività in presenza di una quantità minima di catalizzatore, è preferibile evitare l’accumulo di reagenti di Grignard nell’ambiente di reazione, che devono essere quindi in difetto dinamico rispetto al sale di zinco (il reagente di Grignard viene cioè gocciolato ad una soluzione già contenente il composto 3, il palladio, il legante fosfinico ed il sale di zinco). quantity of 25-120 moles, preferably 35-70, per 100 moles of compound 2. 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 avoid the accumulation of reactants of Grignard in the reaction environment, which must therefore be in dynamic defect with respect to the zinc salt (that is, the Grignard reagent is dropped to a solution already containing compound 3, palladium, phosphine binder and zinc salt).

Secondo una realizzazione preferita dell’invenzione, sono impiegate 0.01-0.1 moli di palladio e 40-70 moli di zinco per 100 moli di composto 2; il rapporto molare tra il palladio ed il composto 2 è inferiore a 1:100. In una seconda realizzazione, sono invece impiegate 0.01-2 moli di nichel per 100 moli di composto 2 (in assenza cioè di sali di zinco). According to a preferred embodiment of the invention, 0.01-0.1 moles of palladium and 40-70 moles of zinc per 100 moles of compound 2 are used; the molar ratio between palladium and compound 2 is less than 1: 100. In a second embodiment, 0.01-2 moles of nickel per 100 moles of compound 2 are used (ie in the absence of zinc salts).

La reazione secondo la presente invenzione può essere inoltre condotta sia in presenza di alchil alogenuri (fino a quantità superiori all'equimolare al Grignard), che di quantità variabili di alchil Grignard. Questo aspetto risulta molto importante da un punto di vista applicativo, poiché le preparazioni di piridil Grignard note in letteratura ( Tetrahedron 2000, 56, 1349 oppure in The reaction according to the present invention can also be carried out both in the presence of alkyl halides (up to quantities higher than the equimolar to Grignard), and in variable quantities of alkyl Grignard. This aspect is very important from an application point of view, since the pyridyl Grignard preparations known in literature (Tetrahedron 2000, 56, 1349 or in

JOC 1959, 24, 504 e Recl. Trav. Chim. Pays-Bas 1965, 84, 439) portano a soluzioni contenenti in quantità variabili alchil alogenuri o alchil magnesio alogenuri. E' quindi possibile utilizzare le soluzioni organiche del piridil Grignard di scelta senza ulteriori purificazioni. JOC 1959, 24, 504 and Recl. Trav. Chim. Pays-Bas 1965, 84, 439) lead to solutions containing alkyl halides or alkyl magnesium halides in varying quantities. It is therefore possible to use the organic solutions of the pyridyl Grignard of choice without further purification.

Secondo la migliore realizzazione della presente invenzione, il composto di formula 2 è ottenuto per reazione della corrispondente alogeno piridina (bromo, iodio) con una quantità catalitica di alogenuro alchilico in presenza di una quantità almeno stechiometrica di magnesio; l alogenuro alchilico è normalmente un cloruro o un bromuro di un alchile C1-C8, preferibilmente etilbromuro o isopropil bromuro o cloruro. According to the best embodiment of the present invention, the compound of formula 2 is obtained by reaction of the corresponding halogen pyridine (bromine, iodine) with a catalytic quantity of alkyl halide in the presence of an at least stoichiometric quantity of magnesium; The alkyl halide is normally a chloride or a bromide of a C1-C8 alkyl, preferably ethylbromide or isopropyl bromide or chloride.

Preferibilmente, 100 moli di alogeno piridina sono fatte reagire con 10÷20 moli di alogenuro alchilico e 100÷120 moli di magnesio. La reazione viene generalmente condotta ad una temperatura di 0÷60° C, preferibilmente a 15÷35° C, in un solvente organico aprotico che non reagisca con un reagente di Grignard, preferibilmente in tetraidrofurano o miscele di tetraidrofurano e toluene; la soluzione così ottenuta viene quindi gocciolata nella soluzione contenente il composto 3 ed il sistema catalitico. Preferably, 100 moles of pyridine halogen 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 that does not react with a Grignard reagent, preferably in tetrahydrofuran or mixtures of tetrahydrofuran and toluene; the solution thus obtained is then dropped into the solution containing compound 3 and the catalytic system.

