DESC:RELATED APPLICATION
This application claims the benefit of priority of Indian patent application number IN201921009977 filed on Mar. 14, 2019, which is incorporated herein by reference.
FIELD OF THE INVENTION
The present invention relates to an improved process for the preparation of pharmaceutically important 5-substituted tetrazoles compounds.
BACKGROUND OF THE INVENTION
5-substituted tetrazoles represented by Formula I, wherein R represents a substituted biphenyl radical.

Several 5-substituted tetrazoles, non-peptide orally active angiotensin-II-receptor antagonist such as Valsartan, Irbesartan, and Losartan potassium among others, are approved for in the treatment of hypertension, heart attack and heart failure.
US 5,629,331 patent discloses preparation of Irbesartan involves Tetrazole ring formation by reacting cyano compound with alkaline azide and triethylamine hydrochloride in an inert polar aprotic solvent.
US 5,744,612 discloses a process for preparing a 5-substituted tetrazole represented by the Formula (3), the process comprising the step of reacting a nitrile represented by the Formula (1) with an inorganic azide salt represented by the Formula (2) in an aromatic hydrocarbon solvent in the presence of an amine salt.
WO 2011/24655 discloses a process of preparing Valsartan, wherein nitrite may be added for removing excess/unreacted azide.
Considering the importance of 5-substituted tetrazole compounds there is provided a process for preparing the same.
SUMMARY OF THE INVENTION
An aspect of the present invention is to provide an improved process of preparation of 5-substituted tetrazoles of Formula-I comprising the step of:
(a) reacting corresponding nitrile compound of Formula R—C=N with sodium azide in presence of water immiscible solvent to obtain the cyclized 5-substituted tetrazole compound;
(b) quenching the reaction mass with water;
(c) separating the aqueous layer from the product layer/organic layer and discarding the aqueous layer ;
(d) washing organic layer/product layer with water or sodium chloride solution, separating layers and discarding the aqueous layer;
(e) charging sodium ion source to organic layer/product layer and stirring;
(f) separating layers and discarding organic layer;
(g) optionally washing aqueous layer with toluene and followed by non-polar solvent;
(h) optionally, acidifying the pH of aqueous layer; and
(i) isolating compound general Formula I.
DETAILED DESCRIPTION OF THE INVENTION
In few embodiments of the invention, the compound of Formula I is Valsartan, Losartan, Candesartan, and Irbesartan.
In an embodiment of the invention, nitrile compound R—C=N is selected from 4'-[(2-Butyl-4-oxo-1,3-diazaspiro[4,4]non-1-en-3-yl)methyl]-[1,1'-biphenyl] -2-carbonitrile, 1-(2'-cyanobiphenyl-4-yl)methyl)-2-ethoxybenzimidazole-7-carboxylic acid methyl ester, N-valeryl-N-[(2'-cyanobiphenyl-4-yl)methyl]-(L)-valine methyl ester and 2-Butyl-4-chloro-1-[(2'-cyanobiphenyl-4-yl)methyl]-5-hydroxymethylimidazole.
In another embodiment of the invention the water immiscible solvent used in step (a) is selected from toluene, xylene, ethyl acetate or mixtures thereof. Accordingly the reaction is conducted at a temperature in the range of room temperature to reflux temperature of the solvent used.
In another embodiment, after completion of reaction the reaction mass is quenched with water thereby is separating the layers which include aqueous layer and product layer and organic layer OR aqueous layer and organic layer containing the product. The term organic layer/product layer defines both of these.
In still another embodiment of the invention the pH of the reaction mass is done using an inorganic acid, such as diluted or concentrated HCl, at a temperature in the range of 5 to 30°C. The pH is preferably adjusted in the range of 4.0 to 5.0.
In yet another embodiment, the discarded aqueous layer in step (c) is treated with sodium nitrate separately, if needed to quench the unreacted azide, by way of this process the contact of nitroso compound or its derivate, which are likely to form as a by-product from said treatment, with product is avoided.
In yet another embodiment, the sodium ion source in step (e) can be selected form but not limited to such as sodium hydroxide, sodium carbonate, and sodium bi-carbonate.
In yet another embodiment, the non-polar solvent in step (g) can be selected form but not limited to such as methyl tert-butyl ether, isopropyl ether and cyclohexane.
In yet another embodiment, the charcoal treatment for purification of reaction mixture or crude compound is carried out after the end of the reaction, hydrolysis and pH adjustment, by adding the reaction mixture or crude compound to the charcoal or vice versa.
In yet another embodiment, 5-substituted tetrazoles of Formula-I or its salt of the present application can be optionally subjected to particle size reduction procedures before or after the completion of drying of the product to produce desired particle sizes and distributions. Milling or micronization can be performed to achieve the desired particle sizes or distributions. Equipment that may be used for particle size reduction includes, without limitation thereto, ball mills, roller mills, hammer mills, and jet mills.
