Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1999-07-08
2001-04-03
Nazario-Gonzalez, Porfirio (Department: 1621)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C556S121000
Reexamination Certificate
active
06211380
ABSTRACT:
The present invention relates to a process for the preparation of heteroaryl-zinc halides and, more particularly, it relates to a process for the preparation of heteroaryl-zinc halides by metallation reaction with metallic zinc.
The organo-zinc compounds are well-known compounds, extensively described in the literature.
More particularly, the heteroaryl-zinc halides such as, for example, 2-furyl, 2-thienyl, 2-pyridyl and 3-pyridyl-zinc chloride have been described by F. Tair Luo et al. in Heterocycles, Vol. 31, No. 12, 1990, 2181-2186.
Such compounds are used as synthetic intermediates for the preparation of many organic compounds, which are useful, for example, in the pharmaceutical and agrochemical field, in the polymer, dyestuff and synthetic fibres industries.
In the co-pending International patent application having the title “Process for the preparation of heteroaryl-phenylalanines” and claiming the Italian priority no. MI96A002738 of Dec. 24, 1996 in the name of the same Applicant, the heteroaryl-zinc halides are used as synthetic intermediates in the cross-coupling reaction for the preparation of heteroaryl-phenylalanines of formula
wherein
R is a hydrogen atom, a C
1
-C
4
straight or branched alkyl group or a benzyl group;
Het is an optionally substituted 5 or 6 membered aromatic heterocyclic group having one or two heteroatoms selected among nitrogen, oxygen and sulphur.
In the literature a few synthetic processes for the preparation of organo-zinc compounds starting from metallic zinc are known.
In particular, as described by L. Zhu et al. in J. Org. Chem. 1991, 56, 1445-1453, some organo-zinc derivatives can be prepared by reaction of the corresponding halo-derivatives with metallic zinc, activated according to conventional procedures.
Substantially such methods of activation include the washing of zinc with aqueous diluted solutions of acids or bases or otherwise the use of particularly reactive alkyl halides able to initiate the metallation reaction such as, for example, 1,2-dibromoethane.
Nevertheless, as reported by the same Author, the use of activated zinc was useful just with respect to particularly reactive alkyl halides, for example alkyl iodides or &agr;-halo-esters.
In the International patent application No. WO 93/15086 (Board of Regents of the University of Nebraska) a process for the preparation of organo-zinc derivatives such as for example, 2-bromo-5-bromozinc-thiophene (that is 5-bromo-2-thienyl-zinc bromide) is described.
More particularly, such a process comprises the reduction of suitable zinc (II) salts with alkaline or alkaline-earth metals, in a non hydroxylic solvent, for example an ether or an hydrocarbon, preferably in the presence of naphthalene derivatives and, subsequently, the reaction with suitable organic halo-derivatives.
Nevertheless, the above process is rather tedious and hard-working and not suitable for industrial application.
Moreover, the use of particularly reactive alkaline or alkaline-earth metals requires proper safety procedures.
In our knowledge, no processes for the preparation of hetero-zinc derivatives by metallation reaction with metallic zinc have never been described in the literature.
Now we have found a process for the preparation of heteroaryl-zinc halides starting from metallic zinc, easy to practice and particularly suitable for industrial application.
Therefore, object of the present invention is a process for the preparation of heteroaryl-zinc halides of formula
Het—Zn—X (II)
wherein
Het is an optionally substituted 5 or 6 membered aromatic heterocyclic group with one or two heteroatoms selected among nitrogen, oxygen or sulphur;
X is a chlorine, bromine or iodine atom;
that comprises the metallation reaction of a compound of formula
Het—X (III)
in which
Het and X have the above reported meanings;
characterised in that the metallation reaction is carried out with metallic zinc, optionally previuosly activated by washing with acids.
The process object of the present invention is easy to be industrially applied and it enables to obtain the compounds of formula II with high yields and with an elevated degree of purity.
The metallic zinc used in the process object of the present invention is powdered zinc
The metallation reaction is carried out by using a molar ratio compound of formula III: zinc from 1:1 to 1:2.
Higher zinc amounts are likewise effective but useless.
Preferably a slight excess of zinc is used.
Zinc can be used as such or it can be useful to activate it if it is desired to increase its reactivity.
The optional activation of the metallic zinc is carried out by washing with acids. preferably by washing with diluted aqueous solutions of mineral acids.
More preferably, diluted aqueous solutions of mineral inorganic acids selected among sulfuric, hydrochloric, hydrobromic and hydroiodic acids are used.
For practical reasons, diluted aqueous solutions of hydrochloric acid are used.
Usually, the concentration of the acid in the aqueous solution is comprised between 0.1% and 10% by weight.
Preferably aqueous solutions containing from 0.5 to 3% of acid are used.
After the activation by washing with acids according to what above reported, the activated zinc will be further washed with water up to neutral pH, optionally with organic solvents too and then dried.
Therefore, the optionally activated metallic zinc is used, according to the present process, in the metallation reaction for the preparation of the compounds of formula II.
The metallation reaction according to the present invention is carried out in the presence of an organic solvent such as, for example, diethyl ether, methyl-tert-butyl ether, dioxane, ethylene glycol dimethyl ether, tetrahydrofuran, toluene, xylene or mixture thereof
Preferably tetrahydrofuran, toluene or mixtures thereof are used.
The reaction temperature is comprised between 20° C. and the reflux temperature of the reaction mixture.
Preferably the reaction is carried out at reflux temperature.
Preferably, the preparation of the compounds of formula II, according to the present process, is carried out starting from a compound of formula III in which X is a bromine atom.
The starting compound of formula III are known compounds or easily obtainable according to known methods as described, for example, in J. Am. Chem. Soc. 1952, 74, 6260-6262.
Also the metallic zinc is an easily available commercial product.
From a practical point of view it is evident to the man skilled in the art that the compounds of formula II will not be isolated but directly used as intermediates in the same reaction medium.
Examples of compounds of formula II obtainable according to the process object of the present invention are the compounds in which the Het group is an aromatic heterocyclic group such as, for example, thiazole, isoxazole, oxazole, isothiazole, pyrazole, imidazole, thiophene, pyrrole, pyridine, pyrimidine, pyrazine, pyridazine and furan.
Preferred compounds of formula II are the compounds in which Het is thiophene or thiazole.
As previously disclosed, the compounds of formula II can be used as synthetic intermediates for the preparation of many organic compounds.
According to a particularly advantageous aspect of the process object of the present invention, the compounds of formula II, prepared as previously described, are directly used as synthetic intermediates in the same reaction medium, for example, for the preparation of the heteroaryl-phenylalanines of formula I as disclosed in the already cited co-pending International patent application.
Therefore, in a preferred practical embodiment thereof, the process object of the present invention is used for the preparation of heteroaryl-phenylalanines disclosed in the aforesaid International patent application.
In a preferred practical embodiment of the process object of the present invention, a compound of formula III is added to a suspension containing a slight excess of powdered metallic zinc in a suitable solvent and at a selected temperature, for example at the boiling temperature.
Then the reaction mixture wa
Fantucci Mario
Santangelo Francesco
Arent Fox Kintner Plotkin & Kahn
Nazario-Gonzalez Porfirio
Zambon Group S.p.A.
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