Questi ed ulteriori aspetti dell’invenzione risulteranno evidenti dagli esempi che seguono e che devono essere considerati illustrativi e non limitativi. These and further aspects of the invention will become evident from the following examples and which must be considered illustrative and not limitative.

PREPARAZIONE DEL REATTIVO DI GRIGNARD ESEMPIO 1 - GRIGNARD A PREPARATION OF GRIGNARD'S REAGENT EXAMPLE 1 - GRIGNARD A

Ad una sospensione di magnesio (0.29g, 0.12 moli) in tetraidrofurano anidro (58.5g) mantenuta a 20°C sotto agitazione in atmosfera inerte si aggiunge etilbromuro (2.2g, 0.02 moli), mantenendo la temperatura interna inferiore a 35°C. Alla soluzione così ottenuta si aggiunge in 3 ore 3bromopiridina (16.0g, 0.101 moli) controllando la temperatura tra 25 e 30°C. Si mantiene la miscela di reazione sotto agitazione a 25°C per ulteriori 3 ore. Ethylbromide (2.2g, 0.02 moles) is added to a suspension of magnesium (0.29g, 0.12 moles) in anhydrous tetrahydrofuran (58.5g) kept at 20 ° C under stirring in an inert atmosphere, keeping the internal temperature below 35 ° C. 3bromopyridine (16.0g, 0.101 moles) is added to the solution thus obtained in 3 hours, controlling the temperature between 25 and 30 ° C. The reaction mixture is kept under stirring at 25 ° C for a further 3 hours.

ESEMPIO 2 - GRIGNARD B EXAMPLE 2 - GRIGNARD B

Ad una soluzione di 2-propilmagnesio cloruro (2M in tetraidrofurano, 50.6 mL, cat Aldrich 2000/2001) mantenuta a 25°C, si aggiunge in 1 ora una soluzione di 2-bromopiridina (16g, 0.101 moli) in tetraidrofurano anidro (5g). Si mantiene la miscela sotto agitazione a 25°C per 4 ore. To a solution of 2-propylmagnesium chloride (2M in tetrahydrofuran, 50.6 mL, cat Aldrich 2000/2001) maintained at 25 ° C, a solution of 2-bromopyridine (16g, 0.101 moles) in anhydrous tetrahydrofuran (5g ). The mixture is kept under stirring at 25 ° C for 4 hours.

ESEMPIO 3 - GRIGNARD C EXAMPLE 3 - GRIGNARD C

Ad una soluzione di 2-bromopiridina (16g, 0.101 moli) in tetraidrofurano anidro (13g), mantenuta a 25°C, si aggiunge in 1 ora una soluzione di 2-propilmagnesio cloruro (2M in tetraidrofurano, 51g, 50.6 mL, cat Aldrich 2000/2001). Si mantiene la miscela sotto agitazione a 25°C per 4 ore. To a solution of 2-bromopyridine (16g, 0.101 moles) in anhydrous tetrahydrofuran (13g), maintained at 25 ° C, a solution of 2-propylmagnesium chloride (2M in tetrahydrofuran, 51g, 50.6 mL, cat Aldrich 2000/2001). The mixture is kept under stirring at 25 ° C for 4 hours.

ESEMPIO 4 - GRIGNARD D EXAMPLE 4 - GRIGNARD D

Ad una sospensione di magnesio (1.96g, 0.08 moli) in tetraidrofurano anidro (53.2g) mantenuta a 20°C sotto agitazione in atmosfera inerte si aggiunge una soluzione di 2-propilmagnesio cloniro (2M in tetraidrofurano, 9.8g, 0.02 moli, cat Aldrich 2000/2001). Quindi si aggiunge in 3 ore 2-bromopiridina (16. Og, 0.101 moli) controllando la temperatura tra 25 e 30°C. Si mantiene la miscela di reazione sotto agitazione a 25°C per 3 ore. To a suspension of magnesium (1.96g, 0.08 moles) in anhydrous tetrahydrofuran (53.2g) kept at 20 ° C under stirring in an inert atmosphere, a solution of clonir 2-propylmagnesium (2M in tetrahydrofuran, 9.8g, 0.02 moles, cat Aldrich 2000/2001). Then 2-bromopyridine (16. Og, 0.101 moles) is added in 3 hours, controlling the temperature between 25 and 30 ° C. The reaction mixture is kept under stirring at 25 ° C for 3 hours.

