Process for the synthesis of 5-(2-flurophenyl)-1H-tetrazole

Details Process for the synthesis of 5-(2-flurophenyl)-1H-tetrazole Process for the synthesis of 5-(2-flurophenyl)-1H-tetrazole

2001-03-13

2001-12-04

Morris, Patricia L. (Department: 1625)

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

Reexamination Certificate

active

06326498

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to a process for the synthesis of 5-(2-flurophenyl)-1H-tetrazole.
BACKGROUND OF THE INVENTION
Tetrazole and its derivatives are used in the preparation of medicines, agricultural chemicals, foaming agents and automobile inflators. [J. Org. Prep. Proced. Int. 1994, 26, 499; CA 1995, 122, 31359r; Comprehensive Heterocyclic Chemistry II; Storr, R. C. Ed. Elsevier; Oxford, Uk, 1996, vol 4, p621-678].
The preparation of Losartan, a non-peptide angiotensin-II receptro antagonist requires the synthesis of 5-(4′-methyl[1,1′-biphenyl]-2-yl)-1H-tetrazole of the formula 3 below as an intermediate. Basically these approaches consist of the tetrazolyation of 2-cyano-4′-methyl biphenyl of the formula 4 below using tributyl tin azide. [J. Org. Chem. 1991, 36, 2395; U.S. Pat. No. 5,130,439].
This approach has several drawbacks like longer reaction times and the usage of highly toxic trialkyl tin azide reagents. This process also requires a rigorous purification from stannous compounds in order to obtain the desired biphenyl tetrazole derivatives.
The second approach for the synthesis of biphenyl tetrazole of formula 3 involves the preparation of 5-phenyl-1H-tetrazole with a proper substituent at the ortho position of the phenyl ring such that the biphenyl linkage can be established subsequently. [J. Org. Chem. 1993, 38, 5023]. It has been observed that the ortho substituent suitable for the establishment of the biphenyl linkage is a fluorine atom. 5-(2-fluorophenyl)-1H-tetrazole can be reacted with p-toluene magnesium bromide via Grignard reaction to give 4′methyl 2′-(tetrazolyl)biphenyl in excellent purity. Under the same conditions 5-(2-chlorophenyl)-1H-tetrazole and 5-(2-bromophenyl)-1H-tetrazole failed to provide the desired biphenyl tetrazoles via Grignard reaction because of intramolecular chelation and steric hindrance.
Prior art available to the applicants discloses only one method for the preparation of 5-(2-fluorophenyl)-1H-tetrazole in 69.8% yield [J. Org. Chem. 1993, 38, 5023]. The disclosure in this reference involves the refluxing of 2-fluoro benzonitrile with sodium azide and acetic acid in butanol for two days. The practical utility of this method is suspect due to the in situ generation of hydrozoic acid, which is poisonous and also explosive.
It is therefore essential to develop an efficient method for the preparation of 5-(2-flurophenyl)-1H-tetrazole in order to achieve an efficient process for the preparation of angiotensin—II receptor antagonist Losartan avoiding the drawbacks of the prior art above.
OBJECTS OF THE INVENTION
It is an object of the invention to provide a process for the preparation of 5-(2-flurophenyl)-1H-tetrazole with improved efficiency.
It is an object of the invention to provide a process for the preparation of 5-(2-flurophenyl)-1H-tetrazole with improved yield.
It is an object of the invention to provide a process for the preparation of 5-(2-flurophenyl)-1H-tetrazole wherein the formation of poisonous material is avoided.
SUMMARY OF THE INVENTION
Accordingly the present invention provides a process of the preparation of 5-(2-flurophenyl)-1H-tetrazole of the formula 2
comprising reacting 2-fluoro benzonitrile of the formula 1 with with an inorganic azide and an amine salt in an aromatic solvent at a temperature in the range in of 80 to 150° C. for a time period in the range of 5 to 12 hours, cooling to room temperature, adding water to the reaction mixture, precipitating with hydrochloric acid, separating the precipitated product.
In one embodiment of the invention, the inorganic azide is sodium azide.
In another embodiment of the invention, the amine salt is triethyl ammonium chloride.
In yet another embodiment of the invention, the aromatic solvent is selected from the group consisting of toluene, benzene and xylene.
In a further embodiment of the invention, the time period ranges from 8 to 10 hours.
In a further embodiment of the invention, the reaction is conducted for a time period in the range of 8-10 hours.
DETAILED DESCRIPTION OF THE INVENTION
The process of the present invention is detailed below.
In the preparation of 5-(2-flurophenyl)-1H-tetrazole of the formula 2, a mixture of 2-fluorobenzonitrile of formula 1, sodium azide and triethyl ammonium hydrochloride and an aromatic solvent such as benzene, toluene or xylene are reacted at a temperature preferably in the range of 80 to 120° C. For a time period prefereably in the range of 6 to 10 hours. After cooling the product was extracted into water, concentrated HCl added to precipitate the 5-(2-flurophenyl)-1H-tetrazole of the formula 2, the resultant product filtered, dried and recrystallised from ethyl acetate and hexane.


REFERENCES:
Russell et al, “Efficient synthesis of 5-, etc” CA 119:160199 (1993).

Affiliated with

Also associated with

Rating

Process for the synthesis of 5-(2-flurophenyl)-1H-tetrazole does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with Process for the synthesis of 5-(2-flurophenyl)-1H-tetrazole, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Process for the synthesis of 5-(2-flurophenyl)-1H-tetrazole will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-2583046