The invention is further exemplified by the following non-limiting examples, which are illustrative representing the preferred modes of carrying out the invention. The invention's scope is not limited to these specific embodiments only but should be read in conjunction with what is disclosed anywhere else in the specification together with those information and knowledge which are within the general understanding of the person skilled in the art.
Examples
Example 1: Preparation of Irbesartan.
To a solution of toluene containing small amount of o-xylene, 4'-[(2-Butyl-4-oxo-1,3-diazaspiro[4,4]non-1-en-3-yl)methyl]-[1,1'-biphenyl]-2-carbonitrile (100g), sodium azide (43 g) and triethyl amine hydrochloride (140 g) were added. The reaction solution was heated to 100-110°C and maintained at this temperature till completion of the reaction. After completion of the reaction, the reaction mass was cooled to 25-50°C, water was added and stirred, allowing the layers to separate. Lower aqueous layer was discarded from remaining organic/product layer. Sodium chloride solution (NaCl in water) was added to reaction mass and stirred, layers were separated and aqueous layer was discarded. Sodium hydroxide solution (NaOH in water) was added to the organic layer and stirred, layers were separated, and organic layer was discarded. Aqueous layer was washed with toluene followed by methyl tert-butyl ether (MTBE). The pH of aqueous layer was adjusted to 4.4-4.8 by using dilute hydrochloric acid at temperature 10-30°C. The product obtained was filtered, washed with water and dried to provide title compound.
Example 2: Preparation of Losartan.
To a solution of toluene and N-methyl-pyrolidine, 4’-{[2-Butyl-4-chloro-5-(hydroxylmethyl) -1H-imidazole-1-yl]methyl}biphenyl-2-carbonitrile (100g), sodium azide (48 g) and triethyl amine hydrochloride (100 g) were added. The reaction solution was heated to 92-98 °C and maintained at this temperature till completion of the reaction. After completion of the reaction, the reaction mass was cooled to 50-60 °C, stirred for 15- 30 min and allowing the layers to separate. Lower aqueous layer was discarded from remaining organic/product layer. Sodium chloride solution (NaCl in water) was added to organic layer and stirred, layers were separated and aqueous layer was discarded. Sodium hydroxide solution (NaOH in water) was added to the organic layer and stirred, layers were separated. The obtained aqueous layer was extracted with toluene and layers were separated. To the obtained aqueous layer acetone and activated charcoal was added, stirred for 30-45 minutes and filtered and filter bed was washed with water. The pH of filtrate was adjusted to 4-5 by using dilute sulfuric acid at temperature 30-40°C. The product obtained was filtered, washed with water and dried to provide title compound.
,CLAIMS:1. A process of preparation of 5-substituted tetrazoles of Formula-I comprising the step of:

(a) reacting nitrile compound of Formula R—C=N with sodium azide in presence of water immiscible solvent to obtain the cyclized 5-substituted tetrazole compound;
(b) quenching the reaction mass with water;
(c) separating the aqueous layer from the product layer/organic layer and discarding the aqueous layer ;
(d) washing organic layer/product layer with water or sodium chloride solution, separating layers and discarding the aqueous layer;
(e) charging sodium ion source to organic layer/product layer and stirring;
(f) separating layers and discarding organic layer;
(g) optionally washing aqueous layer with toluene and followed by non-polar solvent;
(h) optionally, acidifying the pH of aqueous layer; and
(i) isolating compound general Formula I.
2. The process as claimed in claim 1, wherein the nitrile compound of Formula R—C=N is selected from 4'-[(2-Butyl-4-oxo-1,3-diazaspiro[4,4]non-1-en-3-yl)methyl]-[1,1'-biphenyl]-2-carbonitrile, 1-(2'-cyanobiphenyl-4-yl)methyl)-2-ethoxybenzimidazole-7-carboxylic acid methylester, N-valeryl-N-[(2'-cyanobiphenyl-4-yl)methyl]-(L)-valine methylester and 2-Butyl-4-chloro-1-[(2'-cyanobiphenyl-4-yl)methyl]-5-hydroxy-methyl imidazole.
3. The process as claimed in claim 1, wherein the water immiscible solvent used in step (a) is selected from toluene, xylene, ethyl acetate or mixtures thereof.
4. The process as claimed in claim 1, wherein the discarded aqueous layer in step (c) is treated with sodium nitrate.
5. The process as claimed in claim 1, wherein the sodium ion source in step (e) is selected form sodium hydroxide, sodium carbonate, and sodium bi-carbonate.
6. The process as claimed in claim 1, wherein the non-polar solvent in step (g) is selected form methyl tert-butyl ether, isopropyl ether and cyclohexane.
7. The process as claimed in claim 1, wherein the pH of the reaction mass step (h) is adjusted using an inorganic acid, such as diluted or concentrated hydrochloric acid.