REAZIONE DI ACCOPPIAMENTO ESEMPIO 5 - Preparazione di 4-(3’-piridil)benzaldeide COUPLING REACTION EXAMPLE 5 - Preparation of 4- (3'-pyridyl) benzaldehyde

Ad una miscela di cloruro di zinco anidro (2.1g, 15.4 mmoli) in tetraidrofurano anidro (23 g), mantenuta sotto agitazione in atmosfera inerte, si aggiunge 4-bromobenzaldeide dimetil acetale (9.5g, 41.1 mmoli) e palladio tetrakis trifenilfosfina (50mg, 0.04 mmoli). Alla miscela risultante, mantenuta a 50°C sotto agitazione in atmosfera inerte, si aggiunge in 4 ore una soluzione di Grignard A (40.3g). To a mixture of anhydrous zinc chloride (2.1g, 15.4 mmoles) in anhydrous tetrahydrofuran (23 g), kept under stirring in an inert atmosphere, is added 4-bromobenzaldehyde dimethyl acetal (9.5g, 41.1 mmoles) and palladium tetrakis triphenylphosphine (50mg , 0.04 mmol). To the resulting mixture, kept at 50 ° C under stirring in an inert atmosphere, a solution of Grignard A (40.3g) is added in 4 hours.

La miscela di reazione viene mantenuta a 50°C per 30 minuti e quindi raffreddata a 20-25°C. Si ottiene una resa in 4-(3’-piridil)-benzaldeidedimetilacetale dell’ 85% rispetto alla 4-bromobenzaldeide dimetil acetale caricata. Dopo idrolisi acida si ottiene una resa in 4-(3’-piridil)-benzaldeide dell’ 85%. The reaction mixture is kept at 50 ° C for 30 minutes and then cooled to 20-25 ° C. A yield in 4- (3'-pyridyl) -benzaldeidedimethylacetal of 85% is obtained with respect to the charged 4-bromobenzaldehyde dimethyl acetal. After acid hydrolysis, a 4- (3-pyridyl) -benzaldehyde yield of 85% is obtained.

ESEMPIO 6 - Preparazione di 4-(3’-piridil)benzaldeide EXAMPLE 6 - Preparation of 4- (3'-pyridyl) benzaldehyde

L’esempio 1 è ripetuto utilizzando una differente quantità di cloruro di zinco anidro (7.1g, 52.1 mmoli), ottenendo una resa di 4-(3’-piridil)-benzaldeide-dimetilacetale del 70% rispetto alla <* >4-bromobenzaldeide dimetil acetale caricata. Example 1 is repeated using a different amount of anhydrous zinc chloride (7.1g, 52.1 mmoles), obtaining a yield of 4- (3'-pyridyl) -benzaldehyde-dimethylacetal of 70% with respect to <*> 4-bromobenzaldehyde charged dimethyl acetal.

ESEMPIO 7 - Preparazione di 4-(2’-piridil)benzaldeide EXAMPLE 7 - Preparation of 4- (2'-pyridyl) benzaldehyde

Ad una miscela di cloruro di zinco anidro (2.1g, 15.4 mmoli) in tetraidrofurano (23 g), mantenuta sotto agitazione in atmosfera inerte, si aggiunge 4-bromobenzaldeide dimetil acetale (9.5g, 41.1 mmoli) e palladio tetrakis trifenilfosfina (O.lg, 0.087 mmoli). Alla miscela risultante, mantenuta a 50°C sotto agitazione in atmosfera inerte, si aggiunge in 6 ore una soluzione di Grignard C (41.9g). 4-bromobenzaldehyde dimethyl acetal (9.5g, 41.1 mmoles) and palladium tetrakis triphenylphosphine (O. lg, 0.087 mmol). To the resulting mixture, kept at 50 ° C under stirring in an inert atmosphere, a solution of Grignard C (41.9g) is added in 6 hours.

La miscela di reazione viene mantenuta a 50°C per 30 minuti e quindi raffreddata a 20-25°C. Si ottiene una resa in 4-(2’-piridil)-benzaldeidedimetilacetale del 64% rispetto alla 4-bromobenzaldeide dimetil acetale caricata. The reaction mixture is kept at 50 ° C for 30 minutes and then cooled to 20-25 ° C. A yield in 4- (2'-pyridyl) -benzaldeidedimethylacetal of 64% is obtained with respect to the charged 4-bromobenzaldehyde dimethyl acetal.

Claims

CLAIMS 1. Process for the preparation of compounds of formula 1,

starting from compounds of formula 2 and formula 3.

where is it • Met represents Mg or Zn; • Y represents C1, Br, I or acetoxy; • Z represents I, Br, Cl, triflate, sulfonates, phosphates; • R1, R2, R3, R4 equal or different from each other represent hydrogen, a linear and / or branched C1-C4 alkyl, and / or an aryl, and / or a heteroaryl; or R1 and R2 and / or R3 and R4, taken together, form a C3-C8 cycle, an aryl and / or a heteroaryl; • A represents -COR5, where R5 represents hydrogen, a linear and / or branched C 1 -C4 alkyl, and / or an aryl, and / or a heteroaryl, or; • A represents -CR5 (OR6) (OR7) where R5 has the meaning described above and R6 and R7, equal or different from each other, represent a linear and / or branched C1-C4 alkyl, and / or an aryl, and / or a heteroaryl; or R6 and R7, joined together, represent a C1-C8 alkyl or alkenyl; in the presence of catalytic systems based on palladium or nickel.

2. Process according to claim 1 characterized in that palladium and / or nickel are used in quantities of 0.01-10 moles, preferably 0.05-2, per 100 moles of compound 2.

3. Process according to claim 1 characterized in that an organic solution of compound 2 is added to an organic solution containing compound 3 and said catalytic system.

4. Process according to claim 3 characterized in that the solvent is an ethereal solvent, preferably THF, 1,2-dimethoxyethane and / or 1,1-diethoxymethane, or a THF / toluene mixture.

5. Process according to claim 1 characterized by being carried out at a temperature between 20 and 100 ° C, preferably between 40 and 80 ° C.

6. Process according to claim 1 characterized by being carried out in the presence of phosphines and / or phosphites.

7. Process according to claim 6 characterized in that said phosphines and / or phosphites are used in a molar metal: phosphine / phosphite ratio between 1: 1 and 1: 6.

8. Process according to claim 7 characterized in that said phosphines are selected from triarylphosphines, diaryl alkylphosphines, trialkylphosphines and bidentate phosphines.

9. Process according to claim 8 characterized in that palladium is used in the form of complexes with phosphines, preferably as Pd (PPh3) 4.

10. Process according to claim 8 characterized in that palladium is used in the form of a salt, generally acetate or chloride, in combination with a phosphine, preferably triphenylphosphine.

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

12. Process according to claim 1 characterized by being carried out in the presence of zinc salts, preferably ZnC12, ZnBr2 or Zn (OAc) 2.

13. Process according to claim 12 characterized in that the zinc salt is used in quantities of 25-120 moles, preferably 35-70, per 100 moles of compound 2.

14. Process according to claim 13, wherein 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.

15. Process according to claim 14 characterized in that the molar ratio between palladium and compound 2 is lower than 1: 100.

16. Process according to claim 12 characterized in that the compound 3 is used in a dynamic defect with respect to the zinc salt.

17. Process according to claim 1 characterized in that compound 2 is prepared by reaction of the corresponding pyridine halogen with a catalytic quantity of alkyl halide in the presence of at least a stoichiometric quantity of magnesium.

18. A process according to claim 17 characterized in that 100 moles of said halogen pyridine are reacted with 10-20 mols of alkyl halide and 100-120 moles of magnesium.

19. A process according to claim 1-16 characterized in that a solution obtained according to claims 17-18 is dropped into a solution containing compound 3 and the catalytic system.

20. A process 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 process for the preparation of azahexane heterocyclic derivatives with antiviral action characterized by comprising a process according to claims 1-20.